A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives

Saudi Pharmaceutical Journal

Volumn 24, Issue 4, 2016, Pages 413-428

  Muheem, Abdul ^a   Shakeel, Faiyaz ^b   Jahangir, Mohammad Asadullah ^c   Anwar, Mohammed ^a   Mallick, Neha ^a   Jain, Gaurav Kumar ^a   Warsi, Musarrat Husain ^a   Ahmad, Farhan Jalees ^a  

^a HAMDARD UNIVERSITY   (India)

^b KING SAUD UNIVERSITY   (Saudi Arabia)

^c Luqman College of Pharmacy   (India)

Author keywords

Enzyme inhibitor; Insulin; Peptides; Permeability; Peroral; Proteins

Indexed keywords

CALCITONIN; CELL PENETRATING PEPTIDE; CHITOSAN; CYCLOSPORIN A; ENKEPHALIN; ESTERASE; EXENDIN 4; GLUCAGON LIKE PEPTIDE 1 DERIVATIVE; GROWTH HORMONE; HEPARIN; INSULIN; LIPOSOME; MACROGOL; MICROSPHERE; NANOCAPSULE; NANOPARTICLE; OCTREOTIDE; PARATHYROID HORMONE; PENETRATION ENHANCING AGENT; PEPTIDE; POLYMER; POLYPEPTIDE; PRODRUG; PROTEIN; PROTEINASE; PROTEINASE INHIBITOR; SALCATONIN; TRIACYLGLYCEROL LIPASE; UNINDEXED DRUG; VACCINE;

CHEMICAL MODIFICATION; DERIVATIZATION; DRUG ABSORPTION; DRUG CAPSULE; DRUG DELIVERY SYSTEM; DRUG FORMULATION; DRUG TRANSPORT; ENDOCYTOSIS; ENZYME INHIBITION; HUMAN; INTESTINE EPITHELIUM; MACROMOLECULE; MUCOADHESION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; TABLET FORMULATION; TRANSCYTOSIS;

EID: 84903361132     PISSN: 13190164     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jsps.2014.06.004     Document Type: Review

References (131)

