Challenges and Future Prospects for the Delivery of Biologics: Oral Mucosal, Pulmonary, and Transdermal Routes

AAPS Journal

Volumn 19, Issue 3, 2017, Pages 652-668

  Morales, Javier O ^a,b   Fathe, Kristin R ^c   Brunaugh, Ashlee ^c   Ferrati, Silvia ^c   Li, Song ^d   Montenegro Nicolini, Miguel ^a,e   Mousavikhamene, Zeynab ^f   McConville, Jason T ^g   Prausnitz, Mark R ^d   Smyth, Hugh D C ^c  

^a UNIVERSITY OF CHILE   (Chile)

^b Biofísica y Bioinformática   (Chile)

^c UNIVERSITY OF TEXAS AT AUSTIN   (United States)

^d Georgia Institute of Technology   (United States)

^e INSTITUTO DE SALUD PÚBLICA DE CHILE   (Chile)

^f SHARIF UNIVERSITY OF TECHNOLOGY   (Iran)

^g UNIVERSITY OF NEW MEXICO   (United States)

Author keywords

biologics; buccal; inhalation; microenvironment; mucosal; pulmonary; skin; sublingual; transdermal

Indexed keywords

ALPHA 1 ANTITRYPSIN; ALPHA INTERFERON; BIOLOGICAL PRODUCT; BUPRENORPHINE PLUS NALOXONE; CALCITONIN; CAPTOPRIL; CYTOCHROME P450 3A4; DIPHTHERIA TOXIN; DORNASE ALFA; EXENDIN 4; FENTANYL CITRATE; GLUTATHIONE; GOLD NANOPARTICLE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HEPATITIS B SURFACE ANTIGEN; HUMAN INSULIN; INSULIN; LYSOZYME; MYOGLOBIN; NEUROTOXIN; NISIN; OCTREOTIDE; PIG INSULIN; PROGESTERONE; RECOMBINANT HUMAN INSULIN; RECOMBINANT INTERLEUKIN 21; SALCATONIN; SALMONELLOSIS VACCINE; TOLUENE; UNINDEXED DRUG;

ACTIVE TRANSPORT; ARTICLE; BACTERIAL METABOLISM; BUCCAL DRUG ADMINISTRATION; CLINICAL TRIAL (TOPIC); COMPLEX FORMATION; CONTROLLED DRUG RELEASE; CYSTIC FIBROSIS; DIABETES MELLITUS; DRUG ABSORPTION; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG FORMULATION; DRUG RESISTANCE; DRUG SAFETY; DRUG UPTAKE; DRY DEPOSITION; DRY POWDER INHALER; ENZYME METABOLISM; FIBROSIS; FIRST PASS EFFECT; FOOD AND DRUG ADMINISTRATION; GASTROINTESTINAL TRACT; HUMAN; INHALATIONAL DRUG ADMINISTRATION; INSULIN DEPENDENT DIABETES MELLITUS; INTESTINE TRANSIT TIME; IONTOPHORESIS; LUNG ALVEOLUS EPITHELIUM; MALIGNANT NEOPLASM; METERED DOSE INHALER; MICRONEEDLE; NEBULIZER; NON INSULIN DEPENDENT DIABETES MELLITUS; PARTICLE SIZE; PERMEABILITY BARRIER; PH; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRODUCT DEVELOPMENT; PROTEIN DEGRADATION; PROTEIN STRUCTURE; RANDOMIZED CONTROLLED TRIAL (TOPIC); SKIN PERMEABILITY; SUBLINGUAL IMMUNOTHERAPY; TABLET; THERMAL ABLATION DELIVERY DEVICE; TRANSDERMAL DRUG ADMINISTRATION; DRUG ADMINISTRATION ROUTE;

BIOLOGICAL PRODUCTS; DRUG ADMINISTRATION ROUTES; HUMANS;

EID: 85012302294     PISSN: None     EISSN: 15507416     Source Type: Journal    
DOI: 10.1208/s12248-017-0054-z     Document Type: Article

References (200)

1. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655–72.
2. Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21–39.
3. Moroz E, Matoori S, Leroux J-C. Oral delivery of macromolecular drugs: where we are after almost 100 years of attempts. Adv Drug Deliv Rev. 2016;101:108–21.
4. Pavlou AK, Reichert JM. Recombinant protein therapeutics—success rates, market trends and values to 2010. Nat Biotechnol. 2004;22(12):1513–9.
5. Maher S, Ryan B, Duffy A, Brayden DJ. Formulation strategies to improve oral peptide delivery. Pharm Pat Anal. 2014;3(3):313–36.
6. Brayden DJ. Principles underlying peptide, protein and macromolecule interactions with noninjected mucosae: from oral to buccal and nasal delivery. It’s just mucosa get it. 2014;11–8.
7. Rosenmayr-Templeton L. The oral delivery of peptides and proteins: established versus recently patented approaches. Pharm Pat Anal. 2012;2(1):125–45.
8. Senel S, Rathbone MJ, Cansız M, Pather I. Recent developments in buccal and sublingual delivery systems. Expert Opin Drug Deliv. 2012;9(6):615–28.
9. Squier CA, Kremer MJ. Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr. 2001;2001(29):7–15.
10. Squier CA, Wertz PW. Structure and function of the oral mucosa and implications for drug delivery. In: Rathbone MJ, editor. Oral mucosal drug delivery. Informa Health Care. 1996.
11. Gandhi RB, Robinson JR. Oral cavity as a site for bioadhesive drug delivery. Adv Drug Deliv Rev. 1994;13(1–2):43–74.
12. Law S, Wertz PW, Swartzendruber DC, Squier CA. Regional variation in content, composition and organization of porcine epithelial barrier lipids revealed by thin-layer chromatography and transmission electron microscopy. Arch Oral Biol. 1995;40(12):1085–91.
13. Morales JO, McConville JT. Novel strategies for the buccal delivery of macromolecules. Drug Dev Ind Pharm. 2014;40(5):579–90.
14. Caon T, Jin L, Simões CMO, Norton RS, Nicolazzo JA. Enhancing the buccal mucosal delivery of peptide and protein therapeutics. Pharm Res. 2014;29:1–21.
15. Morales JO, McConville JT. Manufacture and characterization of mucoadhesive buccal films. Eur J Pharm Biopharm. 2011;77(2):187–99.
16. Nicolazzo JA, Reed BL, Finnin BC. Buccal penetration enhancers—how do they really work? J Control Release. 2005;105(1–2):1–15.
17. von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivistö KT. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004;75(3):172–83.
18. Gao X, Bhattacharya S, Chan WK, Jasti BR, Upadrashta B, Li X. Expression of P-glycoprotein and CYP3A4 along the porcine oral-gastrointestinal tract: implications on oral mucosal drug delivery. Drug Dev Ind Pharm. 2014;40(5):599–603.
19. Generex Biotechnology Corporation. Generex Oral-lyn delivered by Rapid-Mist spray system evolution of a concept to a viable pharmaceutical product [Internet]. [cited 2016 Feb 3]. Available from: http://www.generex.com/UserFiles/File/GenerexOral-lynWhitePaperAug2015.pdf.
20. Bernstein G. Delivery of insulin to the buccal mucosa utilizing the RapidMist system. Expert Opin Drug Deliv. 2008;5(9):1047–55.
21. Palermo A, Maddaloni E, Pozzilli P. Buccal spray insulin (Oralgen) for type 2 diabetes: what evidence? Expert Opin Biol Ther. 2012;12(6):767–72.
22. Adis Insight. Transbuccal insulin—MidaSol. Drug profile [Internet]. [cited 2016 Feb 3]. Available from: http://adisinsight.springer.com/drugs/800035425.
23. MonoSol Rx. Pharmfilm products [Internet]. [cited 2016 Feb 3]. Available from: http://www.monosolrx.com/content/pharmfilm-products/overview.htm.
24. Dexter AF, Malcolm AS, Middelberg APJ. Reversible active switching of the mechanical properties of a peptide film at a fluid–fluid interface. Nat Mater. 2006;5(6):502–6.
25. de Barros JMS, Scherer T, Charalampopoulos D, Khutoryanskiy VV, Edwards AD. A laminated polymer film formulation for enteric delivery of live vaccine and probiotic bacteria. J Pharm Sci. 2014;103(7):2022–32.
26. Dawson PL, Hirt DE, Rieck JR, Acton JC, Sotthibandhu A. Nisin release from films is affected by both protein type and film-forming method. Food Res Int. 2003;36(9–10):959–68.
27. Padgett T, Han IY, Dawson PL. Incorporation of food-grade antimicrobial compounds into biodegradable packaging films. J Food Prot. 1998;61(10):1330–5.
28. Giovino C, Ayensu I, Tetteh J, Boateng JS. An integrated buccal delivery system combining chitosan films impregnated with peptide loaded PEG-b-PLA nanoparticles. Colloids Surf B Biointerfaces. 2013;112:9–15.
29. Morales JO, Huang S, Williams RO, McConville JT. Films loaded with insulin-coated nanoparticles (ICNP) as potential platforms for peptide buccal delivery. Colloids Surf B Biointerfaces. 2014;122:38–45.
30. Leong KH, Chung LY, Noordin MI, Onuki Y, Morishita M, Takayama K. Lectin-functionalized carboxymethylated kappa-carrageenan microparticles for oral insulin delivery. Carbohydr Polym. 2011;86(2):555–65.
