Recent innovations in oral drug delivery systems: Examining current challenges and future opportunities for enhanced therapeutic efficacy

Mohammed Ahmed Almansour; Mubarak Saad Aldosary; Maysam Taysir Almegbel; Sultan Abdullah Alsubaie; Ahlam Mohammed Alzahrani

doi:10.53730/ijhs.v7nS1.15041

Authors

Mohammed Ahmed Almansour KSA, National Guard Health Affairs
Mubarak Saad Aldosary KSA, National Guard Health Affairs
Maysam Taysir Almegbel KSA, National Guard Health Affairs
Sultan Abdullah Alsubaie KSA, National Guard Health Affairs
Ahlam Mohammed Alzahrani KSA, National Guard Health Affairs

Keywords:

Oral drug delivery, nanomedicines, microfabricated devices, targeted delivery, bioavailability, personalized medicine

Abstract

Introduction: Oral drug delivery remains a cornerstone of therapeutic administration due to its ease of use and broad patient acceptance. However, delivering drugs orally poses significant challenges due to the complex and hostile environment of the gastrointestinal tract (GIT), including anatomical, biochemical, and physiological barriers. Aim: This article aims to explore recent innovations in oral drug delivery systems, focusing on addressing current challenges and identifying future opportunities for enhancing therapeutic efficacy. Methods: The study reviews advancements in oral drug delivery systems, including novel nanomedicines, microfabricated devices, and targeted delivery technologies. It synthesizes research findings from recent literature to highlight the evolution of these technologies and their impact on drug delivery. Results: Recent innovations include nanoparticles, microemulsions, and microfabricated devices, which enhance drug stability, targeting, and bioavailability. Nanoparticles, such as liposomes and solid lipid nanoparticles, protect drugs from the GIT environment and improve their absorption. Microfabricated devices, such as microneedles and micropatches, offer controlled and targeted drug release. Additionally, advancements in smart drug delivery systems, such as pH-sensitive and enzyme-responsive systems, provide precise control over drug release. Conclusion: Advances in oral drug delivery systems have significantly improved the ability to overcome GIT barriers, enhancing the effectiveness of oral medications.

Downloads

Download data is not yet available.

References

He, S.; Liu, Z.; Xu, D. Advance in oral delivery systems for therapeutic protein. J. Drug Target. 2019, 27, 283–291.

Hua, S. Advances in oral drug delivery for regional targeting in the gastrointestinal tract—Influence of physiological, pathophysiological and pharmaceutical factors. Front. Pharmacol. 2020, 11, 524.

Majumder, J.; Taratula, O.; Minko, T. Nanocarrier-based systems for targeted and site specific therapeutic delivery. Adv. Drug Deliv. Rev. 2019, 144, 57–77.

Reinholz, J.; Landfester, K.; Mailander, V. The challenges of oral drug delivery via nanocarriers. Drug Deliv. 2018, 25, 1694–1705.

Shan, W.; Zhu, X.; Liu, M.; Li, L.; Zhong, J.; Sun, W.; Zhang, Z.; Huang, Y. Overcoming the diffusion barrier of mucus and absorption barrier of epithelium by self-assembled nanoparticles for oral delivery of insulin. ACS Nano 2015, 9, 2345–2356.

Ahmad, N.; Ahmad, I.; Umar, S.; Iqbal, Z.; Samim, M.; Ahmad, F.J. PNIPAM nanoparticles for targeted and enhanced nose-to-brain delivery of curcuminoids: UPLC/ESI-Q-ToF-MS/MS-based pharmacokinetics and pharmacodynamic evaluation in cerebral ischemia model. Drug Deliv. 2016, 23, 2095–2114

Sadeghi, S.; Lee, W.K.; Kong, S.N.; Shetty, A.; Drum, C.L. Oral administration of protein nanoparticles: An emerging route to disease treatment. Pharmacol. Res. 2020, 158, 104685.

Ding, C.; Li, Z. A review of drug release mechanisms from nanocarrier systems. Mater. Sci. Eng. C Mater. Biol. Appl. 2017, 76, 1440–1453.

Tran, S.; DeGiovanni, P.J.; Piel, B.; Rai, P. Cancer nanomedicine: A review of recent success in drug delivery. Clin. Transl. Med. 2017, 6, 44.

