Nasal powders of quercetin-ß-cyclodextrin derivatives complexes with mannitol/lecithin microparticles for Nose-to-Brain delivery: In vitro and ex vivo evaluation.

Quercetin, a flavonoid with possible neuroprotective action has been recently suggested for the early-stage treatment of Alzheimer's disease. The low solubility and extended first pass effect render quercetin unsuitable for oral administration. Alternatively, brain targeting is more feasible with nasal delivery, by-passing, non-invasively, Blood-Brain Barrier and ensuring rapid onset of action. Aiming to increase quercetin's disposition into brain, nasal powders consisting of quercetin-cyclodextrins (methyl-ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) lyophilizates blended with spray-dried microparticles of mannitol/lecithin were prepared. Quercetin's solubility at 37 °C and pH 7.4 was increased 19-35 times when complexed with cyclodextrins. Blending lyophilizates in various ratios with mannitol/lecithin microparticles, results in powders with improved morphological characteristics as observed by X-ray Diffraction and Scanning Electron Microscopy analysis. In vitro characterization of these powders using Franz cells, revealed rapid dissolution and permeation 17 (methyl-ß-cyclodextrin) to 48 (hydroxypropyl-ß-cyclodextrin) times higher than that of pure quercetin. Ex vivo powders' transport across rabbit nasal mucosa was found more efficient in comparison with the pure Que. The overall better performance of quercetin-hydroxypropyl-ß-cyclodextrin powders is confirmed by ex vivo experiments revealing amount of quercetin permeated ranging from 0.03 ± 0.01 to 0.22 ± 0.05 µg/cm2 for hydroxypropyl-ß-cyclodextrin and 0.022 ± 0.01 to 0.17 ± 0.04 µg/cm2 for methyl-ß-cyclodextrin powders, while the permeation of pure quercetin was negligible.

Structure and Fate of Nanoparticles Designed for the Nasal Delivery of Poorly Soluble Drugs.

Nanoparticles are promising mediators to enable nasal systemic and brain delivery of active compounds. However, the possibility of reaching therapeutically relevant levels of exogenous molecules in the body is strongly reliant on the ability of the nanoparticles to overcome biological barriers. In this work, three paradigmatic nanoformulations vehiculating the poorly soluble model drug simvastatin were addressed: (i) hybrid lecithin/chitosan nanoparticles (LCNs), (ii) polymeric poly-ε-caprolactone nanocapsules stabilized with the nonionic surfactant polysorbate 80 (PCL_P80), and (iii) polymeric poly-ε-caprolactone nanocapsules stabilized with a polysaccharide-based surfactant, i.e., sodium caproyl hyaluronate (PCL_SCH). The three nanosystems were investigated for their physicochemical and structural properties and for their impact on the biopharmaceutical aspects critical for nasal and nose-to-brain delivery: biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucosa. All three nanoformulations were highly reproducible, with small particle size (∼200 nm), narrow size distribution (polydispersity index (PI) < 0.2), and high drug encapsulation efficiency (>97%). Nanoparticle composition, surface charge, and internal structure (multilayered, core-shell or raspberry-like, as assessed by small-angle neutron scattering, SANS) were demonstrated to have an impact on both the drug-release profile and, strikingly, its behavior at the biological interface. The interaction with the mucus layer and the kinetics and extent of transport of the drug across the excised animal nasal epithelium were modulated by nanoparticle structure and surface. In fact, all of the produced nanoparticles improved simvastatin transport across the epithelial barrier of the nasal cavity as compared to a traditional formulation. Interestingly, however, the permeation enhancement was achieved via two distinct pathways: (a) enhanced mucoadhesion for hybrid LCN accompanied by fast mucosal permeation of the model drug, or (b) mucopenetration and an improved uptake and potential transport of whole PCL_P80 and PCL_SCH nanocapsules with delayed boost of permeation across the nasal mucosa. The correlation between nanoparticle structure and its biopharmaceutical properties appears to be a pivotal point for the development of novel platforms suitable for systemic and brain delivery of pharmaceutical compounds via intranasal administration.

Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake.

Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60 mg/100 ml maintained the positive zeta potential value of about +45 mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively.

Layered lipid microcapsules for mesalazine delayed-release in children.

The goal was to make available a delayed-release dosage form of mesalazine to be dispersed in water to facilitate swallowing in adults and children. Mesalazine microparticles containing carnauba wax were prepared by spray-congealing technique. A second step of spray-congealing of carnauba microparticles dispersed in liquefied stearic acid gave rise to mesalazine lipid microcapsules in which several carnauba microparticles remained embedded as cores in a reservoir structure. In order to favor their water dispersion, the lipid microcapsules were dry coated by tumbling them with different ratios of mannitol/lecithin microparticles prepared by spray-drying. Release rate measurements showed a delayed-release behavior, in particular a pH-dependence with less than 10% of drug released in acidic medium and complete release in phosphate buffer pH 7.4 in 4-5h. The layering with hydrophilic excipient microparticles allowed manufacturing of a pH-dependent dosage form suitable for extemporaneous oral use in adults and children.

Pectin matrix as oral drug delivery vehicle for colon cancer treatment.

Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.

In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: the enhancing effect of potassium sorbate.

Nasal spray products containing desmopressin acetate (DDAVP) were tested in vitro to evaluate the effect of the contained preservatives on drug permeation across rabbit nasal mucosa. Experiments were performed using Franz-type diffusion cells with rabbit nasal mucosa as model barrier. Transport profiles obtained in comparison with a preservative-free solution evidenced that in the presence of preservatives DDAVP permeation in vitro always increased (p<0.05), although at different extents (chlorobutanol

Prolonged duration local anesthesia with lipid-protein-sugar particles containing bupivacaine and dexamethasone.

Glucocorticoids prolong block duration from polymeric microspheres containing bupivacaine, but not from unencapsulated drug. Here we investigate this effect applies to particles with much more rapid drug release and improved long-term biocompatibility. Male Sprague-Dawley rats were given sciatic nerve blocks with 75 mg of 3% or 60% (w/w) dipalmitoylphosphatidylcholine (DPPC) spray-dried lipid-protein-sugar particles (LPSPs) containing 10% (w/w) bupivacaine and 0%, 0.05%, or 0.1% (w/w) dexamethasone. Sensory nerve block from bupivacaine-containing 3% and 60% (w/w) DPPC particles without dexamethasone yielded blocks lasting 301 +/- 56 and 321 +/- 127 min, respectively. Addition of 0.05% (w/w) dexamethasone increased block durations to 610 +/- 182 and 538 +/- 222 min, respectively; increasing dexamethasone loading to 0.1% did not further increase duration. One day after injection, dexamethasone-containing particles resulted in lower inflammation scores and capsule thickness than dexamethasone-free particles, but the difference was gone by day 4. Excipient composition had prominent effects at all time points. For all groups, inflammation was largely resolved by 2 weeks after injection. Dexamethasone approximately doubled the duration of nerve block from bupivacaine-loaded LPSPs, while maintaining excellent biocompatibility. Such formulations could be useful in clinical applications when nerve blockade is needed for 24 hours or less.