31. Rekha MR, Sharma CP. Synthesis and evaluation of lauryl succinyl chitosan particles towards oral insulin delivery and absorption. J Control Release. 2009;135(2):144–51.
32. Yin L, Ding J, He C, Cui L, Tang C, Yin C. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials. 2009;30(29):5691–700.
33. Colonna C, Genta I, Perugini P, Pavanetto F, Modena T, Valli M, et al. 5-Methyl-pyrrolidinone chitosan films as carriers for buccal administration of proteins. AAPS PharmSciTech. 2006;7(3):E107–13.
34. Soudry-Kochavi L, Naraykin N, Nassar T, Benita S. Improved oral absorption of exenatide using an original nanoencapsulation and microencapsulation approach. J Control Release Off J Control Release Soc. 2015;217:202–10.
35. Binkley N, Bolognese M, Sidorowicz-Bialynicka A, Vally T, Trout R, Miller C, et al. A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the oral calcitonin in postmenopausal osteoporosis (ORACAL) trial. J Bone Miner Res. 2012;27(8):1821–9.
36. Farhadian A, Dounighi NM, Avadi M. Enteric trimethyl chitosan nanoparticles containing hepatitis B surface antigen for oral delivery. Hum Vaccin Immunother. 2015;11(12):2811–8.
37. Shukla A, Singh B, Katare OP. Significant systemic and mucosal immune response induced on oral delivery of diphtheria toxoid using nano-bilosomes. Br J Pharmacol. 2011;164(2b):820–7.
38. Jin L, Boyd BJ, White PJ, Pennington MW, Norton RS, Nicolazzo JA. Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases. J Control Release. 2015;199:37–44.
39. Xie E, Kotha A, Biaco T, Sedani N, Zou J, Stashenko P, et al. Oral delivery of a novel recombinant Streptococcus mitis vector elicits robust vaccine antigen-specific oral mucosal and systemic antibody responses and T cell tolerance. PLoS One. 2015;10(11):e0143422.
40. Wang N, Wang T, Zhang M, Chen R, Niu R, Deng Y. Mannose derivative and lipid A dually decorated cationic liposomes as an effective cold chain free oral mucosal vaccine adjuvant-delivery system. Eur J Pharm Biopharm. 2014;88(1):194–206.
41. Zhen Y, Wang N, Gao Z, Ma X, Wei B, Deng Y, et al. Multifunctional liposomes constituting microneedles induced robust systemic and mucosal immunoresponses against the loaded antigens via oral mucosal vaccination. Vaccine. 2015;33(35):4330–40.
42. Ibrahim MA, Ismail A, Fetouh MI, Göpferich A. Stability of insulin during the erosion of poly(lactic acid) and poly(lactic-co-glycolic acid) microspheres. J Control Release. 2005;106(3):241–52.
43. Morales JO, Su R, McConville JT. The influence of recrystallized caffeine on water-swellable polymethacrylate mucoadhesive buccal films. AAPS PharmSciTech. 2013;14(2):475–84.
44. Giovino C, Ayensu I, Tetteh J, Boateng JS. Development and characterisation of chitosan films impregnated with insulin loaded PEG-b-PLA nanoparticles (NPs): a potential approach for buccal delivery of macromolecules. Int J Pharm. 2012;428(1–2):143–51.
45. Cui Z, Mumper RJ. Bilayer films for mucosal (Genetic) immunization via the buccal route in rabbits. Pharm Res. 2002;19(7):947–53.
46. Buanz ABM, Saunders MH, Basit AW, Gaisford S. Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing. Pharm Res. 2011;28:2386–92.
47. Genina N, Janßen EM, Breitenbach A, Breitkreutz J, Sandler N. Evaluation of different substrates for inkjet printing of rasagiline mesylate. Eur J Pharm Biopharm. 2013;85(3B):1075–83.
48. Montenegro-Nicolini M, Miranda V, Morales JO. Inkjet printing of proteins: an experimental approach. AAPS J. 2017;19(1):234–43.
49. Cossé A, König C, Lamprecht A, Wagner KG. Hot melt extrusion for sustained protein release: matrix erosion and in vitro release of PLGA-based implants. AAPS PharmSciTech. 2017;18(1):15–26.
50. Tortora GJ, Derrickson BH. Principles of anatomy and physiology. Wiley; 2008.
51. Narang N, Sharma J. Sublingual mucosa as a route for systemic drug delivery. Int J Pharm Pharm Sci. 2011;3 Suppl 2:18–22.
52. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery. Clin Pharmacokinet. 2002;41(9):661–80.
53. Lueβen HL, Bohner V, Perard D, Langguth P, Verhoef JC, De Boer AG, et al. Mucoadhesive polymers in peroral peptide drug delivery. V. Effect of poly (acrylates) on the enzymatic degradation of peptide drugs by intestinal brush border membrane vesicles. Int J Pharm. 1996;141(1):39–52.
54. Durfee S, Messina J, Khankari R. Fentanyl effervescent buccal tablets. Am J Drug Deliv. 2006;4(1):1–5.
55. Al-Waili NS, Hasan NA. Efficacy of sublingual verapamil in patients with severe essential hypertension: comparison with sublingual nifedipine. Eur J Med Res. 1999;4(5):193–8.
56. van Rooij K, Bloemers J, de Leede L, Goldstein I, Lentjes E, Koppeschaar H, et al. Pharmacokinetics of three doses of sublingual testosterone in healthy premenopausal women. Psychoneuroendocrinology. 2012;37(6):773–81.
