Past, Present, and Future Technologies for Oral Delivery of Therapeutic Proteins

Singh, Rajesh; Singh, Shailesh; Lillard, James W.

doi:10.1002/jps.21183

Cited by 186Advanced Drug Delivery SystemsDrug Solubulity and Delivery SystemsProteins in Food Systems

Past, Present, and Future Technologies for Oral Delivery of Therapeutic Proteins

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Singh, Rajesh, Singh, Shailesh, Lillard, James W.·2008·Journal of Pharmaceutical Sciences

DOI 10.1002/jps.21183PMC PMC4627499

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Abstract

Biological drugs are usually complex proteins and cannot be orally delivered due to problems related to degradation in the acidic and protease-rich environment of the gastrointestinal (GI) tract. The high molecular weight of these drugs often results in poor absorption into the periphery when administered orally. The most common route of administration for these therapeutic proteins is injection. Most of these proteins have short serum half-lives and need to be administered frequently or in high doses to be effective. So, difficulties in the administration of protein-based drugs provides the motivation for developing drug delivery systems (DDSs) capable of maintaining therapeutic drug levels without side effects as well as traversing the deleterious mucosal environment. Employing a polymer as an entrapment matrix is a common feature among the different types of systems currently being pursued for protein delivery. Protein release from these matrices can occur through various mechanisms, such as diffusion through or erosion of the polymer matrix, and sometimes a combination of both. Encapsulation of proteins in liposomes has also been a widely investigated technology for protein delivery. All of these systems have merit and our worthy of pursuit.

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The limited bioavailability of orally administered mAbs is due to limited penetration across the intestinal epithelium and susceptibility to enzymatic degradation by proteases and peptidases in the intestinal lumen.
“The limited bioavailability of orally administered mAbs is due to their limited penetration across the intestinal epithelium16 and susceptibility to enzymatic degradation by proteases and peptidases in the intestinal lumen.17”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [17]

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Research works printed but not linked: 2

[64]Porter CJ Davies MC Davis SS Illum L Domb A 1994 Microparticulate system for site-specific therapy-bone marrow targeting Site specific pharmacotherapy New York Wiley 157 203
[78]Peppas NA Lowman AM Frokjaer S Christrup L Krogsgaard-Larsen P 1998 Protein delivery from novel bioadhesive complexation hydrogels Peptide and protein delivery, Alfred Benzon symposium 43 Copenhagen Munksgaard 206 216

