Skip to main content

Advertisement

Log in

Advanced trends in protein and peptide drug delivery: a special emphasis on aquasomes and microneedles techniques

  • Review Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Proteins and peptides have a great potential as therapeutic agents; they have higher efficiency and lower toxicity, compared to chemical drugs. However, their oral bioavailability is very low; also, the transdermal peptide delivery faces absorption limitations. Accordingly, most of proteins and peptides are administered by parenteral route, but there are many problems associated with this route such as patient discomfort, especially for pediatric use. Thus, it is a great challenge to develop drug delivery systems for administration of proteins and peptides by routes other than parenteral one. This review provides an overview on recent advances adopted for protein and peptide drug delivery, focusing on oral and transdermal routes. This is followed by an emphasis on two recent approaches adopted as delivery systems for protein and peptide drugs, namely aquasomes and microneedles. Aquasomes are nanoparticles fabricated from ceramics developed to enhance proteins and peptides stability, providing an adequate residence time in circulation. It consists of ceramic core coated with poly hydroxyl oligomer, on which protein and peptide drug can be adsorbed. Aquasomes preparation, characterization, and application in protein and peptide drug delivery are discussed. Microneedles are promising transdermal approach; it involves creation of micron-sized pores in the skin for enhancing the drug delivery across the skin, as their length ranged between 150 and 1500 μm. Types of microneedles with different drug delivery mechanisms, characterization, and application in protein and peptide drug delivery are discussed.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Han Y, Gao Z, Chen L, Kang L, Huang W, Jin M, et al. Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins. Acta Pharm Sin B. 2019;9(5):902–22.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Etanercept - Pfizer. Springer; 1994 [updated 28/12/2019; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800003273. Accessed 14 Feb 2020.

  3. Insulin glargine biosimilar - Gan & Lee Pharmaceuticals. Springer; 2015 [updated 31/1/2020; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800043038. Accessed 14 Feb 2020.

  4. Pegfilgrastim biosimilar—CSPC Pharma. Springer; 2016 [updated 27/1/2020; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800045615. Accessed 14 Feb 2020.

  5. Calcitonin oral—Emisphere. Springer; 1998 [updated 4/11/2018; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800009835. Accessed 14 Feb 2020.

  6. Cyclosporine. 2005 [updated 13/2/2020; cited 2020]; Available from: https://www.drugbank.ca/drugs/DB00091. Accessed 14 Feb 2020.

  7. Octreotide - Novartis. Springer; 1996 [updated 7/1/2020; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800006541. Accessed 14 Feb 2020.

  8. Liraglutide—Novo Nordisk. Springer; 1999 [updated 7/2/2020; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800010229. Accessed 14 Feb 2020.

  9. Bivalirudin - The Medicines Company. Springer; 1994 [updated 17/1/2020; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800001841. Accessed 14 Feb 2020.

  10. Desmopressin intranasal—CPX Pharmaceuticals/Serenity Pharmaceuticals. Springer; 2008 [updated 11/3/2019; cited 2020]; Available from: https://adisinsight.springer.com/drugs/800028728. Accessed 14 Feb 2020.

  11. Serrapeptase. Springer; 2016 [updated 8/9/2016; cited 2020]; Available from: https://adisinsight.springer.com/drugsafety/803198426. Accessed 14 Feb 2020.

  12. Seasonal influenza virus vaccine quadrivalent - Sanofi Pasteur. 2003 [updated 11/2/2020]; Available from: https://adisinsight.springer.com/drugs/800019281. Accessed 14 Feb 2020.

  13. Aguirre TA, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Deliv Rev. 2016;106(Pt B):223–41.

    Article  CAS  PubMed  Google Scholar 

  14. Bruno BJ, Miller GD, Lim CS. Basics and recent advances in peptide and protein drug delivery. Ther Deliv. 2013;4(11):1443–67.

    Article  CAS  PubMed  Google Scholar 

  15. Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst. 2003;20(2–3):153–214.

    Article  CAS  PubMed  Google Scholar 

  16. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799–809.

    Article  CAS  PubMed  Google Scholar 

  17. Umashankar MS, Sachdeva RK, Gulati M. Aquasomes: a promising carrier for peptides and protein delivery. Nanomedicine. 2010;6(3):419–26.

    Article  CAS  PubMed  Google Scholar 

  18. Banerjee S, Sen KK. Aquasomes: a novel nanoparticulate drug carrier. J Drug Deliv Sci Technol. 2018;43:446–52.

    Article  CAS  Google Scholar 

  19. Cherian AK, Rana AC, Jain SK. Self-assembled carbohydrate-stabilized ceramic nanoparticles for the parenteral delivery of insulin. Drug Dev Ind Pharm. 2000;26(4):459–63.

  20. Ye Y, Yu J, Wen D, Kahkoska AR, Gu Z. Polymeric microneedles for transdermal protein delivery. Adv Drug Deliv Rev. 2018;127:106–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meredith ME, Salameh TS, Banks WA. Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J. 2015;17(4):780–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Caon T, Jin L, Simoes CM, Norton RS, Nicolazzo JA. Enhancing the buccal mucosal delivery of peptide and protein therapeutics. Pharm Res. 2015;32(1):1–21.

