Title

Biodistribution, pharmacodynamics and pharmacokinetics of oral delivery of exendin-4 using pH-sensitive nanoparticles

Translated Titles

利用pH敏感奈米微粒載體口服Exendin-4之生物分佈,藥物動力學及藥效學探討

Authors

阮胡玉

Key Words

促胰島素分泌素 ; 甲殼素 ; 聚服胺酸 ; 生物分佈 ; 藥效學 ; 藥物動力學 ; 大鼠胰島素 ; exendin-4 ; chitosan ; poly-γ-glutamic acid ; biodistribution ; pharmacodnamic ; pharmacokinetic ; rat insulin

PublicationName

清華大學化學工程學系學位論文

Volume or Term/Year and Month of Publication

2010年

Academic Degree Category

碩士

Advisor

宋信文

Content Language

英文

Chinese Abstract

Abstract Exendin-4 is a 39-amino acid peptide that shares several glucoregulatory activities with the mammalian incretin hormone, glucagon-like peptide-1 (GLP-1). The synthetic form of exendin-4, exenatide, was approved as adjunctive therapy by subcutaneous injection for patients with type 2 diabetes failing to achieve glycemic control with oral antidiabetic agents. Basically, the oral route is the most convenient way of drug administration for patients because it can avoid pain and reduce the complex complication. Base on our previous study, we developed nanoparticles (NPs) composed of chitosan (CS), poly-γ-glutamic acid (γPGA) with Fe ions as the carrier for exendin-4 delivery via the oral route. The size and zeta potential of the prepared NPs were ~300nm and ~30mV, respectively. The exendin-4 loaded in NPs could get ~60% loading efficiency (LE) and ~15% Loading Content (LC). To protect NPs in the acidic stomach environment, gelatin hard capsules filled with NPs were coated with enteric coating polymer. The enteric coating polymer, Eudragit L55-100, was dissolved beyond pH 6.0 that mimetic the pH environment of duodenum in the GI track. In the dissolution study, the test capsule could be dissolved immediately as it reached the duodenal region and NPs could then release exendin-4 into the systemic circulation via the opened paracellular pathway. For the in vivo study, the biodistribution of exendin-4 loaded NPs following the oral administration to rats was performed using the single-photon emission computed tomography (SPECT)/computed tomography (CT). The results obtained in the SPECT/CT study indicate that the orally administered exendin-4 was significantly absorbed into the systemic circulation. There was very high circulating exendin-4 (~48%) in the peripheral tissue and plasma (PP) at 2 h post ingestion. In the pharmacodynamic (PD) and pharmacokinetic (PK) evaluation in a mild diabetic rat model, the orally administered exendin-4 loaded NPs produced a slower hypoglycemic response for a prolonged period of time. The relative bioavailability of exendin-4 orally delivered by test NPs in gelatin capsules coated with 10% Eudragit was found to be 13.7 ± 2.1%. The results suggest the suitability of the NP system to be used as a non-invasive alternative for the basal exendin-4 therapy.

