Franz Cell Research Articles

Optimizing ex vivo penetration tests via quantitative confocal Raman spectroscopy: Impact of incubation time, skin hydration, surfactant treatment and UVA irradiation on caffeine distribution

Ex vivo penetration tests are important tools in cosmetic and pharmaceutical research. However, variability of experimental setups is challenging when reviewing literature. Different skin models, pre-treatments and experimental parameters render comparison difficult. Thus, our aim was to conduct ex vivo penetration tests using caffeine in different setups with varying incubation conditions (ambient vs. Franz cells, infinite vs. finite dose). Additionally, the impact of skin pre-treatment with different aggressors (surfactants, UVA irradiation) should be considered. Possible synergistic barrier damage of surfactants and UVA irradiation should be explored. Analysis was conducted using quantitative confocal Raman spectroscopy. Results showed that incubation time and extensive hydration (20 h in Franz cells) had the greatest impact on penetration behavior. Additional irradiation after pre-treatment with oil-in-water nanoemulsions showed no strong impact on caffeine penetration in general, irrespective of surfactant type. However, in case of sodium lauryl ether sulfate, a trend towards enhanced values was observed due to irradiation (1.3-fold). This suggests cumulative skin barrier damage of irritant surfactants and UVA irradiation, potentially due to stratum corneum alterations. Further studies using different irradiation regimens are planned to confirm this hypothesis.

Development of a nanoemulsion containing Lippia origanoides essential oil with antifungal activity by low energy method: from extraction to formulation

The essential oil of Lippia origanoides is of great pharmacological interest because of a wide variety of attributes, in particular its antifungal action. Due to its low solubility in aqueous media, high volatility, and a high propensity for physicochemical degradation, the search for nanostructured systems to promote the stability of this phytocomplex is necessary. Nanoemulsion is an alternative method to stabilize and preserve this type of active ingredient, especially when generated by a low energy method and using Syagrus coronata (licuri) oil as an active carrier and stabilizer of this nanostructure. The objective of the present investigation was to formulate a stable nanoemulsion with Lippia origanoides essential oil carried through licuri oil with antifungal action by the low energy method. For this, we began with the extraction of the essential oil and the phytochemical characterization obtaining the chemotype B of this Lippia (carvacrol: 49.12%). Then, using the pseudoternary phase diagram, the optimal ratio of the oil phase 6:4 (essential oil: Syagrus coronata oil) was established, adding 15% of surfactant (polysorbate 80) and 75% of the aqueous phase. Then, with the formulated nanoemulsion, the physical-chemical characterization and evaluation of preliminary and accelerated stability were carried out. In addition, cytotoxicity, Franz cell permeation and antifungal activity against dermatophytes were evaluated. A stable nanoemulsion was obtained by the low energy method with the characteristic appearance of a nanoemulsion and a characteristic odor of essential oil. The average size of the nanoparticles was around 167.5 nm, narrow PDI (<0.2 nm), zeta potential below -10.0 mV, acidic pH (5.1), average conductivity 134.4 μSm/cm, refractive index characteristic of a translucent system and low viscosity (<6.0 mPa.S). Regarding cytotoxicity, it proved to be safe at dosages below 90 μg/mL, efficient in terms of permeation (76.7% in 24h) and effective in terms of antifungal activity as it had a minimum inhibitory concentration between 234.4/156.3 μg /mL and 11.2/7.5 μg/mL against the tested dermatophytes. In view of the results, a nanoemulsion containing the essential oil of L. origanoides carried by the oil of Syagrus coronata was shown to be a potential product for the topical treatment of fungal infections like dermatophytosis.

