PLGA nanocapsules improve the delivery of clarithromycin to kill intracellular Staphylococcus aureus and Mycobacterium abscessus.

Drug delivery systems are promising for targeting antibiotics directly to infected tissues. To reach intracellular Staphylococcus aureus and Mycobacterium abscessus, we encapsulated clarithromycin in PLGA nanocapsules, suitable for aerosol delivery by nebulization of an aqueous dispersion. Compared to the same dose of free clarithromycin, nanoencapsulation reduced 1000 times the number of intracellular S. aureus in vitro. In RAW cells, while untreated S. aureus was located in acidic compartments, the treated ones were mostly situated in non-acidic compartments. Clarithromycin-nanocapsules were also effective against M. abscessus (70-80% killing efficacy). The activity of clarithromycin-nanocapsules against S. aureus was also confirmed in vivo, using a murine wound model as well as in zebrafish. The permeability of clarithromycin-nanocapsules across Calu-3 monolayers increased in comparison to the free drug, suggesting an improved delivery to sub-epithelial tissues. Thus, clarithromycin-nanocapsules are a promising strategy to target intracellular S. aureus and M. abscessus.

Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections.

PURPOSE: The aim of this work was to develop clarithromycin microparticles (CLARI-MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti-bacterial efficacy. METHODS: Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI-MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti-antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. RESULTS: Microparticles were of spherical shape, smooth surface and size of about 765 nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8 µm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7 µg/cm(2) of deposited powder were transported to the basolateral compartment after 24 h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria. CONCLUSIONS: The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation.

Mucoadhesive Amphiphilic Methacrylic Copolymer-Functionalized Poly(ε-caprolactone) Nanocapsules for Nose-to-Brain Delivery of Olanzapine.

Nose-to-brain drug delivery has been proposed to overcome the low absorption of drugs in central nervous system due to the absence of brain-blood barrier in the olfactory nerve pathway. However, the presence of a mucus layer and quick clearance limit the use of this route. Herein, amphiphilic methacrylic copolymer-functionalized poly(ε-caprolactone) nanocapsules were proposed as a mucoadhesive system to deliver olanzapine after intranasal administration. In vitro evaluations showed that these nanocapsules were able to interact with mucin (up to 17% of increment in particle size and 30% of reduction of particle concentration) and nasal mucosa (2-fold higher force for detaching), as well as to increase the retention of olanzapine (about 40%) on the nasal mucosa after continuous wash. The olanzapine-loaded amphiphilic methacrylic copolymer-functionalized PCL nanocapsules enhanced the amount of drug in the brain of rats (1.5-fold higher compared to the drug solution). In accordance with this finding, this formulation improved the prepulse inhibition impairment induced by apomorphine, which is considered as an operational measure of pre-attentive sensorimotor gating impairment present in schizophrenia. Besides, nanoencapsulated olanzapine did not affect the nasal mucosa integrity after repeated doses. These data evidenced that the designed nanocapsules are a promising mucoadhesive system for nose-to-brain delivery of drugs.

Nanoencapsulation Improves Relative Bioavailability and Antipsychotic Effect of Olanzapine in Rats.

This study aimed to investigate the pharmacokinetics, tissue distribution and antipsychotic activity of olanzapine administered as free drug (OLA-FREE) or loaded into lipid-core nanocapsules (OLA-LNC). OLA-LNC were successfully developed with a particle size of 142 ± 4 nm and a zeta potential of -19.6 ± 0.6 mV. Pharmacokinetics and tissue distribution studies were carried out after the administration of free and nanoencapsulated olanzapine (10 mg/kg) by intraperitoneal route to male Wistar rats. Higher olanzapine concentrations and AUC(0-12 h) were found in plasma and tissues evaluated after the administration of OLA-LNC compared to the drug in the free form, resulting in a relative bioavailability of 226.7% in the plasma. As a result olanzapine loaded lipid-core nanocapsules presented pronounced and long-lasting effects on central nervous system. These nanocapsules (10 mg/kg, i.p.) significantly diminished the stereotyped behavior induced by D,L-amphetamine up to 12 hours whereas olanzapine free-form (10 mg/kg, i.p.) was effective during 03 hours only. Moreover, olanzapine loaded lipid-core nanocapsules (1.0 mg/kg, i.p.) have shown a marked sedative effect and also prevented the prepulse inhibition disruption induced by apomorphine at lower dose than olanzapine in free-form (2.5 mg/kg, i.p.). Herewith, we point to the nanoencapsulation as a strategy for reducing the concentration of olanzapine in pharmaceutical formulations.

Nanoencapsulation of olanzapine increases its efficacy in antipsychotic treatment and reduces adverse effects.

Olanzapine is an atypical antipsychotic drug, whose chronic use has been associated with the development of potential adverse effects such as weight gain and cardio-metabolic disorders like hypercholesterolemia and diabetes. To circumvent these side effects, the controlled release of olanzapine is a promising approach to improve adhesion of schizophrenic patients to the treatment. An innovative strategy to prolong drug release consists of loading the drug into biodegradable polymeric lipid-core nanocapsules. In this study, particle size, polydispersity, pH, zeta potential and drug loading of olanzapine-loaded lipid-core nanocapsules were analyzed. Weight gain, biochemical parameters and antipsychotic activity were evaluated in male Wistar rats. The lipid-core nanocapsules had a mean diameter of 156 +/- 13 nm, a polydispersity index lower than 0.1, a pH value of 6.12 +/- 0.14, zeta potential of -17 +/- 2.40 mV and encapsulation efficiency close to 100%. The animals treated with olanzapine-loaded lipid-core nanocapsules showed significantly lower weight gain (63.4 +/- 19.6 g) and total cholesterol levels (66.2 +/- 3.5 g x dl(-1)), compared to those administered with free olanzapine (112.6 +/- 10.3 g and 90.4 +/- 2.4 g x dl(-1)), respectively. Additionally, a more prolonged antipsychotic action was observed in the stereotyped behavior animal model induced by D,L-amphetamine, which affords to conclude that nanoencapsulation is a promising alternative to treat schizophrenic patients.