Gold nanoparticles capped with benzalkonium chloride and poly (ethylene imine) for enhanced loading and skin permeability of 5-fluorouracil.

OBJECTIVE: To enhance 5-fluorouracil (5-FU) permeability through the skin by loading onto gold nanoparticles (GNPs) capped with two cationic ligands, benzalkonium chloride (BC) or poly (ethylene imine) (PEI). Whereas 5-FU has excellent efficacy against many cancers, its poor permeability through biological membranes and several adverse effects limit its clinical benefits. BC and PEI were selected to stabilize GNPs and to load 5-FU through ionic interactions. METHODS: 5-FU/BC-GNPs and 5-FU/PEI-GNPs were prepared at different 5-FU/ligand molar ratios and different pH values and were evaluated using different techniques. GNPs stability was tested as a function of salt concentration and storage time. 5-FU release from BC- and PEI-GNPs was evaluated as a function of solution pH. Ex vivo permeability studies of different 5-FU preparations were carried out using mice skin. RESULTS: 5-FU-loaded GNPs size and surface charge were dependent on the 5-FU/ligand molar ratios. 5-FU entrapment efficiency and loading capacity were dependent on the used ligand, 5-FU/ligand molar ratio and solution pH. Maximum drug entrapment efficiency of 59.0 ± 1.7% and 46.0 ± 1.1% were obtained for 5-FU/BC-GNPs and 5-FU/PEI-GNPs, respectively. 5-FU-loaded GNPs had good stability against salinity and after storage for 4 months at room temperature and at 4 °C. In vitro 5-FU release was pH- and ligand-dependent where slower release was observed at higher pH and for 5-FU/BC-GNPs. 5-FU permeability through mice skin was significantly higher for drug-loaded GNPs compared with drug-ligand complex or drug aqueous solution. CONCLUSION: Based on these results, BC- and PEI-GNPs might find applications as effective topical delivery systems of 5-FU.

Transethosomes: Cutting edge approach for drug permeation enhancement in transdermal drug delivery system.

The skin is a major route of drug administration. Despite the high surface area of the skin, drug delivery via the skin route is problematic due to its physiological obstacles. The formulation scientist has developed a vesicular system to enhance the skin's absorption of bioactive substances. Among numerous vesicular systems, concept of transethosomes (TEs) introduced in 2012 are being tested for drug delivery to the dermis. When transferosomes and ethosomes interact, TEs are produced. It consists of water, ethanol, phospholipids, and an edge activator. Ethanol and the edge activator increase the absorption of medication through the skin. In the presence of ethanol and an edge activator, skin permeability can increase. The advantages of TEs include increased patient compliance, bypassing first-pass metabolism, including non-toxic raw components, being a noninvasive method of drug delivery, being more stable, biocompatible, biodegradable, and administered in semisolid form. TEs can be produced through the use of hot, cold, mechanical dispersion, and conventional techniques. The morphology, shape, size, zeta potential, drug loading efficiency, vesicle yield, biophysical interactions, and stability of TEs define them. Recent studies reported successful transdermal distribution of antifungal, antiviral, anti-inflammatory, and cardiovascular bioactive while using ethosomes with significant deeper penetration in skin. The review extensively discussed various claims on TEs developed by researchers, patents, and marketed ethosomes. However, till today no patens being granted on TEs. There are still lingering difficulties related to ethanol-based TEs that require substantial research to fix.

Enhanced Transdermal Delivery of Acyclovir via Hydrogel Microneedle Arrays.

Hydrogel microneedles represent a promising approach to deliver drug molecules across skin into systemic circulation in a sustained release manner and without any polymer residue within skin. Acyclovir is an antiviral drug used for the treatment of several viral infections. However, the oral administration of acyclovir may cause gastrointestinal tract (GIT) disturbances with low bioavailability and poor patient compliance due to its requirement of five daily administrations to produce the desired effect. Therefore, it is thought that the preparation of hydrogel microneedle arrays containing acyclovir would improve the bioavailability and patient compliance by reducing the frequency of administration to once daily as well as overcome the GIT side effects associated with oral administration. A mixture of PEG 10,000 Da and PMVE/MA co-polymer 1,980,000 Da at a ratio of 1:3 (7.5%:22.5% w/w) with Na2CO3 3% w/w was found to produce the optimum hydrogel microneedle array formulation (F8) which showed suitable needle formation with an appropriate mechanical strength and excellent insertion ability, high drug content, sufficient swelling property and a sustained drug release over a period of 24 hours. The Ex vivo permeation study across human skin has demonstrated that the permeation of acyclovir from F8 hydrogel microneedle array was significantly (P≤ 0.05) increased by 39 times in comparison with microneedle-free film (control). The microneedle array has delivered 75.56% ± 4.2 of its loading dose over 24 hours, while the control film was only able to deliver 1.94% ± 0.14 of the total loading dose during the same period. Accordingly, these findings propose the potential application of hydrogel microneedle arrays for the transdermal delivery of acyclovir in a sustained release manner over 24 hours.