Sodium Alginate Microneedles Loaded with Vancomycin for Skin Infections

Background: Skin and soft tissue infections (SSTIs) present significant treatment challenges. These infections often require systemic antibiotics such as vancomycin, which poses a risk for increased bacterial resistance. Topical treatments are hindered by the barrier function of the skin, and microneedles (MNs) offer a promising solution, increasing patient compliance and negating the need for traditional needles. Methods: This study focused on the use of sodium alginate MNs for vancomycin delivery directly to the site of infection via a cost-effective micromolding technique. Dissolving polymeric MNs made of sodium alginate and loaded with vancomycin were fabricated and evaluated in terms of their physical properties, delivery ability, and antimicrobial activity. Results: The MNs achieved a 378 μm depth of insertion into ex vivo skin and a 5.0 ± 0 mm zone of inhibition in agar disc diffusion assays. Furthermore, in ex vivo Franz cell experiments, the MNs delivered 34.46 ± 11.31 μg of vancomycin with around 35% efficiency, with 9.88 ± 0.57 μg deposited in the skin after 24 h. Conclusions: These findings suggest that sodium alginate MNs are a viable platform for antimicrobial agent delivery in SSTIs. Future in vivo studies are essential to confirm the safety and effectiveness of this innovative method for clinical use.

Quantifying skin permeation of a novel metformin lotion using modified hydrophilic interaction liquid chromatography.

Aim: This study aimed to quantify the permeation of metformin (Met) lotion through pig ear skin using high-performance liquid chromatography, specifically hydrophilic interaction liquid chromatography (HILIC), to separate Met from biological contaminants and effectively measure its permeation through skin similar to human skin.Materials & methods: A Franz cell permeation assay was used to assess the permeation kinetics of 6% Met lotion through pig ear skin. Samples were collected at various time points and prepared for high-performance liquid chromatography analysis by removing large biological contaminants. The permeated Met was quantified by monitoring its retention time (RT) at 9min using HILIC, with an acidic, polar mobile phase and a normal-phase column.Results: A distinct Met peak with a RT of approximately 9min was observed in the 6% Met lotion, which was absent in the permeation samples from the 0% Met lotion. This peak (RT 9min) was distinct from the 'biological-contaminants' peaks at RT 2-3min and increased linearly over time, reaching 36.8% of the total applied Met at 24h.Conclusion: These findings demonstrate that the HILIC method effectively separates Met from biological components in pig ear skin, allowing accurate quantification of Met despite the presence of skin lipids and proteins.

Ultrasound-compatible 3D-printed Franz diffusion system for sonophoresis with microbubbles

Sonophoresis is a topical drug delivery approach that utilises ultrasound as a physical stimulus to enhance permeation of active pharmaceutical ingredients through the skin. Only limited research has however been conducted to evaluate the potential of ultrasound-responsive drug carriers, such as gas microbubbles, in sonophoresis. Franz diffusion cells have been extensively used for measuring drug permeation in vitro; however, traditional systems lack compatibility with ultrasound and only limited characterisation of their acoustical behaviour has been carried out in previous research. To overcome this limitation, we designed and manufactured a novel Franz cell donor compartment coupled with a conventional glass receptor, and performed a functional characterisation of the assembly for application in sonophoresis with ultrasound-responsive agents (specifically imiquimod-loaded gas microbubbles). The donor was fabricated using a photoreactive resin via 3D printing and was designed to enable integration with a therapeutically relevant ultrasound source. The assembly was capable of effectively retaining liquids during prolonged incubation and the absorption of imiquimod onto the 3D-printed material was comparable to the one of glass. Moreover, a predictable ultrasound field could be generated at a target surface without any significant spatial distortion. Finally, we demonstrated applicability of the developed assembly in sonophoresis experiments with StratM®, wherein ultrasound stimulation in the presence of microbubbles resulted in significantly enhanced drug permeation through and partitioning within the membrane (2.96 ± 0.25 μg and 3.84 ± 0.39 μg) compared to passive diffusion alone (1.74 ± 0.29 μg and 2.29 ± 0.32 μg), over 24 h.

Assessment of Enzymatically Derived Blackcurrant Extract as Cosmetic Ingredient-Antioxidant Properties Determination and In Vitro Diffusion Study.

