Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts

Advanced Drug Delivery Reviews - Tập 101 - Trang 108-121 - 2016
Elena Moroz1, Simon Matoori1, Jean-Christophe Leroux1
1ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland

Tài liệu tham khảo

Joslin, 1922, Insulin in hospital and home, J. Metab. Res., 2, 651 Choonara, 2014, A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules, Biotechnol. Adv., 32, 1269, 10.1016/j.biotechadv.2014.07.006 Hwang, 2014, Advances in oral macromolecular drug delivery, Expert Opin. Drug Deliv., 11, 1955, 10.1517/17425247.2014.945420 Fuhrmann, 2014, Improving the stability and activity of oral therapeutic enzymes-recent advances and perspectives, Pharm. Res., 31, 1099, 10.1007/s11095-013-1233-y Goldberg, 2003, Challenges for the oral delivery of macromolecules, Nat. Rev. Drug Discov., 2, 289, 10.1038/nrd1067 Ménard, 2010, Multiple facets of intestinal permeability and epithelial handling of dietary antigens, Mucosal Immunol., 3, 247, 10.1038/mi.2010.5 Rieux, 2013, Targeted nanoparticles with novel non-peptidic ligands for oral delivery, Adv. Drug Deliv. Rev., 65, 833, 10.1016/j.addr.2013.01.002 Jepson, 2004, M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery, Adv. Drug Deliv. Rev., 56, 511, 10.1016/j.addr.2003.10.018 Jepson, 1998, Studying M cells and their role in infection, Trends Microbiol., 6, 359, 10.1016/S0966-842X(98)01337-7 Maher, 2012, Overcoming poor permeability: translating permeation enhancers for oral peptide delivery, Drug Discov. Today Technol., 9, e71, 10.1016/j.ddtec.2011.11.006 Tillman, 2008, Oral delivery of antisense oligonucleotides in man, J. Pharm. Sci., 97, 225, 10.1002/jps.21084 Doak, 2014, Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates, Chem. Biol., 21, 1115, 10.1016/j.chembiol.2014.08.013 Wang, 2015, Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies, Protein Cell, 6, 480, 10.1007/s13238-015-0164-2 O'Ryan, 2015, Vaccines for viral and bacterial pathogens causing acute gastroenteritis: part I: overview, vaccines for enteric viruses and Vibrio cholerae, Hum. Vaccin. Immunother., 11, 584, 10.1080/21645515.2015.1011019 O'Ryan, 2015, Vaccines for viral and bacterial pathogens causing acute gastroenteritis: part II: vaccines for Shigella, Salmonella, enterotoxigenic E. coli (ETEC) enterohemorragic E. coli (EHEC) and Campylobacter jejuni, Hum. Vaccin. Immunother., 11, 601, 10.1080/21645515.2015.1011578 Lycke, 2012, Recent progress in mucosal vaccine development: potential and limitations, Nat. Rev. Immunol., 12, 592, 10.1038/nri3251 Jones, 2015, Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications, Crit. Rev. Biotechnol., 10.3109/07388551.2014.992388 Mangsbo, 2009, Complement activation by CpG in a human whole blood loop system: mechanisms and immunomodulatory effects, J. Immunol., 183, 6724, 10.4049/jimmunol.0902374 Pawar, 2014, Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: strategies and industrial perspectives, J. Control. Release, 196, 168, 10.1016/j.jconrel.2014.09.031 Levine, 2006, Vancomycin: a history, Clin. Infect. Dis., 42, S5, 10.1086/491709 van Wageningen, 1998, Sequencing and analysis of genes involved in the biosynthesis of a vancomycin group antibiotic, Chem. Biol., 5, 155, 10.1016/S1074-5521(98)90060-6 Jordan, 1959, Selective inhibition of ribonucleic acid synthesis in Staphylococcus aureus by vancomycin, Nature, 184, 1894, 10.1038/1841894b0 Lemaitre, 2015, Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood, Crit. Care., 19, 10.1186/s13054-015-0772-5 Rao, 2011, Systemic absorption of oral vancomycin in patients with Clostridium difficile infection, Scand. J. Infect. dis., 43, 386, 10.3109/00365548.2010.544671 Mullane, 2014, Fidaxomicin in Clostridium difficile infection: latest