Brain Uptake of a Zidovudine Prodrug after Nasal Administration of Solid Lipid Microparticles

Abstract

Our previous results demonstrated that a prodrug obtained by the conjugation of the antiretroviral drug zidovudine (AZT) with ursodeoxycholic acid (UDCA) represents a potential carrier for AZT in the central nervous system, thus possibly increasing AZT efficiency as an anti-HIV drug. Based on these results and in order to enhance AZT brain targeting, the present study focuses on solid lipid microparticles (SLMs) as a carrier system for the nasal administration of UDCA-AZT prodrug. SLMs were produced by the hot emulsion technique, using tristearin and stearic acid as lipidic carriers, whose mean diameters were 16 and 7 μm, respectively. SLMs were of spherical shape, and their prodrug loading was 0.57 ± 0.03% (w/w, tristearin based) and 1.84 ± 0.02% (w/w, stearic acid based). The tristearin SLMs were able to control the prodrug release, whereas the stearic acid SLMs induced a significant increase of the dissolution rate of the free prodrug. The free prodrug was rapidly hydrolyzed in rat liver homogenates with a half-life of 2.7 ± 0.14 min (process completed within 30 min). The tristearin SLMs markedly enhanced the stability of the prodrug (75% of the prodrug still present after 30 min), whereas the stabilization effect of the stearic acid SLMs was lower (14% of the prodrug still present after 30 min). No AZT and UDCA-AZT were detected in the rat cerebrospinal fluid (CSF) after an intravenous prodrug administration (200 μg). Conversely, the nasal administration of stearic acid based SLMs induced the uptake of the prodrug in the CSF, demonstrating the existence of a direct nose-CNS pathway. In the presence of chitosan, the CSF prodrug uptake increased six times, up to 1.5 μg/mL within 150 min after nasal administration. The loaded SLMs appear therefore as a promising nasal formulation for selective zidovudine brain uptake.

Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries

“…The nasal administration of pure UDCA-AZT as a water suspension did not allow us to obtain detectable amounts of AZT or the prodrug in the blood or in the CSF, respectively, within 180 min of administration, as reported previously (Dalpiaz et al, 2014). In contrast, the nasal administration of the powders constituted by MIX or by the CP microparticles (0.8 mg, 19 approximately 100 µg of UDCA−AZT in each nostril) produced detectable amounts of UDCA−AZT in the CSF of the rats, as reported in Fig.…”

“…Accordingly, we demonstrated that the nasal administration of solid lipid microparticles loaded with the UDCA-AZT prodrug facilitates its uptake into the CSF of rats (Dalpiaz et al, 2014). Nasal administration constitutes a potentially efficacious way of achieving the brain uptake of neuroactive agents (Fine et al, 2014(Fine et al, , 2015Illum, 2000;Vyas et al, 2005).…”

“…At the end of the infusion and at fixed time points, blood samples (100 µL) were collected and CSF samples (50 µL) were withdrawn using the cysternal puncture method described by van den Berg et al (2002), which requires a single needle stick and allows the collection of serial (40-50 µL) CSF samples that are virtually blood-free (Dalpiaz et al, 2014). A total volume of approximately 150 µL of CSF was collected during the experimental session.…”

“…The first procedure consisted of the introduction of 50 µL of an aqueous suspension of UDCA-AZT (2 mg/mL) into each nostril, as described 12 previously (Dalpiaz et al, 2014). After administration, blood (100 µL) and CSF samples (50 µL) were collected at fixed time points and analyzed using the same procedures described above.…”

The nasal delivery of nanoencapsulated statins – an approach for brain delivery

“…In particular, this may provide a much higher residence time in the nasal cavity, pivotal to allow an enhancement of drug availability. 66 For the in vitro release studies, a simulated nasal electrolyte solution containing BSA was preferred to surfactant solutions 48 or mixtures with organic solvents miscible with water 67 , as a physiological dissolution medium. Generally, drug inclusion in nanoparticles is a strategy to prolong the release.…”