Gomes, M.J.; Martins, S.; Ferreira, D.; Segundo, M.A.; Reis, S. Lipid nanoparticles for topical and transdermal application for alopecia treatment: Development, physicochemical characterization, and in vitro release and penetration studies. Int. J. Nanomed. 2014, 9, 1231–1242. [

Krajewska, J.B.; Bartoszek, A.; Fichna, J. New trends in liposome-based drug delivery in colorectal cancer. Mini Rev. Med. Chem. 2019, 19, 3–11.

Zylberberg, C.; Matosevic, S. Pharmaceutical liposomal drug delivery: A review of new delivery systems and a look at the regulatory landscape. Drug Deliv. 2016, 23, 3319–3329.

Shrestha, H.; Bala, R.; Arora, S. Lipid-based drug delivery systems. J. Pharm. 2014, 2014, 801820

Nielsen, L.H.; Keller, S.S.; Boisen, A. Microfabricated devices for oral drug delivery. Lab. Chip. 2018, 18, 2348–2358.

Mazzoni, C.; Tentor, F.; Strindberg, S.A.; Nielsen, L.H.; Keller, S.S.; Alstrom, T.S.; Gundlach, C.; Mullertz, A.; Marizza, P.; Boisen, A. From concept to in vivo testing: Microcontainers for oral drug delivery. J. Control. Release 2017, 268, 343–351.

Zhi, X.; Liu, Y.; Lin, L.; Yang, M.; Zhang, L.; Zhang, L.; Liu, Y.; Alfranca, G.; Ma, L.; Zhang, Q.; et al. Oral pH sensitive GNS@ab nanoprobes for targeted therapy of Helicobacter pylori without disturbance gut microbiome. Nanomedicine 2019, 20, 102019]

Zhu, Y.; Wen, L.M.; Li, R.; Dong, W.; Jia, S.Y.; Qi, M.C. Recent advances of nano-drug delivery system in oral squamous cell carcinoma treatment. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 9445–9453.

Vong, L.B.; Mo, J.; Abrahamsson, B.; Nagasaki, Y. Specific accumulation of orally administered redox nanotherapeutics in the inflamed colon reducing inflammation with dose-response efficacy. J. Control. Release 2015, 210, 19–25.

Din, M.O.; Danino, T.; Prindle, A.; Skalak, M.; Selimkhanov, J.; Allen, K.; Julio, E.; Atolia, E.; Tsimring, L.S.; Bhatia, S.N.; et al. Synchronized cycles of bacterial lysis for in vivo delivery. Nature 2016, 536, 81–85

Fox, C.B.; Kim, J.; Le, L.V.; Nemeth, C.L.; Chirra, H.D.; Desai, T.A. Micro/nanofabricated platforms for oral drug delivery. J. Control. Release 2015, 219, 431–444.

Greenwood-Van Meerveld, B.; Johnson, A.C.; Grundy, D. Gastrointestinal physiology and function. Handb. Exp. Pharmacol. 2017, 239, 1–16.

Targhotra, M.; Chauhan, M.K. An overview on various approaches and recent patents on buccal drug delivery systems. Curr. Pharm. Des. 2020, 26, 5030–5039.

Batchelor, H. Bioadhesive dosage forms for esophageal drug delivery. Pharm. Res. 2005, 22, 175–181.

Zhang, L.; Russell, D.; Conway, B.R.; Batchelor, H. Strategies and therapeutic opportunities for the delivery of drugs to the esophagus. Crit. Rev. Ther. Drug Carrier Syst. 2008, 25, 259–304.

Yoshida, T.; Lai, T.C.; Kwon, G.S.; Sako, K. pH- and ion-sensitive polymers for drug delivery. Expert Opin. Drug Deliv. 2013, 10, 1497–1513.

Ensign, L.M.; Cone, R.; Hanes, J. Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers. Adv. Drug Deliv. Rev. 2012, 64, 557–570.

Bagan, J.; Paderni, C.; Termine, N.; Campisi, G.; Lo Russo, L.; Compilato, D.; Di Fede, O. Mucoadhesive polymers for oral transmucosal drug delivery: A review. Curr. Pharm. Des. 2012, 18, 5497–5514.

