Annals of Biomedical Engineering

, Volume 44, Issue 6, pp 1993–2007 | Cite as

Delivery of Exenatide and Insulin Using Mucoadhesive Intestinal Devices

  • Vivek Gupta
  • Byeong-Hee Hwang
  • Nishit Doshi
  • Amrita Banerjee
  • Aaron C. Anselmo
  • Samir Mitragotri
Emerging Trends in Biomaterials Research


A major disadvantage associated with current diabetes therapy is dependence on injectables for long-term disease management. In addition to insulin, incretin hormone replacement therapies including exenatide have added a new class of drugs for Type-2 diabetes. Although efficacious, patient compliance with current diabetic therapy is poor due to requirement of injections, inability to cross the intestinal epithelium and instability in the gastrointestinal tract. Here, we report the efficacy of a mucoadhesive device in providing therapeutic concentrations of insulin and exenatide via oral administration. Devices were prepared with a blend of FDA-approved polymers, carbopol, pectin and sodium carboxymethylcellulose, and were tested for drug carrying capability, in vitro release, Caco-2 permeability, and in vivo efficacy for insulin and exenatide. Results suggested that mucoadhesive devices successfully provided controlled release of FITC-insulin, released significant amounts of drug, while providing noteworthy enhancement of drug transport across Caco-2 monolayers without compromising monolayer integrity. In-vivo administration of the devices provided significant enhancement of drug absorption with 13- and 80-fold enhancement of relative bioavailability for insulin and exenatide compared to intestinal injections with significant increase in half-lives, thus resulting in prolonged blood glucose reduction. This study validates the efficacy of mucoadhesive devices in promoting oral peptide delivery to improve patient compliance and dose adherence.


Type-2 diabetes Oral delivery Peptides Absorption enhancement Exenatide Insulin 



This research was funded by Otis Williams Fellowship from Santa Barbara Foundation (VG) and Enlight Biosciences. SM is a scientific advisor and shareholder of Entrega Inc.