1. Agarwal, V., Khan, M.A., Current status of the oral delivery of insulin. Pharm. Tech. 25:10 (2001), 76–90.
2. Antunes, F., Andrade, F., Ferreira, D., Morck, N.H., Sarmento, B., Models to predict intestinal absorption of therapeutic peptides and proteins. Curr. Drug Metab. 14:1 (2013), 4–20.
3. Aoki, Y., Morishita, M., Asai, K., Akikusa, B., Hosoda, S., Takayama, K., Region dependent role of the mucous/glycocalyx layers in insulin permeation across rat small intestinal membrane. Pharm. Res. 22:11 (2005), 1854–1862.
4. Aungst, B.J., Intestinal permeation enhancers. J. Pharm. Sci. 89:4 (2000), 429–442.
5. Bai, S., Thummel, R., Godwin, A.R., Nagase, H., Itoh, Y., Li, L., et al. Matrix metalloproteinase expression and function during fin regeneration in zebrafish: analysis of MT1-MMP, MMP2 and TIMP2. Matrix Bio. 24:4 (2005), 247–260.
6. Bakhru, S.H., Furtado, S., Morello, A.P., Mathiowitz, E., Oral delivery of proteins by biodegradable nanoparticles. Adv. Drug Del. Rev. 65:6 (2013), 1–11.
7. Bastian, S.E.P., Walton, P.E., Ballard, F.J., Belford, D.A., Transport of IGF-I across epithelial cell monolayers. J. Endo. 162:3 (1999), 361–369.
8. Basu, A., Yang, K., Wang, M., Liu, S., Chintala, R., Palm, T., Structure-Function Engineering Of Interferon-Beta-1b For Improving Stability, Solubility, Potency, Immunogenicity, And Pharmacokinetic Properties By Site-Selective Mono-Pegylation. Bioconjugate Chem. 17:3 (2006), 618–630.
9. Bernkop-Schnurch, A., Thiomers: a new generation of mucoadhesive polymers. Adv. Drug Del. Rev. 57:11 (2005), 1569–1582.
10. Bernkop-Schnurch, A., Paikl, C., Valenta, C., Novel bioadhesive chitosan-EDTA conjugate protects leucine enkephalin from degradation by aminopeptidase N. Pharm. Res. 14:7 (1997), 917–922.
11. Bernstein, G., Drug delivery in diabetes: oral-lyn needle-free buccal delivery of insulin. Drug Delivery Ltd., 2006, 15–18.
12. Blanchette, J., Kavimandan, N., Peppas, N.A., Principles of transmucosal delivery of therapeutic agents. Biomed. Pharmacol. 58:3 (2004), 142–151.
13. Brayden, D.J., Mrsny, R.J., Oral peptide delivery: prioritizing the leading technologies. Ther. Delivery 2:12 (2011), 1567–1573.
14. Brayden, D.J., Jepson, M.A., Baird, A.W., Keynote review: intestinal Peyer's patch M cells and oral vaccine targeting. Drug Discovery Today 10:11 (2005), 1145–1157.
15. Calceti, P., Salmaso, S., Walker, G., Bernkop-Schnürch, A., Development and in vivo evaluation of an oral insulin-PEG delivery system. Eur. J. Pharm. Sci. 22:4 (2004), 315–323.
16. Camenisch, G., Alsenz, J., Waterbeemd, H.V., Folkers, G., Estimation of permeability by passive diffusion through caco-cell monolayers using the drugs’ lipophilicity and molecular weight. Eur. J. Pharm. Sci. 6:4 (1998), 317–324.
17. Carino, G.P., Jacob, J.S., Mathiowitz, E., Nanosphere based oral insulin delivery. J. Controlled Release 65:1–2 (2000), 261–269.
18. Carvalho, F.C., Bruschi, M.L., Evangelista, R.C., Gremia, M.P.D., Mucoadhesive drug delivery systems. Braz. J. Pharm. Sci. 46:1 (2010), 1–17.
19. Chan, J.M., Valencia, P.M., Zhang, L., Polymeric nanoparticles for drug delivery. Methods Mol. Bio. 624 (2010), 163–175.
20. Chung, H., Kim, J., Um, J.Y., Kwon, I.C., Jeong, S.Y., Self-Assembled ‘Nanocubicle’ As a Carrier for Peroral Insulin Delivery. Diabetologia 45:3 (2002), 448–451.
21. Cilek, A., Celebi, N., Tirnaksiz, F., Lecithin-based microemulsion of a peptide for oral administration: preparation, characterization, and physical stability of the formulation. Drug Del. 13:1 (2006), 19–24.
22. Clement, S., Still, J.G., Kosutic, G., McAllister, R.G., Oral Insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2. Diabetes Tech. Ther. 4:4 (2002), 459–466.
23. Constantinides, P.P., Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res. 12:11 (1995), 1561–1572.
