Development and characterization of poly(lactic-co-glycolic) acid nanoparticles loaded with copaiba oleoresin.

Copaiba oleoresin (CPO), obtained from Copaifera landgroffii, is described as active to a large number of diseases and more recently in the endometriosis treatment. In this work, poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing CPO were obtained using the design of experiments (DOE) as a tool to optimize the production process. The nanoparticles optimized by means of DOE presented an activity in relation to the cellular viability of endometrial cells. The DOE showed that higher amounts of CPO combined with higher surfactant concentrations resulted in better encapsulation efficiency and size distribution along with good stability after freeze drying. The encapsulation efficiency was over 80% for all produced nanoparticles, which also presented sizes below 300 nm and spherical shape. A decrease in viability of endometrial stromal cells from ectopic endometrium of patients with endometriosis and from eutopic endometriotic lesions was demonstrated after 48 h of incubation with the CPO nanoparticles. The nanoparticles without CPO were not able to alter the cell viability of the same cells, indicating that this material was not cytotoxic to the tested cells and suggesting that the effect was specific to CPO. The results indicate that the use of CPO nanoparticles may represent a promising alternative for the treatment of endometriosis.

Development and Characterization of Nisin Nanoparticles as Potential Alternative for the Recurrent Vaginal Candidiasis Treatment.

The aim of this work was the development and characterization of nisin-loaded nanoparticles and the evaluation of its potential antifungal activity. Candidiasis is a fungal infection caused by Candida sp. considered as one of the major public health problem currently. The discovery of antifungal agents that present a reduced or null resistance of Candida sp. and the development of more efficient drug release mechanisms are necessary for the improvement of candidiasis treatment. Nisin, a bacteriocin commercially available for more than 50 years, exhibits antibacterial action in food products with potential antifungal activity. Among several alternatives used to modulate antifungal activity of bacteriocins, polymeric nanoparticles have received great attention due to an effective drug release control and reduction of therapeutic dose, besides the minimization of adverse effects by the preferential accumulation in specific tissues. The nisin nanoparticles were prepared by double emulsification and solvent evaporation methods. Nanoparticles were characterized by dynamic light scattering, zeta potential, Fourier transform infrared, X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy. Antifungal activity was accessed by pour plate method and cell counting using Candida albicans strains. The in vitro release profile and in vitro permeation studies were performed using dialysis bag method and pig vaginal mucosa in Franz diffusion cell, respectively. The results revealed nisin nanoparticles (300 nm) with spherical shape and high loading efficiency (93.88 ± 3.26%). In vitro test results suggest a promising application of these nanosystems as a prophylactic agent in recurrent vulvovaginal candidiasis and other gynecological diseases.

Preparation and evaluation of a new nano pharmaceutical excipients and drug delivery system based in polyvinylpyrrolidone and silicate.

PURPOSE: This work describes the preparation of new nanocomposites based on lamellar silicates (AAM-alkyl ammonium montmorillonite) obtained by the intercalation of PVP K30 and glyceril monostearate. METHODS: By XRD, TGA and DSC analysis the AAM was characterized and its compactation characteristics, functionality and toxicity were also tested. The AAM/PVP K-30 and AAM/GME nanocomposite obtained were evaluated to identify the interlamellar spacing values by XRD diffratograms. Tablets were prepared using methyldopa and theophylline as model drugs and the dissolution tests were carried out in simulated gastric fluid and simulated enteric fluid. RESULTS: AAM showed a good compactability and compressibility characteristics for tablets preparation. The intercalation yields (approximately 25%) of the nanocomposites were efficient. The AAM/PVP K-30 nanocomposites were successfully tested as dissolution enhancers and sustained release matrixes. CONCLUSIONS: The results also suggested the promising use of AAM (viscogel B8) and the new nanocomposite prepared by clay/PVP K-30 intercalation as a new matrix for sustained release and the feasibility of using these new nanocomposites as dissolution enhancer.

Influence of oleic acid on the rheology and in vitro release of lumiracoxib from poloxamer gels.