Blackcurrant is an anthocyanin-rich berry with proven antioxidant and photoprotective activity and emerging prebiotic potential, widely applied in cosmetic products. Hereby, highly efficient enzyme-assisted extraction of blackcurrant polyphenols was performed, giving extract with very high antioxidant activity. Obtained extract was characterized in terms of anthocyanin composition, incorporated into three different cosmetic formulations and subjected to Franz cell diffusion study. Experimental values obtained using cellulose acetate membrane for all four dominant anthocyanins (delphinidin 3-glucoside, delphinidin 3-rutinoside, cyanidin 3-glucoside and cyanidin 3-rutinoside) were successfully fitted with the Korsmeyer-Peppas diffusion model. Calculated effective diffusion coefficients were higher for hydrogel compared to oil-in-water cream gel and oil-in-water emulsion, whereas the highest value was determined for cyanidin 3-rutinoside. On the other hand, after a 72 h long experiment with transdermal skin diffusion model (Strat-M® membrane), no anthocyanins were detected in the receptor fluid, and only 0.5% of the initial quantity from the donor compartment was extracted from the membrane itself after experiment with hydrogel. Present study revealed that hydrogel is a suitable carrier system for the topical delivery of blackcurrant anthocyanins, while dermal and transdermal delivery of these molecules is very limited, which implies its applicability for treatments targeting skin surface (i.e., prebiotic, photoprotective).

Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles

Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (Cmax = 287.39 ± 106.82 ng/mL) and EMNs (Cmax = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration.

Microneedle System Coated with Hydrogels Containing Protoporphyrin IX for Potential Application in Pharmaceutical Technology.

The article aims to outline the potential of treating malignant skin cancer with microneedles covered with polymer layers containing a photosensitizer-protoporphyrin IX disodium salt (PPIX). The usefulness of stereolithography (SLA), which is a form of 3D-printing technology, for the preparation of a microneedle system with protoporphyrin IX was demonstrated. The SLA method allowed for pyramid-shaped microneedles to be printed that were covered with three different 0.1% PPIX hydrogels based on sodium alginate, xanthan, and poloxamer. Rheological tests and microscopic analysis of the hydrogels were performed. Microneedles coated with two layers of poloxamer-based hydrogel containing 0.1% PPIX were subjected to release tests in Franz diffusion cells. The release profile of PPIX initially increased and then remained relatively constant. The amount of substance released after a four-hour test in three Franz cells was 0.2569 ± 0.0683 mg/cm2. Moreover, the acute toxicity of this type of microneedle was assessed using the Microtox system. The obtained results show the usefulness of further development studies on microneedles as carriers of photosensitizing agents.

In vitro assessment of skin permeation properties of enzymatically derived oil-based fatty acid esters of vitamin C.

Current topical formulations containing vitamin C face limitations in therapeutic effectiveness due to the skin's selective properties that impede drug deposition. Consequently, the widespread use of toxic and irritating chemical permeation enhancers is common. Hereby, we investigated enzymatically derived fatty acid ascorbyl esters (FAAEs) obtained using natural oils for their skin permeation properties using the Strat-M® skin model in a Franz cell diffusion study. By evaluating various cosmetic formulations without added enhancers, we found that emulgel is most suitable for enhancing the cutaneous and transdermal delivery of FAAEs. Furthermore, medium-chain coconut oil-derived FAAEs exhibited faster diffusion rates compared to sunflower oil-based FAAEs with long-side acyl residues, including the commonly applied ascorbyl palmitate. Experimental data were successfully fitted using the Peppas and Sahlin model, which accounted for a lag phase and the combined effect of Fickian diffusion and polymer relaxation. In the case of long-chain esters, the lag phase was prolonged, and the calculated effective diffusion coefficients (Deff) were lower compared to medium-chain FAAEs. Accordingly, the highest Deff value was observed for ascorbyl caprylate, being even 60 times higher than for ascorbyl palmitate. These results suggest the emerging potential of emulgel with incorporated coconut oil-derived FAAEs for efficiently delivering vitamin C into the skin.

