While the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Despite the fact oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to make easier oral peptide delivery. As well, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonisation and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed.
Cite this article:
S.D. Mankar, Bhagyashri S. Jadhav, Awantika N. Kale. Basics and Recent Advances in Peptide and Protein Drug Delivery. Asian Journal of Pharmacy and Technology. 2023; 13(3):207-2. doi: 10.52711/2231-5713.2023.00037
S.D. Mankar, Bhagyashri S. Jadhav, Awantika N. Kale. Basics and Recent Advances in Peptide and Protein Drug Delivery. Asian Journal of Pharmacy and Technology. 2023; 13(3):207-2. doi: 10.52711/2231-5713.2023.00037 Available on: https://ajptonline.com/AbstractView.aspx?PID=2023-13-3-10
1. Nelson DL, Cox MM., Lehninger Principles of Biochemistry, 4th Ed., W.H. Freeman and Company, New York, 2005; 85-86.
2. Satyanarayan U, Chakrapani U, Biochemistry, 3rd Ed., Books and allied (p) Ltd., Kolkata, 2008; 43-44.
3. Bummer PM, Koppenol S, Chemical and physical considerations in protein and peptide stability; In: Protein Formulation and Delivery, Drugs and the Pharmaceutical Sciences, McNally EJ, Marcel Dekker, New York, 2000; 15-18.
4. Langer R, Folkman J, Sustained release of macromolecules from polymers, Poly. Del. Systems, Midland Macro. Monograph, 1978; 5: 175-196.
5. Bergh VD, Gregoriadis G, Water-in-sorbitan monostearate organogels (water-in-oil gels), J Pharm Sci., 1999; 88: 615-619.
6. Murdan S, Gregoriadis G, Florence AT, Sorbitan monostearate/polysorbate20 organogels containing neosomes: a delivery vehicle for antigens, Euro J of Pharm Sci, 1999; 8: 177-186.
7. Sawhney AS, Pathak CP, Hubell JA, Bioerodible hydrogels based on photopolymeerized poly(ethyleneglycol)-copoly(alphahydroxy acid) diacrylate macromers, Macromolecules, 1993; 26(4): 581-587.
8. West JL, Hubell JA, Localized intravascular protein delivery from photopolymerized hydrogels, Proc Int Symp Control Rel Bioact Mater, 1995; 22: 17-18.
9. Vyas S.P. and Khar K.R., Targeted and controlled drug delivery Novel carrier system, CBS publishers and distributors, New Delhi. 505,507,511,537.
10. Banga A.K. and Chein Y.W, Systemic delivery of therapeutic peptides and proteins, Int. J. Pharmaceutics, 1988; 48: 15‐50
11. Banerjee P. S. and Ritschel W. A., Int. J. Pharm. 1989; 49: 189‐197.
12. Chein Y. W., Lelawongs P., Siddiqui O., Sun. Y. and W. M. Shi. W. M; Faciliated trandermal delivery of therapeutic peptides/proteins by iontophoretic delivery devices. J. Control. Rel., 1990; 13: 263‐278.
13. Siddiqui O., Sun Y., Liu J. C. and Chein Y. W., Faciliated transdermal trnsport of insulin. J. Pharm. Sci., 1987; 76: 341‐ 345.
14. Sibalis D., Transdermal drug applicator. U. S. Patent, 1987; 4: 708-716.
15. Meyer B. R., Electro‐osmotic transdermal drug delivery, in: 1987 Conference Proceedings on the Latest Developments in Drug Delivery Systems, Aster Publishing, Eugene, Oregon, (1987), 40.
16. Meyer et al. Transdermal delivery of human insulin to albino rabbits using electrical current. Am. J. Med. Sci., 1989; 297: 321‐325.
17. Okabe K., Yamaguchi H. and Kawai Y., New iontophoretic transdermal administration of the beta blocker metaprolol. J. Control. Rel., 1986; 4: 79‐85.
18. Chein Y. W., Siddiqui O. and Liu J. C., Transdermal iontophoretic delivery of therapeutic peptides/proteins. I. Insulin. Ann. N. Y. Acad. Sci., 1988; 507: 32‐51.