PURPOSE: Transdermal delivery of anti-inflammatory lumiracoxib (LM) could be an interesting strategy to avoid the side effects associated with systemic delivery, but it is ineffective due to the drug poor skin penetration. We have investigated the effects of oleic acid (OA), a lipid penetration enhancer, on the in vitro release of LM from poloxamer-based delivery systems (PBDS). The rheological behavior (shear rate dependent viscosity) and gelation temperature through measurements of optimal sol-gel transition temperatures (Tsol-gel) were also carried out in these systems. METHODS: In vitro release studies of LM from PBDS were performed using cellulose acetate as artificial membrane mounted in a diffusion system. The amount of LM released was divided by exposition area (microg/cm2) and these values were plotted as function of the time (h). The flux of the drug across the membrane (J) was calculated from the slope of the linear portion of the plot and expressed as microg/cm2. h -1. The determination of viscosity was carried out at different shear rates (gamma) between 0.1- 1000 S-1 using a parallel plate rheometer. Oscillatory measurements using a cone-plate geometry rheometer surrounded by a double jacket with temperature varying 4-40 degrees C, was used in order to determine Tsol-gel. RESULTS: Increase of both polymer and OA concentrations increases the viscosity of the gels and consequently reduces the in vitro LM release from the PBDS, mainly for gels containing OA at 10.0% compared to other concentrations of the penetration enhancer. Tsol-gel transition temperature was decreased by increasing viscosity; in some cases the formulation was already a gel at room temperature. Rheological studies showed a pseudoplastic behavior, which facilitates the flow and improves the spreading characteristics of the formulations. CONCLUSIONS: Taken together, the results showed that poloxamer gels are good potential delivery systems for LM, leading to a sustained release, and also have appropriate rheological characteristics. Novelty of the work: A transdermal delivery of non-steroidal antinflammatory drugs like lumiracoxib (LM) can be an interesting alternative to the oral route of this drug, since it was recently withdraw of the market due to the liver damage when systemically administered in tablets as dosage form. There are no transdermal formulations of LM and it could be an alternative to treat inflammation caused by arthritis or arthrosis. Then, an adequate delivery system to LM is necessary in order to release the drug properly from the PBDS as well as have good characteristics related to semi-solid preparations for transdermal application, which were evaluated through in vitro release studies and rheological behavior in this paper, respectively.

Nanoparticles Loaded with a New Thiourea Derivative: Development and In vitro Evaluation Against Leishmania amazonensis.

BACKGROUND: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. Current treatments are restricted to a small number of drugs that display both severe side effects and a potential for parasites to develop resistance. A new N-(3,4-methylenedioxyphenyl)-N'- (2-phenethyl) thiourea compound (thiourea 1) has shown promising in vitro activity against Leishmania amazonensis with an IC50 of 54.14 µM for promastigotes and an IC50 of 70 µM for amastigotes. OBJECTIVE: To develop a formulation of thiourea 1 as an oral treatment for leishmaniasis, it was incorporated into Nanoparticles (NPs), a proven approach to provide long-acting drug delivery systems. METHODS: Poly (D,L-Lactic-co-Glycolic Acid) (PLGA) polymeric NPs containing thiourea 1 were obtained through a nanoprecipitation methodology associated with solvent evaporation. The NPs containing thiourea 1 were characterized for Encapsulation Efficiency (EE%), reaction yield (% w/w), surface charge, particle size and morphology by Transmission Electron Microscopy (TEM). RESULTS: NPs with thiourea 1 showed an improved in vitro leishmanicidal activity with a reduction in its cytotoxicity against macrophages (CC50>100 µg/mL) while preserving its IC50 against intracellular amastigotes (1.46 ± 0.09 µg/mL). This represents a parasite Selectivity Index (SI) of 68.49, which is a marked advancement from the reference drug pentamidine (SI = 30.14). CONCLUSION: The results suggest that the incorporation into NPs potentiated the therapeutic effect of thiourea 1, most likely by improving the selective delivery of the drug to the phagocytic cells that are targeted for infection by L. amazonensis. This work reinforces the importance of nanotechnology in the acquisition of new therapeutic alternatives for oral treatments.

Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples.

Poly ɛ-caprolactone nanoparticles loaded with Uncaria tomentosa extract: preparation, characterization, and optimization using the Box-Behnken design.