24. Craik, J.D., Fairlie, D.P., Liras, S., Price, D., The future of peptide-based drugs. Chem. Bio. Drug Design. 81:1 (2013), 136–147.
25. Cronauer, M.V., Schulz, W.A., Burchardt, T., Anastasiadis, A.G., De la Taille, A., Ackermann, R., et al. The androgen receptor in hormone-refractory prostate cancer: relevance of different mechanisms of androgen receptor signalling. Int. J. Onco. 23:4 (2003), 1095–1102.
26. Damge, C., Michael, C., Aprahamian, M., Couvreur, P., New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as oral carrier. Diabetes 37:2 (1988), 247–251.
27. De Coupade, C., Fittipaldi, A., Chagnas, V., Michel, M., Carlier, S., Tasciotti, E., et al. Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules. Biochem. J. 390:2 (2005), 407–418.
28. Degim, Z., Unal, N., Eşsiz, D., Abbasoglu, U., The effect of various liposome formulations on insulin penetration across Caco-2 cell monolayer. Life Sci. 75:23 (2004), 2819–2827.
29. Derossi, D., Calvet, S., Trembleau, A., Brunissen, A., Chassaing, G., Prochiantz, A., Cell internalization of the third helix of the Antennapediahomeodomain is receptor-independent. J. Bio. Chem. 271:1 (1996), 18188–18193.
30. Dollo, G., LeCorre, P., Guérin, A., Chevanne, F., Burgot, J.L., Leverge, R., Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs. Eur. J Pharm. Sci. 19:4 (2003), 273–280.
31. Donovan, M.D., Flynn, G.L., Amidon, G.L., Absorption of polyethylene glycols 600 through 2000: the molecular weight dependence of gastrointestinal and nasal absorption. Pharm. Res. 8 (1990), 863–868.
32. Egelund, R., Rodenburg, K., Andreasen, P., Rasmussen, M., Guldberg, R., Petersen, T., An ester bond linking a fragment of a serine proteinase to its serpin inhibitor. Biochemistry 37:18 (1998), 6375–6379.
33. El-Sayed, K., Morishita, M., Onuki, Y., Takayama, K., Current challenges in non-invasive insulin delivery systems: a comparative review. Adv. Drug Delivery Rev. 59:15 (2007), 1521–1546.
34. Elsayed, A., Remawi, M.A., Qinna, N., Farouk, A., Badwan, A., Formulation and characterization of an oily-based system for oral delivery of insulin. Eur. J. Pharm. Biopharm. 73:2 (2009), 269–279.
35. Fasano, A., Uzzau, S., Modulation Of intestinal tight junctions zona occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J. Clin. Invest. 99:6 (1997), 1158–1164.
36. Foss, A.C., Goto, T., Morishita, M., Peppas, N.A., Development of acrylic-based copolymers for oral insulin delivery. Eur. J. Pharm. Biopharm. 57:10 (2004), 163–169.
37. Frost, S., Merrion pharmaceuticals (2008). http://www.merrionpharma.com/archive/FandS-MP-051108.pdf (Accessed on 8 January 2013.
38. Gamboa, J.M., Leong, K.W., In vitro and in vivo models for the study of oral delivery of nanoparticles. Adv. Drug Delivery Rev. 65:6 (2013), 800–810.
39. Goldberg, M., Gomez-Orellana, I., Challenge for the oral delivery of macromolecules. Nat. Rev. Drug Dis. 2:4 (2003), 289–295.
40. Grosz, A., Heintz, A., Mlynek, G.M., Calvo, L.J., Robinson, J.R., Carrier-enhanced human growth hormone absorption across isolated rabbit intestinal tissue. Int. J. Pharm. 197:1 (2000), 113–121.
41. Gupta, S., Jain, A., Chakraborty, M., Sahni, J.K., Ali, J., Dang, S., Oral delivery of therapeutic proteins and peptides: a review on recent developments. Drug Delivery 20:6 (2013), 237–246.
42. Hamman, J.H., Enslin, G.M., Kotze, A.F., Oral delivery of peptide drugs. BioDrugs 19:3 (2005), 165–177.
43. Hejazi, R., Amiji, M., Chitosan-based gastrointestinal delivery system. J. Controlled Release 89:2 (2003), 151–165.
44. Hess, S., Rotshild, V., Hoffman, A., Investigation Of the enhancing mechanism of sodium N-[8-(2-hydroxybenzoyl)amino)caprylate effect on the intestinal permeability of polar molecules utilizing a voltage clamp method. Eur. J. Pharm. Sci. 25:2–3 (2005), 307–312.
