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Delivery of Exenatide and Insulin Using Mucoadhesive Intestinal Devices

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Abstract

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.

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References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. American Diabetes Association. Standards of medical care in diabetes-2011. Diab. Care 34: S11–S61, 2011.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gordon Still, J. Development of oral insulin: progress and current status. Diabetes Metab. Res. Rev. 18(Suppl 1):S29–S37, 2002.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  22. Heppner, K. M., and D. Perez-Tilve. GLP-1 based therapeutics: simultaneously combating T2DM and obesity. Front. Neurosci. 9:92, 2015.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  35. Prausnitz, M. R., and R. Langer. Transdermal drug delivery. Nat. Biotechnol. 26:1261–1268, 2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  40. Smart, J. D. The basics and underlying mechanisms of mucoadhesion. Adv. Drug Deliv. Rev. 57:1556–1568, 2005.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  43. Tanwani, L. K. Insulin therapy in the elderly patient with diabetes. Am. J. Geriatr. Pharmacother. 9:24–36, 2011.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  45. Usansky J., A. Desai, and T.-L. D. PK functions for Microsoft Excel. 2003.

  46. Whitehead, K., N. Karr, and S. Mitragotri. Discovery of synergistic permeation enhancers for oral drug delivery. J. Control Release 128:128–133, 2008.

    Article  CAS  PubMed  Google Scholar 

  47. Whitehead, K., N. Karr, and S. Mitragotri. Safe and effective permeation enhancers for oral drug delivery. Pharm. Res. 25:1782–1788, 2008.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yim, L. Belonephobia—a fear of needles. Aust. Fam. Phys. 35:623–624, 2006.

    Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106, USA

    Vivek Gupta, Byeong-Hee Hwang, Nishit Doshi, Amrita Banerjee, Aaron C. Anselmo & Samir Mitragotri

  2. School of Pharmacy, Keck Graduate Institute, 535 Watson Dr., Claremont, CA, 91711, USA

    Vivek Gupta

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  1. Vivek Gupta
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  2. Byeong-Hee Hwang
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  3. Nishit Doshi
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  4. Amrita Banerjee
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Correspondence to Samir Mitragotri.

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Associate Editor Akhilesh K. Gaharwar oversaw the review of this article.

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Gupta, V., Hwang, BH., Doshi, N. et al. Delivery of Exenatide and Insulin Using Mucoadhesive Intestinal Devices. Ann Biomed Eng 44, 1993–2007 (2016). https://doi.org/10.1007/s10439-016-1558-x

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