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

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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.

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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

References

  1. E. D. J. Harris. Rheumatoid arthritis: pathophysiology and implications for therapy. New Engl. J. Med. 322:1277–1289 (1990).

    Article  PubMed  Google Scholar 

  2. T. Doanand, and E. Massarotti. Rheumatoid arthritis: an overview of new and emerging therapies. J. Clin. Pharmacol. 45:751–762 (2005).

    Article  CAS  Google Scholar 

  3. J. Steinmeyerand, and Y. T. Konttinen. Oral treatment options for degenerative joint disease-presence and future. Adv. Drug Delv. Rev. 58:168–211 (2006).

    Article  CAS  Google Scholar 

  4. N. Gerwin, C. Hops, and A. Lucke. Intraarticular drug delivery in osteoarthritis. Adv. Drug Delv. Rev. 58:226–242 (2006).

    Article  CAS  Google Scholar 

  5. S. Abramson. Drug delivery in degenerative joint disease: where we are and where to go?. Adv. Drug Delv. Rev. 58:125–127 (2006).

    Article  CAS  Google Scholar 

  6. C. T. Wang, J. Lin, and C. J. Chang. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J. Bone Jt. Surg. 86:538–544 (2004).

    Google Scholar 

  7. X. Ayral. Injections in the treatment of osteoarthritis. Best Pract. Res. Clin Rheumatol. 15:609–626 (2001).

    Article  PubMed  CAS  Google Scholar 

  8. K. E. Brown, K. Leong, C. H. Huang, R. Dalal, G. D. Green, H. B. Haimes, P. A. Jimenez, and J. Bathon. Gelatin/chondroitin 6-sulfate microspheres for the delivery of therapeutic proteins to the joint. Arthritis Rheum. 41:2185–2195 (1998).

    Article  PubMed  CAS  Google Scholar 

  9. M. Trif, C. Guillen, D. M. Vaughan, J. M. Telfer, J. M. Brewer, A. Roseanu, and J. H. Brock. Liposomes as possible carriers for lactoferrin in the local treatment of inflammatory diseases. Exp. Biol. Med. 226:559–564 (2001).

    CAS  Google Scholar 

  10. E. Horisawa, T. Hirota, S. Kawazoe, J. Yamada, H. Yamamoto, H. Takeuchi, and Y. Kawashima. Prolonged anti-inflammatory action of dl-lactide/glycolide copolymer nanospheres containing betamethasone sodium phosphate for an intra-articular delivery system in antigen-induced arthritic rabbit. Pharm. Res. 19:403–410 (2002).

    Article  PubMed  CAS  Google Scholar 

  11. C. Allen, D. Maysinger, and A. Eisenberg. Nano-engineering block copolymer aggregates for drug delivery. Colloids Surf. B 16:3–27 (1999).

    Article  CAS  Google Scholar 

  12. M. C. Jonesand, and J. C. Leroux. Polymeric micelles-a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm. 48:101–111 (1999).

    Article  Google Scholar 

  13. K. Kataoka, A. Harada, and Y. Nagasaki. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Delv. Rev. 47:113–131 (2001).

    Article  CAS  Google Scholar 

  14. Y. Kakizawaand, and K. Kataoka. Block copolymer micelles for delivery of gene and related compounds. Adv. Drug Delv. Rev. 54:203–222 (2002).

    Article  Google Scholar 

  15. R. Duncan. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2:347–360 (2003).

    Article  PubMed  CAS  Google Scholar 

  16. D. Wang, S. C. Miller, M. Sima, D. Parker, H. Buswell, K. C. Goodrich, P. Kopeckova, and J. Kopecek. The arthrotropism of macromolecules in adjuvant-induced arthritis rat model: A preliminary study. Pharm. Res. 21:1741–1749 (2004).

    Article  PubMed  CAS  Google Scholar 

  17. D. Wang, S. C. Miller, X. M. Liu, B. Anderson, X. S. Wang, and S. R. Goldring. Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis. Arthritis Res. Ther. 9:R2 (2007).

    Article  PubMed  Google Scholar 

  18. Y. K. Chang, E. S. Powell, and H. R. Allcock. Environmentally responsive micelles from polystyrene-poly[bis(potassium carboxylatophenoxy)phosphazenel block copolymers. J. Polym. Sci. Pol. Chem. 43:2912–2920 (2005).

    Article  CAS  Google Scholar 

  19. R. Song, Y. J. Jun, J. I. Kim, C. Jin, and Y. S. Sohn. Synthesis, characterization, and tumor selectivity of a polyphosphazene-platinum(II) conjugate. J. Control. Release 105:142–150 (2005).

    Article  PubMed  CAS  Google Scholar 

  20. J. X. Zhang, L. Y. Qiu, K. J. Zhu, and Y. Jin. Thermosensitive micelles self-assembled by novel N-Isopropylacrylamide oligomer grafted polyphosphazene. Macromol. Rapid Commun. 25:1563–1567 (2004).