evidence and clinical guidance, Ther. Adv. Chronic Dis., 5, 69, 10.1177/2040622313511285 Jarrad, 2015, Clostridium difficile drug pipeline: challenges in discovery and development of new agents, J. Med. Chem., 58, 5164, 10.1021/jm5016846 Ivarsson, 2015, Investigational new treatments for clostridium difficile infection, Drug Discov. Today, 20, 602, 10.1016/j.drudis.2014.12.003 Bryant, 2010, Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract, Life Sci., 86, 760, 10.1016/j.lfs.2010.03.015 Busby, 2010, Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit, Eur. J. Pharmacol., 649, 328, 10.1016/j.ejphar.2010.09.019 Castro, 2013, Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3′,5′-monophosphate, Gastroenterology, 145, 1334, 10.1053/j.gastro.2013.08.017 Layer, 2014, Review article: linaclotide for the management of irritable bowel syndrome with constipation, Aliment. Pharm. Ther., 39, 371, 10.1111/apt.12604 Busby, 2013, Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation, J. Pharmacol. Exp. Ther., 344, 196, 10.1124/jpet.112.199430 Liu, 2009, In vivo imaging of human colorectal cancer using radiolabeled analogs of the uroguanylin peptide hormone, Anticancer Res., 29, 3777 Miner, 2013, 925g Plecanatide, a novel guanylate cyclase-C (GC-C) receptor agonist, is efficacious and safe in patients with chronic idiopathic constipation (CIC): results from a 951 patient, 12 week, multi-center trial, Gastroenterology, 144, 10.1016/S0016-5085(13)60585-5 Shailubhai, 2012, SP-333, a guanylate cyclase C agonist, ameliorates DSS-colitis in mice via a novel cyclic GMP-mediated mechanism: P-198, Inflamm. Bowel Dis., 18, S93, 10.1097/00054725-201212001-00231 Chaparro, 2012, Systematic review: antibodies and anti-TNF-α levels in inflammatory bowel disease, Aliment. Pharm. Ther., 35, 971 Lakatos, 2010, Is there an increased risk of lymphoma and malignancies under anti-TNF therapy in IBD?, Curr. Drug Targets, 11, 179, 10.2174/138945010790309867 Ford, 2013, Opportunistic infections with anti-tumor necrosis factor-α therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials, Am. J. Gastroenterol., 108, 1268, 10.1038/ajg.2013.138 Bhol, 2013, AVX-470: a novel oral anti-TNF antibody with therapeutic potential in inflammatory bowel disease, Inflamm. Bowel Dis., 19, 2273, 10.1097/MIB.0b013e3182a11958 Hurley, 2011, Perspectives on immunoglobulins in colostrum and milk, Nutrients, 3, 442, 10.3390/nu3040442 Kelly, 1997, Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract, Antimicrob. Agents Chemother., 41, 236, 10.1128/AAC.41.2.236 Warny, 1999, Bovine immunoglobulin concentrate-clostridium difficile retains C. difficile toxin neutralising activity after passage through the human stomach and small intestine, Gut, 44, 212, 10.1136/gut.44.2.212 Vandenbroucke, 2010, Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis, Mucosal Immunol., 3, 49, 10.1038/mi.2009.116 Fraissl, 2011, Novel formulation of neutral lactase improves digestion of dairy products in case of lactose intolerance, Clin. Transl. Allergy., 1, P104, 10.1186/2045-7022-1-S1-P104 Montalto, 2006, Management and treatment of lactose malabsorption, World J. Gastroenterol., 12, 187, 10.3748/wjg.v12.i2.187 Matoori, 2013, Celiac disease: a challenging disease for pharmaceutical scientists, Pharm. Res., 30, 619, 10.1007/s11095-012-0951-x Fuhrmann, 2013, Sustained gastrointestinal activity of dendronized polymer-enzyme conjugates, Nat. Chem., 5, 582, 10.1038/nchem.1675 Hoskins, 1980, Enzymatic control of phenylalanine intake in phenylketonuria, Lancet, 1, 392, 10.1016/S0140-6736(80)90944-7 Gass, 2005, Fermentation, purification, formulation, and pharmacological evaluation of a prolyl endopeptidase from Myxococcus xanthus: implications for celiac sprue