19. Tahami. Alkhaled and Singh J., Recent patent on drug delivery and formulation, 2007; 1: 65‐71.
20. Vyas S.P. and Khar K.R., Targeted and controlled drug delivery, Novel carrier system, CBS publishers and distributors, New Delhi.561.
21. Chein Y.W., Novel drug delivery systems, volume 50, second edition, 715.
22. Pekar A. H. and Frank B. H., Conformation of proinsulin. A comparison of insulin and proinsulin self‐association at neutral pH. Biochemistry, 1972; 11: 4013‐4016.
23. Banga AK etal; Hydrogel-based iontotherapeutic delivery devices for transdermal delivery of peptides-protein drugs. Pharm Res 1993; 10: 697-702.
24. Lee Ycetal;. Effect of formulation on the systemic absorption of Insulin from enhancer free ocular devices. Int J Pharm 1999; 185: 199-204.
25. Burgess DJ etal; editors. Biotechnology and Pharmacy. New York: Chapman and Hall; 1993; 116-51. 27. Aurora Jetal; delivery of protein and peptide –challenges and opportunities. Business Briefing: Future dry discovery, 2006; 38-40.
26. John M.etal; Shanafelt. Enhancing exposure of protein therapeutics. Drug Discovery today: Technologies 2006; 3: 87-94.
27. Lin SY and Yang JC, Effect of _-cyclodextrin on the in vitro permeation rate an d in vivo rectal absorption of acetaminophen hydrogel preparations. Pharm. Acta Helv., 1990; 65: 262-268.
28. Arima H et al. Use of water soluble _-cyclodextrin derivatives as carriers of anti inflammatory drug bi phenylyl acetic acid in rectal delivery. Yakugaku Zasshi. 1992; 112: 65-72.
29. Brouard A et al. Rectal administration of carbamazepine gel. Clin. Pharm. 1990; 9: 13–14.
30. Levy R et al. Metabolism of Antiepileptic Drugs. Raven Press, New York. 1984; 61–71.
31. Graves NM et al. Relative bioavailability of rectally administered carbamazepine suspension in humans. Epilepsia., 1985; 26: 429–433.
32. Lambroso CT. Intermittent home treatment of status and clusters of seizures. Epilepsia., 1989; 30: S11–S14.
33. Moolenaar F et al. Biopharmaceutics of rectal administration of drugs in man. IX Comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int. J. Pharm. 1980; 5: 127–137.
34. Gail D et al. Current oral and non-oral routes of antiepileptic drug delivery. Advanced Drug Delivery Reviews. 2012; 64: 911-918.
35. Chen HY, Mollstedt O, Tsai MH, Kreider RB. Potential clinical applications of multi-functional milk proteins and peptides in cancer management. Curr Med Chem. 2014; 21(21): 2424- 2437.
36. Wangler C, Buchmann I, Eisenhut M, Haberkorn U, Mier W. Radiolabeled peptides and proteins in cancer therapy. Protein Pept Lett. 2007; 14(3): 273-239.
37. Rekha MR, Sharma Chandra P. Oral delivery of therapeutic protein/peptide for diabetes – Future perspectives. Intl. J Pharm. 2013; 440 (1): 48–62.
38. Wang G. Human antimicrobial peptides and proteins. Pharmaceuticals. 2014; 7(5): 545-594.
39. Bartlomiej D, Marta D. New milk protein-derived peptides with potential antimicrobial activity: An approach based on bioinformatic studies. Int. J. Mol. Sci. 2014; 15: 14531-14545.
40. Gokhale AS, Satyanarayanajois S. Peptides and peptidomimetics as immunomodulators. Immunotherapy. 2014; 6 (6): 755-774
41. Sarah CM, Olga MP, Hancock REW. Host defense peptides: front-line immunomodulators. Trends in Immunology. 2014; 35 (9): 443-450.
42. Kishore U. Neurodegerative disease (ed.) In: Role of protein aggregation in neurodegenerative diseases. Tutar Y, Ozgur A, Tutar L. Chap. 2013; 3 (2013): 55-76.
43. Gene L, Bidwell III, George EM. Maternally sequestered therapeutic polypeptides – a new approach for the management of preeclampsia. Frontiers in Pharmacology. 2014; 5(201):1-9.