Recent advances in polymeric transdermal drug delivery systems.

Transdermal delivery has proven to be one of the most favorable methods among novel drug delivery systems. Since drugs administered by transdermal delivery systems avoid the gastrointestinal tract, and thus avoid conversion by the liver, the likelihood of liver dysfunction and gastrointestinal tract irritation as side effects is low. Drug delivery through the skin has other advantages, such as maintaining an effective rate of drug delivery over time, a steady rate of circulation, and the benefits of a passive delivery system and diffusion. Transdermal drug delivery is achieved using patches which consist of different and specific layers. In the last few decades, many types of patches have been approved worldwide, such as medical plasters, which have been generally applied to the skin for localized diseases. Such patches can be traced back to ancient China (around 2000 BCE) and are the early precursors of today's transdermal patches. With the help of effective design, materials, manufacturing, and evaluation, a large number of drugs can now be administered using this valuable advanced technology. This study reviews different types of polymer patches, their advantages and disadvantages, and different studies related to transdermal drug delivery methods, and the advantages and disadvantages of each method. Different mechanisms of transdermal drug delivery system with patches are also discussed.

Predicting skin permeability of pharmaceutical and cosmetic compounds using retention on octadecyl, cholesterol-bonded and immobilized artificial membrane columns.

In this study, the retention on three types of columns, an immobilized artificial membrane (IAM), a cholesterol-bonded and an octadecyl (C18) column, was applied for the prediction of skin permeability. The first two columns are biomimicking ones, which have certain components of the skin bound to the stationary phase, and were applied in HPLC, while the sub-2 µm C18 column was studied in UHPLC because of its fast features. Fifty-eight compounds were analyzed applying different mobile-phase compositions, with varying percentages of organic modifier on every column, to extrapolate the retention factor to a theoretically purely aqueous mobile phase (log kw). The retention factors, along with two sets of theoretical molecular descriptors, were used to model the skin permeability coefficient (log Kp) using multiple linear regression (MLR) and partial least squares (PLS) regression modelling. Although the retention factors (log k) on the IAM column showed a better correlation with the skin permeability, the overall best model was obtained by applying a stepwise MLR approach on the UHPLC parameters combined with some theoretical descriptors. This model showed a good fit, and on top has potential to accurately predict skin permeability values. Furthermore, the UHPLC method has the advantage of being fast and can thus be classified as a high-throughput approach.

Co-Delivery of Imiquimod and Curcumin by Nanoemugel for Improved Topical Delivery and Reduced Psoriasis-Like Skin Lesions.

The current investigation aimed to improve the topical efficacy of imiquimod in combination with curcumin using the nanoemulsion-based delivery system through a combinatorial approach. Co-delivery of curcumin acts as an adjuvant therapeutic and to minimize the adverse skin reactions that are frequently associated with the topical therapy of imiquimod for the treatment of cutaneous infections and basal cell carcinomas. The low-energy emulsification method was used for the nano-encapsulation of imiquimod and curcumin in the nanodroplet oil phase, which was stabilized using Tween 20 in an aqueous dispersion system. The weak base property of imiquimod helped to increase its solubility in oleic acid compared with ethyl oleate, which indicates that fatty acids should be preferred as the oil phase for the design of imiquimod-loaded topical nanoemulsion compared with fatty acid esters. The phase diagram method was used to optimize the percentage composition of the nanoemulsion formulation. The mean droplet size of the optimized nanoemulsion was 76.93 nm, with a polydispersity index (PdI) value of 0.121 and zeta potential value of -20.5 mV. The optimized imiquimod-loaded nanoemulsion was uniformly dispersed in carbopol 934 hydrogel to develop into a nanoemulgel delivery system. The imiquimod nanoemulgel exhibited significant improvement (p<0.05) in skin permeability and deposition profile after topical application. The in vivo effectiveness of the combination of imiquimod and curcumin nanoemulgel was compared to the imiquimod nanoemulgel and imiquimod gel formulation through topical application for ten days in BALB/c mice. The combination of curcumin with imiquimod in the nanoemulgel system prevented the appearance of psoriasis-like symptoms compared with the imiquimod nanoemulgel and imiquimod gel formulation entirely. Further, the imiquimod nanoemulgel as a mono-preparation slowed and reduced the psoriasis-like skin reaction when compared with the conventional imiquimod gel, and that was contributed to by the control release property of the nano-encapsulation approach.

