Hydrogel-based hybrid membrane enhances in vitro ophthalmic drug evaluation in the OphthalMimic device.

Envisaging to improve the evaluation of ophthalmic drug products while minimizing the need for animal testing, our group developed the OphthalMimic device, a 3D-printed device that incorporates an artificial lacrimal flow, a cul-de-sac area, a moving eyelid, and a surface that interacts effectively with ophthalmic formulations, thereby providing a close representation of human ocular conditions. An important application of such a device would be its use as a platform for dissolution/release tests that closely mimic in vivo conditions. However, the surface that artificially simulates the cornea should have a higher resistance (10 min) than the previously described polymeric films (5 min). For this key assay upgrade, we describe the process of obtaining and thoroughly characterizing a hydrogel-based hybrid membrane to be used as a platform base to simulate the cornea artificially. Also, the OphthalMimic device suffered design improvements to fit the new membrane and incorporate the moving eyelid. The results confirmed the successful synthesis of the hydrogel components. The membrane's water content (86.25 ± 0.35 %) closely mirrored the human cornea (72 to 85 %). Furthermore, morphological analysis supported the membrane's comparability to the natural cornea. Finally, the performance of different formulations was analysed, demonstrating that the device could differentiate their drainage profile through the viscosity of PLX 14 (79 ± 5 %), PLX 16 (72 ± 4 %), and PLX 20 (57 ± 14 %), and mucoadhesion of PLXCS0.5 (69 ± 1 %), PLX16CS1.0 (65 ± 3 %), PLX16CS1.25 (67 ± 3 %), and the solution (97 ± 8 %). In conclusion, using the hydrogel-based hybrid membrane in the OphthalMimic device represents a significant advancement in the field of ophthalmic drug evaluation, providing a valuable platform for dissolution/release tests. Such a platform aligns with the ethical mandate to reduce animal testing and promises to accelerate the development of safer and more effective ophthalmic drugs.

The role of artificial intelligence and data science in nanoparticles development: a review.

Artificial intelligence has revolutionized many sectors with unparalleled predictive capabilities supported by machine learning (ML). So far, this tool has not been able to provide the same level of development in pharmaceutical nanotechnology. This review discusses the current data science methodologies related to polymeric drug-loaded nanoparticle production from an innovative multidisciplinary perspective while considering the strictest data science practices. Several methodological and data interpretation flaws were identified by analyzing the few qualified ML studies. Most issues lie in following appropriate analysis steps, such as cross-validation, balancing data, or testing alternative models. Thus, better-planned studies following the recommended data science analysis steps along with adequate numbers of experiments would change the current landscape, allowing the exploration of the full potential of ML.

[Box: see text].

OphthalMimic: A new alternative apparatus without animal tissue for the evaluation of topical ophthalmic drug products.

The necessity of animal-free performance tests for novel ophthalmic formulation screening is challenging. For this, we developed and validated a new device to simulate the dynamics and physical-chemical barriers of the eye for in vitro performance tests of topic ophthalmic formulations. The OphthalMimic is a 3D-printed device with an artificial lacrimal flow, a cul-de-sac area, a support base, and a simulated cornea comprised of a polymeric membrane containing poly-vinyl alcohol 10 % (w/v), gelatin 2.5 % (w/v), and different proportions of mucin and poloxamer, i.e., 1:1 (M1), 1:2 (M2), and 2:1 (M3) w/v, respectively. The support base is designed to move between 0° and 50° to replicate the movement of an eyelid. We challenged the model by testing the residence performance of poloxamer®407 16 % and poloxamer®407 16 % + chitosan 1 % (PLX16CS10) gels containing fluconazole. The test was conducted with a simulated tear flow of 1.0 mL.min-1 for 5 min. The OphthalMimic successfully distinguished PLX16 and PLX16C10 formulations based on their fluconazole drainage (M1: 65 ± 14 % and 27 ± 10 %; M2: 58 ± 6 % and 38 ± 9 %; M3: 56 ± 5 % and 38 ± 18 %). In conclusion, the OphthalMimic is a promising tool for comparing the animal-free performance of ophthalmic formulations.