57. Roth T, Krystal A, Steinberg FJ, Singh NN, Moline M. Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study. Sleep. 2013;36(2):189.
58. Parry-Strong A, Langdana F, Haeusler S, Weatherall M, Krebs J. Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial. N Z Med J. 2016;129(1436):67.
59. Darwish M, Kirby M, Jiang JG, Tracewell W, Robertson Jr P. Bioequivalence following buccal and sublingual placement of fentanyl buccal tablet 400 μg in healthy subjects. Clin Drug Investig. 2008;28(1):1–7.
60. Bredenberg S, Duberg M, Lennernäs B, Lennernäs H, Pettersson A, Westerberg M, et al. In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance. Eur J Pharm Sci. 2003;20(3):327–34.
61. Sinatra RS, Jahr JS, Watkins-Pitchford JM. The essence of analgesia and analgesics. Cambridge: Cambridge University Press; 2010.
62. Lintzeris N, Leung SY, Dunlop AJ, Larance B, White N, Rivas GR, et al. A randomised controlled trial of sublingual buprenorphine–naloxone film versus tablets in the management of opioid dependence. Drug Alcohol Depend. 2013;131(1):119–26.
63. Bellorini L, Nocelli L, Zoppetti G. Pharmaceutical composition for the sublingual administration of progesterone, and method for its preparation. Google Patents. 2015.
64. Shahtalebi MA, Tabbakhian M, Harandi NS. Formulation and evaluation of orally disintegrating tablets of captopril using natural super disintegrants. J Rep Pharm Sci J Rep Pharm Sci. 2014;3(1):54–64.
65. Davies A. A new fast-acting sublingual fentanyl (Recivit®) for treating breakthrough cancer pain. Eur Oncol Haematol. 2014;10(1):12.
66. Bowen T, Greenbaum J, Charbonneau Y, Hebert J, Filderman R, Sussman G, et al. Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2004;93(5):425–30.
67. Gedulin BR, Smith PA, Jodka CM, Chen K, Bhavsar S, Nielsen LL, et al. Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration. Int J Pharm. 2008;356(1):231–8.
68. Taylor DR. Single-dose fentanyl sublingual spray for breakthrough cancer pain. Clin Pharmacol. 2013;5:131–41.
69. Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov. 2003;2(4):289–95.
70. Patil NH, Devarajan PV. Insulin-loaded alginic acid nanoparticles for sublingual delivery. Drug Deliv. 2016;23(2):429–36.
71. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117(4):802–9.
72. Olsson B, Bondesson E, Borgstrom L, Edsbacker S. Pulmonary drug metabolism, clearance, and absorption. In: Smyth H, Hickey A, editors. Controlled pulmonary drug delivery. Controlled Release Society; 2011.
73. Burmeister Getz E, Fisher DM, Fuller R. Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma. J Clin Pharmacol. 2009;49(9):1025–36.
74. Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2010;181(12):1345–54.
75. Larson JL, Kang SK, Choi BI, Hedlund M, Aschenbrenner LM, Cecil B, et al. A safety evaluation of DAS181, a sialidase fusion protein, in rodents. Toxicol Sci. 2011;122(2):567–78.
76. An open label study to examine the effects of DAS181 administered by dry powder inhaler (DPI) or nebulized formulation in immunocompromised subjects with parainfluenza (PIV) infection (PIV) [Internet]. U.S. National Institutes of Health; 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT01924793?term=DAS181++inhaled&rank=1.
77. Diaz KT, Skaria S, Harris K, Solomita M, Lau S, Bauer K, et al. Delivery and safety of inhaled interferon-gamma in idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv. 2012;25(2):79–87.
78. A randomized, double-blinded, placebo-controlled, phase II inhaled interferon gamma-1b and antimycobacterials to treat pulmonary Mycobacterium Avium complex infections. U.S. National Institutes of Health; 2016.
79. Interferon gamma-1b by inhalation for the treatment of patients with cystic fibrosis [Internet]. U.S. National Institutes of Health; 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT00043316
80. Huland E, Heinzer H, Huland H, Yung R. Overview of interleukin-2 inhalation therapy. Cancer J Sci Am. 2000;6 Suppl 1:S104–12.
81. Posch C, Weihsengruber F, Bartsch K, Feichtenschlager V, Sanlorenzo M, Vujic I, et al. Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients. Br J Cancer. 2014;110(6):1427–32.
82. Aerosol IL-2 for pulmonary metastases [Internet]. U.S. National Institutes of Health; 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT01590069.
83. Inhaled sargramostim in treating patients with first pulmonary (lung) recurrence of osteosarcoma [Internet]. U.S. National Institute of Health; 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT02542813.
84. International study evaluating the safety and efficacy of inhaled, human, alpha-1 antitrypsin (AAT) in alpha-1 antitrypsin deficient patients with emphysema [Internet]. U.S. National Institutes of Health; 2014 [cited 2016 May 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT01217671.
