Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles

Abstract

The objective of the present investigation was to optimize diazepam (Dzp)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) to achieve delivery in the brain through intranasal administration. Dzp nanoparticles (DNP) were formulated by nanoprecipitation and optimized using Box-Behnken design. The influence of various independent process variables (polymer, surfactant, aqueous to organic (w/o) phase ratio, and drug) on resulting properties of DNP (z-average and drug entrapment) was investigated. Developed DNP showed z-average 148-337 d.nm, polydispersity index 0.04-0.45, drug entrapment 69-92%, and zeta potential in the range of -15 to -29.24 mV. Optimized DNP were further analyzed by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), ex-vivo drug release, and in-vitro cytotoxicity. Ex-vivo drug release study via sheep nasal mucosa from DNP showed a controlled release of 64.4% for 24 h. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay performed on Vero cell line showed less toxicity for DNP as compared to Dzp suspension (DS). Gamma scintigraphy and biodistribution study of DNP and DS was performed on Sprague-Dawley rats using technetium-99m-labeled ((99m)Tc) Dzp formulations to investigate the nose-to-brain drug delivery pathway. Brain/blood uptake ratios, drug targeting efficiency, and direct nose-to-brain transport were found to be 1.23-1.45, 258, and 61% for (99m)Tc-DNP (i.n) compared to (99m)Tc-DS (i.n) (0.38-1.06, 125, and 1%). Scintigraphy images showed uptake of Dzp from nose-to-brain, and this observation was in agreement with the biodistribution results. These results suggest that the developed poly(D,L-lactide-co-glycolide) (PLGA) NP could serve as a potential carrier of Dzp for nose-to-brain delivery in outpatient management of status epilepticus.

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

“…36 A total of 17 confirmatory formulation runs were generated with five center points using Design-Expert ® software (version 8.0.0; Stat-Ease, Minneapolis, MN, USA). Table 1 shows the levels of independent and dependent variables.…”

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

“…20 Briefly, mal-PEG-PLGA, mPEG-PLGA and rotigotine were dissolved in the organic phase (acetone) and then added dropwise into the aqueous phase (magnetically-stirred under ice-cold conditions) to completely volatilize the organic solvent, followed by filtration through a 0.45-μm filter (Millipore, Burlington, MA, USA).…”

Nano-Pharmaceuticals in Medicine

“…In a study by Sharma et al a prehospital treatment in the form of a delivery system which could be given via non-invasive route (nasal route) to the patients suffering from SE in emergency conditions was demonstrated. PLGA NPs of Diazepam, lorazepam and midazolam were prepared via nano-precipitation method for nose to brain delivery (Sharma et al, 2016, Sharma et al, 2015. The developed NPs were found to be in nanometric range with high percentage drug entrapment, which was further confirmed by TEM imaging.…”