Paulo Sarango-Granda

Background/Objectives: Crisaborole (CRB) is a phosphodiesterase-4 inhibitor used for the topical treatment of mild-to-moderate atopic dermatitis (AD). However, its low aqueous solubility presents challenges for topical formulation and localized drug delivery. This study aimed to develop a CRB-loaded nanoemulsion (CRB-NE) and evaluate its physicochemical and biopharmaceutical characteristics, tolerability, and anti-inflammatory activity. Methods: CRB-NE (0.5% w/w) was developed using pseudo-ternary phase diagrams. Droplet size, morphology, rheological behavior, spreadability, and stability were characterized. Drug release and ex vivo permeation in human skin were evaluated. Biological compatibility was investigated using HaCaT keratinocytes and the hen’s egg test–chorioallantoic membrane (HET-CAM) assay, while skin barrier compatibility was assessed in healthy volunteers. Anti-inflammatory activity was evaluated through IL-8 secretion in stimulated HaCaT cells and a xylene-induced ear inflammation model in mice. Results: CRB-NE showed a droplet size of 105.3 ± 6.7 nm, a polydispersity index of 0.287 ± 0.012, Newtonian flow behavior, and physical stability over 60 days. Approximately 80% of CRB was released following first-order kinetics. After 24 h, ex vivo experiments showed cutaneous retention of 1098.43 μg CRB/g skin/cm² and cumulative permeation of 23.75 ± 4.44 μg/cm². Keratinocyte viability exceeded 80% at CRB concentrations of 2.5–10 μg/mL, and HET-CAM results indicated low irritation potential. The vehicle did not adversely affect skin barrier measurements in healthy volunteers. CRB-NE significantly reduced IL-8 secretion in TNF-α-stimulated keratinocytes and attenuated erythema, inflammatory cell infiltration, edema, vascular congestion, and tissue damage in vivo. Conclusions: CRB-NE demonstrated favorable physicochemical properties, substantial cutaneous drug retention, and anti-inflammatory activity, supporting its potential as a localized topical delivery system.

Background/Objectives: Baricitinib, a selective JAK1/JAK2 inhibitor, shows therapeutic potential in psoriasis; however, its oral use is associated with systemic adverse effects, encouraging the development of topical formulations. This study aimed at evaluating the influence of petrolatum type on the stability, biopharmaceutical performance, and therapeutic activity of lipid-based formulations containing Baricitinib. Methods: Formulations were prepared with Labrafac^® Lipophile WL 1349 (L) and either liquid (LLV) or solid (LSV) petrolatum at 30% and 60% w/w. Stability, rheology, spreadability, in vitro release, ex vivo permeation, and skin retention were evaluated, along with the safety and efficacy in HET-CAM and imiquimod-induced psoriasis murine models. Results: Only 30% petrolatum formulations remained stable for 60 days. LLV exhibited Newtonian flow, higher spreadability, sustained release (83.7% at 50 h), and superior skin retention (94 µg/g of skin/cm²), whereas LSV showed pseudoplastic behavior, lower spreadability, and reduced release (47.4% at 50 h). Both formulations were non-irritant and improved stratum corneum hydration while reducing transepidermal water loss. In vivo, both reduced erythema, epidermal thickening, edema, and histological alterations, confirming anti-inflammatory efficacy. Conclusions: These results demonstrate that the vehicle occlusivity decisively modulates baricitinib’s release and activity. LLV formulation favored drug retention and enhanced permeation at 24 h. Overall, excipient selection is important in designing safe and effective topical JAK inhibitor formulations.