Dissolving microneedle patches for delivery of amniotic mesenchymal stem cell metabolite products for skin regeneration in UV-aging induced mice

Microneedles offer a promising solution to enhancing dermal delivery of amniotic mesenchymal stem cell metabolite product (AMSC-MP), which contains hydrophilic protein components with high molecular weight, for the purposes of skin rejuvenation and improving human health. This study aimed to evaluate the physicochemical characteristics and in vivo efficacy of AMSC-MP-loaded microneedle patches for effectively regenerating skin tissues in UV-aging induced mice. Dissolving microneedle patches, composed of polyvinyl alcohol with an MW of 9–10 kDa and polyvinylpyrrolidone with an MW of 56 kDa, were fabricated using the double-casting method at three AMSC-MP concentrations: i.e., 30 % (MN30), 25 % (MN25), and 20 % (MN20). The microneedles patches were then evaluated for morphological, mechanical resistance, and insertion properties. An ex vivo release study was also conducted using the Franz cell method, and in vivo efficacy and irritation were then determined through collagen density scores, fibroblast cell counts, and skin irritation studies of UV-aging induced mice. The AMSC-MP microneedles displayed a pyramidal shape with 500 µm sharp tips. Mechanical testing revealed that MN30 achieved its deepest insertion into Parafilm® M (447.44 ± 37.21 µm), while MN25 achieved its deepest insertion into full-thickness porcine skin (717.92 ± 25.40 µm). The study revealed a controlled EGF release for up to 24 h, with MN20 exhibiting the highest deposition (55.94 ± 12.34 %). These findings demonstrate the successful penetration of microneedles through the stratum corneum and viable epidermis. Collagen density scores and fibroblast cell counts were significantly higher in all microneedle formulations than the control, with MN30 having the highest values. Inflammatory cell counts indicated minimal presence suggesting non-irritation in the in vivo study. Dissolving microneedle patches exhibited favorable characteristics and efficiently delivered AMSC-MP with minimal potential for irritation, providing potential technology for delivering biological anti-aging agents for the purposes of fostering skin regeneration.

PVA/titanate nanotube nanocomposites: Evaluating the required structural properties for their performance as macromolecule delivery systems

AbstractBiopolymer‐based nanocomposites are gaining prominence in the fabrication of biomedical devices, with polyvinyl alcohol (PVA) being widely used in smart dressings for drug and protein integration. This study introduces electrospun mats composed of partially hydrolyzed PVA and sodium titanate nanotubes (TiNTs). The investigation involved mats with TiNT concentrations ranging from 0% to 5% at room temperature. The morphological and structural changes resulting from adding TiNTs were examined in detail. The inclusion of TiNTs impacted parameters such as mean fiber diameter (130–190 nm), crystallinity degree (30–50%), and porosity (70–55%) and was closely associated with the viscoelastic properties of the mats. Higher TiNT concentrations led to reductions in either the storage modulus, from 350 to 220 MPa, or in the loss modulus, from 30 to 25 MPa, unveiling an increase in tenacity. Furthermore, in vitro release tests were conducted using bovine serum albumin (BSA) in Franz cells over 48 h. The results indicated that release profiles were best fitted by the Higuchi model (0.95 &gt; R2 &gt; 0.99) for both PVA mats (0% and 5.0% TiNTs), with the 5% TiNTs‐PVA membrane demonstrating greater BSA diffusion when compared to pure PVA. The release constant 𝐾rel, representing the rate of drug diffusion, was found to be 0.006 for 5% TiNT‐PVA mats and 0.002 μg h‐1/2 for pure PVA, respectively. These results suggest the potential of these materials in designing controlled transdermal delivery systems that could significantly improve the efficacy and safety of drug applications.

Novel long-acting treatment for schizophrenia based on paliperidone dissolving and implantable microarray patches