Drucker, D.J. Advances in oral peptide therapeutics. Nat. Rev. Drug Discov. 2020, 19, 277–289.

Lim, Y.F.; Williams, M.A.; Lentle, R.G.; Janssen, P.W.; Mansel, B.W.; Keen, S.A.; Chambers, P. An exploration of the microrheological environment around the distal ileal villi and proximal colonic mucosa of the possum (Trichosurus vulpecula). J. R. Soc. Interface 2013, 10, 20121008.

Wang, Y.; Pi, C.; Feng, X.; Hou, Y.; Zhao, L.; Wei, Y. The influence of nanoparticle properties on oral bioavailability of drugs. Int. J. Nanomed. 2020, 15, 6295–6310.

Coffey, J.W.; Gaiha, G.D.; Traverso, G. Oral biologic delivery: Advances toward oral subunit, DNA, and mRNA vaccines and the potential for mass vaccination during pandemics. Annu. Rev. Pharmacol. Toxicol. 2021, 61, 517–540.

Mowat, A.M.; Agace, W.W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 2014, 14, 667–685.

Amidon, S.; Brown, J.E.; Dave, V.S. Colon-targeted oral drug delivery systems: Design trends and approaches. AAPS PharmSciTech 2015, 16, 731–741

Philip, A.K.; Philip, B. Colon targeted drug delivery systems: A review on primary and novel approaches. Oman Med. J. 2010, 25, 79–87.

Hua, S.; Marks, E.; Schneider, J.J.; Keely, S. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: Selective targeting to diseased versus healthy tissue. Nanomedicine 2015, 11, 1117–1132.

Barbari, G.R.; Dorkoosh, F.A.; Amini, M.; Sharifzadeh, M.; Atyabi, F.; Balalaie, S.; Rafiee Tehrani, N.; Rafiee Tehrani, M. A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides. Int. J. Nanomed. 2017, 12, 3471–3483.

Koziolek, M.; Grimm, M.; Becker, D.; Iordanov, V.; Zou, H.; Shimizu, J.; Wanke, C.; Garbacz, G.; Weitschies, W. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the intellicap((R)) system. J. Pharm. Sci. 2015, 104, 2855–2863.

Renukuntla, J.; Vadlapudi, A.D.; Patel, A.; Boddu, S.H.; Mitra, A.K. Approaches for enhancing oral bioavailability of peptides and proteins. Int. J. Pharm. 2013, 447, 75–93.

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, 569–581.

Ward, P.D.; Tippin, T.K.; Thakker, D.R. Enhancing paracellular permeability by modulating epithelial tight junctions. Pharm. Sci. Technol. Today 2000, 3, 346–358.

Johansson, M.E.; Sjovall, H.; Hansson, G.C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 352–361.

Cone, R.A. Barrier properties of mucus. Adv. Drug Deliv. Rev. 2009, 61, 75–85

Lin, P.Y.; Chuang, E.Y.; Chiu, Y.H.; Chen, H.L.; Lin, K.J.; Juang, J.H.; Chiang, C.H.; Mi, F.L.; Sung, H.W. Safety and efficacy of self-assembling bubble carriers stabilized with sodium dodecyl sulfate for oral delivery of therapeutic proteins. J. Control. Release 2017, 259, 168–175

Pearson, J.P.; Chater, P.I.; Wilcox, M.D. The properties of the mucus barrier, a unique gel—How can nanoparticles cross it? Ther. Deliv. 2016, 7, 229–244.

Pawar, V.K.; Meher, J.G.; Singh, Y.; Chaurasia, M.; Surendar Reddy, B.; Chourasia, M.K. Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: Strategies and industrial perspectives. J. Control. Release 2014, 196, 168–183.

Shan, M.; Gentile, M.; Yeiser, J.R.; Walland, A.C.; Bornstein, V.U.; Chen, K.; He, B.; Cassis, L.; Bigas, A.; Cols, M.; et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 2013, 342, 447–453

Boegh, M.; Garcia-Diaz, M.; Mullertz, A.; Nielsen, H.M. Steric and interactive barrier properties of intestinal mucus elucidated by particle diffusion and peptide permeation. Eur. J. Pharm. Biopharm. 2015, 95, 136–143.