Leishmaniasis is an infectious disease common in tropical and subtropical regions worldwide. This study aimed to develop a topical meglumine antimoniate gel (MA-gel) for the treatment of cutaneous leishmaniasis. The MA-gel was characterized in terms of morphology, pH, swelling, porosity, rheology, and thermal properties by differential scanning calorimetry (DSC). Biopharmaceutical evaluation included in vitro drug release and ex vivo skin permeation. Safety was evaluated through biomechanical skin property measurements and cytotoxicity in HaCaT and RAW 267 cells. Leishmanicidal activity was tested against promastigotes and amastigotes of Leishmania infantum, and in silico studies were conducted to explore possible mechanisms of action. The composition of the MA-gel included 30% MA, 20% Pluronic^® F127 (P407), and 50% water. Scanning electron microscopy revealed a sponge-like and porous internal structure of the MA-gel. This formula exhibited a pH of 5.45, swelling at approximately 12 min, and a porosity of 85.07%. The DSC showed that there was no incompatibility between MA and P407. Drug release followed a first-order kinetic profile, with 22.11 µg/g/cm² of the drug retained in the skin and no permeation into the receptor compartment. The MA-gel showed no microbial growth, no cytotoxicity in keratinocytes, and no skin damage. The IC₅₀ for promastigotes and amastigotes of L. infantum were 3.56 and 23.11 µg/mL, respectively. In silico studies suggested that MA could act on three potential therapeutic targets according to its binding mode. The MA-gel demonstrated promising physicochemical, safety, and antiparasitic properties, supporting its potential as a topical treatment for cutaneous leishmaniasis.

The poor water solubility of apremilast (APR) is the main impediment to the penetration of the drug through the skin barrier. The objective of this study was to evaluate the permeability of APR in different solutions enriched with penetration promoters in ex vivo samples of human skin, and additionally assess its tolerance in vivo. To this end, APR solutions with 5% promoter were developed, and the drug’s ability to penetrate human abdominal skin samples was evaluated; the coefficients of permeability, cumulated amounts permeated, and flow were some of the parameters evaluated; likewise, the in vitro and in vivo tolerance of the solutions was evaluated. The results obtained showed that the solutions containing squalene as a promoter improved the penetration of APR compared to the other promoters evaluated; in the same way, on an in vitro scale in HaCaT cells, the promoters were not toxic, finding a cell viability greater than 80% at the different dilutions evaluated. In the in vivo tests carried out with the solution that presented the best results (APR-Squalene solution), it was observed that it does not cause irritation or erythema on the skin after its colorimetric and histological evaluation of the dorsal region of rats after its application. Squalene becomes an excellent candidate to improve the permeability of the drug in the case of the development of a topical formulation; in addition, it was confirmed that this penetration enhancer is neither toxic nor irritating when in contact with the skin in in vivo tests.

The higher molecular weight and low solubility of amphotericin B (AmB) hinders its topical administration. The aim of this study was to incorporate Bursera graveolens essential oil into an AmB topical gel (AmB + BGEO gel) in order to promote the diffusion of the drug through the skin in the treatment of cutaneous candidiasis. AmB + BGEO gel formulation was determined using a factorial experiment. Physical and chemical parameters, stability, in vitro release profile and ex vivo permeation in human skin were evaluated. In vitro antimicrobial activity was studied using strains of C. albicans, C. glabrata and C. parapsilosis. The tolerability was evaluated using in vitro and in vivo models. AmB + BGEO gel presented appropriate characteristics for topical administration, including pH of 5.85, pseudoplastic behavior, optimal extensibility, as well as high stability and acceptable tolerability. In vitro release studies showed that the formulation releases the drug following a Boltzmann sigmoidal model. Finally, AmB + BGEO gel exhibited higher amount of drug retained inside the skin and lower Minimum Inhibitory Concentration than a formulation sans essential oil. Therefore, these results suggest that the incorporation of B. graveolens essential oil in the formulation could be used as strategy to promote a local effect in the treatment of cutaneous candidiasis.