Schizophrenia is a severe mental disorder that affects millions of people worldwide. Several atypical antipsychotic medications, including paliperidone (PPD), has been developed and proven effective in treating it. To date, four PPD extended-release products have been launched commercially, providing up to six months of therapeutic effect with a single administration. However, the need for hospital injections by professional healthcare workers not only lead to poor patients’ adherence, but also put additional pressure on the healthcare system. Therefore, three PPD microarray patch (PPD MAP) systems based on dissolving microneedle technology and implantable microneedle technology were developed in this work. The two dissolving microarray patch systems contained either PPD crude drug (PPD DMAP-CD) or PPD nanocrystal (PPD DMAP-NC) and the implantable MAP contained PPD crude drug (PPD IMAP). All three types of PPD MAPs showed excellent mechanical and insertion properties as they achieved over 256 µm insertion depth in skin model. In vitro release study showed that PPD released from IMAP in a much more sustained manner (up to 14 days) than PPD did from DMAPs (7 days), with only 20 % initial burst release from IMAP compared with 43–71 % from DMAPs. The MAP dissolution study showed that both DMAPs can be immediately dissolved within less than 3 min once inserted into the skin, indicating a faster action potential compared with IMAP. Ex vivo delivery study showed that 1.68 ± 0.23 mg, 1.39 ± 0.07 mg, and 1.18 ± 0.12 mg were delivered from DMAP-CD, DMAP-NC and IMAP, respectively, demonstrating that over 50 % and up to 70 % of PPD in the MAPs can be delivered into the skin. The IMAP offers most sustained release of PPD whereas DMAP-NC exhibits fastest PPD release (11.19 % vs 20.01 % into Franz cell receiver compartment over 24 h). This work presents a promising alternative for the sustained delivery of antipsychotic drugs, allowing for patient self-administration and extended release concurrently. Patients may potentially use both DMAP and IMAP to achieve a sustained release of PPD while also avoid having an initial therapeutic lag.

Application of PLGA-PEG-PLGA Nanoparticles to Percutaneous Immunotherapy for Food Allergy.

Compared with oral or injection administration, percutaneous immunotherapy presents a promising treatment modality for food allergies, providing low invasiveness and safety. This study investigated the efficacy of percutaneous immunotherapy using hen egg lysozyme (HEL)-loaded PLGA-PEG-PLGA nanoparticles (NPs), as an antigen model protein derived from egg white, compared with that of HEL-loaded chitosan hydroxypropyltrimonium chloride (CS)-modified PLGA NPs used in previous research. The intradermal retention of HEL in excised mouse skin was measured using Franz cells, which revealed a 2.1-fold higher retention with PLGA-PEG-PLGA NPs than that with CS-modified PLGA NPs. Observation of skin penetration pathways using fluorescein-4-isothiocyanate (FITC)-labeled HEL demonstrated successful delivery of HEL deep into the hair follicles with PLGA-PEG-PLGA NPs. These findings suggest that after NPs delivery into the skin, PEG prevents protein adhesion and NPs aggregation, facilitating stable delivery deep into the skin. Subsequently, in vivo percutaneous administration experiments in mice, with concurrent iontophoresis, demonstrated a significant increase in serum IgG1 antibody production with PLGA-PEG-PLGA NPs compared with that with CS-PLGA NPs after eight weeks of administration. Furthermore, serum IgE production in each NP administration group significantly decreased compared with that by subcutaneous administration of HEL solution. These results suggest that the combination of PLGA-PEG-PLGA NPs and iontophoresis is an effective percutaneous immunotherapy for food allergies.

Optimization of Polylactide-Co-Glycolide-Rifampicin Nanoparticle Synthesis, In Vitro Study of Mucoadhesion and Drug Release.

Despite the large number of works on the synthesis of polylactide-co-glycolide (PLGA) nanoparticles (NP) loaded with antituberculosis drugs, the data on the influence of various factors on the final characteristics of the complexes are quite contradictory. In the present study, a comprehensive analysis of the effect of multiple factors, including the molecular weight of PLGA, on the size and stability of nanoparticles, as well as the loading efficiency and release of the antituberculosis drug rifampicin (RIF), was carried out. Emulsification was carried out using different surfactants (polyvinyl alcohol, Tween 80 and Pluronic F127), different aqueous-to-organic phase ratios, and different solvents (dichloromethane, dimethyl sulfoxide, ethyl acetate). In this research, the PLGA nanoemulsion formation process was accompanied by ultrasonic dispersion, at different frequencies and durations of homogenization. The use of the central composite design method made it possible to select optimal conditions for the preparation of PLGA-RIF NPs (particle size 223 ± 2 nm, loading efficiency 67 ± 1%, nanoparticles yield 47 ± 2%). The release of rifampicin from PLGA NPs was studied for the first time using the flow cell method and vertical diffusion method on Franz cells at different pH levels, simulating the gastrointestinal tract. For the purpose of the possible inhalation administration of rifampicin immobilized in PLGA NPs, their mucoadhesion to mucin was studied, and a high degree of adhesion of polymeric nanoparticles to the mucosa was shown (more than 40% within 4 h). In the example of strain H37Rv in vitro, the sensitivity of Mycobacterium tuberculosis to PLGA-RIF NPs was proven by the complete inhibition of their growth.