Customizable Three-Dimensional Printed Earring Tap for Treating Affections Caused by Aesthetic Perforations.

This work aimed to develop a three-dimensional (3D) wearable drug-loaded earring tap to treat affections caused by aesthetic perforations. The initial phase involved a combination of polymers to prepare filaments for fused deposition modeling (FDM) 3D printing using a centroid mixture design. Optimized filament compositions were used in the second phase to produce 3D printed earring taps containing the anti-inflammatory naringenin. Next, samples were assessed via physicochemical assays followed by in vitro skin permeation studies with porcine ear skin. Two filament compositions were selected for the study's second phase: one to accelerate drug release and another with slow drug dissolution. Both filaments demonstrated chemical compatibility and amorphous behavior. The use of the polymer blend to enhance printability has been confirmed by rheological analysis. The 3D devices facilitated naringenin skin penetration, improving drug recovery from the skin's most superficial layer (3D device A) or inner layers (3D device B). Furthermore, the devices significantly decreased transdermal drug delivery compared to the control containing the free drug. Thus, the resulting systems are promising for producing 3D printed earring taps with topical drug delivery and reinforcing the feasibility of patient-centered drug administration through wearable devices.

Iontophoresis use for increasing drug penetration into root canals and dentinal tubules: A proof-of-concept study.

INTRODUCTION: The success of endodontic treatment depends on the significant disinfection of the root canal system, its irregularities, and dentinal tubules. However, achieving complete disinfection remains challenging, with frequent failures and occurrence of secondary infections. Here, we propose using iontophoresis to increase the penetration and distribution of disinfecting agents into root canals, using methylene blue for proof-of-concept. METHODS: The marker was applied in bovine root canals, and the radial distribution of the dye in the dentinal tubules was evaluated by optical microscopy. Iontophoresis was applied at 0.5 and 1.5 mA for 5 and 15 min. RESULTS: A significant statistical difference (p < 0.05) was observed in the marker penetration between passive and iontophoretic applications. Both current density and application time had an important effect on methylene blue distribution, with a greater efficacy delivery to the apical region achieved after 1.5 mA for 5 min or 0.5 mA for 15 min, showing longer application time can compensate for lower application current. CONCLUSION: Iontophoresis increases the penetration and distribution of methylene blue into bovine root canals and dentinal tubules, including its innermost portions. CLINICAL SIGNIFICANCE: Iontophoresis has shown to be a promising technique for root canal and dentinal tubule disinfection.

Enhanced topical paromomycin delivery for cutaneous leishmaniasis treatment: Passive and iontophoretic approaches.

Conventional treatments for cutaneous leishmaniasis, a neglected vector-borne infectious disease, can frequently lead to serious adverse effects. Paromomycin (PAR), an aminoglycoside antibiotic, has been suggested for the topical treatment of disease-related lesions, but even when formulated in high drug-loading dosage forms, presents controversial efficacy. The presence of five ionizable amino groups hinder its passive cutaneous penetration but make PAR an excellent candidate for iontophoretic delivery. The objective of this study was to verify the feasibility of using iontophoresis for cutaneous PAR delivery and to propose a topical passive drug delivery system that could be applied between iontophoretic treatments. For this, in vitro iontophoretic experiments evaluated different application durations (10, 30, and 360 min), current densities (0.1, 0.25, and 0.5 mA/cm2), PAR concentrations (0.5 and 1.0 %), and skin models (intact and impaired porcine skin). In addition, 1 % PAR hydrogel had its penetration profile compared to 15 % PAR ointment in passive transport. Results showed iontophoresis could deliver suitable PAR amounts to dermal layers, even in short times and with impaired skin. Biodistribution assays showed both iontophoretic transport and the proposed hydrogel delivered higher PAR amounts to deeper skin layers than conventional ointment, even though applying 15 times less drug. To our knowledge, this is the first report of PAR drug delivery enhancement by iontophoresis. In summary, the association of iontophoresis with a topical application of PAR gel seems appropriate for improving cutaneous leishmaniasis treatment.