45. Holt, D.W., Mueller, E.A., Kovarik, J.M., Van Bree, J.B., Richard, F., Kutz, K., Sandimmune nerol pharmacokinetics: impact of new oral formulation. Trans. Proc. 27:1 (1995), 1434–1447.
46. Hsieh, P.W., Hung, C.F., Fang, J.Y., Current prodrug design for drug discovery. Curr. Pharm. Design 15:19 (2009), 2236–2250.
47. Source AutoImmune Inc., additional information related data available on http://www.autoimmuneinc.com.
48. Iyer, H., Anand, K., Verma, M., Oral insulin – a review of current status, diabetes. Obes. Met. 12:3 (2010), 179–185.
49. Jana, S., Mandlekar, S., Marathe, P., Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists. Curr. Med. Chem. 17:32 (2010), 3874–3908.
50. Judge, R.A., Forsythe, E.L., Pusey, M.L., The effect of protein impurities on lysozyme crystal growth. Biotech. Bioeng. 59:6 (1998), 776–785.
51. Kafka, A.P., McLeod, B.J., Radesa, T., McDowell, A., Release and bioactivity of PACA nanoparticles containing D-Lys6-GnRH for brushtail possum fertility control. J. Controlled Release 149:3 (2011), 307–313.
52. Karsdal, M.A., Henriksen, K., Bay-Jensen, A.C., Molloy, B., Arnold, M., John, M.R., Lessons learned from the development of oral calcitonin: the first tablet formulation of a protein in phase III clinical trials. J. Clin. Pharmacol. 51:4 (2011), 460–471.
53. Khan, N.M.G., New development in insulin delivery. Drug Dev. Ind. Pharm. 29:3 (2003), 253–265.
54. Kidron, M., Dinh, S., Menachem, Y., Abbas, R., Variano, B., Goldberg, M., et al. A novel per-oral insulin formulation: proof of concept study in non-diabetic subjects. Diabetes Med. 21:4 (2004), 354–357.
55. Kipnes, M., Dandona, P., Tripathy, D., Still, J.G., Kosutic, G., Control of postprandial plasma glucose by an oral insulin product (HIM2) in patients with type 2 diabetes. Diabetes Care 26:2 (2003), 421–426.
56. Kumar, P., 2009. A Five Period, Open Label, Placebo Controlled Study to evaluate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of a Single Ascending Dose of IN-105 under Fed Conditions in T2DM subjects. CTRI/2009/091/000479.
57. Langer, R., Drug delivery and targeting. Nature 392:6679 suppl. (1998), 5–10.
58. Leader, B., Baca, Q.J., Golan, D.E., Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Dis. 7:1 (2008), 21–39.
59. Lecluyse, E.L., Sutton, S.C., In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement. Adv. Drug Delivery Rev. 23:1–3 (1997), 163–183.
60. Lee, S.J., Lee, D.Y., Lee, S.K., Kim, Y., Lee, Y., Byun, Y., A new drug carrier, N α -deoxycholyl-l-lysyl-methylester, for enhancing insulin absorption in the intestine. Diabetes 48:3 (2005), 405–411.
61. Leitner, V.M., Walker, G.F., Bernkop-Schnurch, A., Thiolated polymers: evidence for the formation of disulphide bonds with mucus glycoproteins. Eur. J Pharm. Biopharm. 56:2 (2003), 207–214.
62. Leone-Bay, A., Sato, M., Paton, D., Hunt, A.H., Sarubbi, D., Carozza, M., et al. Oral delivery of biologically active parathyroid hormone. Pharm. Res. 18:7 (2001), 964–970.
63. Leroux, J.C., Cozens, R., Roesel, J.L., Galli, B., Doelker, E., Gurny, R., PH-Sensitive nanoparticles an effective means to improve the oral delivery of HIV-1 protease inhibitors in dogs. Pharm. Res. 13:3 (1996), 485–487.
64. Lim, C.J., Shen, W.C., Comparison of monomeric and oligomeric transferrin as potential carrier in oral delivery of protein drugs. J. Controlled Release 106:3 (2005), 273–286.
65. Lowman, A.M., Peppas, N.A., Analysis of complexation/decomplexation phenomena in graft copolymer networks. Macromolecules 30:10 (1997), 4959–4965.
66. Lueben, H.L., De Leeuw, B.J., Perard, D., Lehr, C.M., De Boer, A.G., Verhoef, J.C., et al. Mucoadhesive polymers in peroral peptide drug delivery: I, influence of mucoadhesive excipients on the proteolytic activity of intestinal enzymes. Eur. J. Pharm. Sci. 4:2 (1996), 117–128.
