[Preparation of huperzine A nasal in situ gel and evaluation of its brain targeting following intranasal administration].
OBJECTIVE
The feasibility of intranasal brain targeting drug delivery system via the olfactory pathway from nose to brain was explored.


METHODS
Using gellan gum, a cation-sensitive gel forming excipient, huperzine A (Hup A) nasal in situ gel was prepared by pH gradient precipitation method. The pharmacokinetics of Hup A in blood and cerebrospinal fluid (CSF) after intranasal, intravenous and intragastric adminstration to rats was studied using cisternal cannulation for serial CSF sampling and femoral artery cannulation for serial blood sampling. The distributions of Hup A into rat brain tissues following intranasal dosing were compared with those after intravenous and intragastric dosing by tissue homogeneization. The therapeutics effects of Hup A nasal in situ gel on cognitive function were tested in mice and rats with Morris water maze, step down test and step through test.


RESULTS
The AUC(0-->6 h) value in plasma obtained after nasal administration was 0.94 of that after intravenous administration, but the AUC(0-->6 h) of CSF after nasal administration was 1.3 and 2.3 times of that after intravenous and intragastric administration. The AUC(0-->6 h), of cerebrum, hippocampus, cerebellum, left olfactory bulb and right olfactory bulb after nasal administration were 1.5, 1.3, 1.0, 1.2 and 1.0 of that after intravenous administration, 2.7, 2.2, 1.9, 3.1 and 2.6 times of that after intragastric administration, respectively. Intranasal adminintration of 17.5-35 microg x kg(-1) showed equal effects after oral adminintration of 70 microg x kg(-1) commercial tablets, which was in good agreement with the results of pharmacokinetics.


CONCLUSIONS
Intranasal administration of huperzine A nasal in situ gel significantly increased the distributions of Hup A into rat brain tissues, especially into cerebrum and hippocampus which should be the target areas of Hup A, and enhanced the brain targeting of Hup A.
Tao
Tao
T
Shanghai Institute of Pharmaceutical Industry, Shanghai 200040, China. taotaosipi@hotmail.com
Zhao
Yan
Y
Yue
Peng
P
Dong
Wen-xin
WX
Chen
Qing-hua
QH
D000281:Administration, Intranasal; D000470:Alkaloids; D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D003071:Cognition / Q000187:drug effects; D004339:Drug Compounding / Q000379:methods; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D009297:Nasal Mucosa / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010316:Particle Size; D011135:Polysaccharides, Bacterial / Q000737:chemistry*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D000470:Alkaloids; D018696:Neuroprotective Agents; D011135:Polysaccharides, Bacterial; D012717:Sesquiterpenes; C050426:huperzine A; C048288:gellan gum