Follicle-Targeted Delivery of Betamethasone and Minoxidil Co-Entrapped in Polymeric and Lipid Nanoparticles for Topical Alopecia Areata Treatment.

Alopecia areata is managed with oral corticosteroids, which has known side effects for patients. Given that a topical application of formulations containing a corticoid and a substance controlling hair loss progression could reduce or eliminate such adverse effects and increase the patient's adherence to the treatment, this study prepares polymeric and lipidic nanoparticles (PNPs and NLCs) to co-entrap minoxidil and betamethasone and compares the follicular drug delivery provided by topical application of these nanoparticles. The prepared PNPs loaded 99.1 ± 13.0% minoxidil and 70.2 ± 12.8% betamethasone, while the NLCs entrapped 99.4 ± 0.1 minoxidil and 80.7 ± 0.1% betamethasone. PNPs and NLCs presented diameters in the same range, varying from 414 ± 10 nm to 567 ± 30 nm. The thermal analysis revealed that the production conditions favor the solubilization of the drugs in the nanoparticles, preserving their stability. In in vitro permeation studies with porcine skin, PNPs provided a 2.6-fold increase in minoxidil penetration into the follicular casts compared to the control and no remarkable difference in terms of betamethasone; in contrast, NLCs provided a significant (specifically, a tenfold) increase in minoxidil penetration into the hair follicles compared to the control, and they delivered higher concentrations of betamethasone in hair follicles than both PNPs and the control. Neither PNPs nor NLCs promoted transdermal permeation of the drugs to the receptor solution, which should favor a topical therapy. Furthermore, both nanoparticles targeted approximately 50% of minoxidil delivery to the follicular casts and NLCs targeted 74% of betamethasone delivery to the hair follicles. In conclusion, PNPs and NLCs are promising drug delivery systems for enhancing follicular targeting of drugs, but NLCs showed superior performance for lipophilic drugs.

Dynamic Ex Vivo Porcine Eye Model to Measure Ophthalmic Drug Penetration under Simulated Lacrimal Flow.

Animal models are still used in the research and development of ophthalmic drug products, mainly due to the difficulty in simulating natural physiological conditions with in vitro models, as there is a lack of dynamic protection mechanisms. Therefore, developing alternative ophthalmic models that evaluate drug penetration in the cornea while applying dynamic protection barriers is a contemporary challenge. This study aimed to develop a dynamic ex vivo model using porcine eyes with a simulated lacrimal flow to evaluate the performance of pharmaceutical drug products. A glass donor cell to support a simulated tear flow was designed, optimized, and custom-made. The system was challenged with different formulations (with fluconazole) including excipients with different viscosities (poloxamer 407) and mucoadhesive properties (chitosan). The results were compared to those obtained from a conventional excised cornea model mounted in Franz-type diffusion cells. The dynamic model could differentiate formulations, while the static model did not, overestimating ex vivo drug penetrated amounts. Hence, the dynamic model with simulated tear flow showed to be a simple and promising new alternative method for the drug penetration of ophthalmic formulations that ultimately can reduce the number of animals used in research.

Extrusion-based systems for topical and transdermal drug delivery.