67. Mahato, R.I., Narang, A.S., Thoma, L., Miller, D.D., Emerging trends in oral delivery of peptide and proteins. Crit. Rev. Ther. Drug Carr. Sys. 20:2–3 (2003), 153–214.
68. Maher, S., Leonard, T.W., Jacobsen, J., Brayden, D.J., Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv. Drug Delivery Rev. 61 (2009), 1427–1449.
69. Makhlof, A., Werle, M., Tozuka, Y., Takeuchi, H., A mucoadhesive nanoparticulate system for the simultaneous delivery of macromolecules and permeation enhancers to the intestinal mucosa. J. Controlled Release 149:1 (2010), 81–88.
70. Margolin, A.L., Novel crystalline catalysts. Tibtech 14:2 (1996), 223–230.
71. Marschutz, M.K., Bernkop-Schnurch, A., Oral peptide drug delivery: polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro. Biomaterials 21:14 (2000), 1499–1507.
72. Mathiowitz, E., Jacob, J.S., Jong, Y.S., Carino, G.P., Chickering, D.E., Chaturvedi, P., Biologically erodible microspheres as potential oral drug delivery systems. Nature 386:6623 (1997), 410–414.
73. Mizuma, T., Ohta, K., Koyanagi, A., Awazu, S., Improvement of intestinal absorption of leucine enkephalin by sugar coupling and peptidase inhibitors. J. Pharm. Sci. 85:8 (1996), 854–857.
74. Morishita, M., Peppas, N.A., Is the oral route possible for peptide and protein drug delivery?. Drug Discovery Today 11:19–20 (2006), 905–910.
75. Munyendo, W.L.L., Huixia, Lv., Benza-Ingoula, H., Baraza, L.D., Zhou, J., Cell penetrating peptides in the delivery of biopharmaceuticals. Biomolecules 2:2 (2012), 187–202.
76. Nakase, I., Takeuchi, T., Tanaka, G., Futaki, S., Methodological and cellular aspects that govern the internalization mechanisms of arginine-rich cell-penetrating peptides. Adv. Drug Delivery Rev. 60:4–5 (2008), 598–607.
77. Noriyasu, K., Nielsen, E.J.B., El-Sayed, K., Takeda-Morishita, M., Noninvasive insulin delivery: the great potential of cell-penetrating peptides. Ther. Delivery 4:3 (2013), 315–326.
78. Obata, Y., Sesumi, T., Takayama, K., Isowa, K., Grosh, S., Wick, S., et al. Evaluation of skin damage caused by percutaneous absorption enhancers using fractal analysis. J. Pharm. Sci. 89:4 (2000), 556–561.
79. Okada, J., Cohen, S., Langer, R., 1998. Oral delivery of vaccines using polymerized liposomes. In US patent 5762, 904.
80. Oppenheim, R.C., Stewart, N.F., Gordon, L., Patel, H.M., The production and evaluation of orally administered insulin nanoparticles. Drug Dev. Ind. Pharm. 8:4 (1982), 531–546.
81. Orive, G., Gascon, A., Hernandez, R., Dominiguez-Gil, A., Pedraz, J., Techniques: new approaches to the delivery of biopharmaceuticals. Trends Pharmacol. Sci. 25:7 (2004), 382–387.
82. Pan, Y., Li, Y.J., Zhao, H.Y., Zheng, J.M., Xu, H., Wei, G., et al. Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int. J. Pharm. 249:1–2 (2002), 139–147.
83. Park, K., Kwon, I.C., Park, K., Oral protein delivery: current status and future prospect. React. Funct. Polym. 71:3 (2011), 280–287.
84. Peppas, N.A., Klier, J., Controlled release by using poly(methacrylic acid-g-ethylene glycol) hydrogels. J. Controlled Release 16:1–2 (1991), 203–214.
85. Peters, A., Incretin-based therapies: review of current clinical trial data. Am. J. Med. 123:3 suppl. (2010), S28–S37.
86. Petrus, A.K., Vorthermsf, A.R., Fairchild, T.J., Doyle, R.P., Vitamin B12 as a carrier for the oral delivery of insulin. Chemmedchem 2:12 (2007), 1717–1721.
87. Ponchel, G., Irache, J.M., Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv. Drug Delivery Rev. 34:23 (1998), 191–219.
88. Prego, C., Garcia, M., Torres, D., Alonso, M.J., Transmucosal Macromolecular Drug Delivery. J. Controlled Release 101:1–3 (2005), 151–162.