Investigation on the effect of deep eutectic formation on drug-polymer miscibility and skin permeability of rotigotine drug-in-adhesive patch.

The aim of present study was to develop a rotigotine (ROT) transdermal patch by converting ROT to a form of deep eutectic 'liquid co-crystal'. Formulation factors including the type of ROT-organic acid deep eutectics, pressure sensitive adhesives (PSAs), drug-loading and patch thickness were investigated by in vitro skin permeation study and the optimized patch was evaluated by pharmacokinetics study. It was particularly concerned about the drug-polymer miscibility and skin permeability of ROT-lactic acid deep eutectics (ROT-LA). FTIR study, thermal analysis and molecular modeling were conducted to investigate the drug-PSA interaction. Multiple linear regression was performed to investigate the mechanism of the promoted skin permeability. The results showed that strong interaction was observed between ROT-LA and hydroxyl PSA, which inhibited the formation of ROT crystals. Skin permeability of ROT-organic acids deep eutectics were improved by the variations of apparent partition coefficient and glass transition temperature. AUC0-t and Cmax of optimized patch were 1290.6 ± 102.7 h ng/mL and 60.7 ± 12.0 ng/mL, respectively, which had no significant difference with commercial product. In conclusion, a reduced administration area (75%) and low risk of crystallization were introduced by the ROT deep eutectics, which demonstrated the feasibility of improving drug-polymer miscibility and skin permeability of transdermal drug.

[Pharmaceutical Properties of Anti-inflammatory Analgesic Patches Using Acrylic Polymer].

The mock patches were prepared with novel acrylic polymers as adhesive layer where biphenyl-4-ylacetic acid (BAA) or 2-(2-fluorobiphenyl-4-yl) propanoic acid (FPA) was used as model active pharmaceutical ingredients (APIs). In addition, the mock patches were formulated with typical ester ingredients for transdermal dosage forms. The molecular state of the model APIs in the adhesive layer was observed by polarized microscope and microscopic Raman spectroscopy, which contains both conventional and low frequency (LF) region. Crystallization behavior would be depended on the interaction between API and polymers in the adhesive layer. In particular, LF Raman measurement was useful to discriminate API polymorphs. The pharmaceutical properties including dissolution and skin permeation of APIs were also evaluated for mock patches. The drug release and transdermal permeation were enhanced with the ester ingredients such as isopropyl myristate and diethyl sebacate due to their diffusion to the test solution or the skin stratum corneum as well as reducing the interaction between API and polymers. Further, the tack strength was not changed, but the peel strength was weakened by the additives. Thus, the adhesive properties were controllable by formulation with the additives. These findings could enable to evaluate the interaction between API and the polymers for adhesive layer and select the appropriate polymer and additives for used APIs when designing the drug products.

Preparation and in vivo evaluation of a highly skin- and nail-permeable efinaconazole topical formulation for enhanced treatment of onychomycosis.

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes-infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.

Hyaluronan-decorated liposomes as drug delivery systems for cutaneous administration.

The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J ∼ 30 ng/cm2/h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems.

Phospholipid-based Immobilized Artificial Membrane (IAM) Chromatography: A Powerful Tool to Model Drug Distribution Processes.

A review of applications of the Immobilized Artificial Membrane (IAM) chromatography in drug discovery is given. IAM chromatography is presented as a tool to predict the interactions of solutes with biomembranes, blood-brain barrier permeability, volume of distribution, oral and skin absorption of drugs and compared to other in vitro techniques used to study drug bioavailability (caco-2 cells, liposome partition). Unbound phosphatidylcholine based stationary phases are also discussed. Some new trends and ideas in the IAM chromatography are presented.

