Lipid-core nanocapsules are an alternative to the pulmonary delivery and to increase the stability of statins.

Aims: Lipid-core nanocapsules (LNCs) loaded with simvastatin (SV, SV-LNC) or lovastatin (LV, LV-LNC) were formulated for pulmonary administration. Methods: The LNC suspensions were characterized physicochemically, their stability was evaluated, and drug delivery by the pulmonary route was tested in vitro. Results: The loaded LNCs had a particle size close to 200 nm, a low polydispersity index, and a zeta potential around -20 mV. The encapsulation efficiency was high for SV (99.21 ± 0.7%) but low for LV (20.34 ± 1.2%). SV release from nanocapsules was slower than it was from SV in solution, with a monoexponential release profile, and the drug emitted and aerosol output rate was higher for SV-LNCs (1.58 µg/s) than for SV in suspension (0.54 µg/s). Conclusions: SV-LNCs had a median aerodynamic diameter of 3.51 µm and a highly respirable fraction (61.9%), indicating that nanoparticles are a suitable system for efficient delivery of simvastatin to the lung.

Microemulsions based on TPGS and isostearic acid for imiquimod formulation and skin delivery.

Imiquimod (IMQ) is an immunostimulant drug topically used for the treatment of actinic keratosis and basal cell carcinoma. IMQ formulation and skin delivery is difficult because of its very low solubility in the most of pharmaceutical excipients and very poor skin penetration properties. The purpose of this study was to develop a microemulsion to optimize imiquimod skin delivery using d­α­tocopherol polyethylene glycol-1000 succinate (TPGS) as surfactant (so as to take advantage of its thickening properties) and isostearic acid as oil phase. This fatty acid was selected since it has demonstrated a good solubilizing power for imiquimod and it has also shown to contribute to its therapeutic activity. We have built pseudo-ternary diagrams using two different co-surfactants (Transcutol® and propylene glycol - PG) in a 1:1 ratio with TPGS and then selected microemulsions in the clear and viscous regions of the diagrams. The systems were characterized in terms of rheology and X-ray scattering; additionally, the capability to promote IMQ skin uptake was evaluated ex-vivo on a porcine skin model. All the formulations selected in the gel-microemulsion regions behaved as viscoelastic solids; X-rays scattering experiments revealed in all cases the presence of an ordered lamellar structure, but with differences in terms of interlamellar distance and flexibility between Transcutol® and PG-containing systems. A higher flexibility and a greater hydrophobic volume, possibly interconnected at some point, was associated to the use of Transcutol® and had an impact on the microemulsion capacity to solubilize IMQ as well as on the capability to enhance drug uptake into the skin. The best performing gel-like microemulsion was composed of ≈26% of water, ≈21% of isostearic acid, ≈26% of TPGS and ≈27% of Transcutol® and accumulated, after 6 h of contact, 3.0 ±â€¯1.1 µg/cm2 of IMQ. This value is higher than the one reported in the literature for the commercial cream (1.9 ±â€¯0.8 µg/cm2), despite the 4-times lower concentration of the vehicle (13 mg/g for the microemulsion vs 50 mg/g for the commercial cream).

The nasal delivery of nanoencapsulated statins - an approach for brain delivery.

PURPOSE: Along with their cholesterol-lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases. However, such effects are extremely elusive via the conventional oral administration. The purpose of the present study was to prepare and characterize the physicochemical properties and the in vivo biodistribution of simvastatin-loaded lecithin/chitosan nanoparticles (SVT-LCNs) suitable for nasal administration in view of an improved delivery of the statins to the brain. MATERIALS AND METHODS: Chitosan, lecithin, and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Particle size distribution, surface charge, structure, simvastatin loading and release, and interaction with mucus of nanoparticles were determined. The nanoparticle nasal toxicity was evaluated in vitro using RPMI 2651 nasal cell lines. Finally, in vivo biodistribution was assessed by gamma scintigraphy via Tc99m labeling of the particles. RESULTS: Among the different types of nanoparticles produced, the SVT-LCN_MaiLab showed the most ideal physicochemical characteristics, with small diameter (200 nm), positive surface charge (+48 mV) and high encapsulation efficiency (EE; 98%). Size distribution was further confirmed by nanoparticle tracking analysis and electron microscopy. The particles showed a relatively fast release of simvastatin in vitro (35.6%±4.2% in 6 hours) in simulated nasal fluid. Blank nanoparticles did not show cytotoxicity, evidencing that the formulation is safe for nasal administration, while cytotoxicity of simvastatin-loaded nanoparticles (IC50) was found to be three times lower than the drug solution (9.92 vs 3.50 µM). In rats, a significantly higher radioactivity was evidenced in the brain after nasal delivery of simvastatin-loaded nanoparticles in comparison to the administration of a similar dose of simvastatin suspension. CONCLUSION: The SVT-LCNs developed presented some of the most desirable characteristics for mucosal delivery, that is, small particle size, positive surface charge, long-term stability, high EE, and mucoadhesion. In addition, they displayed two exciting features: First was their biodegradability by enzymes present in the mucus layer, such as lysozyme. This indicates a new Trojan-horse strategy which may enhance drug release in the proximity of the nasal mucosa. Second was their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma scintigraphy studies.

Formulation design for topical drug and nanoparticle treatment of skin disease.

The skin has evolved to resist the penetration of foreign substances and particles. Topical therapeutic and cosmeceutical delivery is a growing field founded on selectively overcoming this barrier. Both the biology of the skin and the nature of the formulation/active ingredient must be aligned for efficient transcutaneous delivery. This review discusses the biological changes in the skin barrier that occur with common dermatological conditions. This context is the foundation for the discussion of formulation strategies to improve penetration profiles of common active ingredients in dermatology. Finally, we compare and contrast those approaches to recent advances described in the research literature with an eye toward the future of topical formulation design.

Opportunities and challenges for the nasal administration of nanoemulsions.

Nasal delivery has become a growing area of interest for drug administration as a consequence of several practical advantages, such as ease of administration and non-invasiveness. Moreover, the avoidance of hepatic first-pass metabolism and rapid and efficient absorption across the permeable nasal mucosa offer a promising alternative to other traditional administration routes, such as oral or parenteral delivery. In fact, nasal delivery has been proposed for a number of applications, including local, systemic, direct nose-to-brain and mucosal vaccine delivery. Nanoemulsions, due to their stability, small droplet size and optimal solubilization properties, represent a versatile formulation approach suitable for several administration routes. Nanoemulsions demonstrated great potential in nasal drug delivery, increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery. Furthermore, they act as an active component, i.e. an adjuvant, in nasal mucosal vaccinations, displaying the ability to induce robust mucosal immunity, high serum antibodies titres and a cellular immune response avoiding inflammatory response. Interestingly, nanoemulsions have not been proposed for the treatment of local ailments of the nose. Despite the promising results in vitro and in vitro, the application of nanoemulsions for nasal delivery in humans appears mainly hindered by the lack of detailed toxicology studies to determine the effect of these formulations on the nasal mucosa and cilia and the lack of extensive clinical trials.