    Article  CAS  Google Scholar 

  21. J. X. Zhang, L. Y. Qiu, Y. Jin, and K. J. Zhu. Physicochemical characterization of polymeric micelles constructed from novel amphiphilic polyphosphazene with poly(N-isopropylacrylamide) and ethyl 4-aminobenzoate as side groups. Colloids Surf. B 43:123–130 (2005).

    Article  CAS  Google Scholar 

  22. J. X. Zhang, L. Y. Qiu, and K. J. Zhu. Solvent controlled multi-morphological self-assembly of amphiphilic graft copolymers. Macromol. Rapid Commun. 26:1716–1723 (2005).

    Article  CAS  Google Scholar 

  23. J. X. Zhang, L. Y. Qiu, Y. Jin, and K. J. Zhu. Multimorphological self-assemblies of amphiphilic graft polyphosphazenes with oligopoly (N-isopropylacrylamide) and ethyl 4-aminobenzoate as side groups. Macromolecules 39:451–455 (2006).

    Article  CAS  Google Scholar 

  24. G. Chen, and A. S. Hoffman. Graft copolymers that exhibit temperature-induced phase transitions over a wide range of pH. Nature 373:49–52 (1995).

    Article  PubMed  CAS  Google Scholar 

  25. Y. S. Sohn, Y. H. Cho, H. Baek, and O. S. Jung. Synthesis and properties of low molecular weight polyphosphazenes. Macromolecules 28:7566–7568 (1995).

    Article  CAS  Google Scholar 

  26. J. Sato, T. Amizuka, Y. Niida, M. Umetsu, and K. Ito. Simple, rapid and sensitive method for the determination of indomethacin in plasma by high-performance liquid chromatography with ultraviolet detection. J. Chromatogr. B 692:241–244 (1997).

    Article  CAS  Google Scholar 

  27. I. G. Otternessand, and M. L. Bliven. Laboratory models for testing non-steroidal anti-inflammatory drugs. Wiley, New York, 1985.

    Google Scholar 

  28. R. Nagarajan, M. Barry, and E. Ruckenstein. Unusual selectivity in solubilization by block copolymer micelles. Langmuir 2:210–215 (1986).

    Article  CAS  Google Scholar 

  29. J. B. Liu, Y. H. Xiao, and C. Allen. Polymer-drug compatibility: a guide to the development of delivery systems for the anticancer agent, ellipticine. J. Pharm. Sci. 93:132–143 (2004).

    Article  PubMed  CAS  Google Scholar 

  30. A. Benahmed, M. Ranger, and J. C. Leroux. Novel polymeric micelles based on the amphiphilic diblock copolymer poly(N-vinyl-2-pyrrolidone)-blockpoly(D,L-lactide). Pharm. Res. 18:323–328 (2001).

    Article  PubMed  CAS  Google Scholar 

  31. S. E. Andersson, K. Lexmuller, A. Johansson, and G. M. Ekstrom. Tissue and intracellular pH in normal periarticular soft tissue and during different phases of antigen induced arthritis in the rat. J. Rheumatol. 26:2018–2024 (1999).

    PubMed  CAS  Google Scholar 

  32. V. A. Bobkov, T. N. Brylenkova, and R. S. Moiseenko. Acid-base balance of the synovial fluid in patients with RA debute. Terapevt. Arkh. 72:35–38 (2000).

    CAS  Google Scholar 

  33. J. R. Levick. Hypoxia and acidosis in chronic inflammatory arthritis:Relation to vascular supply and dynamic effusion pressure. J. Rheumatol. 17:579–582 (1990).

    PubMed  CAS  Google Scholar 

  34. S. B. La, T. Okano, and K. Kataoka. Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly (ethylene oxide)-poly (β-benzyl L-aspartate) block copolymer micelles. J. Pharm. Sci. 85:85–90 (1996).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

Financial support from National Natural Science Foundation of China (No. 30371768) and Zhejiang Natural Science Foundation (No. R204233) is gratefully acknowledged.

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Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310068, People’s Republic of China

    Jian Xiang Zhang, Mei Qiu Yan, Li Yan Qiu & Yi Jin

  2. Institute of Polymer Science, Zhejiang University, Hangzhou, 310027, People’s Republic of China

    Jian Xiang Zhang & Kang Jie Zhu

  3. Department of New Drug Research Center, Faculty of Basic Medicine, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Xiao Hui Li & Xiao Jing Li

  4. Affiliated Stomatology Hospital, College of Medicine, Zhejiang University, Hangzhou, 310068, People’s Republic of China

    Xiao Dong Li

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  1. Jian Xiang Zhang
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Correspondence to Xiao Hui Li or Li Yan Qiu.

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Zhang, J.X., Yan, M.Q., Li, X.H. et al. Local Delivery of Indomethacin to Arthritis-Bearing Rats through Polymeric Micelles Based on Amphiphilic Polyphosphazenes. Pharm Res 24, 1944–1953 (2007). https://doi.org/10.1007/s11095-007-9322-4

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  • DOI: https://doi.org/10.1007/s11095-007-9322-4

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