    Article  CAS  PubMed  Google Scholar 

  23. Lip Kwok PC, Chan H-K. Chapter 2—pulmonary delivery of peptides and proteins. In: Van Der Walle C, editor. Peptide and protein delivery. Boston: Academic Press; 2011. p. 23–46.

    Chapter  Google Scholar 

  24. Lakshmi Prasanna J, Deepthi B, Rama RN. Rectal drug delivery: a promising route for enhancing drug absorption. Asian J Res Pharm Sci. 2012;2(4):143–9.

    Google Scholar 

  25. Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–9.

    Article  CAS  PubMed  Google Scholar 

  26. Ruan RQ, Wang SS, Wang CL, Zhang L, Zhang YJ, Zhou W, et al. Transdermal delivery of human epidermal growth factor facilitated by a peptide chaperon. Eur J Med Chem. 2013;62:405–9.

    Article  CAS  PubMed  Google Scholar 

  27. Chaulagain B, Jain A, Tiwari A, Verma A, Jain SK. Passive delivery of protein drugs through transdermal route. Artif Cells Nanomed Biotechnol. 2018;46(sup1):472–87.

    Article  CAS  PubMed  Google Scholar 

  28. Olatunji O, Das DB, Garland MJ, Belaid L, Donnelly RF. Influence of array interspacing on the force required for successful microneedle skin penetration: theoretical and practical approaches. J Pharm Sci. 2013;102(4):1209–21.

    Article  CAS  PubMed  Google Scholar 

  29. Kaur M, Ita KB, Popova IE, Parikh SJ, Bair DA. Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate. Eur J Pharm Biopharm. 2014;86(2):284–91.

    Article  CAS  PubMed  Google Scholar 

  30. FDA approves first oral GLP-1 treatment for type 2 diabetes. 2019; Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes. Accessed 11 Nov 2019.

  31. Novo Nordisk gets FDA blessing for Rybelsus. 2019; Available from: https://drugstorenews.com/novo-nordisk-gets-fda-blessing-rybelsus. Accessed 11 Nov 2019.

  32. Lau J, Bloch P, Schaffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–80.

    Article  CAS  PubMed  Google Scholar 

  33. Sood A, Panchagnula R. Peroral route: an opportunity for protein and peptide drug delivery. Chem Rev. 2001;101(11):3275–303.

    Article  CAS  PubMed  Google Scholar 

  34. Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9(1):1–25.

    Article  CAS  PubMed  Google Scholar 

  35. Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des. 2013;81(1):136–47.

    Article  CAS  PubMed  Google Scholar 

  36. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs. 2008;22(5):315–29.

    Article  CAS  PubMed  Google Scholar 

  37. Calceti P, Salmaso S, Walker G, Bernkop-Schnurch A. Development and in vivo evaluation of an oral insulin-PEG delivery system. Eur J Pharm Sci. 2004;22(4):315–23.

    Article  CAS  PubMed  Google Scholar 

  38. Youn YS, Jung JY, Oh SH, Yoo SD, Lee KC. Improved intestinal delivery of salmon calcitonin by Lys18-amine specific PEGylation: stability, permeability, pharmacokinetic behavior and in vivo hypocalcemic efficacy. J Control Release. 2006;114(3):334–42.

    Article  CAS  PubMed  Google Scholar 

  39. Wang J, Wu D, Shen WC. Structure-activity relationship of reversibly lipidized peptides: studies of fatty acid-desmopressin conjugates. Pharm Res. 2002;19(5):609–14.

    Article  CAS  PubMed  Google Scholar 

  40. Wang J, Chow D, Heiati H, Shen WC. Reversible lipidization for the oral delivery of salmon calcitonin. J Control Release. 2003;88(3):369–80.

    Article  CAS  PubMed  Google Scholar 

  41. Hackett MJ, Zaro JL, Shen W-C, Guley PC, Cho MJ. Fatty acids as therapeutic auxiliaries for oral and parenteral formulations. Adv Drug Deliv Rev. 2013;65(10):1331–9.

    Article  CAS  PubMed  Google Scholar 

  42. Miller SM, Simon RJ, Ng S, Zuckermann RN, Kerr JM, Moos WH. Comparison of the proteolytic susceptibilities of homologous L-amino acid, D-amino acid, and N-substituted glycine peptide and peptoid oligomers. Drug Dev Res. 1995;35(1):20–32.

    Article  CAS  Google Scholar 

  43. Tugyi R, Uray K, Ivan D, Fellinger E, Perkins A, Hudecz F. Partial D-amino acid substitution: improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proc Natl Acad Sci U S A. 2005;102(2):413–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bernkop-Schnürch A. The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins. J Control Release. 1998;52(1–2):1–16.

    Article  PubMed  Google Scholar 

  45. Fujii S, Yokoyama T, Ikegaya K, Sato F, Yokoo N. Promoting effect of the new chymotrypsin inhibitor FK-448 on the intestinal absorption of insulin in rats and dogs. J Pharm Pharmacol. 1985;37(8):545–9.

    Article  CAS  PubMed  Google Scholar 

  46. Ziv E, Lior O, Kidron M. Absorption of protein via the intestinal wall. A quantitative model. Biochem Pharmacol. 1987;36(7):1035–9.

