title: 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.
authors.affiliation: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP, 201307, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Marg, Delhi, 110054, India.
authors.forename: Rakesh Kumar
authors.initials: RK
authors.lastname: Sharma
authors.affiliation: Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Marg, Delhi, 110054, India.
authors.forename: Navneet
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP, 201307, India.
authors.forename: Reema
authors.initials: R
authors.lastname: Gabrani
authors.affiliation: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP, 201307, India.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India.
authors.forename: Javed
authors.initials: J
authors.lastname: Ali
authors.affiliation: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP, 201307, India. shweta.dang@jiit.ac.in.
authors.forename: Shweta
authors.initials: S
authors.lastname: Dang
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002152:Calorimetry, Differential Scanning; D002470:Cell Survival / Q000187:drug effects; D011232:Chemical Precipitation; D002522:Chlorocebus aethiops; D003975:Diazepam / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004337:Drug Carriers; D004339:Drug Compounding; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles; D036103:Nanotechnology / Q000379:methods; D065588:Nasal Absorption; D009297:Nasal Mucosa / Q000000981:diagnostic imaging / Q000378:metabolism*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013501:Surface-Active Agents / Q000737:chemistry; D014018:Tissue Distribution; D014709:Vero Cells
chemical_list: D004337:Drug Carriers; D019275:Radiopharmaceuticals; D013501:Surface-Active Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003975:Diazepam
keywords: controlled release; nanoparticles; process optimization; scintigraphy