Lee, S.H.; Bajracharya, R.; Min, J.Y.; Han, J.W.; Park, B.J.; Han, H.K. Strategic approaches for colon targeted drug delivery: An overview of recent advancements. Pharmaceutics 2020, 12, 68.

Das, S.; Kaur, S.; Rai, V.K. Gastro-retentive drug delivery systems: A recent update on clinical pertinence and drug delivery. Drug Deliv. Transl. Res. 2021, 11, 1849–1877.

Awasthi, R.; Kulkarni, G.T. Decades of research in drug targeting to the upper gastrointestinal tract using gastroretention technologies: Where do we stand? Drug Deliv. 2016, 23, 378–394.

Kumar, M.; Kaushik, D. An overview on various approaches and recent patents on gastroretentive drug delivery systems. Recent Pat. Drug Deliv. Formul 2018, 12, 84–92.

Ngwuluka, N.C.; Choonara, Y.E.; Kumar, P.; du Toit, L.C.; Modi, G.; Pillay, V. An optimized gastroretentive nanosystem for the delivery of levodopa. Int. J. Pharm. 2015, 494, 49–65.

Sharma, A.; Goyal, A.K.; Rath, G. Development and characterization of gastroretentive high-density pellets lodged with zero valent iron nanoparticles. J. Pharm. Sci. 2018, 107, 2663–2673.

Hao, S.; Wang, Y.; Wang, B. Sinking-magnetic microparticles prepared by the electrospray method for enhanced gastric antimicrobial delivery. Mol. Pharm. 2014, 11, 1640–1650.

Lopes, C.M.; Bettencourt, C.; Rossi, A.; Buttini, F.; Barata, P. Overview on gastroretentive drug delivery systems for improving drug bioavailability. Int. J. Pharm. 2016, 510, 144–158.

Tripathi, J.; Thapa, P.; Maharjan, R.; Jeong, S.H. Current state and future perspectives on gastroretentive drug delivery systems. Pharmaceutics 2019, 11, 193.

Anothra, P.; Pradhan, D.; Halder, J.; Ghosh, G.; Rath, G. Gastroretentive drug delivery system in cancer chemotherapy. Curr. Drug Deliv. 2022; ahead of print.

Vinchurkar, K.; Sainy, J.; Khan, M.A.; Mane, S.; Mishra, D.K.; Dixit, P. Features and facts of a gastroretentive drug delivery system—A review. Turk. J. Pharm. Sci. 2022, 19, 476–487.

Tort, S.; Han, D.; Steckl, A.J. Self-inflating floating nanofiber membranes for controlled drug delivery. Int. J. Pharm. 2020, 579, 119164.

Dhiman, S.; Philip, N.; Gurjeet Singh, T.; Babbar, R.; Garg, N.; Diwan, V.; Singh, P. An insight on novel approaches & perspectives for gastro-retentive drug delivery systems. Curr. Drug Deliv. 2022; ahead of print.

Rimawi, I.B.; Muqedi, R.H.; Kanaze, F.I. Development of gabapentin expandable gastroretentive controlled drug delivery system. Sci. Rep. 2019, 9, 11675.

Bhalekar, M.R.; Bargaje, R.V.; Upadhaya, P.G.; Madgulkar, A.R.; Kshirsagar, S.J. Formulation of mucoadhesive gastric retentive drug delivery using thiolated xyloglucan. Carbohydr. Polym. 2016, 136, 537–542.

Thakral, S.; Thakral, N.K.; Majumdar, D.K. Eudragit: A technology evaluation. Expert Opin. Drug Deliv. 2013, 10, 131–149.

Sharpe, L.A.; Daily, A.M.; Horava, S.D.; Peppas, N.A. Therapeutic applications of hydrogels in oral drug delivery. Expert Opin. Drug Deliv. 2014, 11, 901–915.

Watkins, K.A.; Chen, R. pH-responsive, lysine-based hydrogels for the oral delivery of a wide size range of molecules. Int. J. Pharm. 2015, 478, 496–503.

Sosnik, A.; Seremeta, K.P. Polymeric hydrogels as technology platform for drug delivery applications. Gels 2017, 3, 25.