85. Hasaneen N, Vu T, Fusiak T, Foda H, Condos R, Smaldone G. Anti-fibrotic role of inhaled interferon-γ in idiopathic pulmonary fibrosis. Eur Respir J. 2015;46(59).
86. Barnes PJ, Dixon CM. The effect of inhaled vasoactive intestinal peptide on bronchial reactivity to histamine in humans. Am Rev Respir Dis. 1984;130(2):162–6.
87. Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339–46.
88. Griese M, Kappler M, Eismann C, Ballmann M, Junge S, Rietschel E, et al. Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. Am J Respir Crit Care Med. 2013;188(1):83–9.
89. Depreter F, Pilcer G, Amighi K. Inhaled proteins: challenges and perspectives. Int J Pharm. 2013;447(1–2):251–80.
90. Bellary S, Barnett AH. Inhaled insulin: new technology, new possibilities. Int J Clin Pract. 2006;60(6):728–34.
91. Muchmore DB, Silverman B, De La Pena A, Tobian J. The AIR inhaled insulin system: system components and pharmacokinetic/glucodynamic data. Diabetes Technol Ther. 2007;9 Suppl 1:S41–7.
92. Steiner S, Pfutzner A, Wilson BR, Harzer O, Heinemann L, Rave K. Technosphere/insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes. 2002;110(1):17–21.
93. Thipphawong J, Otulana B, Clauson P, Okikawa J, Farr SJ. Pulmonary insulin administration using the AERx insulin diabetes system. Diabetes Technol Ther. 2002;4(4):499–504.
94. TM—inhalable insulin product candidate for diabetes. Newswire P, editor. 2013 [cited 2016 Mar 21]; Available from: http://www.prnewswire.com/news-releases/dance-biopharm-announces-encouraging-clinical-data-for-adagio---inhalable-insulin-product-candidate-for-diabetes-219384281.html.
95. Pfutzner A, Forst T. Pulmonary insulin delivery by means of the Technosphere drug carrier mechanism. Expert Opin Drug Deliv. 2005;2(6):1097–106.
96. Patton JS, Trinchero P, Platz RM. Special issue proceedings of the sixth international symposium on recent advances in drug delivery systems bioavailability of pulmonary delivered peptides and proteins: α-interferon, calcitonins and parathyroid hormones. J Control Release. 1994;28(1):79–85.
97. Martin PL, Vaidyanathan S, Lane J, Rogge M, Gillette N, Niggemann B, et al. Safety and systemic absorption of pulmonary delivered human IFN-beta1a in the nonhuman primate: comparison with subcutaneous dosing. J Interferon Cytokine Res. 2002;22(6):709–17.
98. Vallee S, Rakhe S, Reidy T, Walker S, Lu Q, Sakorafas P, et al. Pulmonary administration of interferon beta-1a-fc fusion protein in non-human primates using an immunoglobulin transport pathway. J Interferon Cytokine Res. 2012;32(4):178–84.
99. Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir Res. 2001;2(4):198–209.
100. Inhaled interleukin-2 in treating patients with metastatic or unresectable cancer [Internet]. U.S. National Institutes of Health; 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT00003009.
101. Niven R, Lott F, Cribbs J. Pulmonary absorption of recombinant methionyl human granulocyte colony stimulating factor (r-huG-CSF) after intratracheal instillation to the hamster. Pharm Res. 1993;10(11):1604–10.
102. Niven RW, Whitcomb KL, Shaner L, Ip AY, Kinstler OB. The pulmonary absorption of aerosolized and intratracheally instilled rhG-CSF and monoPEGylated rhG-CSF. Pharm Res. 1995;12(9):1343–9.
103. Walvoord EC, de la Pena A, Park S, Silverman B, Cuttler L, Rose SR, et al. Inhaled growth hormone (GH) compared with subcutaneous GH in children with GH deficiency: pharmacokinetics, pharmacodynamics, and safety. J Clin Endocrinol Metab. 2009;94(6):2052–9.
104. Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ, et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci U S A. 2004;101(26):9763–8.
105. Dumont JA, Bitonti AJ, Clark D, Evans S, Pickford M, Newman SP. Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. J Aerosol Med. 2005;18(3):294–303.
106. Belser JA, Lu X, Szretter KJ, Jin X, Aschenbrenner LM, Lee A, et al. DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection. J Infect Dis. 2007;196(10):1493–9.
107. Bendstrup KE, Gram J, Jensen JI. Effect of inhaled heparin on lung function and coagulation in healthy volunteers. Eur Respir J. 2002;19(4):606–10.
108. Glas GJ, Muller J, Binnekade JM, Cleffken B, Colpaert K, Dixon B, et al. HEPBURN—investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial. Trials. 2014;15:91.
109. Low SC, Nunes SL, Bitonti AJ, Dumont JA. Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis. Hum Reprod. 2005;20(7):1805–13.
110. Ryszka F, Dolinska B. Initial studies on the administration route of prolactin. Boll Chim Farm. 2001;140(3):169–71.
111. Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 2004;1:338–44.
