Pharmaceutical Research

, Volume 24, Issue 10, pp 1944–1953

Local Delivery of Indomethacin to Arthritis-Bearing Rats through Polymeric Micelles Based on Amphiphilic Polyphosphazenes

  • Jian Xiang Zhang
  • Mei Qiu Yan
  • Xiao Hui Li
  • Li Yan Qiu
  • Xiao Dong Li
  • Xiao Jing Li
  • Yi Jin
  • Kang Jie Zhu
Research Paper



Preparation, in vitro and in vivo evaluation of indomethacin-loaded polymeric micelles based on amphiphilic polyphosphazene.


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.


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.


The promising results of current preliminary study suggest that this type of amphiphilic copolymers could be used as injectable drug carriers for hydrophobic drugs.

Key words

amphiphilic copolymers arthritis indomethacin local drug delivery polymeric micelles 



2-aminoethanethiol hydrochloride


area under the concentration–time curve


2, 2′-azobisisobutyronitrile


area under the first moment of the plasma concentration–time curve


complete Freund’s adjuvant


critical micelle concentration








dimethyl sulphoxide


differential scanning calorimeter


ethyl 4-aminobenzoate


gel permeation chromatography


high-performance liquid chromatography








lower critical solution temperature


mean residence time


medroxyprogesterone acetate




phosphate buffered solution


poly (N-isopropylacrylamide)


amphiphilic polyphosphazene with PNIPAAm and EAB as side groups


predinisone acetate


rheumatoid arthritis


standard deviation




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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Jian Xiang Zhang
    • 1
    • 2
  • Mei Qiu Yan
    • 1
  • Xiao Hui Li
    • 3
  • Li Yan Qiu
    • 1
  • Xiao Dong Li
    • 4
  • Xiao Jing Li
    • 3
  • Yi Jin
    • 1
  • Kang Jie Zhu
    • 2
  1. 1.College of Pharmaceutical SciencesZhejiang UniversityHangzhouPeople’s Republic of China
  2. 2.Institute of Polymer ScienceZhejiang UniversityHangzhouPeople’s Republic of China
  3. 3.Department of New Drug Research Center, Faculty of Basic MedicineThird Military Medical UniversityChongqingPeople’s Republic of China
  4. 4.Affiliated Stomatology Hospital, College of MedicineZhejiang UniversityHangzhouPeople’s Republic of China

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