Topic Category 工學院 > 化學工程學系
工程學 > 化學工業
Reference
  1. [1] J.H. Hamman, G.M. Enslin, A.F. Kotze, Oral delivery of peptide drugs: barriers and
    連結:
  2. developments, Bio Drugs 19 (2005) 165–177.
    連結:
  3. Pharm. Res. 13 (1996) 1760–1764.
    連結:
  4. [4] Zambanini A, Newson RB, Maisey M, Feher MD. Injection related anxiety in insulin-
    連結:
  5. treated diabetes. Diabetes Res Clin Pract 1999;46(3):239–46.
    連結:
  6. [5] Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med
    連結:
  7. nanoparticles with pH-responsive characteristics for oral delivery of protein drugs. J
    連結:
  8. Control Release 2008;132(2):141–9.
    連結:
  9. and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials
    連結:
  10. [9] Thanou M, Verhoef JC, Junginger HE. Oral drug absorption enhancement by chitosan
    連結:
  11. and its derivatives. Adv Drug Deliv Rev 2001;52(2):117–26.
    連結:
  12. biodistribution and bioavailability of a chitosan-based nanoparticulate system for the oral
    連結:
  13. delivery of heparin. Biomaterials 2009;30(34):6629–37.
    連結:
  14. function of future liver remnant of cirrhotic rats after portal vein ligation: a bonus other
    連結:
  15. vivo. Int J Pharm 2002;249(1–2):139–47.
    連結:
  16. characterization of nanoparticles shelled with chitosan for oral insulin delivery.
    連結:
  17. Biomacromolecules 2007;8(1):146–52.
    連結:
  18. [15] He X, Sugawara M, Takekuma Y, Miyazaki K. Absorption of ester prodrugs in Caco-2
    連結:
  19. and rat intestine models. Antimicrob Agents Chemother 2004;48(7):2604–9.
    連結:
  20. [16] Dodane V, Amin Khan M, Merwin JR. Effect of chitosan on epithelial permeability and
    連結:
  21. structure. Int J Pharm 1999;182(1):21–32.
    連結:
  22. [19] O’Connor SD, Summers RM. Revisiting oral barium sulfate contrast agents. Acad Radiol
    連結:
  23. coupled polymeric microparticles and micromagnets for modulating the bioavailability of
    連結:
  24. orally delivered macromolecules. Biomaterials 2008;29(9):1216–23.
    連結:
  25. [21] Koide SS. Chitin-chitosan: properties, benefits and risks. Nutr Res 1998;18:1091–101.
    連結:
  26. [25] Roe RJ. Methods of X-ray and neutron scattering in polymer science. New York: Oxford
    連結:
  27. University Press; 2000 [Chapter 5].
    連結:
  28. insulin. Pharm Res 1994;11(1):21–9.
    連結:
  29. [27] Hidalgo I, Raub T, Borchardt R. Characterization of the human colon carcinoma cell line
    連結:
  30. [28] Ward PD, Tippin TK, Thakker DR. Enhancing paracellular permeability by modulating
    連結:
  31. other polycations on tight junction permeability in the human intestinal Caco-2 cell line. J
    連結:
  32. Nutr Biochem 2002;13(3):157–67.
    連結:
  33. [30] Ammar HO, Khalil RM. Preparation and evaluation of sustained-release solid dispersions
    連結:
  34. gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988;29(8):1035–
    連結:
  35. effects in db/db mice. J Control Release 2009;133:172–7.
    連結:
  36. [34] J. Eng,W.A. Kleinman, L. Singh, G. Singh, J.P. Raufman, Isolation and characterization
    連結:
  37. of exendin-4, an exendin-3 analogue from Heloderma suspectum venom, J. Biol. Chem.
    連結:
  38. [35] B. Gallwitz, New therapeutic strategies for the treatment of type 2 diabetes mellitus based
    連結:
  39. [36] J.F. Todd, S.R. Bloom, Incretins and other peptides in the treatment of diabetes, Diabet.
    連結:
  40. [37] O.G. Kolterman, B. Buse, M.S. Fineman, E. Gaines, S. Heintz, T.A. Bicsak, K. Taylor,
    連結:
  41. diabetes, J. Clin. Endocrinol. Metab. 88 (2003) 3082–3089.
    連結:
  42. Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of
    連結:
  43. receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes, Lancet 2006;
    連結:
  44. (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects
    連結:
  45. with Type 2 Diabetes, The Journal of Clinical Endocrinology & Metabolism 88(7):3082–
    連結:
  46. [44] Sonaje K, Lin KJ, Wey SP, Lin CK, Yeh TH, Nguyen HN, Biodistribution,
    連結:
  47. pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: Oral
    連結:
  48. [45] A.J. Varmaa, S.V. Deshpande, J.F. Kennedy, Metal complexation by chitosan and its
    連結:
  49. derivatives: a review, Carbohydrate Polymers 55 (2004) 77–93.  
    連結:
  50. dried chitosan/poly(g-glutamic acid) nanoparticles for oral insulin delivery, Biomaterials
    連結:
  51. 31 (2010) 3384–3394.
    連結:
  52. model of Type 2 diabetes mellitus: A glance, India Journal of pharmacology, 36 (2004)
    連結:
  53. info.php, 2010.
    連結:
  54. References
  55. [2] J.A. Fix, Oral controlled release technology for peptides: status and future prospects,
  56. [3] Carino GP, Mathiowitz E. Oral insulin delivery. Adv Drug Deliv Rev 1999;35(2–3):249–
  57. 57.
  58. 2003;20(11):886–98.
  59. [6] Khafagy ES, Morishita M, Onuki Y, Takayama K. Current challenges in noninvasive
  60. insulin delivery systems: a comparative review. Adv Drug Deliv Rev 2007;59(15):1521–
  61. 46.