INTRODUCTION: Although the administration of drugs on the skin is a safe and noninvasive therapeutic alternative, producing formulations capable of disrupting the cutaneous barriers is still a challenge. In this scenario, extrusion-based techniques have emerged as disruptive technologies to ensure unique drug-excipient interactions that facilitate drug skin diffusion for systemic or local effect and even mean the key to obtain viable industrial products. AREAS COVERED: This article presents a comprehensive overview of extrusion-based techniques in developing pharmaceutical dosage forms for topical or transdermal drug delivery. First, the theoretical basis of how extrusion-based techniques can optimize the permeation of drugs through the skin is examined. Then, the current state-of-the-art of drug products developed by extrusion-based techniques, specifically by hot-melt extrusion (HME) and fused deposition modeling (FDM) 3D printing, are discussed and contrasted with the current pharmaceutical processes. EXPERT OPINION: A wide variety of pharmaceutical products can be obtained using HME and FDM 3D printing, including new dosage forms designed for a perfect anatomical fit. Despite the limitations of pharmaceutical products produced with HME and FDM 3D printing regarding thermal stability and available excipients, the advantages in industrial adaptability and improved bioavailability allied with patient-match devices certainly deserve full attention and investment.

Methodologies to Evaluate the Hair Follicle-Targeted Drug Delivery Provided by Nanoparticles.

Nanotechnology has been investigated for treatments of hair follicle disorders mainly because of the natural accumulation of solid nanoparticles in the follicular openings following a topical application, which provides a drug "targeting effect". Despite the promising results regarding the therapeutic efficacy of topically applied nanoparticles, the literature has often presented controversial results regarding the targeting of hair follicle potential of nanoformulations. A closer look at the published works shows that study parameters such as the type of skin model, skin sections analyzed, employed controls, or even the extraction methodologies differ to a great extent among the studies, producing either unreliable results or precluding comparisons altogether. Hence, the present study proposes to review different skin models and methods for quantitative and qualitative analysis of follicular penetration of nano-entrapped drugs and their influence on the obtained results, as a way of providing more coherent study protocols for the intended application.

Chromatographic method for dacarbazine quantification in skin permeation experiments.

Dacarbazine (DTIC) is a chemotherapeutic drug currently used for the systemic treatment of melanomas. Considering the easy access to these tumors, a topical route of drug administration could provide a more comfortable and less toxic treatment. However, DTIC quantification aiming at the design of topical formulations is challenging, pondering all the interferents present in the drug samples recovered from the skin. Hence, this work intended to validate a selective chromatographic method for DTIC determination in skin permeation studies. A reversed-phase C18 column was used as a stationary phase, and gradient elution of a mobile phase consisting of methanol and pH 6.5 sodium phosphate monohydrate buffer (0.01 mol/L) at a flow rate of 1.0 mL/min was implemented. DTIC was detected at 364 nm. The method was selective against skin interferents, linear (r = 0.9995) in a concentration range of 1.0-15.0 µg/mL, precise with an overall variation coefficient lower than 3.8%, accurate achieving recovery from the skin layers within 91-112%, and sensitive for the proposed application (detection limit = 0.10 µg/ mL, quantification limit = 0.30 µg/mL). Furthermore, the analytical method was successfully tested in in vitro skin permeation studies. In conclusion, the developed method is appropriate for DTIC analysis from the skin sample matrix.

In-situ formation of nanoparticles from drug-loaded 3D polymeric matrices.

The in-situ formation of nanoparticles from polymer-based solid medicines, although previously described, has been overlooked despite its potential to interfere with oral drug bioavailability. Such polymeric pharmaceuticals are becoming increasingly common on the market and can become even more popular due to the dizzying advance of 3D printing medicines. Hence, this work aimed to study this phenomenon during the dissolution of 3D printed tablets produced with three different polymers, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl alcohol (PVA), and Eudragit RL PO® (EUD RL) combined with plasticizers and the model drug naringenin (NAR). The components' interaction, dissolution behavior, and characteristics of the formed particles were investigated employing thermal, spectroscopic, mechanical, and chromatographic assays. All the systems generated stable spherical-shaped particles throughout 24 h, encapsulating over 25% of NAR. Results suggest encapsulation efficiencies variations may depend on interactions between polymer-drug, drug-plasticizer, and polymer-plasticizer, which formed stable nanoparticles even in the drug absence, as observed with the HPMCAS and EUD RL formulations. Additionally, components solubility in the medium and previous formulation treatments are also a decisive factor for nanoparticle formation. In particular, the treatment provided by hot-melt extrusion and FDM 3D printing affected the dissolution efficiency enhancing the interaction between the components, reverberating on particle size and particle formation kinetics mainly for HPMCAS and EUD RL. In conclusion, the 3D printing process influences the in-situ formation of nanoparticles, which can directly affect oral drug bioavailability and needs to be monitored.

