Renata Vidor Contri

Improving drug biological effects by encapsulation into polymeric nanocapsules

This review is based on selected reports from 2004 to 2014 and provides a comprehensive and updated overview of the state of the art related to the drug delivery advantages of polymeric nanocapsules, which are a specific type of polymeric nanoparticles used for improvement of biological effects. Special attention is given to the application of nanocapsules to increase the chemical and photostability of drugs, to modulate the interaction with cells and tissues, to reduce adverse effects of drugs, and to increase the drug efficiency and/or bioavailability. Moreover, this review covers in vitro and in vivo studies, highlighting interesting examples of drugs from several therapeutic classes for which efficacy is improved by encapsulation in different types of nanocapsules, especially in lipid-core nanocapsules. We also briefly present the first results obtained so far attesting to the safety of using polymeric nanocapsules for drug delivery.

Chitosan gel containing polymeric nanocapsules: a new formulation for vaginal drug delivery

The vaginal route of administration is an alternative for several treatments for either local or systemic pharmacological effects. However, the permanence of a drug in this route represents a challenge for formulation development that can be overcome by using nanoencapsulation and chitosan gel. Thus, this work aimed to evaluate the performance of chitosan hydrogels containing cationic and anionic acrylic-based nanocapsules (Eudragit® RS 100 and Eudragit® S 100, respectively) with Nile red as a model of lipophilic substance in the vaginal route of administration, as measured by increases in the residence time and the penetration of these formulations. Several formulations were prepared with increasing chitosan concentrations, and were analyzed in terms of pH and rheological behavior so that the most suitable formulation could be selected. The enhancement of the adhesion (tensile stress test and washability profile) and penetration (confocal laser scanning microscopy and extraction followed by quantification) properties of the formulations, when applied to porcine vaginal mucosa, were evaluated. The nanocapsule suspensions produced presented adequate properties: size of approximately 200 nm (polydispersity index of ≤v0.2); zeta potential around +10 mV for the cationic formulation and -10 mV for the anionic formulation; and pH values of 6.1±0.1 (Eudragit RS 100), 5.3±0.2 (Eudragit S 100), 6.2±0.1 (Nile red loaded Eudragit RS 100), and 5.1±0.1 (Nile red loaded Eudragit S 100). The chitosan formulation presented suitable viscosity for vaginal application and acidic pH (approximately 4.5). The tensile stress test showed that both formulations containing polymeric nanocapsules presented higher mucoadhesion when compared with the formulation without nanocapsules. In the washability experiment, no significant differences were found between formulations. Confocal microscopy and fluorescence quantification after extraction from the mucosa showed higher penetration of Nile red when it was nanoencapsulated, particularly in cationic nanocapsules. The formulations developed based on chitosan gel vehicle at 2.5% weight/weight containing polymeric nanocapsules, especially the cationic nanocapsules, demonstrated applicability for the vaginal delivery of hydrophobic substances.

Innovative Sunscreen Formulation Based on Benzophenone-3-Loaded Chitosan-Coated Polymeric Nanocapsules

Aim: To evaluate the effect of cationic coating of polymeric nanocapsules in sunscreen formulations on the in vitro skin penetration of benzophenone-3. Methods: Benzophenone-3-loaded nanocapsules were prepared by the interfacial deposition of poly(Ε-caprolactone) and coated by using a chitosan solution. The nanoparticles were characterized and incorporated in hydrogels. The presence of nanoparticles in hydroxyethyl cellulose gels was observed by transmission electron microscopy and photon correlation spectroscopy. Penetration studies were carried out using Franz cells with porcine skin membranes. Results: Benzophenone-3-loaded chitosan-coated nanocapsules presented a mean size of 202 ± 7 nm and positive zeta potential (+21 ± 1 mV), while these values for the uncoated nanocapsules were 175 ± 1 nm and –8 ± 1 mV. Penetration profiles showed that a higher amount of benzophenone-3 remained at the skin surface and a lower amount was found in the receptor compartment after the application of the formulation containing chitosan-coated nanocapsules compared to a formulation containing its free form. Conclusions: Hydrogel containing benzophenone-3 chitosan-coated nanocapsules represents an innovative formulation to overcome limitations of sunscreen daily use.