    Article  CAS  PubMed  Google Scholar 

  47. Agarwal V, Khan MA. Current status of the oral delivery of insulin. Pharm Technol. 2001;10:76–90.

    Google Scholar 

  48. Marschutz MK, Bernkop-Schnurch A. Oral peptide drug delivery: polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro. Biomaterials. 2000;21(14):1499–507.

    Article  CAS  PubMed  Google Scholar 

  49. Renukuntla J, Vadlapudi AD, Patel A, Boddu SH, Mitra AK. Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm. 2013;447(1–2):75–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Thanou M, Verhoef J, Junginger H. Chitosan and its derivatives as intestinal absorption enhancers. Adv Drug Deliv Rev. 2001;50:S91–S101.

    Article  CAS  PubMed  Google Scholar 

  51. Cano-Cebrian MJ, Zornoza T, Granero L, Polache A. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery. Curr Drug Deliv. 2005;2(1):9–22.

    Article  CAS  PubMed  Google Scholar 

  52. Schipper NG, Vårum KM, Artursson P. Chitosans as absorption enhancers for poorly absorbable drugs. 1: influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells. Pharm Res. 1996;13(11):1686–92.

    Article  CAS  PubMed  Google Scholar 

  53. Lindmark T, Nikkila T, Artursson P. Mechanisms of absorption enhancement by medium chain fatty acids in intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther. 1995;275(2):958–64.

    CAS  PubMed  Google Scholar 

  54. Sawada T, Ogawa T, Tomita M, Hayashi M, Awazu S. Role of paracellular pathway in nonelectrolyte permeation across rat colon epithelium enhanced by sodium caprate and sodium caprylate. Pharm Res. 1991;8(11):1365–71.

    Article  CAS  PubMed  Google Scholar 

  55. Fasano A, Uzzau S. Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J Clin Invest. 1997;99(6):1158–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Niu Z, Conejos-Sanchez I, Griffin BT, O'Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Adv Drug Deliv Rev. 2016;106(Pt B):337–54.

    Article  CAS  PubMed  Google Scholar 

  57. Ahmad J, Singhal M, Amin S, Rizwanullah M, Akhter S, Kamal MA, et al. Bile salt stabilized vesicles (Bilosomes): a novel nano-pharmaceutical design for oral delivery of proteins and peptides. Curr Pharm Des. 2017;23(11):1575–88.

    Article  CAS  PubMed  Google Scholar 

  58. Conacher M, Alexander J, Brewer JM. Oral immunisation with peptide and protein antigens by formulation in lipid vesicles incorporating bile salts (bilosomes). Vaccine. 2001;19(20–22):2965–74.

    Article  CAS  PubMed  Google Scholar 

  59. Chatterjee B, Hamed Almurisi S, Ahmed Mahdi Dukhan A, Mandal UK, Sengupta P. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view. Drug Deliv. 2016;23(9):3639–52.

    Article  CAS  PubMed  Google Scholar 

  60. Friedl H, Dunnhaupt S, Hintzen F, Waldner C, Parikh S, Pearson JP, et al. Development and evaluation of a novel mucus diffusion test system approved by self-nanoemulsifying drug delivery systems. J Pharm Sci. 2013;102(12):4406–13.

    Article  CAS  PubMed  Google Scholar 

  61. Mahmood A, Bernkop-Schnurch A. SEDDS: a game changing approach for the oral administration of hydrophilic macromolecular drugs. Adv Drug Deliv Rev. 2018.

  62. Phan TNQ, Le-Vinh B, Efiana NA, Bernkop-Schnurch A. Oral self-emulsifying delivery systems for systemic administration of therapeutic proteins: science fiction? J Drug Target. 2019;27(9):1017–24 1–27.

    Article  CAS  PubMed  Google Scholar 

  63. Karamanidou T, Karidi K, Bourganis V, Kontonikola K, Kammona O, Kiparissides C. Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems. Eur J Pharm Biopharm. 2015;97(Pt A):223–9.

    Article  CAS  PubMed  Google Scholar 

  64. Menzel C, Holzeisen T, Laffleur F, Zaichik S, Abdulkarim M, Gumbleton M, et al. In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide. J Control Release. 2018;277:165–72.

    Article  CAS  PubMed  Google Scholar 

  65. Liu Z, Jiao Y, Wang Y, Zhou C, Zhang Z. Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev. 2008;60(15):1650–62.

    Article  CAS  PubMed  Google Scholar 

  66. Sonaje K, Lin YH, Juang JH, Wey SP, Chen CT, Sung HW. In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials. 2009;30(12):2329–39.

    Article  CAS  PubMed  Google Scholar 

  67. Su FY, Lin KJ, Sonaje K, Wey SP, Yen TC, Ho YC, et al. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials. 2012;33(9):2801–11.

    Article  CAS  PubMed  Google Scholar 

  68. Jafary Omid N, Bahari Javan N, Dehpour AR, Partoazar A, Rafiee Tehrani M, Dorkoosh F. In-vitro and in-vivo cytotoxicity and efficacy evaluation of novel glycyl-glycine and alanyl-alanine conjugates of chitosan and trimethyl chitosan nano-particles as carriers for oral insulin delivery. Int J Pharm. 2018;535(1–2):293–307.

