Development, characterization and application of in situ gel systems for intranasal delivery of tacrine.
The present study aimed to develop an in situ gel formulation for intranasal delivery of tacrine (THA), an anti-Alzheimer's drug. Thermosensitive polymer Pluronic F-127 was used to prepare THA in situ gels. Sol-gel transition temperature (Tsol-gel), rheological properties, in vitro release, and in vivo nasal mucociliary transport time were optimized. The pharmacokinetics and brain dispositions of in situ gel were compared with that from THA oral solution in rats. The in situ gel demonstrated a liquid state with Newtonian fluid behavior under 20 °C, while it exhibited as non-flowing gel with pseudoplastic fluid behavior beyond its Tsol-gel of 28.5 °C. Based on nasal mucociliary transport time, the in situ gel significantly prolonged its retention in nasal cavity compared to solution form. Moreover, the in situ gel achieved 2-3 fold higher peak plasma concentration (Cmax) and area under the curve (AUC) of THA in plasma and brain tissue, but lowered Cmax and AUC of the THA metabolites compared to that of oral solution. The enhanced nasal residence time, improved bioavailability, increased brain uptake of parent drug and decreased exposure of metabolites suggested that the in situ gel could be an effective intranasal formulation for THA.
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, PR China.
Shuai
S
Qian
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, PR China.
Yin Cheong
YC
Wong
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, PR China. Electronic address: joanzuo@cuhk.edu.hk.
Zhong
Z
Zuo
D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D005782:Gels; D008297:Male; D009079:Mucociliary Clearance; D009296:Nasal Cavity / Q000378:metabolism; D044367:Phase Transition; D020442:Poloxamer / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012212:Rheology; D012995:Solubility; D013619:Tacrine / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods; D044366:Transition Temperature
D002800:Cholinesterase Inhibitors; D004337:Drug Carriers; D005782:Gels; D020442:Poloxamer; D011092:Polyethylene Glycols; D013619:Tacrine; D048271:Chitosan
In situ gel; Intranasal; Pharmacokinetics; Pluronic F-127; Tacrine