Brain Targeting of Temozolomide via the Intranasal Route Using Lipid-Based Nanoparticles: Brain Pharmacokinetic and Scintigraphic Analyses.
The aim of the present work was to investigate the efficacy of temozolomide nanostructured lipid carriers (TMZ-NLCs) to enhance brain targeting via nasal route administration. The formulation was optimized by applying a four-factor, three-level Box-Behnken design. The developed formulations and the functional relationships between their independent and dependent variables were observed. The independent variables used in the formulation were gelucire (X1), liquid lipid/total lipid (X2), Tween 80 (X3), and sonication time (X4), and their effects were observed with regard to size (Y1), % drug release (Y2), and drug loading (Y3). The optimized TMZ-NLC was further evaluated for its surface morphology as well as ex vivo permeation and in vivo studies. All TMZ-NLC formulations showed sizes in the nanometer range, with high drug loading and prolonged drug release. The optimized formulation (TMZ-NLCopt) showed an entrapment efficiency of 81.64 ± 3.71%, zeta potential of 15.21 ± 3.11 mV, and polydispersity index of less than 0.2. The enhancement ratio was found to be 2.32-fold that of the control formulation (TMZ-disp). In vivo studies in mice showed that the brain/blood ratio of TMZ-NLCopt was found to be significantly higher compared to that of TMZ-disp (intranasal, intravenous). Scintigraphy images of mouse brain showed the presence of a high concentration of TMZ. The AUC ratio of TMZ-NLCopt to TMZ-disp in the brain was the highest among the organs. The findings of this study substantiate the existence of a direct nose-to-brain delivery route for NLCs.
Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University , New Delhi 110062, India.
Anam
A
Khan
Department of Pharmaceutics, Glocal School of Pharmacy, Glocal University , Saharanpur 247121, Uttar Pradesh, India.
Syed Sarim
SS
Imam
Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University , New Delhi 110062, India.
Mohammed
M
Aqil
Department of Pharmaceutics, College of Pharmacy, King Saud University , P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Abdul
A
Ahad
Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University , New Delhi 110062, India.
Yasmin
Y
Sultana
Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University , New Delhi 110062, India.
Asgar
A
Ali
Fermish Clinical Technologies Private Limited , Noida 201301, Uttar Pradesh, India.
Khalid
K
Khan
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004339:Drug Compounding / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009297:Nasal Mucosa / Q000378:metabolism*; D011136:Polysorbates / Q000737:chemistry; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D000077204:Temozolomide
D011136:Polysorbates; D003606:Dacarbazine; D000077204:Temozolomide
NLCs; brain targeting; gamma scintigraphy; pharmacokinetic; temozolomide