    Article  CAS  PubMed  Google Scholar 

  69. Millotti G, Laffleur F, Perera G, Vigl C, Pickl K, Sinner F, et al. In vivo evaluation of thiolated chitosan tablets for oral insulin delivery. J Pharm Sci. 2014;103(10):3165–70.

    Article  CAS  PubMed  Google Scholar 

  70. Soudry-Kochavi L, Naraykin N, Nassar T, Benita S. Improved oral absorption of exenatide using an original nanoencapsulation and microencapsulation approach. J Control Release. 2015;217:202–10.

    Article  CAS  PubMed  Google Scholar 

  71. Lee S, Kim YC, Park JH. Zein-alginate based oral drug delivery systems: protection and release of therapeutic proteins. Int J Pharm. 2016;515(1–2):300–6.

    Article  CAS  PubMed  Google Scholar 

  72. Song Y, Gan W, Li Q, Guo Y, Zhou J, Zhang L. Alkaline hydrolysis and flocculation properties of acrylamide-modified cellulose polyelectrolytes. Carbohydr Polym. 2011;86(1):171–6.

    Article  CAS  Google Scholar 

  73. Liu L, Yao W, Rao Y, Lu X, Gao J. pH-responsive carriers for oral drug delivery: challenges and opportunities of current platforms. Drug Deliv. 2017;24(1):569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2001;53(3):321–39.

    Article  CAS  PubMed  Google Scholar 

  75. Asfour MH, Mohsen AM. Formulation and evaluation of pH-sensitive rutin nanospheres against colon carcinoma using HCT-116 cell line. J Adv Res. 2018;9:17–26.

    Article  CAS  PubMed  Google Scholar 

  76. Dai J, Nagai T, Wang X, Zhang T, Meng M, Zhang Q. pH-sensitive nanoparticles for improving the oral bioavailability of cyclosporine a. Int J Pharm. 2004;280(1–2):229–40.

    Article  CAS  PubMed  Google Scholar 

  77. Wang XQ, Zhang Q. pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs. Eur J Pharm Biopharm. 2012;82(2):219–29.

    Article  CAS  PubMed  Google Scholar 

  78. Cui F, Qian F, Zhao Z, Yin L, Tang C, Yin C. Preparation, characterization, and oral delivery of insulin loaded carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles. Biomacromolecules. 2009;10(5):1253–8.

    Article  CAS  PubMed  Google Scholar 

  79. Thanou M, Verhoef JC, Verheijden JH, Junginger HE. Intestinal absorption of octreotide using trimethyl chitosan chloride: studies in pigs. Pharm Res. 2001;18(6):823–8.

    Article  CAS  PubMed  Google Scholar 

  80. Jelvehgari M, Zakeri-Milani P, Siahi-Shadbad MR, Loveymi BD, Nokhodchi A, Azari Z, et al. Development of pH-sensitive insulin nanoparticles using Eudragit L100-55 and chitosan with different molecular weights. AAPS PharmSciTech. 2010;11(3):1237–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zheng Y, Yang W, Wang C, Hu J, Fu S, Dong L, et al. Nanoparticles based on the complex of chitosan and polyaspartic acid sodium salt: preparation, characterization and the use for 5-fluorouracil delivery. Eur J Pharm Biopharm. 2007;67(3):621–31.

    Article  CAS  PubMed  Google Scholar 

  82. Cao SJ, Xu S, Wang HM, Ling Y, Dong J, Xia RD, et al. Nanoparticles: oral delivery for protein and peptide drugs. AAPS PharmSciTech. 2019;20(5):190.

    Article  PubMed  CAS  Google Scholar 

  83. Kristensen M, Nielsen HM. Cell-penetrating peptides as carriers for oral delivery of biopharmaceuticals. Basic Clin Pharmacol Toxicol. 2016;118(2):99–106.

    Article  CAS  PubMed  Google Scholar 

  84. Liang JF, Yang VC. Insulin-cell penetrating peptide hybrids with improved intestinal absorption efficiency. Biochem Biophys Res Commun. 2005;335(3):734–8.

    Article  CAS  PubMed  Google Scholar 

  85. el Khafagy S, Morishita M, Ida N, Nishio R, Isowa K, Takayama K. Structural requirements of penetratin absorption enhancement efficiency for insulin delivery. J Control Release. 2010;143(3):302–10.

    Article  CAS  Google Scholar 

  86. Andreani T, de Souza AL, Kiill CP, Lorenzon EN, Fangueiro JF, Calpena AC, et al. Preparation and characterization of PEG-coated silica nanoparticles for oral insulin delivery. Int J Pharm. 2014;473(1–2):627–35.

    Article  CAS  PubMed  Google Scholar 

  87. Kamari Y, Ghiaci P, Ghiaci M. Study on montmorillonite/insulin/TiO2 hybrid nanocomposite as a new oral drug-delivery system. Mater Sci Eng C. 2017;75:822–8.

    Article  CAS  Google Scholar 

  88. Díaz A, David A, Pérez R, González ML, Báez A, Wark SE, et al. Nanoencapsulation of insulin into zirconium phosphate for oral delivery applications. Biomacromolecules. 2010;11(9):2465–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Zhang Y, Zhang L, Ban Q, Li J, Li CH, Guan YQ. Preparation and characterization of hydroxyapatite nanoparticles carrying insulin and gallic acid for insulin oral delivery. Nanomedicine. 2018;14(2):353–64.