112. Gupta S, Moussy F, Dalby RN, Miekka SI, Bruley DF. Pulmonary delivery of human protein c and factor IX. In: Nemoto EM, et al., editors. Advances in experimental medicine and biology. New York: Springer; 1997. p. 429–35.
113. Kang KA, Anis NA, Eldefrawi ME, Drohan W, Bruley DF. Reusable, real-time, immuno-optical protein C biosensor. In: Nemoto EM, et al., editors. Oxygen transport to tissue XVIII. New York: Springer; 1997. p. 437–44.
114. Woods A, Patel A, Spina D, Riffo-Vasquez Y, Babin-Morgan A, de Rosales RT, et al. In vivo biocompatibility, clearance, and biodistribution of albumin vehicles for pulmonary drug delivery. J Control Release. 2015;210:1–9.
115. Deftos LJ, Nolan JJ, Seely BL, Clopton PL, Cote GJ, Whitham CL, et al. Intrapulmonary drug delivery of salmon calcitonin. Calcif Tissue Int. 1997;61(4):345–7.
116. Adjei A, Sundberg D, Miller J, Chun A. Bioavailability of leuprolide acetate following nasal and inhalation delivery to rats and healthy humans. Pharm Res. 1992;9(2):244–9.
117. Adjei A, Garren J. Pulmonary delivery of peptide drugs: effect of particle size on bioavailability of leuprolide acetate in healthy male volunteers. Pharm Res. 1990;7(6):565–9.
118. Lizio R, Klenner T, Borchard G, Romeis P, Sarlikiotis AW, Reissmann T, et al. Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation in anesthetized rats. Eur J Pharm Sci. 2000;9(3):253–8.
119. Kuehl PJ, Boyden T, Dobry DE, Doyle-Eisele M, Friesen DT, McDonald JD, et al. Inhaled PYY(3–36) dry-powder formulation for appetite suppression. Drug Dev Ind Pharm. 2015;26:1–7.
120. A study designed to determine the safety and pharmacological response of MKC253 inhalation powder in adults with type 2 diabetes mellitus. U.S. National Institutes of Health; 2016.
121. Prankerd RJ, Nguyen TH, Ibrahim JP, Bischof RJ, Nassta GC, Olerile LD, et al. Pulmonary delivery of an ultra-fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries. PLoS One. 2013;8(12):e82965.
122. Bennett DB, Tyson E, Nerenberg CA, Mah S, de Groot JS, Teitelbaum Z. Pulmonary delivery of detirelix by intratracheal instillation and aerosol inhalation in the briefly anesthetized dog. Pharm Res. 1994;11(7):1048–55.
123. Sheehy AM, Hoover JL, Rush BD, Wilkinson KF, et al. Intrapulmonary delivery of renin inhibitory peptides results in sustained release because of saturable transport. Pharm Res. 1993;10(10):1548–51.
124. Taljanski W, Pierzynowski SG, Lundin PD, Westrom BR, Eirefelt S, Podlesny J, et al. Pulmonary delivery of intratracheally instilled and aerosolized cyclosporine A to young and adult rats. Drug Metab Dispos. 1997;25(8):917–20.
125. Welschoff J, Matthey M, Wenzel D. RGD peptides induce relaxation of pulmonary arteries and airways via beta3-integrins. FASEB J. 2014;28(5):2281–92.
126. Vasoactive intestinal peptide in COPD [Internet]. U.S. National Institutes of Health; 2007 [cited 2016 Jun 3]. Available from: https://clinicaltrials.gov/ct2/show/NCT00464932?term=vasoactive+intestinal+peptide&rank=2.
127. Leuchte HH, Baezner C, Baumgartner RA, Bevec D, Bacher G, Neurohr C, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32(5):1289–94.
128. Ca C. Excipient selection for protein stabilization. Pharm Technol. 2015;39(18):s35–9.
129. Bosquillon C, Lombry C, Preat V, Vanbever R. Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance. J Control Release. 2001;70(3):329–39.
130. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6(1):67–74.
131. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56(6):588–99.
132. Takano M, Kawami M, Aoki A, Yumoto R. Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells. Expert Opin Drug Deliv. 2015;12(5):813–25.
133. Taylor A, Townsley MI, Korthuis RJ. Macromolecule transport across the pulmonary microvessel walls. Exp Lung Res. 1985;8(2–3):97–123.
134. Champion JA, Walker A, Mitragotri S. Role of particle size in phagocytosis of polymeric microspheres. Pharm Res. 2008;25(8):1815–21.
135. Champion JA, Mitragotri S. Shape induced inhibition of phagocytosis of polymer particles. Pharm Res. 2009;26(1):244–9.
136. Edwards DA, Hanes J, Caponetti G, Hrkach J, et al. Large porous particles for pulmonary drug delivery. Science. 1997;276(5320):1868–72.
137. Morita T, Yamamoto A, Takakura Y, Hashida M, Sezaki H. Improvement of the pulmonary absorption of (Asu1,7)-eel calcitonin by various protease inhibitors in rats. Pharm Res. 1994;11(6):909–13.
138. Kim KJ, Malik AB. Protein transport across the lung epithelial barrier. Am J Physiol Lung Cell Mol Physiol. 2003;284(2):L247–59.
139. Weers JG, Bell J, Chan HK, Cipolla D, Dunbar C, Hickey AJ, et al. Pulmonary formulations: what remains to be done? J Aerosol Med Pulm Drug Deliv. 2010;23 Suppl 2:S5–23.
140. Morales JO, Peters JI, Williams III RO. Surfactants—their critical role in enhancing drug delivery to the lungs. Ther Deliv. 2011;2(5):623–41.