  1. 1.
    Ahn, S., I. H. Lee, E. Lee, H. Kim, Y. C. Kim, and S. Jon. Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan. J. Control Release 170:226–232, 2013.CrossRefPubMedGoogle Scholar
  2. 2.
    Al-Tabakha, M. M. Future prospect of insulin inhalation for diabetic patients: the case of Afrezza versus Exubera. J. Control Release 215:25–38, 2015.CrossRefPubMedGoogle Scholar
  3. 3.
    American Diabetes Association. Standards of medical care in diabetes-2011. Diab. Care 34: S11–S61, 2011.Google Scholar
  4. 4.
    Cahn, A., R. Miccoli, A. Dardano, and S. Del Prato. New forms of insulin and insulin therapies for the treatment of type 2 diabetes. Lancet Diabetes Endocrinol. 3:638–652, 2015.CrossRefPubMedGoogle Scholar
  5. 5.
    Camenisch, G., J. Alsenz, H. van de Waterbeemd, and G. Folkers. Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs’ lipophilicity and molecular weight. Eur. J. Pharm. Sci. 6:317–324, 1998.PubMedGoogle Scholar
  6. 6.
    Caramella, C. M., G. Sandri, S. Rossi, M. Mori, M. Cristina Bonferoni, F. Ferrari, C. Del Fante, and C. Perotti. New therapeutic platforms for the treatment of epithelial and cutaneous lesions. Curr. Drug Deliv. 10:18–31, 2013.CrossRefPubMedGoogle Scholar
  7. 7.
    Castro, P. M., P. Fonte, F. Sousa, A. R. Madureira, B. Sarmento, and M. E. Pintado. Oral films as breakthrough tools for oral delivery of proteins/peptides. J. Control Release 211:63–73, 2015.CrossRefPubMedGoogle Scholar
  8. 8.
    Cemeroglu, A. P., A. Can, A. T. Davis, O. Cemeroglu, L. Kleis, M. S. Daniel, J. Bustraan, and T. J. Koehler. Fear of needles in children with type 1 diabetes mellitus on multiple daily injections and continuous subcutaneous insulin infusion. Endocr. Pract. 21:46–53, 2015.CrossRefPubMedGoogle Scholar
  9. 9.
    Cervera, A., E. Wajcberg, A. Sriwijitkamol, M. Fernandez, P. Zuo, C. Triplitt, N. Musi, R. A. DeFronzo, and E. Cersosimo. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 294:E846–E852, 2008.CrossRefPubMedGoogle Scholar
  10. 10.
    Chaturvedi, K., K. Ganguly, A. R. Kulkarni, W. E. Rudzinski, L. Krauss, M. N. Nadagouda, and T. M. Aminabhavi. Oral insulin delivery using deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles. Nanomedicine (Lond) 10:1569–1583, 2015.CrossRefGoogle Scholar
  11. 11.
    Chuang, E. Y., K. J. Lin, P. Y. Lin, H. L. Chen, S. P. Wey, F. L. Mi, H. C. Hsiao, C. T. Chen, and H. W. Sung. Self-assembling bubble carriers for oral protein delivery. Biomaterials 64:115–124, 2015.CrossRefPubMedGoogle Scholar
  12. 12.
    Chuang, E. Y., G. T. Nguyen, F. Y. Su, K. J. Lin, C. T. Chen, F. L. Mi, T. C. Yen, J. H. Juang, and H. W. Sung. Combination therapy via oral co-administration of insulin- and exendin-4-loaded nanoparticles to treat type 2 diabetic rats undergoing OGTT. Biomaterials 34:7994–8001, 2013.CrossRefPubMedGoogle Scholar
  13. 13.
    Fonte, P., F. Araujo, C. Silva, C. Pereira, S. Reis, H. A. Santos, and B. Sarmento. Polymer-based nanoparticles for oral insulin delivery: revisited approaches. Biotechnol. Adv. 33:1342–1354, 2015.CrossRefPubMedGoogle Scholar
  14. 14.
    Garcia-Perez, L. E., M. Alvarez, T. Dilla, V. Gil-Guillen, and D. Orozco-Beltran. Adherence to therapies in patients with type 2 diabetes. Diabetes Ther. 4:175–194, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gordon Still, J. Development of oral insulin: progress and current status. Diabetes Metab. Res. Rev. 18(Suppl 1):S29–S37, 2002.CrossRefPubMedGoogle Scholar
  16. 16.
    Govindasamy, P., B. R. Kesavan, and J. K. Narasimha. Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa. Asian Pac. J. Trop. Biomed. 3:995–1002, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Grover, M., and P. Utreja. Recent advances in drug delivery systems for anti-diabetic drugs: a review. Curr. Drug Deliv. 11:444–457, 2014.CrossRefPubMedGoogle Scholar
  18. 18.