    Article  CAS  PubMed  Google Scholar 

  90. Kalluri H, Banga AK. Transdermal delivery of proteins. AAPS PharmSciTech. 2011;12(1):431–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jitendra SPK, Bansal S, Banik A. noninvasive routes of proteins and peptides drug delivery. Indian J Pharm Sci. 2011;73(4):367–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Andrews SN, Jeong E, Prausnitz MR. Transdermal delivery of molecules is limited by full epidermis, not just stratum corneum. Pharm Res. 2013;30(4):1099–109.

    Article  CAS  PubMed  Google Scholar 

  94. Badkar AV, Smith AM, Eppstein JA, Banga AK. Transdermal delivery of interferon alpha-2B using microporation and iontophoresis in hairless rats. Pharm Res. 2007;24(7):1389–95.

    Article  CAS  PubMed  Google Scholar 

  95. Bloom BS, Brauer JA, Geronemus RG. Ablative fractional resurfacing in topical drug delivery: an update and outlook. Dermatol Surg. 2013;39(6):839–48.

    Article  CAS  PubMed  Google Scholar 

  96. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Denet AR, Vanbever R, Preat V. Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev. 2004;56(5):659–74.

    Article  CAS  PubMed  Google Scholar 

  98. Herwadkar A. A.K B. Peptide and protein transdermal drug delivery. Drug Discov Today Technol. 2012;9(2):e147–e54.

    Article  CAS  Google Scholar 

  99. Ghosh B, Iyer D, Nair AB, Sree HN. Prospects of iontophoresis in cardiovascular drug delivery. J Basic Clin Pharm. 2012;4(1):25–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Barry B. Action of skin penetration enhancers—the lipid protein partitioning theory. Int J Cosmet Sci. 1988;10(6):281–93.

    Article  CAS  PubMed  Google Scholar 

  101. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56(5):603–18.

    Article  CAS  PubMed  Google Scholar 

  102. Dragicevic N, Atkinson J, Maibach H. Chemical penetration enhancers: classification and mode of action. In: Dragicevic N, Maibach H, editors. Percutaneous penetration enhancers chemical methods in penetration enhancement. Berlin: Springer; 2015.

    Chapter  Google Scholar 

  103. Koren E, Torchilin VP. Cell-penetrating peptides: breaking through to the other side. Trends Mol Med. 2012;18(7):385–93.

    Article  CAS  PubMed  Google Scholar 

  104. Dupont E, Prochiantz A, Joliot A. Penetratin story: an overview. Methods Mol Biol. 2015;1324:29–37.

    Article  PubMed  Google Scholar 

  105. Lindgren M, Langel U. Classes and prediction of cell-penetrating peptides. Methods Mol Biol. 2011;683:3–19.

    Article  CAS  PubMed  Google Scholar 

  106. Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by magainin pore-forming peptide. J Control Release. 2007;122(3):375–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Touitou E. Drug delivery across the skin. Expert Opin Biol Ther. 2002;2(7):723–33.

    Article  CAS  PubMed  Google Scholar 

  108. Bundgaard H. (C) Means to enhance penetration: (1) Prodrugs as a means to improve the delivery of peptide drugs. Adv Drug Deliv Rev. 1992;8(1):1–38.

    Article  CAS  Google Scholar 

  109. Pandey RS, Sahu S, Sudheesh MS, Madan J, Kumar M, Dixit VK. Carbohydrate modified ultrafine ceramic nanoparticles for allergen immunotherapy. Int Immunopharmacol. 2011;11(8):925–31.

    Article  CAS  PubMed  Google Scholar 

  110. Kossovsky N, Gelman A, Rajguru S, Nguyen R, Sponsler E, Hnatyszyn HJ, et al. Control of molecular polymorphisms by a structured carbohydrate / ceramic delivery vehicle—aquasomes. J Control Release. 1996;39(2):383–8.

    Article  CAS  Google Scholar 

  111. Goyal AK, Khatri K, Mishra N, Mehta A, Vaidya B, Tiwari S, et al. Aquasomes—a nanoparticulate approach for the delivery of antigen. Drug Dev Ind Pharm. 2008;34(12):1297–305.

    Article  CAS  PubMed  Google Scholar 

  112. Narang N Aquasomes: Self-assembled systems for the delivery of bioactive molecules. Asian J Pharm. 2014;6(2).

  113. Shahabade Gururaj S, Bhosale Ashok V, Mutha Swati S, Bhosale Nilesh R, Khade Prashant H, Bhadane Nishant P, et al. An overview on nanocarrier technology-Aquasomes. J Pharm Res. 2009;2(7):1174–7.

    Google Scholar 

  114. Kaushik JK, Bhat R. Why is trehalose an exceptional protein stabilizer? An analysis of the thermal stability of proteins in the presence of the compatible osmolyte trehalose. J Biol Chem. 2003;278(29):26458–65.

    Article  CAS  PubMed  Google Scholar 

  115. Pandey S, Badola A, Bhatt GK, Kothiyal P. An overview on aquasomes. Int J Pharm Chem Sci. 2013;2(3):1282–7.

    Google Scholar 

  116. Vengala P, Dintakurthi S, Subrahmanyam CVS. Lactose coated ceramic nanoparticles for oral drug delivery. J Pharm Res. 2013;7(6):540–5.

