Search Results (19)

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. Full article

Background/Objectives: Leishmaniasis is a neglected tropical disease caused by a protozoan parasite of Leishmania. This study aimed to evaluate the in vitro efficacy and toxicity of a previously developed amphotericin gel as a possible treatment for cutaneous leishmaniasis. Methods: First, quality control of the AmB-gel was carried out, including microbiological stability. The permeated and retained drug was tested on healthy and lacerated human skin. Tolerance to the AmB-gel was tested in vitro using HaCaT, RAW 264.7, and J774 cell lines and by an irritation test (HET-CAM). Promastigotes and amastigotes of various Leishmania species were tested, and the microscopic morphology of promastigotes exposed to the formulation was analyzed. Computational analysis was performed on the drug, polymer, and ergosterol in the promastigote. Results: The AmB-gel presented appropriate characteristics for topical use, including no microbial contamination after storage. The amount of drug retained on the intact and injured skin was 1180.00 ± 13.54 µg/g/cm² and 750.18 ± 5.43 µg/g/cm², respectively. The AmB-gel did not cause significant signs of toxicity. The IC₅₀ of the AmB-gel for promastigotes was less than 1 µg/mL for the four species examined, i.e., Leishmania infantum, Leishmania tropica, Leishmania major, and Leishmania braziliensis, and less than 2 µg/mL for amastigotes of Leishmania infantum and Leishmania tropica. The AmB-gel caused notable effects on the surface of promastigotes. Computational analysis revealed primarily hydrophobic and van der Waals interactions between AmB and Pluronic^® F127 and ergosterol. Conclusions: Based on the drug retention content and IC₅₀ values observed for both parasite stages, the AmB-gel may be a promising candidate for in vivo studies in patients with cutaneous leishmaniasis. Full article

The use of nanoparticles improves the stability, solubility, and skin permeability of natural compounds in skincare products. Based on these advantages, this study aimed to incorporate the Phlomis crinita extract into polymeric nanoparticles to improve its topical skin delivery for wound healing purposes. The study involved the preparation of nanoparticles of PLGA and PLGA-PEG (PCE-PLGA-NPs and PCE-PLGA-PEG-NPs) using the solvent displacement method, physicochemical and biopharmaceutical characterization, tolerance studies by the HET-CAM assay and evaluation of skin integrity parameters, and in vitro efficacy via a scratch wound healing experiment. The prepared nanoparticles were nanometer-sized with spherical form and demonstrated an encapsulation efficiency greater than 90%. The major component (luteolin) was released following a kinetic model of hyperbola for PCE-PLGA-PEG-NPs and one-phase exponential association for PCE-PLGA-NPs. Moreover, the important permeability of luteolin skin was observed, especially for PCE-PLGA-PEG-NPs. Both formulations exhibited no irritation and no damaging effects on skin integrity, suggesting their safety. Finally, the results of the scratch wound healing experiment using 3T3-L1 cells revealed significant cell migration and proliferation, with an improved efficacy for PCE-PLGA-PEG-NPs compared to the free extract, demonstrating the potential of this formulation in the treatment of wound healing. Full article

Rosacea is a common skin condition with quite a relevance. It currently affects at least 10% of the European population at some point after the age of 30. It is a chronic disorder that mainly affects the skin on the face and is characterized by outbreaks and remissions. Under normal circumstances, the skin face presents a wide range of commensal organisms, such as Staphylococcus epidermidis or Demodex folliculorum, but dysbiosis of the skin flora plays a relevant role in inflammatory processes and the development of the disease. Metronidazole (MD) is one of the main treatments indicated to reduce redness on the cheeks, nose, chin, or forehead and also to treat flushing, erythema, pimples, and other symptoms due in part to its anti-inflammatory action. On the other hand, clindamycin (CM) is another antibiotic used for rosacea, especially for its action against anaerobic and Gram-positive bacteria. Background/Objectives: This study aimed to develop an emulgel formulation that includes MD and CM, using excipients with non-comedogenic and non-irritating properties. Methods: The formulation was characterised physiochemically, rheological measurements were made, and short-term stability studies were carried out. In vitro release, permeation studies, toxicity an in vitro inflammation model were evaluated in a HaCaT cell model. To determine the interaction between the antibiotics, the minimum inhibitory concentration was determined separately and together using the broth microdilution method. To determine the formulation’s antimicrobial activity, an agar diffusion method was used. Results: The MD-CM-gel droplet size was measured by laser diffraction and the diameter obtained was less than 2.68 ± 0.18 µm in 50% of the particles. Suitable results was observed for the short-term stability. Release and permeation data revealed sustained drug release and adequate permeation through human skin. Non-toxicity was detected and the MD showed an anti-inflammatory effect with non-interference of CM. Also, there is no antagonism between the two antibiotics and the MD-CM-gel shows better results when compared to the formulations with the antibiotics separately and to commercial formulations. Conclusions: It is suggested that, following detailed preclinical and clinical studies, MD-CM-gel could be considered as an alternative for treating rosacea. Full article