141. Zheng J, Zheng Y, Chen J, Fang F, He J, Li N, et al. Enhanced pulmonary absorption of recombinant human insulin by pulmonary surfactant and phospholipid hexadecanol tyloxapol through Calu-3 monolayers. Pharmazie. 2012;67(5):448–51.
142. Yamamoto A, Tanaka H, Okumura S, Shinsako K, Ito M, Yamashita M, et al. Evaluation of insulin permeability and effects of absorption enhancers on its permeability by an in vitro pulmonary epithelial system using Xenopus pulmonary membrane. Biol Pharm Bull. 2001;24(4):385–9.
143. Shao ZLY, Li Y, Mitra AK. Cyclodextrins as mucosal absorption promoters of insulin. III: pulmonary route of delivery. Eur J Pharm Biopharm. 1994;40:283–8.
144. Mack GS. Pfizer dumps Exubera. Nat Biotechnol. 2007;25(12):1331–2.
145. Siekmeier R, Scheuch G. Inhaled insulin—does it become reality? J Physiol Pharmacol. 2008;59 Suppl 6:81–113.
146. Hickey AJ. Back to the future: inhaled drug products. J Pharm Sci. 2013;102(4):1165–72.
147. Newman SP. Principles of metered-dose inhaler design. Respir Care. 2005;50(9):1177–90.
148. Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011;105(6):930–8.
149. Adjei A, Gupta P. Pulmonary delivery of therapeutic peptides and proteins. J Control Release. 1994;29(3):361–73.
150. Byron PR. Determinants of polypeptide bioavailability from aerosols delivered to the lung. Adv Drug Deliv Rev. 1990;5(1–2):107–32.
151. Shoyele SA, Slowey A. Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery. Int J Pharm. 2006;314(1):1–8.
152. Quinn EA, Forbes RT, Williams AC, Oliver MJ, McKenzie L, Purewal TS. Protein conformational stability in the hydrofluoroalkane propellants tetrafluoroethane and heptafluoropropane analysed by Fourier transform Raman spectroscopy. Int J Pharm. 1999;186(1):31–41.
153. Hertel SP, Winter G, Friess W. Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev. 2015;93:79–94.
154. Carpenter JF. Rational design of stable protein formulations: theory and practice. In: Carpenter J, et al., editors. Rational design of stable protein formulations: theory and practice. Springer; 2002.
155. Islam N, Gladki E. Dry powder inhalers (DPIs)—a review of device reliability and innovation. Int J Pharm. 2008;360(1–2):1–11.
156. Yang M, Lai SK, Wang YY, Zhong W, Happe C, Zhang M, et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew Chem Int Ed Engl. 2011;50(11):2597–600.
157. Chen D, Xia D, Li X, Zhu Q, Yu H, Zhu C, et al. Comparative study of Pluronic((R)) F127-modified liposomes and chitosan-modified liposomes for mucus penetration and oral absorption of cyclosporine A in rats. Int J Pharm. 2013;449(1–2):1–9.
158. Leach CL, Kou M, Bueche B, et al. Modifying the pulmonary absorption and retention of proteins through PEGylation. Respir Drug Deliv IX. 2004;1:69–77.
159. Foldvari M, Chen DW, Nafissi N, Calderon D, Narsineni L, Rafiee A. Non-viral gene therapy: gains and challenges of non-invasive administration methods. J Control Release [Internet]. 2015 Dec 11; Available from: http://www.ncbi.nlm.nih.gov/pubmed/26686079.
160. Griesenbach U, Pytel KM, Alton EW. Cystic fibrosis gene therapy in the UK and elsewhere. Hum Gene Ther. 2015;26(5):266–75.
161. Mastorakos P, da Silva AL, Chisholm J, Song E, Choi WK, Boyle MP, et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc Natl Acad Sci U S A. 2015;112(28):8720–5.
162. Feng F, Harper RL, Reynolds PN. BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-beta-mediated pulmonary cell signalling. Respirology [Internet]. 2015 Dec 21; Available from: http://www.ncbi.nlm.nih.gov/pubmed/26689975.
163. Schoellhammer CM, Blankschtein D, Langer R. Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert Opin Drug Deliv. 2014;11(3):393–407.
164. Singh N, Kalluri H, Herwadkar A, Badkar A, Banga AK. Transcending the skin barrier to deliver peptides and proteins using active technologies. Crit Rev Ther Drug Carrier Syst. 2012;29(4):265–98.
165. Choy YB, Prausnitz MR. The rule of five for non-oral routes of drug delivery: ophthalmic, inhalation and transdermal. Pharm Res. 2011;28(5):943–8.
166. Rothbard JB, Garlington S, Lin Q, Kirschberg T, Kreider E, McGrane PL, et al. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat Med. 2000;6(11):1253–7.
167. Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by magainin pore-forming peptide. J Control Release. 2007;122(3):375–83.
168. Hsu T, Mitragotri S. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc Natl Acad Sci U S A. 2011;108(38):15816–21.
169. Chen Y, Shen Y, Guo X, Zhang C, Yang W, Ma M, et al. Transdermal protein delivery by a coadministered peptide identified via phage display. Nat Biotechnol. 2006;24(4):455–60.
170. Karande P, Mitragotri S. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim Biophys Acta. 2009;1788(11):2362–73.