    CAS  Google Scholar 

  117. Vengala P, Aslam S, Subrahmanyam C. Development and in vitro evaluation of ceramic nanoparticles of piroxicam. Lat Am J Pharm. 2013;32(8):1124–30.

    CAS  Google Scholar 

  118. Damera DP, Kaja S, Janardhanam LSL, Alim S, VVK V, Nag A. Synthesis, detailed characterization and dual drug delivery application of BSA loaded Aquasomes. ACS App Bio Mater. 2019.

  119. Kaur K, Kush P, Pandey RS, Madan J, Jain UK, Katare OP. Stealth lipid coated aquasomes bearing recombinant human interferon-alpha-2b offered prolonged release and enhanced cytotoxicity in ovarian cancer cells. Biomed Pharmacother. 2015;69:267–76.

    Article  CAS  PubMed  Google Scholar 

  120. Rojas-Oviedo I, Salazar-López RA, Reyes-Gasga J, Quirino-Barreda CT. Elaboration and structural analysis of aquasomes loaded with indomethacin. Eur J Pharm Sci. 2007;32(3):223–30.

    Article  CAS  PubMed  Google Scholar 

  121. Khopade A, Khopade S, Jain N. Development of hemoglobin aquasomes from spherical hydroxyapatite cores precipitated in the presence of half-generation poly (amidoamine) dendrimer. Int J Pharm. 2002;241(1):145–54.

    Article  CAS  PubMed  Google Scholar 

  122. Rawat M, Singh D, Saraf S, Saraf S. Development and in vitro evaluation of alginate gel–encapsulated, chitosan-coated ceramic nanocores for oral delivery of enzyme. Drug Dev Ind Pharm. 2008;34(2):181–8.

    Article  CAS  PubMed  Google Scholar 

  123. Patil S, Pancholi SS, Agrawal S, Agrawal GP. Surface-modified mesoporous ceramics as delivery vehicle for haemoglobin. Drug Deliv. 2004;11(3):193–9.

    Article  CAS  PubMed  Google Scholar 

  124. Giudice EL, Campbell JD. Needle-free vaccine delivery. Adv Drug Deliv Rev. 2006;58(1):68–89.

    Article  CAS  PubMed  Google Scholar 

  125. Nir Y, Paz A, Sabo E, Potasman I. Fear of injections in young adults: prevalence and associations. Am J Trop Med Hyg. 2003;68(3):341–4.

    Article  PubMed  Google Scholar 

  126. Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012;64(14):1547–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Indermun S, Luttge R, Choonara YE, Kumar P, du Toit LC, Modi G, et al. Current advances in the fabrication of microneedles for transdermal delivery. J Control Release. 2014;185:130–8.

    Article  CAS  PubMed  Google Scholar 

  128. Akhtar N. Microneedles: an innovative approach to transdermal delivery—a review. Int J Pharm Pharm Sci. 2014;6:18–25.

    CAS  Google Scholar 

  129. Prausnitz MR. Engineering microneedle patches for vaccination and drug delivery to skin. Annu Rev Chem Biomol Eng. 2017;8:177–200.

    Article  CAS  PubMed  Google Scholar 

  130. Wilke N, Mulcahy A, Ye S-R, Morrissey A. Process optimization and characterization of silicon microneedles fabricated by wet etch technology. Microelectron J. 2005;36(7):650–6.

    Article  CAS  Google Scholar 

  131. Donnelly RF, Majithiya R, Singh TRR, Morrow DI, Garland MJ, Demir YK, et al. Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique. Pharm Res. 2011;28(1):41–57.

    Article  CAS  PubMed  Google Scholar 

  132. Jin CY, Han MH, Lee SS, Choi YH. Mass producible and biocompatible microneedle patch and functional verification of its usefulness for transdermal drug delivery. Biomed Microdevices. 2009;11(6):1195.

    Article  CAS  PubMed  Google Scholar 

  133. Moon SJ, Lee SS, Lee H, Kwon T. Fabrication of microneedle array using LIGA and hot embossing process. Microsyst Technol. 2005;11(4–5):311–8.

    Article  CAS  Google Scholar 

  134. Park JH, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release. 2005;104(1):51–66.

    Article  CAS  PubMed  Google Scholar 

  135. Martanto W, Davis SP, Holiday NR, Wang J, Gill HS, Prausnitz MR. Transdermal delivery of insulin using microneedles in vivo. Pharm Res. 2004;21(6):947–52.

    Article  CAS  PubMed  Google Scholar 

  136. Bystrova S, Luttge R. Micromolding for ceramic microneedle arrays. Microelectron Eng. 2011;88(8):1681–4.

    Article  CAS  Google Scholar 

  137. Waghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M, et al. Microneedles: a smart approach and increasing potential for transdermal drug delivery system. Biomed Pharmacother. 2019;109:1249–58.

