Current progresses on nanodelivery systems for the treatment of neuropsychiatric diseases: Alzheimer's and schizophrenia.

Currently Alzheimer's disease and schizophrenia are both well-established neuropsychiatric diseases. Nonetheless, the treatment of these disorders is not unanimous and fully effective. As a consequence, several approaches have been studied to improve patient's conditions. In this context, the development of new drug nanodelivery systems to increase drug bioavailability and reduce adverse effects has been claimed as a good option. Among these systems we focus on the ones that seem to be most promising, such as lipidbased systems (e.g. liposomes, nanoemulsions and lipid nanoparticles), drug nanocrystals, polymeric nanoparticles and micelles. Moreover, the application of these systems by means of alternative administration routes is also discussed. Regardless of the satisfactory results and the associated progresses that have been done in the last years, more studies are required to quickly licence the application of drug nanodelivery systems in human medicines.

A novel lipid nanocarrier for insulin delivery: production, characterization and toxicity testing.

A novel nanocarrier based on solid lipid nanoparticles (SLNs) was developed for insulin delivery using a novel double emulsion method. Physical stability of particles was assessed by size analysis using dynamic light scattering (DLS), matrix crystallinity by differential scanning calorimetry (DSC) and toxicity analysis by Drosophila melanogaster testing. Insulin-SLNs were composed of Softisan®100 1.25% wt, Lutrol®F68 1% wt, soybean lecithin 0.125% wt, and loaded with 0.73-0.58 mg/mL peptide. Placebo-SLNs (insulin-free) also contained 0.025% wt Tween®80. Mean particle sizes of placebo-SLN and insulin-SLN were 958 ± 9.5 and 978 ± 8.3 nm, respectively. The polydispersity index (PI) was 0.28 ± 0.018 and 0.29 ± 0.013, respectively. Polarized light microscopy analysis depicted no aggregation of developed particles. DSC analysis allowed characterizing SLN with 43-51% matrix crystallinity. Using Drosophila melanogaster test, no toxicity was reported for SLN and for the bulk lipid. This study shows that SLNs are promising and helpful to overcome conventional insulin therapy, in particular for their lack of toxicity for oral delivery.

Solid lipid nanoparticles (SLN)--based hydrogels as potential carriers for oral transmucosal delivery of risperidone: preparation and characterization studies.

Two different solid lipid nanoparticles (SLN)-based hydrogels (HGs) formulations were developed as potential mucoadhesive systems for risperidone (RISP) oral transmucosal delivery. The suitability of the prepared semi-solid formulations for application on oral mucosa was assessed by means of rheological and textural analysis, during 30 days. Plastic flows with thixotropy and high adhesiveness were obtained for all the tested systems, which predict their success for the oral transmucosal application proposed. The SLN remained within the colloidal range after HGs preparation. However, after 30 days of storage, a particle size increase was detected in one type of the HGs formulations. In vitro drug release studies revealed a more pronounced RISP release after SLN hydrogel entrapment, when compared to the dispersions alone. In addition, a pH-dependent release was observed as well. The predicted in vivo RISP release mechanism was Fickian diffusion alone or combined with erosion.

Cationic solid lipid nanoparticles (cSLN): structure, stability and DNA binding capacity correlation studies.

Cationic solid lipid nanoparticles (cSLN) are promising lipid nanocarriers for intracellular gene delivery based on well-known and widely accepted materials. cSLN containing single-chained cationic lipid cetyltrimethylammonium bromide were produced by high pressure homogenization and characterized in terms of (a) particle size distribution by photon correlation spectroscopy (PCS) and laser diffractometry (LD), (b) thermal behaviour using differential scanning calorimetry (DSC) and (c) the presence of various polymorphic phases was confirmed by X-ray diffraction (WAXD). SLN composed of Imwitor 900P (IMW) showed different pDNA stability and binding capacity in comparison to those of Compritol 888 ATO (COM). IMW-SLN, having z-ave=138-157 nm and d(0.5)=0.15-0.158 µm could maintain this size for 14 days at room temperature. COM-SLN had z-ave=334 nm and d(0.5)=0.42 µm on the day of production and could maintain similar size during 90 days. IMW-SLN revealed improved pDNA binding capacity. We attempted to explain these differences by different interactions between the solid lipid and the tested cationic lipid.

Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): high pressure homogenization versus ultrasound.

The suitability of solid lipid nanoparticles (SLN) for the encapsulation of risperidone (RISP), an antipsychotic lipophilic drug, was assessed for oral administration. The hot high pressure homogenization (HPH) and the ultrasound (US) technique were used as production methods for SLN. All the studies on the SLN formulations were done in parallel, in order to compare the results and conclude about the advantages and limitations of both techniques. The particle sizes were in the nanometer range for all prepared SLN formulations and the zeta potential absolute values were high, predicting good long-term stability. Optical analyses demonstrated the achievement of stable colloidal dispersions. Physicochemical characterization of dispersions and bulk lipids, performed by differential scanning calorimetry (DSC) and X-ray assays, support prediction of occurrence of drug incorporation in the SLN and good long term stability of the systems. The toxicity of SLN with Caco-2 cells and the existence of contaminations derived from the production equipments were assessed by the (4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay. The results showed 90% of cell viability after SLN exposure, with no significant differences within all prepared formulations (p > 0.05). From this study, we conclude that SLN can be considered as efficient carriers for RISP encapsulation. Moreover, HPH and US revealed to be both effective methods for SLN production.