  62. [7] Lin YH, Sonaje K, Lin KM, Juang JH, Mi FL, Yang HW, et al. Multi-ion-crosslinked
  63. [8] Sonaje K, Lin YH, Juang JH, Wey SP, Chen CT, Sung HW. In vivo evaluation of safety
  64. 2009;30(12):2329–39.
  65. [10] Chen MC, Wong HS, Lin KJ, Chen HL, Wey SP, Sonaje K, et al. The characteristics,
  66. [11] Lin KJ, Liao CH, Hsiao IT, Yen TC, Chen TC, Jan YY, et al. Improved hepatocyte
  67. than volume shifting. Surgery 2009;145(2):202–11.  
  68. 40 
  69.  
  70. [12] Pan Y, Li Y, Zhao H, Zheng J, Xu H, Wei G, et al. Bioadhesive polysaccharide in protein
  71. delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in
  72. [13] Lin YH, Mi FL, Chen CT, Chang WC, Peng SF, Liang HF, et al. Preparation and
  73. [14] Lin YH, Chen CT, Liang HF, Kulkarni AR, Lee PW, Chen CH, et al. Novel nanoparticles
  74. for oral insulin delivery via the paracellular pathway. Nanotechnology
  75. 2007;18(10):105102.
  76. [17] Ma Z, Lim L-Y. Uptake of chitosan and associated insulin in Caco-2 cell monolayers: a
  77. comparison between chitosan molecules and chitosan nanoparticles. Pharm Res
  78. 2003;20(11):1812–9.
  79. [18] Damge C, Maincent P, Ubrich N. Oral delivery of insulin associated to polymeric
  80. nanoparticles in diabetic rats. J Control Release 2007;117(2):163–70.
  81. 2007;14(1):72–80.
  82. [20] Teply BA, Tong R, Jeong SY, Luther G, Sherifi I, Yim CH, et al. The use of charge-
  83. [22] Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles:
  84. formulation, process and storage considerations. Adv Drug Deliv Rev 2006;58(15):1688–
  85. 713.
  86. [23] Abdelwahed W, Degobert G, Fessi H. A pilot study of freeze drying of poly(- epsilon-
  87. caprolactone) nanocapsules stabilized by poly(vinyl alcohol): formulation and process
  88. optimization. Int J Pharm 2006;309(1–2):178–88.  
  89. 41 
  90.  
  91. [24] Liuquan C, Deanna S, Joanna S, David O, Kathleen LG, Xiaolin T, et al. Mechanism of
  92. protein stabilization by sugars during freeze-drying and storage: native structure
  93. preservation, specific interaction, and/or immobilization in a glassy matrix? J Pharm Sci
  94. 2005;94(7):1427–44.
  95. [26] Costantino HR, Langer R, Klibanov AM. Moisture-induced aggregation of lyophilized
  96. (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology
  97. 1989;96(3):736–49.
  98. epithelial tight junctions. Pharm Sci Tech Today 2000;3(10):346–58.
  99. [29] Ranaldi G, Marigliano I, Vespignani I, Perozzi G, Sambuy Y. The effect of chitosan and
  100. of drugs with Eudragit polymers. Drug Dev Ind Pharm 1997;23(11):1043–54.
  101. [31] Khan MZI, Prebeg Z, Kurjakovic N. A pH-dependent colon targeted oral drug delivery
  102. system using methacrylic acid copolymers: I. manipulation of drug release using
  103. Eudragit_ L100-55 and Eudragit_ S100 combinations. J Control Release 1999;58(2):215–
  104. 22.
  105. [32] Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of
  106. 41.
  107. [33] Jin CH, Chae SY, Son S, Kim TH, Um KA, et al. A new orally available glucagon-like
  108. peptide-1 receptor agonist, biotinylated exendin-4, displays improved hypoglycemic
  109. 267 (1992) 7402–7405.  
  110. 42 
  111.  
  112. on incretins, Rev. Diabet. Stud. 2 (2005) 61–69.
  113. Med. 24 (2007) 223–232.
  114. D. Kim, M. Aispoma, Y. Wang, A.D. Baron, Synthetic exendin-4 (exenatide)
  115. significantly reduces postprandial and fasting plasma glucose in subjects with type 2
  116. [38] BYETTA (exenatide) injection, prescribing information. http://www.byetta.com, 2009.
  117. [39] Amylin pharmaceuticals, Inc. Exenatide reversed phase HPLC method, 2009.
  118. [40] Bronislava R. Gedulin, Pamela A. Smith, Carolyn M. Jodka, Kim Chen,
  119. administration, International Journal of Pharmaceutics 356 (2008) 231–238.
  120. [41] Daniel J Drucker, Michael A Nauck, The incretin system: glucagon-like peptide-1
  121. 368: 1696–705.
  122. [42] Orville G., John B., Mark S., Eling Gaines, Sonja Heintz, Synthetic Exendin-4
  123. 3089.
  124. [43] R. Gentilella, C. Bianchi, A. Rossi and C. M. Rotella, Exenatide: a review from
  125. pharmacology to clinical practice, Diabetes, Obesity and Metabolism, 11, 2009, 544–556.
  126. delivery using pH-Responsive nanoparticles vs. subcutaneous injection, Biomaterials xxx
  127. (2010) 1-10.
  128. 43 
  129.  
  130. [46] Sonaje K, Chen YC, Chen HL, Nguyen HN, Enteric-coated capsules filled with freeze-
  131. [47] Srinivasan K., Viswanad B., Lydia Asrat, Kaul C.L., Ramarao P., Combination of high-
  132. fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and
  133. pharmacological screening, Pharmacological Research 52 (2005) 313–320.
  134. [48] Arulmozhi DK, Veeranjaneyulu A, Bodhankar SL, Neonatal streptozotocin-induced rat
  135. 217-221.
  136. [49] Phoenix Pharmaceutical Inc., Exendin-4 EIA, www.phoenixpeptide.com/catalog/product-
  137. [50] Mercodia Corp., Rat Insulin ELISA. www.mercodia.se/products/rat-mouse.html, 2010.