Colloidal copper oxide nanoparticles leading to a biphasic dose-response in growth inhibition of Staphylococcus aureus.

Aim: The dose response in growth inhibition of Staphylococcus aureus treated with colloidal copper oxide nanoparticles (CuO-NP) was evaluated. Methods: An in vitro microbial viability assay was conducted with CuO-NP concentrations spreading over the 0.4-848.0 µg/ml range. The dose-response curve was modeled with a double Hill equation. UV-Visible absorption and photoluminescence spectroscopies allowed tracking concentration-dependent modifications in CuO-NP. Results: Two specific phases separated by the critical concentration of 26.5 µg/ml were observed in the dose-response curve, with each exhibiting proper IC50 parameters, Hill coefficients and relative amplitudes. Spectroscopy techniques reveal the occurrence of a concentration-triggered aggregation of CuO-NP starting from this critical concentration. Conclusion: The findings demonstrate a dose-related change in S. aureus sensitivity to CuO-NP, which probably arises from the aggregation of this agent.

Antibacterial agents are often used to stop the growth of bacteria such as Staphylococcus aureus (S. aureus). Copper oxide nanoparticles (CuO-NP) stand as a promising candidate for this purpose. Generally, the agent´s effectiveness is inspected following a dose-response curve in which de agent´s antibacterial response is plotted against its dose (concentration). In this work, employing an extended mathematical interpretation we were capable of discerning experimentally the existence of two stages of dose-response (biphasic dose-response) in the treatment of S. aureus with CuO-NP. These results in combination with insights from spectroscopic techniques lead to the understanding that the biphasic behavior arises from the aggregation of CuO-NP at high concentrations. Therefore, according to the adopted concentration to treat S. aureus, the agent can behave as a dispersed nanoparticle or as an aggregated nanoparticle. In summary, understanding whether antibacterial agents transform as a function of concentration is important in determining their practical applications.

Iontophoresis for the cutaneous delivery of nanoentraped drugs.

INTRODUCTION: The skin is an attractive route for drug delivery. However, the stratum corneum is a critical limiting barrier for drug permeation. Nanoentrapment is a way to enhance cutaneous drug delivery, by diverse mechanisms, with a notable trend of nanoparticles accumulating into the hair follicles when topically applied. Iontophoresis is yet another way of increasing drug transport by applying a mild electrical field that preferentially passes through the hair follicles, for being the pathway of lower resistance. So, iontophoresis application to nanocarriers could further increase actives accumulation into the hair follicles, impacting cutaneous drug delivery. AREAS COVERED: In this review, the authors aimed to discuss the main factors impacting iontophoretic skin transport when combining nanocarriers with iontophoresis. We further provide an overview of the conditions in which this combination has been studied, the characteristics of nanosystems employed, and hypothesize why the association has succeeded or failed to enhance drug permeation. EXPERT OPINION: Nanocarriers and iontophoresis association can be promising to enhance cutaneous drug delivery. For better results, the electroosmotic contribution to the iontophoretic transport, mainly of negatively charged nanocarriers, charge density, formulation pH, and skin models should be considered. Moreover, the transfollicular pathway should be considered, especially when designing the nanocarriers.

Stability and Antioxidant Activity of Pouteria macrophylla Fruit Extract, a Natural Source of Gallic Acid.