Potential use of nanostructured lipid carriers for topical delivery of flurbiprofen.

The potential use of nanostructured lipid carriers (NLC) composed of a fatty acid [stearic acid (SA)] or a triglyceride (glyceryl behenate) as solid lipids, and a mixture of medium chain triglycerides and castor oil as liquid lipids, for skin administration of flurbiprofen (FB), has been explored. Two different optimized NLC formulations (FB-SANLC based on SA vs. FB-C888NLC based on glyceryl behenate), with respect to the morphometrical properties (particle size and polydispersity index) and the entrapment efficiency, were used in this study. The ex vivo permeation profiles of FB-C888NLC, FB-SANLC and conventional FB solution were evaluated using human skin. An improved FB permeation was observed when the drug was delivered by skin application of FB-C888NLC, attributed to the particle size and matrix crystallinity. The differential scanning calorimetry and X-ray diffraction studies suggested major polymorphic transitions in the lipid matrix of FB-C888NLC. A good correlation between polymorphic transitions and increased drug permeation was observed. However, both NLC dispersions showed a penetration-enhancing ratio (ER) higher than conventional FB solution. The in vitro and in vivo irritancy and local tolerability were assessed by running, respectively, the SKINTEX™ and Draize test. Both FB-C888NLC and FB-SANLC were classified as nonirritant.

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery.

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol(®) 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween(®) 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (∼90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC.

Packaging small drug molecules, such as non-steroidal anti-inflammatory drugs (NSAIDs) into nanoparticulate systems has been reported as a promising approach to improve the drug's bioavailability, biocompatibility and safety profiles. In the last 20 years, lipid nanoparticles (lipid dispersions) entered the nanoparticulate library as novel carrier systems due to their great potential as an alternative to other systems such as polymeric nanoparticles and liposomes for several administration routes. For ocular instillation nanoparticulate carriers are required to have a low mean particle size, with the lowest polydispersity as possible. The purpose of this work was to study the combined influence of 2-level, 4-factor variables on the formulation of flurbiprofen (FB), a lipophilic NSAID, in lipid carriers currently named as nanostructured lipid carriers (NLC). NLC were produced with stearic acid (SA) and castor oil (CO) stabilized by Tween® 80 (non-ionic surfactant) in aqueous dispersion. A 2(4) full factorial design based on 4 independent variables was used to plan the experiments, namely, the percentage of SA with regard to the total lipid, the FB concentration, the stabilizer concentration, and the storage conditions (i.e., storage temperature). The effects of these parameters on the mean particle size, polydispersity index (PI) and zeta potential (ZP) were investigated as dependent variables. The optimization process was achieved and the best formulation corresponded to the NLC formulation composed of 0.05 (wt%) FB, 1.6 (wt%) Tween® 80 and a 50:50 ratio of SA to CO, with an average diameter of 288 nm, PI 0.245 of and ZP of -29 mV. This factorial design study has proven to be a useful tool in optimizing FB-loaded NLC formulations. Stability of the optimized NLC was predicted using a TurbiScanLab® and the ocular tolerance was assessed in vitro and in vivo by the Eytex® and Draize test, respectively. The developed systems were shown physico-chemically stable with high tolerance for eye instillation.

Optimization and physicochemical characterization of a triamcinolone acetonide-loaded NLC for ocular antiangiogenic applications.

The purpose of this study was to develop a novel nanostructured lipid carrier (NLC) for the intravitreal-targeting delivery of triamcinolone acetonide (TA) by direct ocular instillation. A five-level central composite rotable design was used to study the influence of four different variables on the physicochemical characteristics of NLCs. The analysis of variance (ANOVA) statistical test was used to assess the optimization of NLC production parameters. The systems were produced by high pressure homogenization using Precirol ATO5 and squalene as solid and liquid lipids respectively, and Lutrol F68 as surfactant. Homogenization at 600 bar for 3 cycles of the optimized formulation resulted in the production of small NLC (mean diameter < 200 nm) with a homogeneous particle size distribution (polydispersity index (PI) approximately 0.1), of negatively charged surface (approximately |45| mV) and high entrapment efficiency (approximately 95%). Surface morphology was assessed by SEM which revealed fairly spherical shape. DSC, WAXS and FT-IR analyses confirmed that TA was mostly entrapped into the NLC, characterized by an amorphous matrix. In vivo Draize test showed no signs of ocular toxicity.