Vegetable oils as core of cationic polymeric nanocapsules: influence on the physicochemical properties

Vegetable oils might be alternatives to mineral or synthetic oils used in nanostructured systems for cutaneous application, due to their advantages with regard to skin care and protection. In this study, we propose the use of vegetable oils (Brazil nut, sunflower seed, olive, rose hip, grape seed and carrot oils) as oily core of Eudragit RS100® nanocapsules and determine their influence on the physicochemical properties of those nanoparticles, in comparison with nanocapsules with capric/caprylic triglycerides as oily core. The formulations containing vegetable oils as core presented pH values suitable for topical application, average diameter close to 280 nm (SPAN around 2.5) and zeta potential close to +7 mV, due to the cationic properties of the polymer. Their viscosities were not affected by the type of oil used as core. By means of multiple light scattering, a reversible particle creaming phenomenon was observed for all the formulations. The nanocapsules prepared using Brazil nut, sunflower seed, olive, grape seed, rose-hip and carrot oils presented some distinct physicochemical properties when compared to nanocapsules obtained with capric/caprylic triglycerides: a higher size and SPAN value, a lower number of particles and a higher tendency to reversible creaming. Those findings are probably related to the lower density and higher viscosity of the vegetable oils.

Chitosan Hydrogel Containing Capsaicinoids-Loaded Nanocapsules: An Innovative Formulation for Topical Delivery

The aim of the present work was to develop and characterize a chitosan hydrogel containing capsaicinoids-loaded nanocapsules intended for topical delivery. Such system is promising since it brings together the skin bioadhesion and film forming capability of chitosan and the control of the drug release due to the reservoir property of the nanocapsules. The hydrogels showed pH values between 4.2 and 4.4, suitable for topical administration, as a consequence of lactic acid in the formulations. The consistence values (Pa.sn) /flow indexes (n = dimensionless) were 19.64 ± 2.61/ 0.76 ± 0.03 and 13.12 ± 0.93/0.82 ± 0.01 for the gels containing the nanocapsule suspension or exclusively water, respectively, demonstrating the effect of the nanocapsules on the slight increase of the gel consistence. The nanocapsules may also interfere in the interaction between chitosan chains and in the polymer network. The pseudoplastic behavior of the hydrogels did not change after the incorporation of nanocapsules. The release study showed a more controlled release of capsaicin and dihydrocapsaicin from the hydrogel containing nanocapsules comparing with the hydrogels containing free capsaicinoids. This chitosan hydrogel containing drug-loaded nanocapsules is likely interesting when a controlled release is intended.

Skin penetration and dermal tolerability of acrylic nanocapsules: Influence of the surface charge and a chitosan gel used as vehicle

For an improved understanding of the relevant particle features for cutaneous use, we studied the effect of the surface charge of acrylic nanocapsules (around 150nm) and the effect of a chitosan gel vehicle on the particle penetration into normal and stripped human skin ex vivo as well as local tolerability (cytotoxicity and irritancy). Rhodamin-tagged nanocapsules penetrated and remained in the stratum corneum. Penetration of cationic nanocapsules exceeded the penetration of anionic nanocapsules. When applied on stripped skin, however, the fluorescence was also recorded in the viable epidermis and dermis. Cationic surface charge and embedding the particles into chitosan gel favored access to deeper skin. Keratinocytes took up the nanocapsules rapidly. Cytotoxicity (viability<80%), following exposure for ≥24h, appears to be due to the surfactant polysorbate 80, used for nanocapsuleś stabilization. Uptake by fibroblasts was low and no cytotoxicity was observed. No irritant reactions were detected in the HET-CAM test. In conclusion, the surface charge and chitosan vehicle, as well as the skin barrier integrity, influence the skin penetration of acrylic nanocapsules. Particle localization in the intact stratum corneum of normal skin and good tolerability make the nanocapsules candidates for topical use on the skin, provided that the polymer wall allows the release of the active encapsulated substance.

