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

Abstract

Purpose

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.

Key words

amphiphilic copolymers arthritis indomethacin local drug delivery polymeric micelles 

Abbreviations

AET·HCl

2-aminoethanethiol hydrochloride

AUC

area under the concentration–time curve

AIBN

2, 2′-azobisisobutyronitrile

AUMC

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

CFA

complete Freund’s adjuvant

CMC

critical micelle concentration

DMS

dexamethasone

DMAc

dimethylacetamide

DMF

N,N-dimethylformamide

DMSO

dimethyl sulphoxide

DSC

differential scanning calorimeter

EAB

ethyl 4-aminobenzoate

GPC

gel permeation chromatography

HPLC

high-performance liquid chromatography

IBU

ibuprofen

IND

indomethacin

KET

ketoprofen

LCST

lower critical solution temperature

MRT

mean residence time

MPG

medroxyprogesterone acetate

NAP

naproxen

PBS

phosphate buffered solution

PNIPAAm

poly (N-isopropylacrylamide)

PNIPAAm/EAB-PPP

amphiphilic polyphosphazene with PNIPAAm and EAB as side groups

PNS

predinisone acetate

RA

rheumatoid arthritis

SD

standard deviation

THF

tetrahydrofuran

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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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