Diazepam nanocapsules as an alternative for sleep induction: Development study and toxicity assessment

Diazepam (DZP) is a sedative medication prescribed to treat anxiety and as a sleep inducer, although its residual effects are unfavorable to patients. Nanotechnology represents a tool to improve the pharmacological characteristics of drugs, reducing their side effects. This study aimed to develop and characterize DZP nanocapsules and to evaluate their toxicity in alternative models and the hypnotic-sedative effect in mice. Nanocapsules were prepared by the nanoprecipitation method and properly characterized. Long-term and accelerated stability studies were performed. The in vitro release profile was determined by diffusion in Franz cells. The safety of the formulation was evaluated in the Caenorhabditis elegans (C. elegans) and the oral acute toxicity in mice. Pharmacological evaluation was performed using thiopental-induced sleeping time. DZP was successfully incorporated into Poly-(ɛ-caprolactone) (PCL) nanocapsules, with high entrapment efficiency. The nanocapsule did not affect the development or survival of C. elegans, different from the free drug, which affected the nematode development at the higher tested dose. No signs of toxicity, nor body mass or feed consumption changes were observed during the 14 days evaluated. Finally, this innovative formulation carrying DZP can produce a hypnotic-effect at a reduced dose compared to the free drug, with no toxicity in alternative models.

Study of xymedone release from hydrogels with zinc oxide nanoparticles

In this work the approaches to assess of the xymedone release from hydrophilic gels with zinc oxide nanoparticles were proposed using a vertical Franz diffusion cell at 37 ℃. A partial validation protocol included the varying of the membrane polarity (lipophilic or hydrophilic cellulose acetate), the acceptor chamber volume (4,35 mL or 12,71 mL), the gel composition (with or without zinc oxide nanoparticles), as well as the metrological characteristics for the xymedone assay when it was released through the membrane in a Franz cell. It was estimated that the Franz cell with the volume of 12,71 mL, and the lipophilic membrane made it possible to estimate the amount of xymedone released with less error (RSD no more than 2%). We showed that the xymedone immobilization into zinc oxide nanoparticles increased the efficiency of xymedone release from the hydrophilic gel by 30%. The xymedone release through the both hydrophilic and lipophilic membranes is described by a pseudo-second-order equation that typical for desorption process from the polymer matrix. The proposed partial validation protocol to assessing the drug release using the Franz cell can be useful for selection of optimal composition of dermal topical dosage forms with hydrophilic pharmaceutical active substances. Keywords: hydrogels, release, xymedone, zinc oxide nanoparticles, partial validation protocol

Comparison of permeability of topical Cream drug through polymer synthetic membranes of different structures using Franz Cell diffusion test

In this study, in-vitro release experiments were performed using a Franz Diffusion Cell system for Terbinafine Hydrochloride, which is used in the treatment of various fungal infections in the skin caused by many susceptible dermatophytes. In order to evaluate TH transdermally, it was aimed to compare the permeability between polymeric membranes synthesized with polyvinyl alcohol and chitosan mixtures and commercial membranes. In the transdermal drug delivery system calculations, the Fick Diffusion Law was modified and the obtained data were compared. The study was evaluated according to the USP <1724> topical drug products in semisolid form - performance tests. A new high-performance liquid chromatography method was validated for the assay of TH released into the receptor medium in accordance with the ICH guideline. According to the results obtained during the validation process, the limit of detection value was calculated as 0.005 µg/mL and the limit of quantification value was 0.013 µg/mL. Since polymer-based synthetic membranes provide permeability according to molecular size, properties and the ideal environment for measuring and analyzing the diffusion rate of a compound, in experiments conducted using membranes of different structures, the permeability profiles of selected polymer synthetic membranes were statistically evaluated. It has been noted that the hydroxyl groups in PVA and the hydrophilic CS-g-PNDMAAm graft copolymer act at varying rates to enhance or reduce the permeability across the membrane by promoting its diffusion. NaY zeolite has been shown to function as an adsorbent against the medication, lessening the impact of hydrophilic PVA without supplying permeability.