Verma, A.; Sharma, S.; Gupta, P.K.; Singh, A.; Teja, B.V.; Dwivedi, P.; Gupta, G.K.; Trivedi, R.; Mishra, P.R. Vitamin B12 functionalized layer by layer calcium phosphate nanoparticles: A mucoadhesive and pH responsive carrier for improved oral delivery of insulin. Acta Biomater. 2016, 31, 288–300.

Dai, W.; Guo, Y.; Zhang, H.; Wang, X.; Zhang, Q. Sylysia 350/Eudragit S100 solid nanomatrix as a promising system for oral delivery of cyclosporine A. Int. J. Pharm. 2015, 478, 718–725.

Zhang, S.; Bellinger, A.M.; Glettig, D.L.; Barman, R.; Lee, Y.A.; Zhu, J.; Cleveland, C.; Montgomery, V.A.; Gu, L.; Nash, L.D.; et al. A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices. Nat. Mater. 2015, 14, 1065–1071.

Aleksovski, A.; Dreu, R.; Gasperlin, M.; Planinsek, O. Mini-tablets: A contemporary system for oral drug delivery in targeted patient groups. Expert Opin. Drug Deliv. 2015, 12, 65–84.

Pujara, N.; Giri, R.; Wong, K.Y.; Qu, Z.; Rewatkar, P.; Moniruzzaman, M.; Begun, J.; Ross, B.P.; McGuckin, M.; Popat, A. pH-responsive colloidal carriers assembled from beta-lactoglobulin and epsilon poly-L-lysine for oral drug delivery. J Colloid Interface Sci 2021, 589, 45–55.

Al-Gousous, J.; Tsume, Y.; Fu, M.; Salem, I.S.; Langguth, P. Unpredictable performance of pH-dependent coatings accentuates the need for improved predictive in vitro test systems. Mol. Pharm. 2017, 14, 4209–4219.

Felton, L.A.; Porter, S.C. An update on pharmaceutical film coating for drug delivery. Expert Opin. Drug Deliv. 2013, 10, 421–435.

Kang, J.H.; Hwang, J.Y.; Seo, J.W.; Kim, H.S.; Shin, U.S. Small intestine- and colon-specific smart oral drug delivery system with controlled release characteristic. Mater. Sci. Eng. C Mater. Biol. Appl. 2018, 91, 247–254.

Lahner, E.; Annibale, B.; Delle Fave, G. Systematic review: Impaired drug absorption related to the co-administration of antisecretory therapy. Aliment. Pharmacol. Ther. 2009, 29, 1219–1229.

Xu, B.; Zhang, W.; Chen, Y.; Xu, Y.; Wang, B.; Zong, L. Eudragit(R) L100-coated mannosylated chitosan nanoparticles for oral protein vaccine delivery. Int. J. Biol. Macromol. 2018, 113, 534–542.

Banerjee, A.; Lee, J.; Mitragotri, S. Intestinal mucoadhesive devices for oral delivery of insulin. Bioeng. Transl. Med. 2016, 1, 338–346.

Harloff-Helleberg, S.; Fliervoet, L.A.L.; Fano, M.; Schmitt, M.; Antopolski, M.; Urtti, A.; Nielsen, H.M. Exploring the mucoadhesive behavior of sucrose acetate isobutyrate: A novel excipient for oral delivery of biopharmaceuticals. Drug Deliv. 2019, 26, 532–541

Banerjee, A.; Mitragotri, S. Intestinal patch systems for oral drug delivery. Curr. Opin. Pharmacol. 2017, 36, 58–65.

Kumar, A.; Naik, P.K.; Pradhan, D.; Ghosh, G.; Rath, G. Mucoadhesive formulations: Innovations, merits, drawbacks, and future outlook. Pharm. Dev. Technol. 2020, 25, 797–814.

Homayun, B.; Lin, X.; Choi, H.J. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics 2019, 11, 129.

Teruel, A.H.; Gonzalez-Alvarez, I.; Bermejo, M.; Merino, V.; Marcos, M.D.; Sancenon, F.; Gonzalez-Alvarez, M.; Martinez-Manez, R. New insights of oral colonic drug delivery systems for inflammatory bowel disease therapy. Int. J. Mol. Sci. 2020, 21, 6502.