    Gupta, V., N. Doshi, and S. Mitragotri. Permeation of insulin, calcitonin and exenatide across Caco-2 monolayers: measurement using a rapid, 3-day system. PLoS One 8:e57136, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gupta, V., B. H. Hwang, N. Doshi, and S. Mitragotri. A permeation enhancer for increasing transport of therapeutic macromolecules across the intestine. J. Control Release 172:541–549, 2013.CrossRefPubMedGoogle Scholar
  20. 20.
    Gupta, V., B. H. Hwang, J. Lee, A. C. Anselmo, N. Doshi, and S. Mitragotri. Mucoadhesive intestinal devices for oral delivery of salmon calcitonin. J Control Release 172:753–762, 2013.CrossRefPubMedGoogle Scholar
  21. 21.
    He, H., P. Wang, C. Cai, R. Yang, and X. Tang. VB-coated Gel-Core-SLN containing insulin: another way to improve oral absorption. Int. J. Pharm. 493:451–459, 2015.CrossRefPubMedGoogle Scholar
  22. 22.
    Heppner, K. M., and D. Perez-Tilve. GLP-1 based therapeutics: simultaneously combating T2DM and obesity. Front. Neurosci. 9:92, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hubatsch, I., E. G. Ragnarsson, and P. Artursson. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc. 2:2111–2119, 2007.CrossRefPubMedGoogle Scholar
  24. 24.
    Jimmy, B., J. Jose, Z. A. Al-Hinai, I. K. Wadair, and G. H. Al-Amri. Adherence to medications among Type 2 diabetes mellitus patients in three districts of Al Dakhliyah Governorate, Oman: A cross-sectional pilot study. Sultan Qaboos Univ. Med. J. 14:e231–e235, 2014.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Kahn, S. E. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46:3–19, 2003.CrossRefPubMedGoogle Scholar
  26. 26.
    Karamanidou, T., K. Karidi, V. Bourganis, K. Kontonikola, O. Kammona, and C. Kiparissides. Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems. Eur. J. Pharm. Biopharm. 97:223–229, 2015.CrossRefPubMedGoogle Scholar
  27. 27.
    Khafagy el, S., M. Morishita, Y. Onuki, and K. Takayama. Current challenges in non-invasive insulin delivery systems: a comparative review. Adv. Drug Deliv. Rev. 59:1521–1546, 2007.CrossRefGoogle Scholar
  28. 28.
    Lopes, M., S. Simoes, F. Veiga, R. Seica, and A. Ribeiro. Why most oral insulin formulations do not reach clinical trials. Ther. Deliv. 6:1–15, 2015.CrossRefGoogle Scholar
  29. 29.
    Mansourpour, M., R. Mahjub, M. Amini, S. N. Ostad, E. S. Shamsa, M. Rafiee-Tehrani, and F. A. Dorkoosh. Development of acid-resistant alginate/trimethyl chitosan nanoparticles containing cationic beta-cyclodextrin polymers for insulin oral delivery. AAPS PharmSciTech 16:952–962, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mazzarino, L., R. Borsali, and E. Lemos-Senna. Mucoadhesive films containing chitosan-coated nanoparticles: a new strategy for buccal curcumin release. J. Pharm. Sci. 103:3764–3771, 2014.CrossRefPubMedGoogle Scholar
  31. 31.
    Morishita, M., and N. A. Peppas. Is the oral route possible for peptide and protein drug delivery? Drug Discov. Today 11:905–910, 2006.CrossRefPubMedGoogle Scholar
  32. 32.
    Nielsen, E. J., S. Yoshida, N. Kamei, R. Iwamae, S. Khafagy el, J. Olsen, U. L. Rahbek, B. L. Pedersen, K. Takayama, and M. Takeda-Morishita. In vivo proof of concept of oral insulin delivery based on a co-administration strategy with the cell-penetrating peptide penetratin. J. Control Release 189:19–24, 2014.CrossRefPubMedGoogle Scholar
  33. 33.
    Peh, K. K., and C. F. Wong. Polymeric films as vehicle for buccal delivery: swelling, mechanical, and bioadhesive properties. J. Pharm. Pharm. Sci. 2:53–61, 1999.PubMedGoogle Scholar
  34. 34.
    Ponchel, G., and J. Irache. Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv. Drug Deliv. Rev. 34:191–219, 1998.CrossRefPubMedGoogle Scholar
  35. 35.