Vitamin K1-loaded lipid-core nanocapsules: physicochemical characterization and in vitro skin permeation.

The incorporation of substances in nanocarriers can modulate and/or manage their delivery profiles (immediate or sustained) and permeation through skin. Consequently, drug nanencapsulation intended for topical treatment can reduce the systemic absorption of the substance.

The use of nanoencapsulation to decrease human skin irritation caused by capsaicinoids.

Capsaicin, a topical analgesic used in the treatment of chronic pain, has irritant properties that frequently interrupt its use. In this work, the effect of nanoencapsulation of the main capsaicinoids (capsaicin and dihydrocapsaicin) on skin irritation was tested in humans. Skin tolerance of a novel vehicle composed of chitosan hydrogel containing nonloaded nanocapsules (CH-NC) was also evaluated. The chitosan hydrogel containing nanoencapsulated capsaicinoids (CH-NC-CP) did not cause skin irritation, as measured by an erythema probe and on a visual scale, while a formulation containing free capsaicinoids (chitosan gel with hydroalcoholic solution [CH-ET-CP]) and a commercially available capsaicinoids formulation caused skin irritation. Thirty-one percent of volunteers reported slight irritation one hour after application of CH-NC-CP, while moderate (46% [CH-ET-CP] and 23% [commercial product]) and severe (8% [CH-ET-CP] and 69% [commercial product]) irritation were described for the formulations containing free capsaicinoids. When CH-NC was applied to the skin, erythema was not observed and only 8% of volunteers felt slight irritation, which demonstrates the utility of the novel vehicle. A complementary in vitro skin permeation study showed that permeation of capsaicinoids through an epidermal human membrane was reduced but not prevented by nanoencapsulation.

Co-encapsulation of imiquimod and copaiba oil in novel nanostructured systems: promising formulations against skin carcinoma

In this study, two types of cutaneous-directed nanoparticles are proposed for the co-encapsulation of imiquimod (a drug approved for the treatment of basal cell carcinoma) and copaiba oil (oil that exhibits anti-proliferative properties). Nanostructured copaiba capsules (NCCImq) were prepared using the interfacial deposition method, and nanostructured Brazilian lipids (NBLImq) were prepared by high-pressure homogenization. The formulations exhibited average diameter, zeta potential, pH and drug content of approximately 200nm, -12mV, 6 and 1mgmL(-1), respectively. In addition, the formulations exhibited homogeneity regarding particle size, high encapsulation efficiency and stability. Both nanocarriers controlled imiquimod release, and NBLImq exhibited slower drug release (p < 0.05), likely due to increased interaction of the drug with the solid lipid (cupuaçu seed butter). The in vitro evaluation of the imiquimod-loaded nanocarriers was performed using healthy skin cells (keratinocytes, HaCaT); no alteration was observed, suggesting the biocompatibility of the nanocarriers. In addition, in vitro skin permeation/penetration using pig skin was performed, and NCCImq led to increased drug retention in the skin layers and reduced amounts of drug found in the receiver solution. Thus, NCCImq is considered the most promising nanoformulation for the treatment of skin carcinoma.

Structural analysis of chitosan hydrogels containing polymeric nanocapsules.

The incorporation of different concentrations of polymeric nanocapsule suspensions into chitosan hydrogels is proposed, in order to study the structure of a formulation with the properties of great tissue adhesion and controlled release of the nanoencapsulated drugs, represented here by capsaicinoids. The gels presented acceptable acid pH values and the nanoparticles were visually observed in the system. A transition from the micrometer to the nanometer scales suggested that the nanocapsules are initially agglomerated in the hydrogel. A sedimentation tendency of the nanocapsules in the system was observed and only physical interaction between the chitosan chains and polymeric nanocapsules was verified. The hydrogels, despite the presence of nanocapsules, presented shear-thinning properties and an elastic behavior under low and high frequencies, showing a very structured gel network. The observed variation in the elasticity of the hydrogels may arise from a decrease in the number of interactions and degree of entanglement between the chitosan chains, caused by the presence of nanoparticles.