Pouteria macrophylla (cutite) fruits are rich in phenolic acids, resulting in antioxidant and skin depigmenting activity. The aim of this study, then, is to evaluate the cutite extract stability under three variations of light, time, and temperature using a Box-Behnken experimental design to analyze through the surface response the variations of the total phenolic content (TPC), antioxidant activity (AA), and gallic acid content (GA). A colorimetric assay was also performed, and a decrease in the darkening index was noticed due to the high phenolic coloration in the presence of light, indicating less degradation to extract stability. The experimental planning showed variations in all responses, and second-order polynomial models were calculated and considered predictable, as well as the effects were significant. The TPC exhibited a variation in less concentrated samples (0.5% p/v) at higher temperatures (90 °C). In contrast, the temperature was the only influential variable for AA, where only higher temperatures (60-90 °C) were able to destabilize the fruit extract. Differently, GA showed only the concentration as the influential variable, exhibiting that neither temperature nor time of exposure could affect the gallic acid content stability of P. macrophylla extract. For this, P. macrophylla extract was shown to be highly stable, providing a great perspective on cosmetic application.

In Vitro Performance Analysis of a Minoxidil Thermosensitive Gel with Reduced Runoff for Eyebrow Hair Growth.

There is a growing interest in innovative products for eyebrow hair loss treatment with fewer adverse effects. Nevertheless, a fundamental formulation aspect of preventing the fragile skin from the ocular region from being irritated is that the formulations remain restricted to the application region and do not run off. Consequently, the methods and protocols in drug delivery scientific research must be adapted to fulfill such performance analysis demand. Thus, this work aimed to propose a novel protocol to evaluate the in vitro performance of a topical gel formulation with a reduced runoff for minoxidil (MXS) delivery to eyebrows. MXS was formulated with 16% poloxamer 407 (PLX) and 0.4% of hydroxypropyl methylcellulose (HPMC). The sol/gel transition temperature, viscosity at 25 °C, and formulation runoff distance on the skin were evaluated to characterize the formulation. The release profile and skin permeation were evaluated in Franz vertical diffusion cells for 12 h and compared to a control formulation (4% PLX and 0.7% HPMC). Then, the formulation's performance at promoting minoxidil skin penetration with minimum runoff was evaluated in a vertical custom-made permeation template (divided into three areas: superior, middle, and inferior). The MXS release profile from the test formulation was comparable to that from the MXS solution and the control formulation. There was also no difference in the MXS amount that penetrated the skin in the permeation experiments in Franz diffusion cells using the different formulations (p > 0.05). However, the test formulation demonstrated a localized MXS delivery at the application site in the vertical permeation experiment. In conclusion, the proposed protocol could differentiate the test formulation from the control, attesting to its better performance in efficiently delivering MXS to the site of interest (middle third of application). The vertical protocol can be easily employed to evaluate other gels with a drip-free appeal.

Novel technologies to improve the treatment of endodontic microbial infections: Inputs from a drug delivery perspective.

Endodontic microbial infections are still a challenge for an effective treatment for being biofilm-mediated and very refractory to conventional therapies. Biomechanical preparation and chemical irrigants cannot fully eradicate biofilms due to the anatomic structure of the root canal system. Instruments employed in biomechanical preparation and irrigants solution cannot reach the narrow and deepest portion of root canals, especially the apical thirds. In addition, aside from the dentin surface, biofilms can also infiltrate dentine tubules and periapical tissues, compromising treatment success. Therefore, different technologies have been investigated to achieve a more effective outcome in the control of endodontic infections. However, these technologies continue to face great difficulties in reaching the apical region and eradicating biofilms to avoid the recurrence of infection. Here, we present an overview of the fundamentals of endodontics infections and review technologies currently available for root canal treatment. We discuss them from a drug delivery perspective, highlighting each technology's strength to envision the best use of these technologies.

Curcumin quantification in skin and mucosa: Optimization of extraction and chromatographic method validation.