Development of a membrane impregnated with a poly(dimethylsiloxane)/poly(ethylene glycol) copolymer for a high-throughput screening of the permeability of drugs, cosmetics, and other chemicals across the human skin.

We aimed to develop a high-throughput screening (HTS) system for preliminary predictions of human skin permeability by using an artificial membrane that can mimic the permeation behaviour of lipophilic and hydrophilic compounds across the human skin. In this study, we synthesized a copolymer containing poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEG) 6000 and impregnated it onto a supportive membrane filter to prepare a PDMS/PEG 6000 copolymer-impregnated membrane. In addition, we synthesized another polymer without PEG units and used it to prepare an impregnated membrane for determining the role of PEG 6000 units in the PDMS/PEG 6000 copolymer-impregnated membrane. The permeation characteristics of the impregnated membranes were evaluated on the basis of the permeability coefficients of 12 model compounds with different lipophilicities, by using a 2-chamber diffusion cell, and these permeability coefficients were compared with those across the human skin. We obtained a good correlation between the permeability coefficients across the PDMS/PEG 6000 copolymer-impregnated membrane and human skin. Further, we evaluated the permeation characteristics of a 96-well plate model of the PDMS/PEG 6000 copolymer by using 6 model compounds. We obtained an ideal correlation between the permeability coefficients across the PDMS/PEG 6000 copolymer using a 96-well plate and those across the human skin. Thus, the PDMS/PEG 6000 copolymer would be a good candidate for preliminary evaluation of the permeability of lipophilic and hydrophilic compounds across the human skin.

Preparation of redispersible liposomal dry powder using an ultrasonic spray freeze-drying technique for transdermal delivery of human epithelial growth factor.

In this work, an ultrasonic spray freeze-drying (USFD) technique was used to prepare a stable liposomal dry powder for transdermal delivery of recombinant human epithelial growth factor (rhEGF). Morphology, particle size, entrapment efficiency, in vitro release, and skin permeability were systematically compared between rhEGF liposomal dry powder prepared using USFD and that prepared using a conventional lyophilization process. Porous and spherical particles with high specific area were produced under USFD conditions. USFD effectively avoided formation of ice crystals, disruption of the bilayer structure, and drug leakage during the liposome drying process, and maintained the stability of the rhEGF liposomal formulation during storage. The reconstituted rhEGF liposomes prepared from USFD powder did not show significant changes in morphology, particle size, entrapment efficiency, or in vitro release characteristics compared with those of rhEGF liposomes before drying. Moreover, the rhEGF liposomal powder prepared with USFD exhibited excellent enhanced penetration in ex vivo mouse skin compared with that for powder prepared via conventional lyophilization. The results suggest that ultrasonic USFD is a promising technique for the production of stable protein-loaded liposomal dry powder for application to the skin.

17ß-carboxamide steroids--in vitro prediction of human skin permeability and retention using PAMPA technique.

In this paper, twenty-two 17ß-carboxamide steroids were synthesized from five corticosteroids (hydrocortisone, prednisolone, methylprednisolone, dexamethasone and betamethasone) in two steps. The first step was periodic acid oxydation of these corticosteroids to corresponding cortienic acids and the second step was amidation of thus obtained cortienic acids with esterified l-amino acids. These compounds are potential soft corticosteroids with local anti-inflammatory activity in the skin. Parallel artificial membrane permeability assay (PAMPA) was applied in order to predict permeability and retention of these compounds in human skin. Comparison of permeability and retention parameters between 17ß-carboxamide steroids and corresponding corticosteroids was performed. Compounds with significantly higher retention were identified and the derivative that does not have significantly higher permeability was underlined. Molecular structures of all compounds were optimized by use of Gaussian semiempirical/PM3 method. Geometrical, thermodynamic, physicochemical and electronical molecular parameters of the optimized structures were calculated and quantitative structure-property relationship (QSPR) analysis was performed in order to explain permeability and retention of these compounds. ANN-, PLS- and MLR-QSPR models were created. Quality of these models was evaluated by commonly used statistical parameters and the most reliable models were selected. Analyzing descriptors in the selected models, main molecular properties that influence permeability and retention in the PAMPA artificial membrane were identified. Based on these data, further structural modifications could be applied in order to increase retention without significant increase of permeability, which can positively affect potential local anti-inflammatory activity of these compounds. Selected QSPR models could be used as in silico tool for predicting human skin permeability and retention of novel 17ß-carboxamide steroids without performing PAMPA experiments.