Jornada, D.H.; dos Santos Fernandes, G.F.; Chiba, D.E.; de Melo, T.R.; dos Santos, J.L.; Chung, M.C. The prodrug approach: A successful tool for improving drug solubility. Molecules 2015, 21, 42

Shahdadi Sardo, H.; Saremnejad, F.; Bagheri, S.; Akhgari, A.; Afrasiabi Garekani, H.; Sadeghi, F. A review on 5-aminosalicylic acid colon-targeted oral drug delivery systems. Int. J. Pharm. 2019, 558, 367–379.

Sousa, T.; Yadav, V.; Zann, V.; Borde, A.; Abrahamsson, B.; Basit, A.W. On the colonic bacterial metabolism of azo-bonded prodrugsof 5-aminosalicylic acid. J. Pharm. Sci. 2014, 103, 3171–3175.

Kim, S.; Lee, S.; Lee, H.; Ju, S.; Park, S.; Kwon, D.; Yoo, J.W.; Yoon, I.S.; Min, D.S.; Jung, Y.S.; et al. A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats. Pharmaceutics 2020, 12, 843.

Chen, J.; Li, X.; Chen, L.; Xie, F. Starch film-coated microparticles for oral colon-specific drug delivery. Carbohydr. Polym. 2018, 191, 242–254.

Gunter, E.A.; Popeyko, O.V. Calcium pectinate gel beads obtained from callus cultures pectins as promising systems for colon-targeted drug delivery. Carbohydr. Polym. 2016, 147, 490–499.

Lee, Y.; Kim, J.; Kim, W.; Nam, J.; Jeong, S.; Lee, S.; Yoo, J.W.; Kim, M.S.; Jung, Y. Celecoxib coupled to dextran via a glutamic acid linker yields a polymeric prodrug suitable for colonic delivery. Drug Des. Dev. Ther. 2015, 9, 4105–4113

Qiao, H.; Fang, D.; Chen, J.; Sun, Y.; Kang, C.; Di, L.; Li, J.; Chen, Z.; Chen, J.; Gao, Y. Orally delivered polycurcumin responsive to bacterial reduction for targeted therapy of inflammatory bowel disease. Drug Deliv. 2017, 24, 233–242.

Zhu, A.Z.; Ho, M.D.; Gemski, C.K.; Chuang, B.C.; Liao, M.; Xia, C.Q. Utilizing in vitro dissolution-permeation chamber for the quantitative prediction of pH-dependent drug-drug interactions with acid-reducing agents: A comparison with physiologically based pharmacokinetic modeling. AAPS J. 2016, 18, 1512–1523.

Barclay, T.G.; Day, C.M.; Petrovsky, N.; Garg, S. Review of polysaccharide particle-based functional drug delivery. Carbohydr. Polym. 2019, 221, 94–112.

Grisham, M.B. Oxidants and free radicals in inflammatory bowel disease. Lancet 1994, 344, 859–861.

Zhang, Q.; Tao, H.; Lin, Y.; Hu, Y.; An, H.; Zhang, D.; Feng, S.; Hu, H.; Wang, R.; Li, X.; et al. A superoxide dismutase/catalase mimetic nanomedicine for targeted therapy of inflammatory bowel disease. Biomaterials 2016, 105, 206–221.

Huang, Y.; Canup, B.S.B.; Gou, S.; Chen, N.; Dai, F.; Xiao, B.; Li, C. Oral nanotherapeutics with enhanced mucus penetration and ROS-responsive drug release capacities for delivery of curcumin to colitis tissues. J. Mater. Chem. B 2021, 9, 1604–1615.

Vong, L.B.; Nagasaki, Y. Combination treatment of murine colon cancer with doxorubicin and redox nanoparticles. Mol. Pharm. 2016, 13, 449–455.

Song, Q.; Jia, J.; Niu, X.; Zheng, C.; Zhao, H.; Sun, L.; Zhang, H.; Wang, L.; Zhang, Z.; Zhang, Y. An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy. Nanoscale 2019, 11, 15958–15970.

Varum, F.; Freire, A.C.; Bravo, R.; Basit, A.W. OPTICORE, an innovative and accurate colonic targeting technology. Int. J. Pharm. 2020, 583, 119372.

Naeem, M.; Bae, J.; Oshi, M.A.; Kim, M.S.; Moon, H.R.; Lee, B.L.; Im, E.; Jung, Y.; Yoo, J.W. Colon-targeted delivery of cyclosporine A using dual-functional Eudragit((R)) FS30D/PLGA nanoparticles ameliorates murine experimental colitis. Int. J. Nanomed. 2018, 13, 1225–1240.