44. Zhang XX, Eden HS, Chen X. Peptides in cancer nanomedicine: Drug carriers, targeting ligands and protease substrates. J. Control. Release. 2012; 159: 2–13.
45. Regberg J, Srimanee A, Langel U. Applications of Cell-Penetrating Peptides for Tumor Targeting and Future Cancer Therapies. Pharmaceuticals. 2012; 5, 991-1007.
46. Harada, H, Kizaka-Kondoh S, Hiraoka M. Antitumor protein therapy; application of the protein transduction domain to the development of a protein drug for cancer treatment. Breast Cancer 2006; 13: 16–26.
47. Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci. 2005; 6: 603–14.
48. Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006; 110:167–73.
49. Chiba T, Yamada M, Sasabe J, Terashita K, Aiso S, et al.. Colivelin prolongs survival of an ALS model mouse. Biochem Biophys Res Commun. 2006; 343:793–798.
50. Popiel HA, Burke J, Warren RJ, et al.. The Aggregation Inhibitor Peptide QBP1 as a Therapeutic Molecule for the Polyglutamine Neurodegenerative Diseases. Journal of Amino Acids, 2011.
51. Velden WJ, Van Iersel, TM, Blijlevens NM, Donnelly JP. Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11).In BMC Med. 2009; 7: 44.
52. Bals R. Epithelial antimicrobial peptides in host defense against infection. Respirat. Research. 2000; 1 (3): 141-150.
53. Schuerholz T, Brandenburg K, Marx G. The anti-inflammatory effect of the synthetic antimicrobial peptide 19-2.5 in a murine sepsis model: a prospective randomized study. Critical Care 2012; 16: 207.
54. Kaspar Allan A. and Reichert, JM. Future directions for peptide therapeutics development. Drug Discovery Today, 2013; 1-11
55. Wahren J, Kallas A, et al.. The clinical potential of C-peptide replacement in type-1 diabetes. 2012; 61: 1-12.
56. Luppi P, Cifarelli V, Wahren J. C-peptide and long-term complications of diabetes. Pediatr Diabetes 2011; 12: 276–292.
57. Carrillo-Sepulveda, MA, Matsumoto T, Nunes KP, and Webb RC. Therapeutic implications of peptide interactions with G-protein-coupled receptors in diabetic vasculopathy. Acta Physiol 2014; 211: 20–35.
58. Clare DA, Catignani GL, Swaisgood HE. Biodefense properties of milk: the role of antimicrobial proteins and peptides. Current Pharmaceutical Design 2003; 29: 1239-1255.
59. Moller NP, Scholz-Ahrens KE, Roos N, Schrezenmeir J. Bioactive peptides and proteins from foods: indication for health effects. European J. Nutr. 2008; 47, 171-182.
60. Krol J, Brodziak A, Litwińczuk Z, Szwajkowska M. Wykorzystanie białek serwatkowych w promocji zdrowia (Whey protein utilization in health promotion). In Polish, summary in English. Żywienie człowieka i metabolizm XXXVIII 2011; (1): 36-45.
61. Kamau SM, Cheison SC, Chen W, Liu XM, Lu RR. Alpha-Lactalbumin: its production technologies and bioactive peptides. Comprehensive Reviews in Food Science and Food Safety 2010; 9: 197-212.
62. Prioult G, Pecquet S, Fliss I. Stimulation of interleukin-10 production by acidic beta-lactoglobulin-derived peptides hydrolyzed with Lactobacillus paracasei NCC2461 peptidases. Clinical and Diagnostic Laboratory Immunology 2004; 11: 266-271.
63. Szwajkowska M, Wolanciuk A, Barłowska J, Król J, Zygmunt Litwińczuk. Bovine milk proteins as the source of bioactive peptides influencing the consumers’ immune system – a review. Animal Science Papers and Reports 2011; 29 (4): 269-280.
64. Rodrigo TS, Salvatore A. Immunomodulatory Effects by a Heat Shock Protein dnaJ Derived Peptide in Rheumatoid Arthritis. Specific Immunotherapy of Chronic Autoimmune Diseases. 1999; 63-71.