Apremilast (APM) is a novel drug for the treatment of psoriasis and psoriatic arthritis. APM is a phosphodiesterase 4 (PDE4) inhibitor, raising intracellular cAMP levels and thereby decreasing the inflammatory response by modulating the expression of TNF-α, IL-17, IL-23, and other inflammatory cytokines. The goal of this study is to develop APM gels as a new pharmaceutical formulation for the treatment of topical psoriasis. APM was solubilized in Transcutol-P and incorporated into Pluronic F127, Sepigel, and carbomer bases at different proportions. All formulations were characterized physiochemically. A biopharmaceutical study (release profile) was performed, and ex vivo permeation was evaluated using a human skin model. A toxicity assay was carried out on the HaCaT cell line. A mouse model of imiquimod-induced psoriasis skin inflammation was carried out to determine its efficacy by histological analysis, RNA extraction, and RT-qPCR assays. APM gel formulations showed good physicochemical characteristics and a sustained release profile. There was no permeation of any gel measured through human skin, indicating a high retained amount of APM on the skin. Cell viability was greater than 80% at most dilution concentrations. APM gels treated the psoriasis mouse model, and it shows a reduction in the proinflammatory cytokines (IL-8, IL-17A, IL-17F, and IL-23). APM gels could be a new approach for the treatment of topical psoriasis. Full article

Pranoprofen (PRA)-loaded nanostructured lipid carriers (NLC) have been dispersed into blank gels composed of 1% of Carbomer 940 (PRA-NLC-Car) and 3% of Sepigel^® 305 (PRA-NLC-Sep) as a novel strategy to refine the biopharmaceutical profile of PRA, for dermal administration in the treatment of skin inflammation that may be caused by possible skin abrasion. This stratagem intends to improve the joining of PRA with the skin, improving its retention and anti-inflammatory effect. Gels were evaluated for various parameters such as pH, morphology, rheology, and swelling. In vitro drug release research and ex vivo permeation through the skin were carried out on Franz diffusion cells. Additionally, in vivo assays were carried out to evaluate the anti-inflammatory effect, and tolerance studies were performed in humans by evaluating the biomechanical properties. Results showed a rheological profile common of semi-solid pharmaceutical forms for dermal application, with sustained release up to 24 h. In vivo studies using PRA-NLC-Car and PRA-NLC-Sep in Mus musculus mice and hairless rats histologically demonstrated their efficacy in an inflammatory animal model study. No signs of skin irritation or modifications of the skin’s biophysical properties were identified and the gels were well tolerated. The results obtained from this investigation concluded that the developed semi-solid formulations represent a fitting drug delivery carrier for PRA’s transdermal delivery, enhancing its dermal retention and suggesting that they can be utilized as an interesting and effective topical treatment for local skin inflammation caused by a possible abrasion. Full article

The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is miscible in water, to evaluate the drug uptake in human skin and porcine tissues (sclera, cornea, oral, sublingual, and vaginal), and to subsequently extract the drug from the tissues so as to determine the drug recovery using in vitro techniques. Analytical methods were developed and validated for the quantification of BCT in Transcutol using absorption and fluorescence spectroscopies, which are complementary to each other and permit the detection of the drug across a broad range of concentrations. Results show that Transcutol permits an increased drug solubility, and that BCT is able to penetrate the tissues studied. The solutions of BCT in Transcutol were stable for at least one week. Hence, Transcutol may be a suitable solvent for further development of topical formulations. Full article

