Local delivery of indomethacin to arthritis-bearing rats through polymeric micelles based on amphiphilic polyphosphazenes.
OBJECTIVE
Preparation, in vitro and in vivo evaluation of indomethacin-loaded polymeric micelles based on amphiphilic polyphosphazene.


METHODS
Amphiphilic polyphosphazenes (PNIPAAm/EAB-PPPs) with poly (N-isopropylacrylamide) (PNIPAAm) and ethyl 4-aminobenzoate (EAB) as side groups were synthesized through thermal ring-opening polymerization and subsequent substitution reactions. Indomethacin (IND) loaded polymeric micelles based on PNIPAAm/EAB-PPPs were prepared by dialysis procedure. In vitro IND release kinetics was investigated in 0.1 M PBS (pH 7.4), while in vivo pharmacokinetics was performed in Sprague-Dawley rats. In vivo pharmacodynamic study was carried out based on two animal models, i.e. carrageenan-induced acute paw edema and complete Freund's adjuvant (CFA) induced ankle arthritis model.


RESULTS
Drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in PBS suggested that there was no significant difference in release rate between micelles based on copolymers with various EAB content. Compared with the rats administered with free IND aqueous solution, IND concentration in rats' plasma showed a prolonged maintenance in experimental group treated with IND-loaded polymeric micelles. In vivo pharmacodynamic study indicated that sustained therapeutic efficacy could be achieved through topical injection of the aqueous solution of IND-loaded micelles. Local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration as evidenced by ulceration evaluation.


CONCLUSIONS
The promising results of current preliminary study suggest that this type of amphiphilic copolymers could be used as injectable drug carriers for hydrophobic drugs.
Zhang
Jian Xiang
JX
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310068, People's Republic of China.
Yan
Mei Qiu
MQ
Li
Xiao Hui
XH
Qiu
Li Yan
LY
Li
Xiao Dong
XD
Li
Xiao Jing
XJ
Jin
Yi
Y
Zhu
Kang Jie
KJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000517:prevention & control*; D002351:Carrageenan; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005620:Freund's Adjuvant; D057927:Hydrophobic and Hydrophilic Interactions; D007213:Indomethacin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007270:Injections, Intra-Articular; D007279:Injections, Subcutaneous; D008297:Male; D008823:Micelles; D009943:Organophosphorus Compounds / Q000138:chemical synthesis*; D011108:Polymers / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents / Q000138:chemical synthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D008823:Micelles; D009943:Organophosphorus Compounds; D011108:Polymers; D013501:Surface-Active Agents; C108974:poly(phosphazene); D002351:Carrageenan; D005620:Freund's Adjuvant; D007213:Indomethacin