    Prausnitz, M. R., and R. Langer. Transdermal drug delivery. Nat. Biotechnol. 26:1261–1268, 2008.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Rekha, M. R., and C. P. Sharma. Oral delivery of therapeutic protein/peptide for diabetes–future perspectives. Int. J. Pharm. 440:48–62, 2013.CrossRefPubMedGoogle Scholar
  37. 37.
    Remunan-Lopez, C., A. Portero, J. L. Vila-Jato, and M. J. Alonso. Design and evaluation of chitosan/ethylcellulose mucoadhesive bilayered devices for buccal drug delivery. J. Control Release 55:143–152, 1998.CrossRefPubMedGoogle Scholar
  38. 38.
    Sheng, J., L. Han, J. Qin, G. Ru, R. Li, L. Wu, D. Cui, P. Yang, Y. He, and J. Wang. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. ACS Appl. Mater. Interfaces 7:15430–15441, 2015.CrossRefPubMedGoogle Scholar
  39. 39.
    Sicras-Mainar, A., R. Navarro, L. Ruiz, and R. Morano. Adherence and persistence in patients initiating treatment with injectable therapies for Type 2 diabetes mellitus (T2 dm) in Spain. Value Health 18:A612, 2015.CrossRefPubMedGoogle Scholar
  40. 40.
    Smart, J. D. The basics and underlying mechanisms of mucoadhesion. Adv. Drug Deliv. Rev. 57:1556–1568, 2005.CrossRefPubMedGoogle Scholar
  41. 41.
    Sun, S., N. Liang, H. Yamamoto, Y. Kawashima, F. Cui, and P. Yan. pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin. Int. J. Nanomed. 10:3489–3498, 2015.CrossRefGoogle Scholar
  42. 42.
    Tang, C., Y. X. Guan, S. J. Yao, and Z. Q. Zhu. Preparation of ibuprofen-loaded chitosan films for oral mucosal drug delivery using supercritical solution impregnation. Int. J. Pharm. 473:434–441, 2014.CrossRefPubMedGoogle Scholar
  43. 43.
    Tanwani, L. K. Insulin therapy in the elderly patient with diabetes. Am. J. Geriatr. Pharmacother. 9:24–36, 2011.CrossRefPubMedGoogle Scholar
  44. 44.
    Tirnaksiz, F., and J. R. Robinson. Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F-127/polycarbophil mixed gel systems. Pharmazie 60:518–523, 2005.PubMedGoogle Scholar
  45. 45.
    Usansky J., A. Desai, and T.-L. D. PK functions for Microsoft Excel. 2003.Google Scholar
  46. 46.
    Whitehead, K., N. Karr, and S. Mitragotri. Discovery of synergistic permeation enhancers for oral drug delivery. J. Control Release 128:128–133, 2008.CrossRefPubMedGoogle Scholar
  47. 47.
    Whitehead, K., N. Karr, and S. Mitragotri. Safe and effective permeation enhancers for oral drug delivery. Pharm. Res. 25:1782–1788, 2008.CrossRefPubMedGoogle Scholar
  48. 48.
    Whitehead, K., Z. Shen, and S. Mitragotri. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J. Control Release 98:37–45, 2004.CrossRefPubMedGoogle Scholar
  49. 49.
    Wong, C. F., K. H. Yuen, and K. K. Peh. An in vitro method for buccal adhesion studies: importance of instrument variables. Int. J. Pharm. 180:47–57, 1999.CrossRefPubMedGoogle Scholar
  50. 50.
    Xu, Q., N. J. Boylan, S. Cai, B. Miao, H. Patel, and J. Hanes. Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus. J. Control Release 170:279–286, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Yim, L. Belonephobia—a fear of needles. Aust. Fam. Phys. 35:623–624, 2006.Google Scholar
  52. 52.
    Zhang, B., D. He, Y. Fan, N. Liu, and Y. Chen. Oral delivery of exenatide via microspheres prepared by cross-linking of alginate and hyaluronate. PLoS One 9:e86064, 2014.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Zhu S., S. Chen, Y. Gao, F. Guo, F. Li, B. Xie, J. Zhou and H. Zhong. Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec). Drug Deliv 1–12, 2015.Google Scholar

Copyright information

© Biomedical Engineering Society 2016

Authors and Affiliations

  • Vivek Gupta
    • 1
    • 2
  • Byeong-Hee Hwang
    • 1
  • Nishit Doshi
    • 1
  • Amrita Banerjee
    • 1
  • Aaron C. Anselmo
    • 1
  • Samir Mitragotri
    • 1
  1. 1.Department of Chemical EngineeringUniversity of CaliforniaSanta BarbaraUSA
  2. 2.School of PharmacyKeck Graduate InstituteClaremontUSA

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