89. Rekha, M.R., Sharma, C.P., Oral delivery of therapeutic protein/peptide for diabetes – Future Perspectives. Int. J. Pharm. 440:1 (2013), 48–62.
90. Renukuntla, J., Vadlapudi, A.D., Patel, A., Boddu, S.H.S., Mitra, A.K., Approaches for enhancing oral bioavailability of peptides and proteins. Int. J. Pharm. 447:1–2 (2013), 75–93.
91. Rieux, D., Ragnarsson, E.G., Gullberg, E., Préat, V., Schneider, Y.J., Artursson, P., Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium. Eur. J. Pharm. Sci. 25:4–5 (2005), 455–465.
92. Rubinstein, A., Approaches and opportunities in colon specific drug delivery. Crit. Rev. Ther. Drug Car. Sys. 12 (1995), 101–149.
93. Russell-Jones, G.J., Use of targeting agents to increase uptake and localization of drugs to the intestinal epithelium. J. Drug Target. 12:2 (2004), 113–123.
94. Sachdeva, A., Gulati, R., Gupta, U., Bapna, J.S., Comparative bioavailability of two brands of cyclosporine. Ind. J. Pharmacol. 29:2 (1997), 135–137.
95. Sadeghi, M., Avadi, M.R., Ejtemaimehr, S., Abashzadeh, S., Partoazar, A., Dorkoosh, F., et al. Development of a gas empowered drug delivery system for peptide delivery in the small intestine. J. Controlled Release 134:1 (2009), 11–17.
96. Sakuma, S., Hayashi, M., Akashi, M., Design of nanoparticles composed of graft copolymers for oral peptide delivery. Adv. Drug Delivery Rev. 47:1 (2001), 21–37.
97. Salama, N.N., Eddington, N.D., Fasano, A., Tight junction modulation and its relationship to drug delivery. Adv. Drug Delivery Rev. 58:2 (2006), 15–28.
98. Salama, P., Mamluk, R., Marom, K., Weinstein, I., Tzabari, M., 2010. Pharmaceutical Combinations And Related Methods Of Delivery. (LandoAndAnastasi), USP Application 01056275A1.
99. Salamat-Miller, N., Chittchang, M., Johnston, T.P., The use of mucoadhesive polymers in buccal drug delivery. Adv. Drug Delivery Rev. 57:11 (2005), 1666–1691.
100. Sang, H.Y., Park, T.G., Biodegradable nanoparticles containing protein, fatty acid complexes for oral delivery of salmon calcitonin. J. Pharm. Sci. 93:2 (2004), 488–495.
101. Schwartz, S., Geho, B., Rosenberg, L., Lau, J., A 2-week randomized, active comparator study of two HDV-Insulin routes (SC and oral) and SC human insulin in patients with type 1 diabetes mellitus. Diabetes, 57(1 suppl.), 2008, A124.
102. Senel, S., Kremer, M.J., Kas, S., Wertz, P.W., Hincal, A.A., Squier, C.A., Enhancing effect of chitosan on peptide drug delivery across buccal mucosa. Biomaterials 21:20 (2000), 2067–2071.
103. Shah, R.B., Ahsan, F., Khan, M.A., Oral delivery of proteins: progress and prognostication. Crit. Rev. Ther. Drug Car. Sys. 19:2 (2002), 135–169.
104. Shaji, J., Patole, V., Protein and peptide drug delivery: oral approaches. Ind. J Pharm. Sci. 70:3 (2008), 269–277.
105. Shakweh, M., Besnard, M., Nicolas, V., Fattal, E., Poly (lactide-co-glycolide) particles of different physicochemical properties and their uptake by peyer's patches in mice. Eur. J. Pharm. Biopharm. 61:1–2 (2005), 1–13.
106. Shen, W.C., Oral peptide and protein delivery: unfulfilled promises?. Drug Discovery Today 8:14 (2003), 607–608.
107. Sizer, P.J.H., Towards an oral influenza vaccine. Trends Biotech. 15:8 (1997), 282–285.
108. Skyler, J.S., Krischer, J.P., Wolfsdorf, J., Cowie, C., Palmer, J.P., Greenbaum, C., et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial-type 1. Diabetes Care 28:5 (2005), 1068–1076.
109. Sood, A., Panchagnula, R., Peroral route: an opportunity for protein and peptide drug delivery. Chem. Rev. 101:11 (2001), 3275–3303.
110. Source Apollo life sciences, Apollo life science press release (2010) on additional clinical data from http://www.apollolifesciences.com.