therapy, Biotechnol. Bioeng., 92, 674, 10.1002/bit.20643 Schulz, 2015, Site-specific polymer conjugation stabilizes therapeutic enzymes in the gastrointestinal tract, Adv. Mater. Limaye, 2013, Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy, Cancer, 119, 4268, 10.1002/cncr.28365 Caluwaerts, 2010, AG013, a mouth rinse formulation of Lactococcus lactis secreting human trefoil factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis, Oral Oncol., 46, 564, 10.1016/j.oraloncology.2010.04.008 Vermeire, 2010, 46 A phase 2a randomized placebo-controlled double-blind multi-center dose escalation study to evaluate the safety, tolerability, pharmacodynamics and efficacy of AG011 in patients with moderately active ulcerative colitis, Gastroenterology, 138, 10.1016/S0016-5085(10)60041-8 Galipeau, 2014, Novel role of the serine protease inhibitor elafin in gluten-related disorders, Am. J. Gastroenterol., 109, 748, 10.1038/ajg.2014.48 Lee, 2013, Is there a future for cell-penetrating peptides in oligonucleotide delivery?, Eur. J. Pharm. Biopharm., 85, 5, 10.1016/j.ejpb.2013.03.021 Kriegel, 2013, Multi-compartmental oral delivery systems for nucleic acid therapy in the gastrointestinal tract, Adv. Drug Deliv. Rev., 65, 891, 10.1016/j.addr.2012.11.003 O'Neill, 2011, Intestinal delivery of non-viral gene therapeutics: physiological barriers and preclinical models, Drug Discov. Today, 16, 203, 10.1016/j.drudis.2011.01.003 An, 2014, Non-enzymatic depurination of nucleic acids: factors and mechanisms, PLoS ONE, 9, 10.1371/journal.pone.0115950 Putney, 1981, A DNA fragment with an alpha-phosphorothioate nucleotide at one end is asymmetrically blocked from digestion by exonuclease III and can be replicated in vivo, Proc. Natl. Acad. Sci. U. S. A., 78, 7350, 10.1073/pnas.78.12.7350 Deleavey, 2012, Designing chemically modified oligonucleotides for targeted gene silencing, Chem. Biol., 19, 937, 10.1016/j.chembiol.2012.07.011 Monteleone, 2015, Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease, N. Engl. J. Med., 372, 1104, 10.1056/NEJMoa1407250 Monteleone, 2012, Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease, Mol. Ther., 20, 870, 10.1038/mt.2011.290 Vegter, 2013, Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis, Aliment. Pharm. Ther., 38, 284, 10.1111/apt.12369 Miner, 2004, An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis, Aliment. Pharm. Ther., 19, 281, 10.1111/j.1365-2036.2004.01863.x Inomata, 1996, Alteration of beta-catenin expression in colonic epithelial cells of familial adenomatous polyposis patients, Cancer Res., 56, 2213 Vaze, 2014, Engineering of trans kingdom RNAi (tkRNAi) against gastrointestinal polyps, Cancer Res., 72, 5706, 10.1158/1538-7445.AM2012-5706 Lee, 2014, Activatable cell penetrating peptide–peptide nucleic acid conjugate via reduction of azobenzene PEG chains, J. Am. Chem. Soc., 136, 12868, 10.1021/ja507547w Wang, 2015, Toward oral delivery of biopharmaceuticals: an assessment of the gastrointestinal stability of 17 peptide drugs, Mol. Pharm., 12, 966, 10.1021/mp500809f Pohl, 1995, Structure of octreotide, a somatostatin analogue, Acta Crystallogr. D., 51, 48, 10.1107/S0907444994006104 Thanou, 2000, Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo, J. Pharm. Sci., 89, 951, 10.1002/1520-6017(200007)89:7<951::AID-JPS13>3.0.CO;2-1 Köhler, 1987, Absorption of an aqueous solution of a new synthetic somatostatin analogue administered to man by gavage, Eur. J. Clin. Pharmacol., 33, 167, 10.1007/BF00544562 Tuvia, 2014, A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms, Pharm. Res., 31, 2010, 10.1007/s11095-014-1303-9 Tuvia, 2012, Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression, J. Clin. Endocrinol. Metab., 97, 2362, 10.1210/jc.2012-1179 Melmed, 