65. Buchau AS. Schauber J, Hultsch T, Stuetz A, Gallo RL. Pimecrolimus enhances TLR2/6- induced expression of antimicrobial peptides in keratinocytes. J. Invest. Dermatol. 2008; 128: 2646-2654.
66. Rosenberger CM, Gallo RL, Finlay BB. Interplay between antibacterial effectors: a macrophage antimicrobial peptide impairs intracellular Salmonella replication. Proc. Natl. Acad. Sci. USA 2004; 101: 2422-2427.
67. Maloney CM et al. The rectal administration of MS contin: clinical implications of use in end stage therapy cancer. Am. J. Hosp Care. 1989; 6(4): 34-35.
68. Batul N et al. Pharmacokinetics of two novel rectal controlled release morphine formulations. J. Pain Symptom Manage. 1992; 7(7): 400-405.
69. Warren DE. Practical use of rectal medications in palliative care. J. Pain Symptom Manage. 1996; 11(6): 378-387.
70. Sarwar, G. The protein digestibility-corrected amino acid score method overestimates quality of proteins containing antinutritional factors and of poorly digestible proteins supplemented with limiting amino acids in rats. Journal of Nutrition 1997; 127: 758-764.
71. Schaafsma, G. The protein digestibility-corrected amino acid score. Journal of Nutrition, 2000; 130: 1865S-1867S.
72. Sellmeyer, D.E., Stone, K.L., Sebastian, A. and Cummings, S.R. A high ratio of dietary animal to vegetable protein increases the rate of bone loss and risk of fracture in postmenopausal women. American Journal of Clinical Nutrition 2001; 73: 118-122.
73. St. Jeor, S.T., Howard, B.V., Prewitt, E., Bovee, V., Bazzarre, T. and Eckel, R.H. A statement for healthcare professionals from the nutrition committee of the council on nutrition, physical activity, and metabolism of the American Heart Association. Circulation 2001; 104: 1869-1874.
74. Tarnopolsky, M.A., Atkinson, S.A., MacDougall, J.D., Chesley, A., Phillips, S.M. and Schwarcz, H. Evaluation of protein requirements for trained strength athletes. Journal of Applied Physiology 1992; 73: 1986-1995.
75. Tarnolpolsky, M.A., MacDougall, J.D. and Atkinson, S.A. Influence of protein intake and training status on nitrogen balance and lean body mass. Journal of Applied Physiology 1988; 64: 187-193.
76. Tikkanen, M.J., Wahala, K., Ojala, S., Vihma, V., and Adlecrerutz, H. Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance. Proclamations of the National Academy of Science 1998; 95: P3106-P3110.
77. Chein YW. Novel drug delivery systems, second edition, 1992; 50: 637-679.
78. Vyas SP, Khar KR. Targeted and controlled drug delivery, Novel carrier system, CBS publishers and distributors, New Delhi. 2002; 505-537.
79. Chien YW, Chang SF. Intranasal drug delivery for systemic medication. Crit. Rev. Ther. Drug. Carrier. Syst. 1987; 4: 67- 194.
80. Chein YW. Novel drug delivery systems, second edition, 1992; 50: 637-679.
81. Banga AK, Chein YW. Systemic delivery of therapeutic peptides and proteins. Int. J. Pharm. 1988; 48: 15-50.
82. Wieriks J. Resorption of alpha amylase upon buccal application. Arch. Int. Pharmacodyn. Ther. 1964; 151: 126-135.
83. Tregear RT. The permeability of skin to albumin, dextrans and Polyvinylpyrrolidone. J. Invest. Dermatol. 1996; 46: 2427.
84. Menasche. Pharmacological studies on elastin peptides (kappa-elastin). Blood clearance, percutaneous penetration and tissue distribution. Pathol. Biol. 1981; 29: 548-554.
85. Brunette BR, Marreco D. Comparison between the iontophoretic and passive transport of thyrotropin releasing hormone across excised nude mouse skin. J Pharm. Sci. 1986; 75: 738- 743.
86. Siddiqui O, Sun Y, Liu JC, Chein YW. Facilitated transdermal transport of insulin. J Pharm. Sci. 1987; 76: 341-345.