Curcumin is a natural phenol found in the rhizome of Curcuma longa. It has been studied to treat several human carcinomas, such as melanomas and breast, head and neck, prostate, and ovary cancers. Here, we develop and validate a method for recovering curcumin from the skin layers and mucosa and selectively quantifying it, aiming to support permeation studies in developing topical formulations containing the natural compound. Recovery of curcumin from the stratum corneum, remaining skin, and mucosa was performed using ethanol, DMSO/ethanol, and DMSO, respectively, under mild stirring for specific periods. The separation of curcumin from the other curcuminoids, skin, and mucosa interferents was obtained using a C18 column as a stationary phase. The mobile phase was composed of pH 3.0 phosphoric acid at 1.0 mmol/L and acetonitrile (47:53, v/v), which flowed at 1 mL min-1. UV-Vis detection of curcumin was at 424 nm. The chromatographic method was selective, linear (r > 0.999), with a regression curve in the concentration range from 1.0 to 30.0 µg mL-1, robust, precise, and accurate, with curcumin recovery rates higher than 95 ± 7 % from the mucosa, 82 ± 2 % from the stratum corneum, and 65 ± 10 % from the remaining skin. Finally, the method was successfully used in a skin permeation test performed with porcine skin and mucosa. The validated method is, therefore, suitable for the recovery and quantification of curcumin from the skin layers and mucosa, favoring the development of new topical formulations destined for these sites of administration.

α-Cyclodextrin-based poly(pseudo)rotaxane for antifungal drug delivery to the vaginal mucosa.

This work aimed to evaluate poly(pseudo)rotaxanes (PPRs) potential for vaginal antifungal delivery. For this, PPRs containing terbinafine (TB) 2 % were obtained using two small surfactants, Kolliphor® RH40 and Gelucire® 48/16, and different α-cyclodextrin (α-CD) concentrations (5 and 10 %). PPRs were characterized by their physicochemical characteristics, irritation, and mucoadhesion capabilities. Formulations' performance was assessed in a vertical penetration model, which uses ex vivo entire porcine vagina. Conventional penetration experiments with excised vaginal tissue were performed as a control. Results showed all formulations were non-irritant according to the HET-CAM test. Furthermore, PPRs with 10 % αCD showed superior mucoadhesion (p < 0.05). Conventional horizontal penetration studies could not differentiate formulations (p > 0.05). However, PPRs with 10 % αCD presented a better performance in vertical ex vivo studies, achieving higher drug penetration into the vaginal mucosa (p < 0.05), which is probably related to the formulation's prolonged residence time. In addition, the antifungal activity of the formulations was maintained against Candida albicans and C. glabrata cultures. More importantly, the formulation's viscosity and drug delivery control had no negative impact on the antifungal activity. In conclusion, the best performance in a more realistic model evidenced the remarkable potential of PPRs for vaginal drug delivery.

Iontophoresis application for drug delivery in high resistivity membranes: nails and teeth.

Iontophoresis has been vastly explored to improve drug permeation, mainly for transdermal delivery. Despite the skin's electrical resistance and barrier properties, it has a relatively high aqueous content and is permeable to many drugs. In contrast, nails and teeth are accessible structures for target drug delivery but possess low water content compared to the skin and impose significant barriers to drug permeation. Common diseases of these sites, such as nail onychomycosis and endodontic microbial infections that reach inaccessible regions for mechanical removal, often depend on time-consuming and ineffective treatments relying on drug's passive permeation. Iontophoresis application in nail and teeth structures may be a safe and effective way to improve drug transport across the nail and drug distribution through dental structures, making treatments more effective and comfortable for patients. Here, we provide an overview of iontophoresis applications in these "hard tissues," considering specificities such as their high electrical resistivity. Iontophoresis presents a promising option to enhance drug permeation through the nail and dental tissues, and further developments in these areas could lead to widespread clinical use.