111. Source Chiasma Pharma, Chiasma press release (2011) on additional clinical data from phase III oral TPE available from URL: http://www.chiasmapharma.com/page.asp?id=20.
112. Source Emisphere Technologies, Inc. Emisphere's press release (October 6, 2006) on additional clinical data from phase 2 oral insulin trial. Available from URL: http://www.emisphere.com.
113. Source FDA. Gov, (November 2003), on additional clinical data from oral cyclosporine trial (Novartis). Available from URL: http://www.accessdata.fda.gov/scripts/cderfob/docsltempai.cfm.
114. Source Generex biotechnology corporation, Press release (2009) on additional clinical data from http://www.generex.com.
115. Source Tarsa Therapeutics, http://www.tarsatherapeutics.com/News/091811.Html (Accessed November 10th, 2013).
116. Strous, G.J., Dekker, J., Mucin-type glycoproteins. Crit. Rev. Biochem. Mol. Bio. 27:1–2 (1992), 57–92.
117. Takka, S., Acarturk, F., Calcium alginate microparticles for oral administration. I: effect of sodium alginate type on drug release and drug entrapment efficiency. J. Microencap. 16:3 (1999), 275–290.
118. Toorisaka, E., Ono, H., Arimori, K., Kamiya, N., Goto, M., Hypoglycemic effect of surfactant-coated insulin solubilized in a novel solid-in-oil-in-water (S/O/W) emulsion. Int. J. Pharm. 252:1–2 (2003), 271–274.
119. Tozaki, H., Emi, Y., Horisaka, E., Fujita, T., Yamamoto, A., Muranishi, S., Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: implications in peptide delivery to the colon”. J. Pharm. Pharmacol. 49:2 (1997), 164–168.
120. Vadlapudi, A.D., Vadlapatla, R.K., Kwatra, D., Earla, R., Samanta, S.K., Pal, D., et al. Targeted lipid based drug conjugates: a novel strategy for drug delivery. Int. J. Pharm. 434:1–2 (2012), 315–324.
121. Van den, M.G., Kinget, R., Oral colon-specific drug delivery: a review. Drug Delivery 2 (1995), 81–93.
122. Varma, M.V.S., Ashokraj, Y., Dey, C.S., Panchagnula, R., P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol. Res. 48:4 (2003), 347–359.
123. Wajberg, E., Miyazaki, Y., Triplitt, C., Cersosimo, E., Defronzo, R.A., Dose-response effect of a single administration of oral hexyl-insulin monoconjugate 2 in healthy non-diabetic subjects. Diabetes Care 27:12 (2004), 2868–2874.
124. Walsh, E.G., Adamczyk, B.E., Chalasani, K.B., Maher, S., Toole, E.B.O., Fox, J.S., Oral Delivery of Macromolecules: Rationale Underpinning Gastrointestinal Permeation Enhancement Technology (GIPET1). Ther. Delivery 2:12 (2011), 1595–1610.
125. Werle, V., Brigitta, L., Daniel, E., Florian, F., Design and evaluation of chitosan-aprotinin conjugate for the peroral delivery of therapeutic peptides and protein susceptible to enzymatic degradation. J. Drug Target., 15(5), 2007 327-323.
126. Whitelaw, C. D., Kelly, C. A., Ironmonger, W., Cunliffe, C., New, R., Phillips, J. N., 2005. Absorption Of Orally Ingested Insulin In Human Type 1 Diabetic Subjects: Proof Of Concept Study. San Diego: American Diabetes Ass. 65th Scientific Sessions.
127. Wu, S.J., Robinson, J.R., Transport of human growth hormone across Caco-2 cells with novel delivery agents: evidence for P-glycoprotein involvement. J. Controlled Release 62:1–2 (1999), 171–177.
128. Yamamoto, T.T., Rikyuu, K., Tsuji, T., Fujita, T., Murakami, M., Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. Pharm. Res. 11:10 (1994), 1496–1500.
129. Yoshida, H., Lehr, C.M., Kok, W., Junginger, H.E., Verhoef, J.C., Bouwistra, J.A., Niosomes for oral delivery of peptide drugs. J. Controlled Release 21:1–3 (1992), 145–153.
130. Zheng, J., Yue, X., Dai, Z., Wang, Y., Liu, S., Yan, X., Novel iron polysaccharide multilayered microcapsules for controlled insulin release. Actabiomaterialia 5:5 (2009), 1499–1507.
131. Zorko, M., Langel, U., Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv. Drug Delivery Rev. 57:4 (2005), 529–545.