Oshi, M.A.; Naeem, M.; Bae, J.; Kim, J.; Lee, J.; Hasan, N.; Kim, W.; Im, E.; Jung, Y.; Yoo, J.W. Colon-targeted dexamethasone microcrystals with pH-sensitive chitosan/alginate/Eudragit S multilayers for the treatment of inflammatory bowel disease. Carbohydr. Polym. 2018, 198, 434–442.

Bazan, L.; Bendas, E.R.; El Gazayerly, O.N.; Badawy, S.S. Comparative pharmaceutical study on colon targeted micro-particles of celecoxib: In-vitro-in-vivo evaluation. Drug Deliv. 2016, 23, 3339–3349.

Chen, Q.; Luo, R.; Han, X.; Zhang, J.; He, Y.; Qi, S.; Pu, X.; Nie, W.; Dong, L.; Xu, H.; et al. Entrapment of macrophage-target nanoparticles by yeast microparticles for rhein delivery in ulcerative colitis treatment. Biomacromolecules 2021, 22, 2754–2767.

Parodi, A.; Buzaeva, P.; Nigovora, D.; Baldin, A.; Kostyushev, D.; Chulanov, V.; Savvateeva, L.V.; Zamyatnin, A.A., Jr. Nanomedicine for increasing the oral bioavailability of cancer treatments. J. Nanobiotechnol. 2021, 19, 354.

Wong, C.Y.; Al-Salami, H.; Dass, C.R. Recent advancements in oral administration of insulin-loaded liposomal drug delivery systems for diabetes mellitus. Int. J. Pharm. 2018, 549, 201–217.

Kim, J.M.; Kim, D.H.; Park, H.J.; Ma, H.W.; Park, I.S.; Son, M.; Ro, S.Y.; Hong, S.; Han, H.K.; Lim, S.J.; et al. Nanocomposites-based targeted oral drug delivery systems with infliximab in a murine colitis model. J. Nanobiotechnol. 2020, 18, 133.

Brayden, D.J.; Hill, T.A.; Fairlie, D.P.; Maher, S.; Mrsny, R.J. Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches. Adv. Drug Deliv. Rev. 2020, 157, 2–36.

Vela Ramirez, J.E.; Sharpe, L.A.; Peppas, N.A. Current state and challenges in developing oral vaccines. Adv. Drug Deliv. Rev. 2017, 114, 116–131

Lee, S.H.; Back, S.Y.; Song, J.G.; Han, H.K. Enhanced oral delivery of insulin via the colon-targeted nanocomposite system of organoclay/glycol chitosan/Eudragit((R))S100. J. Nanobiotechnol. 2020, 18, 104.

Cao, P.; Han, F.Y.; Grondahl, L.; Xu, Z.P.; Li, L. Enhanced oral vaccine efficacy of polysaccharide-coated calcium phosphate nanoparticles. ACS Omega 2020, 5, 18185–18197.

Sabu, C.; Raghav, D.; Jijith, U.S.; Mufeedha, P.; Naseef, P.P.; Rathinasamy, K.; Pramod, K. Bioinspired oral insulin delivery system using yeast microcapsules. Mater. Sci. Engl. C Mater. Biol. Appl. 2019, 103, 109753.

Ren, T.; Zheng, X.; Bai, R.; Yang, Y.; Jian, L. Utilization of PLGA nanoparticles in yeast cell wall particle system for oral targeted delivery of exenatide to improve its hypoglycemic efficacy. Int. J. Pharm. 2021, 601, 120583.

Abramson, A.; Caffarel-Salvador, E.; Soares, V.; Minahan, D.; Tian, R.Y.; Lu, X.; Dellal, D.; Gao, Y.; Kim, S.; Wainer, J.; et al. A luminal unfolding microneedle injector for oral delivery of macromolecules. Nat. Med. 2019, 25, 1512–1518.

Abramson, A.; Caffarel-Salvador, E.; Khang, M.; Dellal, D.; Silverstein, D.; Gao, Y.; Frederiksen, M.R.; Vegge, A.; Hubalek, F.; Water, J.J.; et al. An ingestible self-orienting system for oral delivery of macromolecules. Science 2019, 363, 611–615.