PURPOSE: The aim of this research was to develop and optimize a process for obtaining poly ɛ-caprolactone (PCL) nanoparticles loaded with Uncaria tomentosa (UT) extract. METHODS: Nanoparticles were produced by the oil-in-water emulsion solvent evaporation method. Preliminary experiments determined the initial conditions of the organic phase (OP) and of the aqueous phase (AP) that would be utilized for this study. Ultimately, a three-factor three-level Box-Behnken design (BBD) was employed during the optimization process. PCL and polyvinyl alcohol (PVA) concentrations (X(1) and X(2), respectively) and the AP/OP volume ratio (X(3)) were the independent variables studied, while entrapment efficiency (Y(1)), particle mean diameter (Y(2)), polydispersity (Y(3)), and zeta potential (Y(4)) served as the evaluated responses. RESULTS: PRELIMINARY EXPERIMENTS REVEALED THAT THE OPTIMAL INITIAL CONDITIONS FOR THE PREPARATION OF NANOPARTICLES WERE AS FOLLOWS: OP composed of 5 mL ethyl acetate/acetone (3/2) mixture containing UT extract and PCL, and an AP of buffered PVA (pH 7.5) solution. Statistical analysis of the BBD results indicated that all of the studied factors had significant effects on the responses Y(1), Y(2), and Y(4,) and these effects are closely described or fitted by regression equations. Based on the obtained models and the selected desirability function, the nanoparticles were optimized to maximize Y(1) and minimize Y(2). These optimal conditions were achieved using 3% (w/v) PCL, 1% (w/v) PVA, and an AP/OP ratio of 1.7, with predicted values of 89.1% for Y(1) and 280 nm for Y(2). Another batch was produced under the same optimal conditions. The entrapment efficiency of this new batch was measured at 81.6% (Y(1)) and the particles had a mean size of 247 nm (Y(2)) and a polydispersity index of 0.062 (Y(3)). CONCLUSION: This investigation obtained UT-loaded nanoparticle formulations with desired characteristics. The BBD approach was a useful tool for nanoparticle development and optimization, and thus should be useful especially in the realm of phytotherapeutics, in which varied compositions may be assessed in quantitative and qualitative terms.

Characterization of a new TiF(4) and ß-cyclodextrin inclusion complex and its in vitro evaluation on inhibiting enamel demineralization.

Titanium tetrafluoride (TiF(4)) is an effective but instable caries preventive agent. As the stability problems could be minimized through the use of drug carriers this study aimed to prepare and characterize a new TiF(4) nanoinclusion complex and to evaluate its potential in inhibiting enamel demineralization under pH cycling conditions. The TiF(4) nanosystems were prepared using ß-cyclodextrin (ßCD) and sodium montmorillonite (MMTNa). Bovine enamel blocks (n=48) with known surface microhardness (SMH), were randomly assigned to 4 groups (n=12) and submitted to one of the following treatments: distilled deionized water (as negative control) and solutions containing 1% ßCD, 1% TiF(4) and TiF(4):ßCD. The solutions were blinded applied once on the blocks with a microbrush(®) on the surface for 1min before pH-cycling. After that, samples were reavaluated by SMH, %SMH loss, cross-sectional microhardness (CSMH), scanning electron microscope (SEM) and energy dispersive spectrometry (EDX). The inclusion complex of TiF(4):ßCD offered better protection against demineralization in the subsurface. The SEM analysis showed that TiF(4) and TiF(4):ßCD samples presented the most intact enamel than the control. The EDX analysis identified titanium in TiF(4) and TiF(4):ßCD groups. TiF(4):ßCD has higher potential on inhibiting demineralization in the inner enamel. TiF(4):ßCD is a new alternative to TiF(4) stabilization in order to reduce enamel subsurface demineralization.

Nanostructured systems containing babassu (Orbignya speciosa) oil as a potential alternative therapy for benign prostatic hyperplasia.

The oil of babassu tree nuts (Orbignya speciosa) is a potential alternative for treatment and prophylaxis of benign prostatic hyperplasia. Improved results can be obtained by drug vectorization to the hyperplastic tissue. The main objective of this work was the preparation and characterization of poly(lactic-co-glycolic acid) (PLGA) nanoparticle and clay nanosystems containing babassu oil (BBS). BBS was extracted from the kernels of babassu tree nuts and characterized by gas chromatography-mass spectrometry as well as 1H and 13C nuclear magnetic resonance. BBS-clay nanosystems were obtained by adding polyvinylpyrrolidone, Viscogel B8®, and BBS at a 2:1:1 mass ratio and characterized by X-ray diffraction, thermogravimetric analysis, infrared spectroscopy, and laser diffraction. The PLGA-BBS nanoparticles were prepared by the precipitation-solvent evaporation method. Mean diameter, polydispersity, zeta potential, and scanning electron microscopic images of the nanosystems were analyzed. Thermogravimetric analysis showed successful formation of the nanocomposite. PLGA nanoparticles containing BBS were obtained, with a suitable size that was confirmed by scanning electron microscopy. Both nanostructured systems showed active incorporation yields exceeding 90%. The two systems obtained represent a new and potentially efficient therapy for benign prostatic hyperplasia.