Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles

• Published in: AAPS PharmSciTech Vol. 16; no. 5; pp. 1108 - 1121
• Main Authors: Sharma, Deepak, Sharma, Rakesh Kumar, Sharma, Navneet, Gabrani, Reema, Sharma, Sanjeev K., Ali, Javed, Dang, Shweta
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2015
• Subjects: Administration, Intranasal; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Brain - diagnostic imaging; Brain - metabolism; Calorimetry, Differential Scanning; Cell Survival - drug effects; Cercopithecus aethiops; Chemical Precipitation; Diazepam - administration & dosage; Diazepam - chemistry; Diazepam - metabolism; Diazepam - toxicity; Drug Carriers; Drug Compounding; Lactic Acid - chemistry; Male; Nanoparticles; Nanotechnology - methods; Nasal Absorption; Nasal Mucosa - diagnostic imaging; Nasal Mucosa - metabolism; Particle Size; Pharmacology/Toxicology; Pharmacy; Polyglycolic Acid - chemistry; Radiopharmaceuticals - administration & dosage; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - toxicity; Rats, Sprague-Dawley; Research Article; Solubility; Spectroscopy, Fourier Transform Infrared; Surface-Active Agents - chemistry; Tissue Distribution; Vero Cells; process optimization; controlled release; nanoparticles; scintigraphy
• DOI: 10.1208/s12249-015-0294-0
• ISSN: 1530-9932

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.