Efficacy and safety of a 0.05 % nanoencapsulated imiquimod hydrogel for the treatment of actinic cheilitis: Drug release analysis and clinical study

Actinic cheilitis (AC) is a lip disorder, with no standard treatment. Imiquimod (IMIQ) is an immunomodulator that treat precancerous lesions; however, its commercial form causes severe adverse effects. This study aimed to assess IMQ release from a chitosan hydrogel containing 0.05 % nanoencapsulated (NANO) imiquimod (IMIQ-0.05 %-NANO) and its efficacy in AC treatment. The hydrogels were prepared by incorporating chitosan into polymeric nanocapsules (NCimiq) loaded with IMQ, produced using the interfacial deposition of preformed polymer method. IMQ release was evaluated using automated Franz Cells. A triple-blind randomized controlled trial (49 subjects) compared the efficacy of: IMIQ-0.05 %-NANO, 5 % free imiquimod (IMIQ-5 %), 0.05 % free imiquimod (IMIQ-0.05 %), and placebo hydrogel. The IMIQ-NANO-0.05 % and IMIQ-5 % groups exhibited significantly higher rates of clinical improvement (p < 0.05); however, the IMIQ-5 % group experienced more adverse effects (92.3 % of subjects) compared to other groups (p < 0.05). In conclusion, in the studied sample, IMIQ-NANO-0.05 % was a safe and effective option to treat AC.

Microemulsions strongly promoted the activity of α-bisabolol against different Leishmania species and its skin permeation

This study aimed to develop microemulsions (MEs) containing α-bisabolol for the topical treatment of cutaneous leishmaniasis (CL). Initially, pseudoternary phase diagrams were developed using α-bisabolol as the oil phase, Eumulgin® CO 40 as the surfactant, Polymol® HE as the co-surfactant, and distilled water as the aqueous phase. Two transparent liquid systems (TLS) containing 5% of α-bisabolol were selected and characterized (F5E25 and F5EP25). Next, skin permeation and retention assays were performed using Franz cells. The interaction of the formulation with the stratum corneum (SC) was evaluated using the FTIR technique. The cytotoxicity was evaluated in murine peritoneal macrophages. Finally, the antileishmanial activity of microemulsions was determined in promastigotes and amastigotes of L. amazonensis (strain MHOM/BR/77/LTB 0016). As a result, the selected formulations showed isotropy, nanometric size (below 25 nm), Newtonian behavior and pH ranging from 6.5 to 6.9. The MEs achieved a 2.5-fold increase in the flux and skin-permeated amount of α-bisabolol. ATR-FTIR results showed that microemulsions promoted fluidization and extraction of lipids and proteins of the stratum corneum, increasing the diffusion coefficient and partition coefficient of the drug in the skin. Additionally, F5E25 and F5EP25 showed higher activity against promastigotes (IC50 13.27 and 18.29, respectively) compared to unencapsulated α-bisabolol (IC50 53.8). Furthermore, F5E25 and F5EP25 also showed antileishmanial activity against intracellular amastigotes of L. amazonensis, with IC50 50 times lower than free α-bisabolol and high selectivity index (up to 15). Therefore, the systems obtained are favorable to topical administration, with significant antileishmanial activity against L. amazonensis promastigotes and amastigotes, being a promising system for future in vivo trials.

Mesoporous Silica-Based Membranes in Transdermal Drug Delivery: The Role of Drug Loss in the Skin.

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO3H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes.