Electrostimulable polymeric films with hyaluronic acid and lipid nanoparticles for simultaneous topical delivery of macromolecules and lipophilic drugs.

This study focused on developing electrically stimulable hyaluronic acid (HA) films incorporating lipid nanoparticles (NPs) designed for the topical administration of lipophilic drugs and macromolecules. Based on beeswax and medium-chain triglycerides, NPs were successfully integrated into silk fibroin/chitosan films containing HA (NP-HA films) at a density of approximately 1011 NP/cm2, ensuring a uniform distribution. This integration resulted in a 40% increase in film roughness, a twofold decrease in Young's modulus, and enhanced film flexibility and bioadhesion work. The NP-HA films, featuring Ag/AgCl electrodes, demonstrated the capability to conduct a constant electrical current of 0.2 mA/cm2 without inducing toxicity in keratinocytes and fibroblasts during a 15-min application. Moreover, the NPs facilitated the homogeneous distribution of lipophilic drugs within the film, effectively transporting them to the skin and uniformly distributing them in the stratum corneum upon film administration. The sustained release of HA from the films, following Higuchi kinetics, did not alter the macroscopic characteristics of the film. Although anodic iontophoresis did not noticeably affect the release of HA, it did enhance its penetration into the skin. This enhancement facilitated the permeation of HA with a molecular weight (MW) of up to 2 × 105 through intercellular and transcellular routes. Confocal Raman spectroscopy provided evidence of an approximate 100% increase in the presence of HA with a MW in the range of 1.5-1.8 × 106 in the viable epidermis of human skin after only 15 min of iontophoresis applied to the films. Combining iontophoresis with NP-HA films exhibits substantial potential for noninvasive treatments focused on skin rejuvenation and wound healing.

New Insights of Turmeric Extract-Loaded PLGA Nanoparticles: Development, Characterization and In Vitro Evaluation of Antioxidant Activity.

Here, we presented new insights of the development of poly(lactic-co-glycolic acid) nanoparticles containing turmeric compounds (turmeric-PLGA-NPs) using emulsion-solvent evaporation method. The nanoparticulate system was characterized by size, zeta potential, morphology, release profile, partition parameter, stability and encapsulation efficiency (%EE). Antioxidant activity studies were also evaluated. The Korsmeyer-Peppas model (Mt/M∞ vs. t) was used to determine the release mechanisms of the studied system. Our results demonstrated the emulsion-solvent evaporation method was shown advantageous for producing turmeric-PLGA-NPs in the range of 145 nm with high homogeneity in size distribution, zeta potential of -21.8 mV and %EE about 72%. Nanoparticles were stable over a period of one month. In vitro study showed a release of curcumin governed by diffusion and relaxation of the polymeric matrix. The partition parameter of the extract in relation to blank-PLGA-NPs was 0.111 ± 0.008 M-1, indicating a low affinity of curcumin for the polymer matrix. Antioxidant ability of the turmeric-PLGA-NPs in scavenging the radical 2,2-azinobis (3-ethylbenzothiazoline- 6-sulfonic acid) (ABTS) was inferior to free turmeric extract and showed a concentration and time-dependent profile. The study concluded that PLGA nanoparticles are potential carriers for turmeric extract delivery.

A New Approach to Atopic Dermatitis Control with Low-Concentration Propolis-Loaded Cold Cream.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is difficult to treat. Traditional cold cream, a water-in-oil emulsion made from beeswax, is used to alleviate AD symptoms in clinical practice, although its effectiveness has not been scientifically proven. The addition of propolis has the potential to impart anti-inflammatory properties to cold cream. However, in high concentrations, propolis can trigger allergic reactions. Thus, the objective of this work was to develop a cold cream formulation based on purified beeswax containing the same amount of green propolis present in raw beeswax. The impact of adding this low propolis concentration to cold cream on AD control was evaluated in patients compared to cold cream without added propolis (CBlank). Raw beeswax was chemically characterized to define the propolis concentration added to the propolis-loaded cold cream (CPropolis). The creams were characterized as to their physicochemical, mechanical, and rheological characteristics. The effect of CPropolis and CBlank on the quality of life, disease severity, and skin hydration of patients with AD was evaluated in a triple-blind randomized preclinical study. Concentrations of 34 to 120 ng/mL of green propolis extract reduced TNF-α levels in LPS-stimulated macrophage culture. The addition of propolis to cold cream did not change the cream's rheological, mechanical, or bioadhesive properties. The preclinical study suggested that both creams improved the patient's quality of life. Furthermore, the use of CPropolis decreased the disease severity compared to CBlank.

Besifloxacin liposomes with positively charged additives for an improved topical ocular delivery.

Topical ophthalmic antibiotics show low efficacy due to the well-known physiological defense mechanisms of the eye, which prevents the penetration of exogenous substances. Here, we aimed to incorporate besifloxacin into liposomes containing amines as positively charged additives and to evaluate the influence of this charge on drug delivery in two situations: (i) iontophoretic and (ii) passive treatments. Hypothesis are (i) charge might enhance the electromigration component upon current application improving penetration efficiency for a burst drug delivery, and (ii) positive charge might prolong formulation residence time, hence drug penetration. Liposomes elaborated with phosphatidylcholine (LP PC) or phosphatidylcholine and spermine (LP PC: SPM) were stable under storage at 6 ºC for 30 days, showed mucoadhesive characteristics, and were non-irritant, according to HET-CAM tests. Electron paramagnetic resonance spectroscopy measurements showed that neither the drug nor spermine incorporations produced evident alterations in the fluidity of the liposome's membranes, which retained their structural stability even under iontophoretic conditions. Mean diameter and zeta potential were 177.2 ± 2.7 nm and - 5.7 ± 0.3 mV, respectively, for LP PC; and 175.4 ± 1.9 nm and + 19.5 ± 1.0 mV, respectively, for LP PC:SPM. The minimal inhibitory concentration (MIC) and the minimal bactericide concentration (MBC) of the liposomes for P. aeruginosa showed values lower than the commercial formulation (Besivance). Nevertheless, both formulations presented a similar increase in permeability upon the electric current application. Hence, liposome charge incorporation did not prove to be additionally advantageous for iontophoretic therapy. Passive drug penetration was evaluated through a novel in vitro ocular model that simulates the lacrimal flow and challenges the formulation resistance in the passive delivery situation. As expected, LP PC: SPM showed higher permeation than the control (Besivance). In conclusion, besifloxacin incorporation into positively charged liposomes improved passive topical delivery and can be a good strategy to improve topical ophthalmic treatments.

Nanoemulsion as a Platform for Iontophoretic Delivery of Lipophilic Drugs in Skin Tumors.

Lipophilic drugs do not usually benefit from iontophoresis mainly because they do not solubilize in aqueous formulations suitable for the application of electric current. To explore the influence of iontophoresis on penetration of these drugs, a cationic nanoemulsion was developed to solubilize zinc phthalocyanine (ZnPc), a promising drug for the treatment of skin cancer. To verify the influence of particle size on iontophoresis, an emulsion of nanoemulsion-like composition was also developed. The formulations were characterized and cutaneous and tumor penetration studies were performed in vitro and in vivo, respectively. With particles of about 200 nm, the nanoemulsion solubilized 2.5-fold more ZnPc than the 13-µm emulsion. At the same concentration of ZnPc, in vitro passive penetration studies showed that the nanoemulsion increased, after 1 h of treatment, by almost 4 times the penetration of ZnPc into the viable layers of the skin when compared to the emulsion, whereas iontophoresis of nanoemulsion resulted in a 16-fold increase in ZnPc penetration in only 30 min. An in vivo study in a murine model of melanoma showed that ZnPc reached the tumor after iontophoresis of the nanoemulsion. Therefore, iontophoresis of nanoemulsions appears to be a promising strategy for the topical treatment of tumors with lipophilic drugs.

Resveratrol-loaded nanocapsules inhibit murine melanoma tumor growth.

In this study, resveratrol-loaded nanocapsules were developed and its antitumor activity tested on a melanoma mice model. These nanocapsules were spherically-shaped and presented suitable size, negative charge and high encapsulation efficiency for their use as a modified-release system of resveratrol. Nanoencapsulation leads to the drug amorphization. Resveratrol-loaded nanoparticles reduced cell viability of murine melanoma cells. There was a decrease in tumor volume, an increase in the necrotic area and inflammatory infiltrate of melanoma when resveratrol-loaded nanocapsules were compared to free resveratrol in treated mice. Nanoencapsulation of resveratrol also prevented metastasis and pulmonary hemorrhage. This modified-release technology containing resveratrol can be used as a feasible approach in order to inhibit murine melanoma tumor growth.

Delivery of vanillin by poly(lactic-acid) nanoparticles: Development, characterization and in vitro evaluation of antioxidant activity.

Poly(lactic acid) (PLA) nanoparticles containing vanillin were prepared using an emulsion-solvent evaporation technique and were characterized and assessed for their in vitro antioxidant potential. Physicochemical properties of the nanoparticles were characterized by size, polydispersity index, zeta potential, encapsulation efficiency and stability. Solid state and thermal properties were assessed using X-ray diffraction and differential scanning calorimetry, while in vitro drug release profile was also evaluated. Results showed PLA nanoparticles having a characteristic amorphous structure, sizes in the range of 240 nm with high homogeneity in size distribution, zeta potential of -22 mV and vanillin encapsulation efficiency of 41%. In vitro release study showed a slow and sustained release of vanillin governed by diffusion. Nanoparticles were stable over a period of three months. Antioxidant ability of the vanillin-loaded PLA nanoparticles in scavenging the radical 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) was inferior to free vanillin and due to its prolonged release showed a profile that was both time and concentration dependent, while free vanillin showed concentration-dependent activity. The study concluded that PLA nanoparticles are potential carriers for vanillin delivery.

Influence of the Formulation Parameters on the Particle Size and Encapsulation Efficiency of Resveratrol in PLA and PLA-PEG Blend Nanoparticles: A Factorial Design.

Polymeric nanoparticles are colloidal systems that promote protection and modification of physicochemical characteristics of a drug and that also ensure controlled and extended drug release. This paper reports a 2(3) factorial design study to optimize poly(lactide) (PLA) and poly(lactide)-polyethylene glycol (PLA-PEG) blend nanoparticles containing resveratrol (RVT) for prolonged release. The independent variables analyzed were solvent composition, surfactant concentration and ratio of aqueous to organic phase (two levels each factor). Mean particle size and RVT encapsulation efficiency were set as the dependent variables. The selected optimized parameters were set as organic phase comprised of a mixture of dichloromethane and ethyl acetate, 1% of surfactant polyvinyl alcohol and a 3:1 ratio of aqueous to organic phase, for both PLA and PLA-PEG blend nanoparticles. This formulation originated nanoparticles with size of 228 ± 10 nm and 185 ± 70 nm and RVT encapsulation efficiency of 82 ± 10% and 76 ± 7% for PLA and PLA-PEG blend nanoparticles, respectively. The in vitro release study showed a biphasic pattern with prolonged RVT release and PEG did not influence the RVT release. The in vitro release data were in favor of Higuchi-diffusion kinetics for both nanoformulations and the Kossmeyer-Peppas coefficient indicated that anomalous transport was the main release mechanism of RVT. PLA and PLA-PEG blend nanoparticles produced with single emulsion-solvent evaporation technology were found to be a promising approach for the incorporation of RVT and promoted its controlled release. The factorial design is a tool of great value in choosing formulations with optimized parameters.

Poly(L-lactide) Nanoparticles Reduce Amphotericin B Cytotoxicity and Maintain Its In Vitro Antifungal Activity.

In this study, poly(L-lactide) (PLA) nanoparticles containing amphotericin B (AmB) were developed, and the in vitro cytotoxicity to human erythrocytes and efficacy on strains of Candida spp. were evaluated. The nanoparticles were prepared using an emulsion/solvent evaporation method and were characterized with respect to size, size distribution, AmB encapsulation efficiency, AmB state of aggregation, and AmB in vitro release profile. The mean particle size was 225 nm, and the AmB encapsulation efficiency was over 69%. The AmB in vitro release profile revealed a burst effect within the first 24 h, which released approximately 10% of AmB, followed by a sustained release of approximately 30% of AmB over 30 days. The AmB nanoparticles presented a very low index of hemolysis compared to free AmB, which lysed more than 80% of erythrocytes in the first 2 h of incubation. The AmB-loaded PLA nanoparticles were as effective as free AmB against strains of Candida spp., considering their sustained release profile. Thus, PLA nanoparticles can deliver AmB with reduced toxicity while maintaining its antifungal activity.

Pharmacokinetics of curcumin-loaded PLGA and PLGA-PEG blend nanoparticles after oral administration in rats.

The aim of this study was to assess the potential of nanoparticles to improve the pharmacokinetics of curcumin, with a primary goal of enhancing its bioavailability. Polylactic-co-glycolic acid (PLGA) and PLGA-polyethylene glycol (PEG) (PLGA-PEG) blend nanoparticles containing curcumin were obtained by a single-emulsion solvent-evaporation technique, resulting in particles size smaller than 200 nm. The encapsulation efficiency was over 70% for both formulations. The in vitro release study showed that curcumin was released more slowly from the PLGA nanoparticles than from the PLGA-PEG nanoparticles. A LC-MS/MS method was developed and validated to quantify curcumin in rat plasma. The nanoparticles were orally administered at a single dose in rats, and the pharmacokinetic parameters were evaluated and compared with the curcumin aqueous suspension. It was observed that both nanoparticles formulations were able to sustain the curcumin delivery over time, but greater efficiency was obtained with the PLGA-PEG nanoparticles, which showed better results in all of the pharmacokinetic parameters analyzed. The PLGA and PLGA-PEG nanoparticles increased the curcumin mean half-life in approximately 4 and 6h, respectively, and the C(max) of curcumin increased 2.9- and 7.4-fold, respectively. The distribution and metabolism of curcumin decreased when it was carried by nanoparticles, particularly PLGA-PEG nanoparticles. The bioavailability of curcumin-loaded PLGA-PEG nanoparticles was 3.5-fold greater than the curcumin from PLGA nanoparticles. Compared to the curcumin aqueous suspension, the PLGA and PLGA-PEG nanoparticles increased the curcumin bioavailability by 15.6- and 55.4-fold, respectively. These results suggest that PLGA and, in particular, PLGA-PEG blend nanoparticles are potential carriers for the oral delivery of curcumin.