Transmucosal delivery is commonly used to prevent or treat local diseases. Pranoprofen is an anti-inflammatory drug prescribed in postoperative cataract surgery, intraocular lens implantation, chorioretinopathy, uveitis, age-related macular degeneration or cystoid macular edema. Pranoprofen can also be used for acute and chronic management of osteoarthritis and rheumatoid arthritis. Quality by Design (QbD) provides a systematic approach to drug development and maps the influence of the formulation components. The aim of this work was to develop and optimize a nanostructured lipid carrier by means of the QbD and factorial design suitable for the topical management of inflammatory processes on mucosal tissues. To this end, the nanoparticles loading pranoprofen were prepared by a high-pressure homogenization technique with Tween 80 as stabilizer and Lanette^® 18 as the solid lipid. From, the factorial design results, the PF-NLCs-N6 formulation showed the most suitable characteristics, which was selected for further studies. The permeability capacity of pranoprofen loaded in the lipid-based nanoparticles was evaluated by ex vivo transmucosal permeation tests, including buccal, sublingual, nasal, vaginal, corneal and scleral mucosae. The results revealed high permeation and retention of pranoprofen in all the tissues tested. According to the predicted plasma concentration at the steady-state, no systemic effects would be expected, any neither were any signs of ocular irritancy observed from the optimized formulation when tested by the HET-CAM technique. Hence, the optimized formulation (PF-NLCs-N6) may offer a safe and attractive nanotechnological tool in topical treatment of local inflammation on mucosal diseases. Full article

Drug-loaded nanocarriers (NCs) are new systems that can greatly improve the delivery and targeting of drugs to specific tissues and organs. In our work, a PPAR-γ agonist loaded into polymeric NCs was prepared, stabilized by spray-drying, and tested in vitro, ex vivo, and in vivo (animal models) to provide a safe formulation for optical anti-inflammatory treatments. The NCs were shown to be well tolerated, and no signs of irritancy or alterations of the eye properties were detected by the in vitro HET-CAM test and in vivo Draize test. Furthermore, no signs of cytotoxicity were found in the NC formulations on retinoblastoma cells (Y-79) analyzed using the alamarBlue assay, and the transmittance experiments evidenced good corneal transparency with the formulations tested. The ocular anti-inflammatory study confirmed the significant prevention efficacy using the NCs, and these systems did not affect the corneal tissue structure. Moreover, the animal corneal structure treated with the NCs was analyzed using X-ray diffraction using synchrotron light. Small-angle X-ray scattering (SAXS) analysis did not show a significant difference in corneal collagen interfibrillar spacing after the treatment with freshly prepared NCs or NCs after the drying process compared to the corresponding negative control when inflammation was induced. Considering these results, the PPAR-γ agonist NCs could be a safe and effective alternative for the treatment of inflammatory ocular processes. Full article

Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) enhance the delivery of therapeutic enzymes for replacement therapy of lysosomal storage disorders. Previous studies examined NPs encapsulating or coated with enzymes, but these formulations have never been compared. We examined this using hyaluronidase (HAse), deficient in mucopolysaccharidosis IX, and acid sphingomyelinase (ASM), deficient in types A–B Niemann–Pick disease. Initial screening of size, PDI, ζ potential, and loading resulted in the selection of the Lactel II co-polymer vs. Lactel I or Resomer, and Pluronic F68 surfactant vs. PVA or DMAB. Enzyme input and addition of carrier protein were evaluated, rendering NPs having, e.g., 181 nm diameter, 0.15 PDI, −36 mV ζ potential, and 538 HAse molecules encapsulated per NP. Similar NPs were coated with enzyme, which reduced loading (e.g., 292 HAse molecules/NP). NPs were coated with targeting antibodies (> 122 molecules/NP), lyophilized for storage without alterations, and acceptably stable at physiological conditions. NPs were internalized, trafficked to lysosomes, released active enzyme at lysosomal conditions, and targeted both peripheral organs and the brain after i.v. administration in mice. While both formulations enhanced enzyme delivery compared to free enzyme, encapsulating NPs surpassed coated counterparts (18.4- vs. 4.3-fold enhancement in cells and 6.2- vs. 3-fold enhancement in brains), providing guidance for future applications. Full article