171. Ita K. Perspectives on transdermal electroporation. Pharmaceutics [Internet]. 2016;8(1). Available from: http://www.ncbi.nlm.nih.gov/pubmed/26999191.
172. Sen A, Daly ME, Hui SW. Transdermal insulin delivery using lipid enhanced electroporation. Biochim Biophys Acta Biomembr. 2002;1564(1):5–8.
173. Prausnitz MR, Edelman E, Gimm J, Langer R, Weaver J. Transdermal delivery of heparin by skin electroporation. Biotechnology. 1995;13(11):1205–9.
174. Azagury A, Khoury L, Enden G, Kost J. Ultrasound mediated transdermal drug delivery. Adv Drug Deliv Rev. 2014;72:127–43.
175. Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery. Science. 1995;269(5225):850–3.
176. Mitragotri S, Kost J. Transdermal delivery of heparin and low-molecular weight heparin using low-frequency ultrasound. Pharm Res. 2001;18(8):1151–6.
177. Dahlan A, Alpar HO, Stickings P, Sesardic D, Murdan S. Transcutaneous immunisation assisted by low-frequency ultrasound. Int J Pharm. 2009;368(1):123–8.
178. Tran MA, Gowda R, Park E, Adair J, Smith N, Kester M, et al. Noninvasive drug delivery using ultrasound: targeting melanoma using siRNA against mutant (V600E) B‐Raf. AIP Conf Proc. 2009;1113(1):423–7.
179. Li YZ, Quan YS, Zang L, Jin MN, Kamiyama F, Katsumi H, et al. Trypsin as a novel potential absorption enhancer for improving the transdermal delivery of macromolecules. J Pharm Pharmacol. 2009;61(8):1005–12.
180. Huang Y, Yu F, Park YS, Wang J, Shin MC, Chung HS, et al. Co-administration of protein drugs with gold nanoparticles to enable percutaneous delivery. Biomaterials. 2010;31(34):9086–91.
181. Gratieri T, Kalaria D, Kalia YN. Non-invasive iontophoretic delivery of peptides and proteins across the skin. Expert Opin Drug Deliv. 2011;8(5):645–63.
182. Kochhar C, Imanidis G. In vitro transdermal iontophoretic delivery of leuprolide under constant current application. J Control Release. 2004;98(1):25–35.
183. Langkjaer L, Brange J, Grodsky GM, Guy RH. Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment. J Control Release. 1998;51(1):47–56.
184. Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.
185. Levin G, Gershonowitz A, Sacks H, Stern M, Sherman A, Rudaev S, et al. Transdermal delivery of human growth hormone through RF-microchannels. Pharm Res. 2005;22(4):550–5.
186. 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.
187. Mikszta JA, Alarcon JB, Brittingham JM, Sutter DE, Pettis RJ, Harvey NG. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat Med. 2002;8(4):415–9.
188. Glenn GM, Flyer DC, Ellingsworth LR, Frech SA, Frerichs DM, Seid RC, et al. Transcutaneous immunization with heat-labile enterotoxin: development of a needle-free vaccine patch. Expert Rev Vaccines. 2007;6(5):809–19.
189. Andrews S, Lee JW, Choi SO, Prausnitz MR. Transdermal insulin delivery using microdermabrasion. Pharm Res. 2011;28(9):2110–8.
190. Caffarel-Salvador E, Donnelly RF. Transdermal drug delivery mediated by microneedle arrays: innovations and barriers to success. Curr Pharm Des. 2016;22(9):1105–17.
191. Gill HS, Denson DD, Burris BA, Prausnitz MR. Effect of microneedle design on pain in human volunteers. Clin J Pain. 2008;24(7):585–94.
192. Norman JJ, Arya JM, McClain MA, Frew PM, Meltzer MI, Prausnitz MR. Microneedle patches: usability and acceptability for self-vaccination against influenza. Vaccine. 2014;32(16):1856–62.
193. Arya J, Prausnitz MR. Microneedle patches for vaccination in developing countries. J Control Release [Internet]. 2015 Nov 18; Available from: http://www.ncbi.nlm.nih.gov/pubmed/26603347.
194. Rini CJ, McVey E, Sutter D, Keith S, Kurth HJ, Nosek L, et al. Intradermal insulin infusion achieves faster insulin action than subcutaneous infusion for 3-day wear. Drug Deliv Transl Res. 2015;5(4):332–45.
195. Norman JJ, Brown MR, Raviele NA, Prausnitz MR, Felner EI. Faster pharmacokinetics and increased patient acceptance of intradermal insulin delivery using a single hollow microneedle in children and adolescents with type 1 diabetes. Pediatr Diabetes. 2013;14(6):459–65.
196. Skountzou I, Compans RW. Skin immunization with influenza vaccines. Curr Top Microbiol Immunol. 2015;386:343–69.
197. Cosman F, Lane NE, Bolognese MA, Zanchetta JR, Garcia-Hernandez PA, Sees K, et al. Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2010;95(1):151–8.
198. Pettis RJ, Harvey AJ. Microneedle delivery: clinical studies and emerging medical applications. Ther Deliv. 2012;3(3):357–71.
199. Leroux-Roels I, Weber F. Intanza ((R)) 9 microg intradermal seasonal influenza vaccine for adults 18 to 59 years of age. Hum Vaccin Immunother. 2013;9(1):115–21.
200. Hirobe S, Azukizawa H, Hanafusa T, Matsuo K, Quan YS, Kamiyama F, et al. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Biomaterials. 2015;57:50–8.