2015, Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial, J. Clin. Endocrinol. Metab., 100, 1699, 10.1210/jc.2014-4113 Robinson, 1976, DDAVP in the treatment of central diabetes insipidus, N. Engl. J. Med., 294, 507, 10.1056/NEJM197603042941001 Lundin, 1990, Absorption of a vasopressin analogue, 1-deamino-8-d-arginine-vasopressin (dDAVP), in a human intestinal epithelial cell line, CaCO-2, Int. J. Pharm., 64, 181, 10.1016/0378-5173(90)90267-8 Fjellestad-Paulsen, 1993, Pharmacokinetics of 1-deamino-8-D-arginine vasopressin after various routes of administration in healthy volunteers, Clin. Endocrinol., 38, 177, 10.1111/j.1365-2265.1993.tb00990.x Osterberg, 2006, Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults, J. Clin. Pharmacol., 46, 1204, 10.1177/0091270006291838 Rittig, 1998, Effect of food intake on the pharmacokinetics and antidiuretic activity of oral desmopressin (DDAVP) in hydrated normal subjects, Clin. Endocrinol., 48, 235, 10.1046/j.1365-2265.1998.00340.x Robson, 2007, The comparative safety of oral versus intranasal desmopressin for the treatment of children with nocturnal enuresis, J. Urol., 178, 24, 10.1016/j.juro.2007.03.015 Fricker, 1996, Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation, Br. J. Pharmacol., 118, 1841, 10.1111/j.1476-5381.1996.tb15612.x Beck, 2012, Intestinal permeability of cyclic peptides: common key backbone motifs identified, J. Am. Chem. Soc., 134, 12125, 10.1021/ja303200d Choc, 1997, Bioavailability and pharmacokinetics of cyclosporine formulations: neoral vs sandimmune, Int. J. Dermatol., 36, 1, 10.1046/j.1365-4362.36.s1.2.x Kovarik, 1994, Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation, J. Pharm. Sci., 83, 444, 10.1002/jps.2600830336 Mueller, 1994, Influence of a fat-rich meal on the pharmacokinetics of a new oral formulation of cyclosporine in a crossover comparison with the market formulation, Pharm. Res., 11, 151, 10.1023/A:1018922517162 Rivier, 1995, Gonadotropin-releasing hormone antagonists: novel members of the azaline B family, J. Med. Chem., 38, 2649, 10.1021/jm00014a017 Leonard, 2006, Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET, Expert Opin. Drug Del., 3, 685, 10.1517/17425247.3.5.685 Amory, 2009, Oral administration of the GnRH antagonist acyline, in a GIPET-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics, Cancer Chemother. Pharmacol., 64, 641, 10.1007/s00280-009-1038-1 Chesnut, 2008, Salmon calcitonin: a review of current and future therapeutic indications, Osteoporos. Int., 19, 479, 10.1007/s00198-007-0490-1 Petersen, 2013, Colonic absorption of salmon calcitonin using tetradecyl maltoside (TDM) as a permeation enhancer, Eur. J. Pharm. Sci., 48, 726, 10.1016/j.ejps.2013.01.009 Karsdal, 2008, Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: the effect of water and timing of meal intake on oral delivery of Salmon Calcitonin, BMC Clin. Pharmacol., 8, 10.1186/1472-6904-8-5 Karsdal, 2010, The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study, Osteoarthr. Cartil., 18, 150, 10.1016/j.joca.2009.08.004 Binkley, 2012, 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., 27, 1821, 10.1002/jbmr.1602 Welling, 2014, The role of citric acid in oral peptide and protein formulations: relationship between calcium chelation and proteolysis inhibition, Eur. J. Pharm. Biopharm., 86, 544, 10.1016/j.ejpb.2013.12.017 Binkley, 2014, Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized, placebo-controlled trial, Osteoporos. Int., 25, 2649, 10.1007/s00198-014-2796-0 Lempicki, 2014, Cancer risk associated with calcitonin use, J. Am. Geriatr. Soc., 62, 2447, 10.1111/jgs.13167 Lorenz, 2013, Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity, Bioorg. Med. Chem. Lett., 23, 4011, 10.1016/j.bmcl.2013.05.022 Heinemann, 