    Article  CAS  PubMed  Google Scholar 

  138. Gill HS, Prausnitz MR. Coating formulations for microneedles. Pharm Res. 2007;24(7):1369–80.

    Article  CAS  PubMed  Google Scholar 

  139. Saurer EM, Flessner RM, Sullivan SP, Prausnitz MR, Lynn DM. Layer-by-layer assembly of DNA- and protein-containing films on microneedles for drug delivery to the skin. Biomacromolecules. 2010;11(11):3136–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. DeMuth PC, Su X, Samuel RE, Hammond PT, Irvine DJ. Nano-layered microneedles for transcutaneous delivery of polymer nanoparticles and plasmid DNA. Adv Mater. 2010;22(43):4851–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gill HS, Prausnitz MR. Coated microneedles for transdermal delivery. J Control Release. 2007;117(2):227–37.

    Article  CAS  PubMed  Google Scholar 

  142. Cormier M, Johnson B, Ameri M, Nyam K, Libiran L, Zhang DD, et al. Transdermal delivery of desmopressin using a coated microneedle array patch system. J Control Release. 2004;97(3):503–11.

    Article  CAS  PubMed  Google Scholar 

  143. Chen X, Prow TW, Crichton ML, Jenkins DW, Roberts MS, Frazer IH, et al. Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin. J Control Release. 2009;139(3):212–20.

    Article  CAS  PubMed  Google Scholar 

  144. Kim YC, Quan FS, Compans RW, Kang SM, Prausnitz MR. Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity. J Control Release. 2010;142(2):187–95.

    Article  CAS  PubMed  Google Scholar 

  145. Chen J, Huang W, Huang Z, Liu S, Ye Y, Li Q, et al. Fabrication of tip-dissolving microneedles for transdermal drug delivery of meloxicam. AAPS PharmSciTech. 2018;19(3):1141–51.

    Article  CAS  PubMed  Google Scholar 

  146. Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29(13):2113–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Fukushima K, Ise A, Morita H, Hasegawa R, Ito Y, Sugioka N, et al. Two-layered dissolving microneedles for percutaneous delivery of peptide/protein drugs in rats. Pharm Res. 2011;28(1):7–21.

    Article  CAS  PubMed  Google Scholar 

  148. Chu LY, Choi SO, Prausnitz MR. Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: bubble and pedestal microneedle designs. J Pharm Sci. 2010;99(10):4228–38.

    Article  CAS  PubMed  Google Scholar 

  149. Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharm Res. 2006;23(5):1008–19.

    Article  CAS  PubMed  Google Scholar 

  150. Martin CJ, Allender CJ, Brain KR, Morrissey A, Birchall JC. Low temperature fabrication of biodegradable sugar glass microneedles for transdermal drug delivery applications. J Control Release. 2012;158(1):93–101.

    Article  CAS  PubMed  Google Scholar 

  151. Ita K. Transdermal delivery of drugs with microneedles-potential and challenges. Pharmaceutics. 2015;7(3):90–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Cheung K, Han T, Das DB. Effect of force of microneedle insertion on the permeability of insulin in skin. J Diabetes Sci Technol. 2014;8(3):444–52.

    Article  PubMed  PubMed Central  Google Scholar 

  153. van der Maaden K, Jiskoot W, Bouwstra J. Microneedle technologies for (trans)dermal drug and vaccine delivery. J Control Release. 2012;161(2):645–55.

    Article  PubMed  CAS  Google Scholar 

  154. Suzuki M, Takahashi T, Aoyagi S. 3D laser lithographic fabrication of hollow microneedle mimicking mosquitos and its characterisation. Int J Nanotechnol. 2018;15(1–3):157–73.

    Article  Google Scholar 

  155. Davis SP, Martanto W, Allen MG, Prausnitz MR. Hollow metal microneedles for insulin delivery to diabetic rats. IEEE Trans Biomed Eng. 2005;52(5):909–15.

    Article  PubMed  Google Scholar 

  156. Roxhed N, Gasser TC, Griss P, Holzapfel GA, Stemme G. Penetration-enhanced ultrasharp microneedles and prediction on skin interaction for efficient transdermal drug delivery. J Microelectromech Syst. 2007;16(6):1429–40.

    Article  Google Scholar 

  157. Perennes F, Marmiroli B, Matteucci M, Tormen M, Vaccari L, Di Fabrizio E. Sharp beveled tip hollow microneedle arrays fabricated by LIGA and 3D soft lithography with polyvinyl alcohol. J Micromech Microeng. 2006;16(3):473.

    Article  CAS  Google Scholar 

  158. Luttge R, Berenschot EJ, De Boer MJ, Altpeter DM, Vrouwe EX, Van Den Berg A, et al. Integrated lithographic molding for microneedle-based devices. J Microelectromech Syst. 2007;16(4):872–84.

    Article  CAS  Google Scholar 

  159. Ma B, Liu S, Gan Z, Liu G, Cai X, Zhang H, et al. A PZT insulin pump integrated with a silicon microneedle array for transdermal drug delivery. Microfluid Nanofluid. 2006;2(5):417–23.

    Article  CAS  Google Scholar 

  160. Donnelly RF, Singh TRR, Alkilani AZ, McCrudden MTC, O’Neill S, O’Mahony C, et al. Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety. Int J Pharm. 2013;451(1):76–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wang J, Ye Y, Yu J, Kahkoska AR, Zhang X, Wang C, et al. Core–shell microneedle gel for self-regulated insulin delivery. ACS Nano. 2018;12(3):2466–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Courtenay AJ, McCrudden MTC, McAvoy KJ, McCarthy HO, Donnelly RF. Microneedle-mediated transdermal delivery of Bevacizumab. Mol Pharm. 2018;15(8):3545–56.

