Complex Polysaccharide-Based Nanocomposites for Oral Insulin Delivery.

Polyelectrolyte nanocomposites rarely reach a stable state and aggregation often occurs. Here, we report the synthesis of nanocomposites for the oral delivery of insulin composed of alginate, dextran sulfate, poly-(ethylene glycol) 4000, poloxamer 188, chitosan, and bovine serum albumin. The nanocomposites were obtained by Ca2+-induced gelation of alginate followed by an electrostatic-interaction process among the polyelectrolytes. Chitosan seemed to be essential for the final size of the nanocomposites and there was an optimal content that led to the synthesis of nanocomposites of 400-600 nm hydrodynamic size. The enhanced stability of the synthesized nanocomposites was assessed with LUMiSizer after synthesis. Nanocomposite stability over time and under variations of ionic strength and pH were assessed with dynamic light scattering. The rounded shapes of nanocomposites were confirmed by scanning electron microscopy. After loading with insulin, analysis by HPLC revealed complete drug release under physiologically simulated conditions.

First-time oral administration of resveratrol-loaded layer-by-layer nanoparticles to rats - a pharmacokinetics study.

trans-Resveratrol (RSV) is a plant-derived polyphenol endowed with a broad spectrum of promising therapeutic activities. The applicability of RSV in vivo has, however, had limited success so far, largely due to its inefficient systemic delivery resulting from its low water solubility. Layer-by-Layer (LbL) nanotechnology constitutes an innovative formulation strategy to address this concern, and is based on the design of tunable onion-like multilayered nanoarchitectures on the surface of low solubility drug nanocores, such as RSV. The purpose of this study was the investigation of the bioavailability of an LbL nanoformulation composed of 5.5 bilayers of polyallylamine hydrochloride (PAH) and dextran sulfate (DS) (LbL NPs) by pharmacokinetic studies following oral dosing to Wistar rats (20 mg kg-1). The systemic exposure of LbL NPs was compared to the respective nanoformulation without LbL coatings (RSV nanocores) and the free RSV suspension. The results demonstrated that both LbL NPs and RSV nanocores significantly enhanced, respectively, 1.76-fold and 2.74-fold the systemic exposure of RSV compared to the free RSV suspension, emphasizing their biopharmaceutical advantage. Surprisingly, besides the modified drug release potential of the LbL NPs, these exhibited a slightly lower systemic exposure (0.36-fold) in comparison with non-LbL modified RSV nanocores. These results were justified only by the electrostatic interactions composition of the LbL shell composition, requiring further research towards the application of stronger interactions. For this study, due to the key role of the bioanalytical method in the in vivo data acquisition, a rapid, selective, and sensitive HPLC-DAD method has been successfully optimized and fully validated to confidently quantify RSV levels in the rat plasma matrix, together with the optimization of the sample preparation procedure. Moreover, the chemical stability of RSV was evaluated for 24 h in simulated gastric and intestinal fluids with enzymes. Overall, our findings suggest that LbL NPs should be given great attention, representing a potential drug delivery system for RSV in view of the application of RSV not solely as a supplement but also as a therapeutic drug.

Nanotechnology for the development of new cosmetic formulations.

INTRODUCTION: Nanotechnology is an increasingly widespread area of research for its various applications and advantages. Accordingly, nanotechnology has been the focus of investment in different areas of science, namely as a technological strategy for the development of cosmetics formulations. Nanosystems allow for a profit skin penetration and an effective release profile of ingredients, which contributes to superior technological and cosmetic effects. The applications of nanocosmetics are numerous, from anti-aging care, make-up, nails, deodorants, oral care, sunscreens, and hair care. However, as an area of emerging knowledge, it has now begun to encourage investigations into its toxicology profile, particularly regarding health damage and environmental pollution. Also, the regulatory area saw its adaptation concerning the use of formulations containing nanotechnology. AREAS COVERED: A description of the nanosystems so far applied in the development of cosmetics is presented. Moreover, an outline concerning lipid-based-nanosystems, polymeric-based nanoparticles, metal-based nanoparticles, silica nanoparticles, and additional nanosystems (dendrimers, nanocrystals, fullerenes, nanodiamonds, and cyclodextrins) towards the obtainment of effective cosmetic outcomes is addressed. The concerning toxicological as well as the regulatory aspects are also discussed. EXPERT OPINION: This innovative and timely review emphasizes that nanosystems constitute a highly promising technology strategy towards the obtainment of superior and ground-breaking cosmetic formulations.

Subcutaneous delivery of biotherapeutics: challenges at the injection site.

INTRODUCTION: Biotherapeutics are primarily delivered subcutaneously due to better compliance and prolonged rate of absorption compared to other parenteral administration routes. Recent research has allowed for the development of biotherapeutic formulations for subcutaneous delivery that require a lower frequency of administration by increasing drug half-life. Formulations determine shelf-life stability as well as features and transient behaviors that influence stability once implanted in the subcutaneous space. AREAS COVERED: This review provides an overview of the factors affecting subcutaneous absorption with a focus on transient effects at the injection site following administration of biotherapeutics and the subsequent impact on absorption and stability. EXPERT OPINION: Advances have been made in understanding subcutaneous tissue and the complex interplay of factors that regulate its homeostasis. The issue of poor stability after injection has been neglected, and many biotherapeutics are hampered by low bioavailability. With the advent of new in vitro techniques that account for properties of the injection site, stability studies evaluating subcutaneous tissues and impacts on pharmacokinetics of biotherapeutics may be useful in the development of new formulations.