2009, Oral insulin and buccal insulin: a critical reappraisal, J. Diabetes Sci. Technol., 3, 568, 10.1177/193229680900300323 Zijlstra, 2014, Oral insulin reloaded: a structured approach, J. Diabetes Sci. Technol., 8, 458, 10.1177/1932296814529988 Fonte, 2013, Oral insulin delivery: how far are we?, J. Diabetes Sci. Technol., 7, 520, 10.1177/193229681300700228 Maher, 2014, Formulation strategies to improve oral peptide delivery, Pharm. Pat. Anal., 3, 313, 10.4155/ppa.14.15 Luzio, 2010, The glucose lowering effect of an oral insulin (capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes, Diabetes Obes. Metab., 12, 82, 10.1111/j.1463-1326.2009.01146.x Eldor, 2010, Open-label study to assess the safety and pharmacodynamics of five oral insulin formulations in healthy subjects, Diabetes Obes. Metab., 12, 219, 10.1111/j.1463-1326.2009.01153.x Eldor, 2013, Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled type 1 diabetes: a pilot study, PLoS ONE, 8, 10.1371/journal.pone.0059524 Kidron, 2004, A novel per-oral insulin formulation: proof of concept study in non-diabetic subjects, Diabet. Med., 21, 354, 10.1111/j.1464-5491.2004.01160.x Hazra, 2010, Development of a process to manufacture PEGylated orally bioavailable insulin, Biotechnol. Prog., 26, 1695, 10.1002/btpr.487 Hazra, 2012, A novel one-pot de-blocking and conjugation reaction step leads to process intensification in the manufacture of PEGylated insulin IN-105, Bioprocess Biosyst. Eng., 35, 1333, 10.1007/s00449-012-0722-4 Khedkar, 2010, A dose range finding study of novel oral insulin (IN-105) under fed conditions in type 2 diabetes mellitus subjects, Diabetes Obes. Metab., 12, 659, 10.1111/j.1463-1326.2010.01213.x Geho, 2009, Hepatic-directed vesicle insulin: a review of formulation development and preclinical evaluation, J. Diabetes Sci. Technol., 3, 1451, 10.1177/193229680900300627 Geho, 2014, A single-blind, placebo-controlled, dose-ranging trial of oral hepatic-directed vesicle insulin add-on to oral antidiabetic treatment in patients with type 2 diabetes mellitus, J. Diabetes Sci. Technol., 8, 551, 10.1177/1932296814524871 Bernstein, 2008, Delivery of insulin to the buccal mucosa utilizing the RapidMist system, Expert Opin. Drug Del., 5, 1047, 10.1517/17425247.5.9.1047 Palermo, 2011, Buccal spray insulin in subjects with impaired glucose tolerance: the prevoral study, Diabetes Obes. Metab., 13, 42, 10.1111/j.1463-1326.2010.01312.x Khatsenko, 2000, Absorption of antisense oligonucleotides in rat intestine: effect of chemistry and length, Antisense Nucleic Acid Drug Dev., 10, 35, 10.1089/oli.1.2000.10.35 Dirin, 2013, Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides, Expert. Opin. Biol. Ther., 13, 875, 10.1517/14712598.2013.774366 Raoof, 2004, Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate, J. Pharm. Sci., 93, 1431, 10.1002/jps.20051 Brenner, 2003, The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis, FASEB J., 17, 214, 10.1096/fj.02-0609com Sussman, 2008, Antisense treatment for myasthenia gravis: experience with monarsen, Ann. N. Y. Acad. Sci., 1132, 283, 10.1196/annals.1405.022 Angelini, 2013, New treatments for myasthenia: a focus on antisense oligonucleotides, Drug Des. Devel. Ther., 7, 13, 10.2147/DDDT.S25716 Sussman, 2012, Further developments with antisense treatment for myasthenia gravis, Ann. N. Y. Acad. Sci., 1275, 13, 10.1111/j.1749-6632.2012.06825.x Bernkop-Schnürch, 1998, The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins, J. Control. Release, 52, 1, 10.1016/S0168-3659(97)00204-6 Watanabe, 1992, Mediation of trypsin inhibitor-induced pancreatic hypersecretion by secretin and cholecystokinin in rats, Gastroenterology, 102, 621, 10.1016/0016-5085(92)90111-B Otsuki, 1987, Effect of synthetic