Kesisoglou, F.; Panmai, S.; Wu, Y. Nanosizing—Oral formulation development and biopharmaceutical evaluation. Adv. Drug Deliv. Rev. 2007, 59, 631–644.

Chuang, E.-Y.; Lin, K.-J.; Huang, T.-Y.; Chen, H.-L.; Miao, Y.-B.; Lin, P.-Y.; Chen, C.-T.; Juang, J.-H.; Sung, H.-W. an intestinal “transformers”-like nanocarrier system for enhancing the oral bioavailability of poorly water-soluble drugs. ACS Nano 2018, 12, 6389–6397.

Naserifar, M.; Hosseinzadeh, H.; Abnous, K.; Mohammadi, M.; Taghdisi, S.M.; Ramezani, M.; Alibolandi, M. Oral delivery of folate-targeted resveratrol-loaded nanoparticles for inflammatory bowel disease therapy in rats. Life Sci. 2020, 262, 118555.

Aouadi, M.; Tesz, G.J.; Nicoloro, S.M.; Wang, M.; Chouinard, M.; Soto, E.; Ostroff, G.R.; Czech, M.P. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 2009, 458, 1180–1184.

Zhou, X.; Zhang, X.; Han, S.; Dou, Y.; Liu, M.; Zhang, L.; Guo, J.; Shi, Q.; Gong, G.; Wang, R.; et al. Yeast microcapsule-mediated targeted delivery of diverse nanoparticles for imaging and therapy via the oral route. Nano Lett. 2017, 17, 1056–1064

Hu, X.; Zhang, J. Yeast capsules for targeted delivery: The future of nanotherapy? Nanomedicine 2017, 12, 955–957

Zhou, X.; Ling, K.; Liu, M.; Zhang, X.; Ding, J.; Dong, Y.; Liang, Z.; Li, J.; Zhang, J. Targeted delivery of cisplatin-derived nanoprecursors via a biomimetic yeast microcapsule for tumor therapy by the oral route. Theranostics 2019, 9, 6568–6586.

Song, Q.; Zheng, C.; Jia, J.; Zhao, H.; Feng, Q.; Zhang, H.; Wang, L.; Zhang, Z.; Zhang, Y. A probiotic spore-based oral autonomous nanoparticles generator for cancer therapy. Adv. Mater. 2019, 31, e1903793.

Xu, C.; Yin, L.; Teng, Z.; Zhou, X.; Li, W.; Lai, Q.; Peng, C.; Zhang, C.; Lou, J.; Zhou, X. Prevention of obesity related diseases through laminarin-induced targeted delivery of Bindarit. Theranostics 2020, 10, 9544–9560.

Zhang, L.; Zhang, W.; Peng, H.; Li, Y.; Leng, T.; Xie, C.; Zhang, L. Oral gene therapy of HFD-obesity via nonpathogenic yeast microcapsules mediated shRNA delivery. Pharmaceutics 2021, 13, 1536.

Miao, Y.B.; Chen, K.H.; Chen, C.T.; Mi, F.L.; Lin, Y.J.; Chang, Y.; Chiang, C.S.; Wang, J.T.; Lin, K.J.; Sung, H.W. A noninvasive gut-to-brain oral drug delivery system for treating brain tumors. Adv. Mater. 2021, 33, e2100701

Zhang, X.; Xu, X.; Chen, Y.; Dou, Y.; Zhou, X.; Li, L.; Li, C.; An, H.; Tao, H.; Hu, H.; et al. Bioinspired yeast microcapsules loaded with self-assembled nanotherapies for targeted treatment of cardiovascular disease. Mater. Today 2017, 20, 301–313.

Zhang, L.; Peng, H.; Feng, M.; Zhang, W.; Li, Y. Yeast microcapsule-mediated oral delivery of IL-1beta shRNA for post-traumatic osteoarthritis therapy. Mol. Ther. Nucleic Acids 2021, 23, 336–346.

Lou, J., Duan, H., Qin, Q., Teng, Z., Gan, F., Zhou, X., & Zhou, X. (2023). Advances in oral drug delivery systems: Challenges and opportunities. Pharmaceutics, 15(2), 484.