Nanotechnological breakthroughs in the development of topical phytocompounds-based formulations.

Cosmeceuticals are a type of cosmetic products distinguished by the presence of active ingredients that, in addition to their cosmetic effects, also hold therapeutic outcomes. This review is focused on phytocompounds (PHYTOCs)-based cosmeceuticals, an established segment of cosmetic industry, due to the great demand for vitamins and plant-derived products. PHYTOCs beauty and health-related applications are due to their anti-oxidant, anti-bacterial, wound-healing, anti-aging, sun protection, cytoprotective, anticarcinogenic and anti-inflammatory activities. However, PHYTOCs present disadvantages, precisely the poor solubility, instability, reduced skin permeation and low skin retention time, which strongly restrict their topical application. Therefore, and since the cosmetic industry constantly pursues groundbreaking technological products, nanotechnology emerges as an innovative strategy to tackle the PHYTOCs recognized limitations. Nanotechnology manipulates and reduces materials size to 1 and 100 nm, creating structures able to encapsulate active ingredients, such as PHYTOCs, with the purpose of overcoming their limitations and delivering them in a controlled manner to the skin. This review highlights the potential properties of PHYTOCs loaded in several types of nanocarriers (liposomes, niosomes, ethosomes, transferosomes, cubosomes, phytosomes, nanoemulsions, nanocrystals, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, carbon nanotubes, fullerenes, and dendrimers) used to overcome PHYTOCs free form limitations and potentiate their cosmeceutical properties. An approach to the "green" chemical synthesis of metallic nanoparticles taking advantage of PHYTOCS as natural reducing agents is exposed as well. Nanocosmeceuticals toxicity concerns and regulatory aspects are also addressed.

Sonication-assisted Layer-by-Layer self-assembly nanoparticles for resveratrol delivery.

This paper advances the development of a novel drug nanodelivery solution to the oral administration of resveratrol (RSV), a low soluble drug whose recognized therapeutic applications are circumscribed when administered in the free compound form. Layer-by-Layer (LbL) self-assembly is an emergent nanotechnology proposed to address this concern with means to afford control over key formulation parameters, which are able to ultimately promote an improved pharmacokinetics. LbL self-assembly consists in the sequential adsorption of oppositely charged polyelectrolytes upon a low soluble drug nanoparticle (NP) template, giving rise to onion-like multilayered nanoarchitectures. In this work, RSV nanoprecipitation followed by LbL self-assembly of polyelectrolytes, led by a washless approach, was carried out by using the cationic poly(allylamine hydrochloride) (PAH) and the anionic dextran sulfate (DS) as polyelectrolytes towards the nanoencapsulation of RSV. Each saturated polyelectrolyte layer deposition involved the rigorous polyelectrolyte concentration assessment which was accomplished by tracing titration curves. This way, aqueous RSV nanocores and RSV LbL nanoformulations with a distinct number of PAH/DS bilayers were developed, including 2.5 (RSV-(PAH/DS)2.5 NPs), 5.5 (RSV-(PAH/DS)5.5 NPs) and 7.5 (RSV-(PAH/DS)7.5 NPs) bilayered nanoformulations. Homogenous particle size distributions at the desired nanoscale interval (ca. 116-220 nm; polydispersity index below 0.15), good colloidal (zeta potential magnitudes ca. ± 20-30 mV) and chemical stabilizations, high encapsulation efficiency (above 90%) together with an excellent cytocompatibility with Caco-2 cells (cell viability above 90%) were observed for all the nanoformulations. Eventfully, LbL NPs promoted a controlled release of RSV pursuant to the number of polyelectrolyte bilayers under simulated gastrointestinal conditions, particularly in the intestine medium, emphasizing their biopharmaceutical advantage. Our findings manifestly pinpoint that LbL PAH/DS NPs constitute a promising nanodelivery system for the oral delivery of RSV, providing a rational strategy to enlarge the implementation range of this interesting polyphenol, which is possibly the most actively investigated phytochemical worldwide.

Probing insulin bioactivity in oral nanoparticles produced by ultrasonication-assisted emulsification/internal gelation.

Alginate-dextran sulfate-based particles obtained by emulsification/internal gelation technology can be considered suitable carriers for oral insulin delivery. A rational study focused on the emulsification and particle recovery steps was developed in order to reduce particles to the nanosize range while keeping insulin bioactivity. There was a decrease in size when ultrasonication was used during emulsification, which was more pronounced when a cosurfactant was added. Ultrasonication add-on after particle recovery decreased aggregation and led to a narrower nanoscale particle-size distribution. Insulin encapsulation efficiency was 99.3%±0.5%, attributed to the strong pH-stabilizing electrostatic effect between insulin and nanoparticle matrix polymers. Interactions between these polymers and insulin were predicted using molecular modeling studies through quantum mechanics calculations that allowed for prediction of the interaction model. In vitro release studies indicated well-preserved integrity of nanoparticles in simulated gastric fluid. Circular dichroism spectroscopy proved conformational stability of insulin and Fourier transform infrared spectroscopy technique showed rearrangements of insulin structure during processing. Moreover, in vivo biological activity in diabetic rats revealed no statistical difference when compared to nonencapsulated insulin, demonstrating retention of insulin activity. Our results demonstrate that alginate-dextran sulfate-based nanoparticles efficiently stabilize the loaded protein structure, presenting good physical properties for oral delivery of insulin.