protease inhibitor camostate on pancreatic exocrine function in rats, Pancreas, 2, 164, 10.1097/00006676-198703000-00007 Melmed, 1976, Hypertrophy and hyperplasia of the neonatal rat exocrine pancreas induced by orally administered soybean trypsin inhibitor, Biochim. Biophys. Acta, 421, 280, 10.1016/0304-4165(76)90294-4 Ge, 1993, The effect of trypsin inhibitor on the pancreas and small intestine of mice, Br. J. Nutr., 70, 333, 10.1079/BJN19930126 Hastewell, 1995, The colonic absorption of human calcitonin: the effects of increasing local concentration and co-administration with a protease inhibitor, Int. J. Pharm., 126, 245, 10.1016/0378-5173(95)04134-6 Yamamoto, 1994, Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats, Pharm. Res., 11, 1496, 10.1023/A:1018968611962 Drapeau, 1992, Dissociation of the antimicrobial activity of bacitracin USP from its renovascular effects, Antimicrob. Agents Chemother., 36, 955, 10.1128/AAC.36.5.955 Gibo, 2005, Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity, Lab. Investig., 85, 75, 10.1038/labinvest.3700203 Coote, 2009, Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease, J. Pharmacol. Exp. Ther., 329, 764, 10.1124/jpet.108.148155 Aungst, 2012, Absorption enhancers: applications and advances, AAPS J., 14, 10, 10.1208/s12248-011-9307-4 Maher, 2009, Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic, Adv. Drug Deliv. Rev., 61, 1427, 10.1016/j.addr.2009.09.006 Krug, 2013, Sodium caprate as an enhancer of macromolecule permeation across tricellular tight junctions of intestinal cells, Biomaterials, 34, 275, 10.1016/j.biomaterials.2012.09.051 Quan, 1998, Effectiveness and toxicity screening of various absorption enhancers using Caco-2 cell monolayers, Biol. Pharm. Bull., 21, 615, 10.1248/bpb.21.615 Raoof, 2002, Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs, Eur. J. Pharm. Sci., 17, 131, 10.1016/S0928-0987(02)00162-8 Chao, 1999, In vitro and in vivo evaluation of effects of sodium caprate on enteral peptide absorption and on mucosal morphology, Int. J. Pharm., 191, 15, 10.1016/S0378-5173(99)00213-6 Lindmark, 1997, Mechanism of absorption enhancement in humans after rectal administration of ampicillin in suppositories containing sodium caprate, Pharm. Res., 14, 930, 10.1023/A:1012112219578 Alani, 2008, Mechanistic understanding of oral drug absorption enhancement of cromolyn sodium by an amino acid derivative, Pharm. Res., 25, 48, 10.1007/s11095-007-9438-6 Riley, 2009, Subchronic oral toxicity of salcaprozate sodium (SNAC) in Sprague–Dawley and Wistar rats, Int. J. Toxicol., 28, 278, 10.1177/1091581809337737 Hess, 2005, Investigation of the enhancing mechanism of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate effect on the intestinal permeability of polar molecules utilizing a voltage clamp method, Eur. J. Pharm. Sci., 25, 307, 10.1016/j.ejps.2005.03.003 Bittner, 2012, Phase I clinical study to select a novel oral formulation for ibandronate containing the excipient sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC), Pharmazie, 67, 233 Castelli, 2011, Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects, Clin. Ther., 33, 934, 10.1016/j.clinthera.2011.05.088 Steinert, 2010, Oral administration of glucagon-like peptide 1 or peptide YY 3-36 affects food intake in healthy male subjects, Am. J. Clin. Nutr., 92, 810, 10.3945/ajcn.2010.29663 Lerner, 2015, Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease, Autoimmun. Rev., 14, 479, 10.1016/j.autrev.2015.01.009 Chassaing, 2015, Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 519, 92, 10.1038/nature14232 Mrázek, 2010, PCR-DGGE-based study of fecal microbial stability during the long-term chitosan supplementation of humans, Folia Microbiol., 55, 352, 10.1007/s12223-010-0057-y