The mouth can be affected by important inflammatory processes resulting from localized or systemic diseases such as diabetes, AIDS and leukemia, among others, and are manifested in various types of buccal sores typically presenting pain. This work focuses on the design, formulation, and characterization of four semisolid formulations for oral mucosa in order to symptomatically treat these painful processes. The formulations have two active pharmaceutical ingredients, triamcinolone acetonide (TA) and lidocaine hydrochloride (LIDO). The formula also contains, as an excipient, Orabase^®, which is a protective, hydrophobic, and anhydrous adhesive vehicle, used to retain or facilitate the application of active pharmaceutical ingredients to the oral mucosa. After designing the formulations, an analytical method for TA was validated using HPLC so as to achieve reliable analytical results. Franz-type diffusion cells were used to perform drug release studies using synthetic membrane, and permeation studies using buccal mucosa, estimating the amount and rate of TA permeated across the tissue. Additionally, sublingual permeation studies were carried out to evaluate a scenario of a continuous contact of the tongue with the applied formulation. Permeation fluxes and the amount of TA retained within sublingual mucosa were similar to those in buccal mucosa, also implying anti-inflammatory activity in the part of the tongue that is in direct contact with the formulation. In addition, the dynamic conditions of the mouth were recreated in terms of the presence of phosphate buffered saline, constant movement of the tongue, pH, and temperature, using dissolution equipment. The amount of TA released into the phosphate buffered saline in dynamic conditions (subject to being ingested) is well below the normal oral doses of TA, for which the formulation can be considered safe. The formulations applied to buccal or sublingual mucosas under dynamic conditions permit the successful retention of TA within either tissue, where it exerts anti-inflammatory activity. The four formulations studied show a pseudoplastic and thixotropic behavior, ideal for topical application. These results evidence the potential of these topical formulations in the treatment of inflammatory processes in the buccal mucosa.

Apremilast (APR) is a selective phosphodiesterase 4 inhibitor administered orally in the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. The low solubility and permeability of this drug hinder its dermal administration. The purpose of this study was to design and characterize an apremilast-loaded microemulsion (APR-ME) as topical therapy for local skin inflammation. Its composition was determined using pseudo-ternary diagrams. Physical, chemical and biopharmaceutical characterization were performed. Stability of this formulation was studied for 90 days. Tolerability of APR-ME was evaluated in healthy volunteers while its anti-inflammatory potential was studied using in vitro and in vivo models. A homogeneous formulation with Newtonian behavior and droplets of nanometric size and spherical shape was obtained. APR-ME released the incorporated drug following a first-order kinetic and facilitated drug retention into the skin, ensuring a local effect. Anti-inflammatory potential was observed for its ability to decrease the production of IL-6 and IL-8 in the in vitro model. This effect was confirmed in the in vivo model histologically by reduction in infiltration of inflammatory cells and immunologically by decrease of inflammatory cytokines IL-8, IL-17A and TNFα. Consequently, these results suggest that this formulation could be used as an attractive topical treatment for skin inflammation.

The mouth can be affected by important inflammatory processes resulting from localized or systemic diseases, such as diabetes, AIDS, and leukemia, among others, which are manifested in various types of buccal sores, typically presenting pain [1]. The present work focuses on the design, formulation, and characterization of four semi-solid formulations for oral mucosa in order to symptomatically treat these painful processes. The formulations have two active pharmaceutical ingredients: triamcinolone acetonide (TA) and lidocaine hydrochloride (LIDO). The formulations also contain Orabase^® as an excipient, which is a protective, hydrophobic, and anhydrous adhesive vehicle, used to retain or facilitate the application of active pharmaceutical ingredients (APIs) to the oral mucosa. After designing the formulations, the validation of the analytical method was performed to achieve reliable analytical results. Franz-type diffusion cells were used to perform drug release studies using synthetic membrane, and permeation studies using buccal mucosa, permitting the estimation of the amount and rate of TA permeated across this mucous membrane. Further, the amount of TA retained within the tissue was estimated, as this is where it performs its anti-inflammatory activity, and showed no significant differences between the 0.05% TA + LIDO and 0.1% TA + LIDO formulations (p > 0.05). Therefore, the results demonstrate the suitability of the administration of the lowest concentration of TA tested, which achieved a similar efficacy as higher concentrations and reduced the potential systemic effects of corticoid administration. Furthermore, sublingual permeation studies were carried out to evaluate a scenario of continuous contact of the tongue with the applied formulation. The four formulations studied show pseudoplastic and thixotropic behavior, ideal for topical application. These results provide evidence for the potential of these topical formulations for the treatment of inflammatory processes in the buccal mucosa.