    Article  CAS  PubMed  Google Scholar 

  163. Thakur RR, Tekko IA, Al-Shammari F, Ali AA, McCarthy H, Donnelly RF. Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery. Drug Deliv Transl Res. 2016;6(6):800–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pan J, Ruan W, Qin M, Long Y, Wan T, Yu K, et al. Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles. Sci Rep. 2018;8(1):1117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Nguyen HX, Bozorg BD, Kim Y, Wieber A, Birk G, Lubda D, et al. Poly (vinyl alcohol) microneedles: fabrication, characterization, and application for transdermal drug delivery of doxorubicin. Eur J Pharm Biopharm. 2018;129:88–103.

    Article  CAS  PubMed  Google Scholar 

  166. Springernature; [cited 2019]; Available from: http://creativecommons.org/licenses/by/4.0/. Accessed 3 Dec 2019.

  167. Jeong H-R, Kim J-Y, Kim S-N, Park J-H. Local dermal delivery of cyclosporin A, a hydrophobic and high molecular weight drug, using dissolving microneedles. Eur J Pharm Biopharm. 2018;127:237–43.

    Article  CAS  PubMed  Google Scholar 

  168. Liu S, Yeo DC, Wiraja C, Tey HL, Mrksich M, Xu C. Peptide delivery with poly(ethylene glycol) diacrylate microneedles through swelling effect. Bioeng Transl Med. 2017;2(3):258–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ito Y, Hagiwara E, Saeki A, Sugioka N, Takada K. Sustained-release self-dissolving micropiles for percutaneous absorption of insulin in mice. J Drug Target. 2007;15(5):323–6.

    Article  CAS  PubMed  Google Scholar 

  170. Fukushima K, Yamazaki T, Hasegawa R, Ito Y, Sugioka N, Takada K. Pharmacokinetic and pharmacodynamic evaluation of insulin dissolving microneedles in dogs. Diabetes Technol Ther. 2010;12(6):465–74.

    Article  CAS  PubMed  Google Scholar 

  171. Ito Y, Yamazaki T, Sugioka N, Takada K. Self-dissolving micropile array tips for percutaneous administration of insulin. J Mater Sci Mater Med. 2010;21(2):835–41.

    Article  CAS  PubMed  Google Scholar 

  172. Nordquist L, Roxhed N, Griss P, Stemme G. Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control: an initial comparison with subcutaneous administration. Pharm Res. 2007;24(7):1381–8.

    Article  CAS  PubMed  Google Scholar 

  173. Li QY, Zhang JN, Chen BZ, Wang QL, Guo XD. A solid polymer microneedle patch pretreatment enhances the permeation of drug molecules into the skin. RSC Adv. 2017;7(25):15408–15.

    Article  CAS  Google Scholar 

  174. Daddona PE, Matriano JA, Mandema J, Maa YF. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharm Res. 2011;28(1):159–65.

    Article  CAS  PubMed  Google Scholar 

  175. Fernando GJP, Hickling J, Jayashi Flores CM, Griffin P, Anderson CD, Skinner SR, et al. Safety, tolerability, acceptability and immunogenicity of an influenza vaccine delivered to human skin by a novel high-density microprojection array patch (Nanopatch). Vaccine. 2018;36(26):3779–88.

    Article  CAS  PubMed  Google Scholar 

  176. Kolluru C, Gomaa Y, Prausnitz MR. Development of a thermostable microneedle patch for polio vaccination. Drug Deliv Transl Res. 2019;9(1):192–203.

    Article  CAS  PubMed  Google Scholar 

  177. Vicente-Perez EM, Larrañeta E, McCrudden MTC, Kissenpfennig A, Hegarty S, McCarthy HO, et al. Repeat application of microneedles does not alter skin appearance or barrier function and causes no measurable disturbance of serum biomarkers of infection, inflammation or immunity in mice in vivo. Eur J Pharm Biopharm. 2017;117:400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Kaushik S, Hord AH, Denson DD, McAllister DV, Smitra S, Allen MG, et al. Lack of pain associated with microfabricated microneedles. Anesth Analg. 2001;92(2):502–4.

    Article  CAS  PubMed  Google Scholar 

  179. Arya J, Henry S, Kalluri H, McAllister DV, Pewin WP, Prausnitz MR. Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. Biomaterials. 2017;128:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. BD Soluvia™ Microinjection System Used For First Approved Intradermal Influenza Vaccine in the European Union. 2009; Available from: https://www.bd.com/contentmanager/b_article.asp?Item_ID=23817&ContentType_ID=1&BusinessCode=20001&d=&s=&dTitle=&dc=&dcTitle=. Accessed 14 Nov 2019.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marwa Hasanein Asfour.

Ethics declarations

Conflict of interest

The author confirms that this article content has no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Asfour, M.H. Advanced trends in protein and peptide drug delivery: a special emphasis on aquasomes and microneedles techniques. Drug Deliv. and Transl. Res. 11, 1–23 (2021). https://doi.org/10.1007/s13346-020-00746-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-020-00746-z

Keywords

Navigation