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

Pioglitazone-loaded PLGA-PEG nanoparticles (NPs) were stabilized by the spray drying technique as an alternative to the treatment of ocular inflammatory disorders. Pioglitazone-NPs were developed and characterized physiochemically. Interaction studies, biopharmaceutical behavior, ex vivo corneal and scleral permeation, and in vivo bioavailability evaluations were conducted. Fibrillar diameter and interfibrillar corneal spacing of collagen was analyzed by synchrotron X-ray scattering techniques and stability studies at 4 °C and was carried out before and after the spray drying process. NPs showed physicochemical characteristics suitable for ocular administration. The release was sustained up to 46 h after drying; ex vivo corneal and scleral permeation profiles of pioglitazone-NPs before and after drying demonstrated higher retention and permeation through cornea than sclera. These results were correlated with an in vivo bioavailability study. Small-angle X-ray scattering (SAXS) analysis did not show a significant difference in the organization of the corneal collagen after the treatment with pioglitazone-NPs before and after the drying process, regarding the negative control. The stabilization process by Nano Spray Dryer B-90 was shown to be useful in preserving the activity of pioglitazone inside the NPs, maintaining their physicochemical characteristics, in vivo bioavailability, and non-damage to corneal collagen function after SAXS analysis was observed. Full article

Pioglitazone (PGZ) is an oral anti-hyperglycemic agent, belongs to the class of thiazolidinediones, and is used for the treatment of diabetes mellitus type 2. In recent years, its anti-inflammatory activity has also been demonstrated in the literature for different diseases, including ocular inflammatory processes. Additionally, this drug belongs to Class II of the Biopharmaceutical Classification System, i.e., slightly soluble and highly permeable. The main objective of this study was to validate a new analytical HPLC-MS/MS method to quantify free-PGZ and PGZ from polymeric NPs to conduct nanoparticle application studies loaded with this active ingredient to transport it within ocular tissues. An accurate, sensitive, selective, reproducible and high throughput HPLC-MS/MS method was validated to quantify PGZ in cornea, sclera, lens, aqueous humor, and vitreous humor. The chromatographic separation was achieved in 10 min on a Kinetex C18 column. Linear response of PGZ was observed over the range of 5–100 ng/mL. The recovery of free-PGZ or PGZ from NPs was in the range of 85–110% in all tissues and levels tested. The intra-day and inter-day precision were <5% and <10%, respectively. The extracts were shown to be stable in various experimental conditions in all matrices studied. The range of concentrations covered by this validation is 80–1600 µg/kg of PGZ in ocular tissues. It is concluded that this method can be applied to quantify PGZ for in vivo and ex vivo biodistribution studies related to the ocular administration of free-PGZ and PGZ from nanoparticles. Full article

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. Full article

Pioglitazone (PGZ) is a drug used to treat type 2 diabetes mellitus that has been reported to show additional therapeutic activities on diverse inflammatory parameters. The aim of this study was to optimize a topical PGZ-loaded nanoemulsion (PGZ-NE) in order to evaluate its effectiveness for treating atopic dermatitis (AD). The composition of the nanoformulation was established by pseudo-ternary diagram. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined. The efficacy study was carried out using oxazolone-induced AD model in hairless mice. PGZ-NE released the drug following a hyperbolic kinetic. Additionally, its properties provided high retention potential of drug inside the skin. Therapeutic benefits of PGZ-NE were confirmed on diverse events of the inflammatory process, such as reduction of lesions, enhancement of skin barrier function, diminished infiltration of inflammatory cells, and expression of pro-inflammatory cytokines. These results were reinforced by atomic force microscope (AFM), which demonstrated the ability of the formulation to revert the rigidification caused by oxazolone and consequently improve the elasticity of the skin. These results suggest that PGZ-NE may be a promising treatment for inflammatory dermatological conditions such as AD. Full article