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Microneedles for drug and vaccine delivery
Kim, Y., Park, J., & Prausnitz, M. R. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.04.005 · Cited by 1,776 · see citing works
“Oral delivery largely overcomes these problems, but many drugs cannot be given by this route due to poor absorption and drug degradation in the gastrointestinal tract and liver [6].”
Background
Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Correlations of Therapeutic Peptides
Diao, L., & Meibohm, B. (2013) · Clinical Pharmacokinetics · doi:10.1007/s40262-013-0079-0 · Cited by 376 · see citing works
“Without this minimum degree of lipophilicity, there is no passive transcellular permeation, whereas the alternative paracellular pathway is restricted to small compounds less than 200 Da [16].”
Background
Therapeutic application of peptides and proteins: parenteral forever?
Antošová, Z., Macková, M., Král, V., & Macek, T. (2009) · Trends in biotechnology · doi:10.1016/j.tibtech.2009.07.009 · Cited by 325 · see citing works
Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development
Ovacik, M., & Lin, K. (2018) · Clinical and Translational Science · doi:10.1111/cts.12567 · Cited by 299 · see citing works
Oral protein delivery: Current status and future prospect
Park, K., Kwon, I. C., & Park, K. (2010) · Reactive and Functional Polymers · doi:10.1016/j.reactfunctpolym.2010.10.002 · Cited by 266 · see citing works
An overview of microneedle applications, materials, and fabrication methods
Rad, Z. F., Prewett, P. D., & Davies, G. J. (2021) · Beilstein Journal of Nanotechnology · doi:10.3762/bjnano.12.77 · Cited by 259 · see citing works
Light controlled protein release from a supramolecular hydrogel
Peng, K., Tomatsu, I., & Kros, A. (2010) · Chemical Communications · doi:10.1039/c002565h · Cited by 244 · see citing works
Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications
Kuriakose, A., Chirmule, N. B., & Nair, P. (2016) · Journal of Immunology Research · doi:10.1155/2016/1298473 · Cited by 231 · see citing works
“Interestingly, exposure via gut mucosa is generally tolerogenic; however the challenge is the effective oral delivery with bioavailability of the biotherapeutic [71].”
Polysaccharide-based micro/nanohydrogels for delivering macromolecular therapeutics
Ganguly, K., Chaturvedi, K., More, U. A., Nadagouda, M. N., & Aminabhavi, T. M. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.05.014 · Cited by 177 · see citing works
Recent Advancement of Chitosan-Based Nanoparticles for Oral Controlled Delivery of Insulin and Other Therapeutic Agents
Chaudhury, A., & Das, S. (2010) · AAPS PharmSciTech · doi:10.1208/s12249-010-9561-2 · Cited by 174 · see citing works
Nanomedicine: Novel approaches in human and veterinary therapeutics
Irache, J. M., Esparza, I., Gamazo, C., Agüeros, M., & Espuelas, S. (2011) · Veterinary Parasitology · doi:10.1016/j.vetpar.2011.05.028 · Cited by 152 · see citing works
New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases
Núñez, M. T., & Chaná‐Cuevas, P. (2018) · Pharmaceuticals · doi:10.3390/ph11040109 · Cited by 150 · see citing works
“Compliance of treatment is better with oral drugs than those injected on a daily basis during long-term treatments [140]; (2) low molecular weight and high membrane permeability.”
Background
Is nanotechnology a boon for oral drug delivery?
Agrawal, U., Sharma, R. K., Gupta, M., & Vyas, S. P. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.04.011 · Cited by 146 · see citing works
Oral peptide and protein delivery: intestinal obstacles and commercial prospects
Smart, A. L., Gaisford, S., & Basit, A. W. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.917077 · Cited by 143 · see citing works
“They have been reviewed extensively elsewhere [38-41].”
Recent advances in nanocarrier-based mucosal delivery of biomolecules
Kammona, O., & Kiparissides, C. A. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.05.040 · Cited by 142 · see citing works
Protein Nanocapsule Weaved with Enzymatically Degradable Polymeric Network
Gu, Z., Yan, M., Hu, B., Joo, K., Biswas, A., Huang, Y., Lu, Y., Wang, P., & Tang, Y. (2009) · Nano Letters · doi:10.1021/nl902935b · Cited by 141 · see citing works
Challenges in delivering therapeutic peptides and proteins: A silk-based solution
Wu, J., Sahoo, J. K., Li, Y., Xu, Q., & Kaplan, D. L. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.02.011 · Cited by 139 · see citing works
Oral colon delivery of insulin with the aid of functional adjuvants
Maroni, A., Zema, L., Curto, M. D. D., Foppoli, A., & Gazzaniga, A. (2011) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2011.10.006 · Cited by 127 · see citing works
Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems
Karamanidou, T., Karidi, K., Bourganis, V., Kontonikola, K., Kammona, O., & Kiparissides, C. A. (2015) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2015.04.013 · Cited by 127 · see citing works
The role of mucus as an invisible cloak to transepithelial drug delivery by nanoparticles
García-Díaz, M., Birch, D., Wan, F., & Nielsen, H. M. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.11.002 · Cited by 120 · see citing works
“The ability of a DDS to deliver the active drug molecule to the site for absorption may be hampered by hostile environments as resembled in the intestinal tract lumen with high enzymatic and hydrolytic activity, since this may lead to degradation of both the DDS and the macromolecular cargo [4].”
Dextran based photodegradable hydrogels formed via a Michael addition
Peng, K., Tomatsu, I., van den Broek, B., Cui, C., Korobko, A. V., van Noort, J., Meijer, A. H., Spaink, H. P., & Kros, A. (2011) · Soft Matter · doi:10.1039/c1sm05291h · Cited by 119 · see citing works
Agile delivery of protein therapeutics to CNS
Yi, X., Manickam, D. S., Brynskikh, A. M., & Kabanov, A. V. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.06.017 · Cited by 115 · see citing works
Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs
Managuli, R. S., Raut, S. Y., Reddy, M. S., & Mutalik, S. (2018) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2018.1503249 · Cited by 112 · see citing works
Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy
Mahran, R. I., Hagras, M. M., Sun, D., & Brenner, D. E. (2016) · The AAPS Journal · doi:10.1208/s12248-016-0003-2 · Cited by 103 · see citing works
“Particle sizes >100 nm are hepatically extracted and are not systemically bioavailable (72).”
Background
The dynamic gastric environment and its impact on drug and formulation behaviour
Abeele, J. V. D., Rubbens, J., Brouwers, J., & Augustijns, P. (2016) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2016.08.060 · Cited by 102 · see citing works
“intraluminal degradation due to gastric (and intestinal) peptidase activity and subsequently to poor bioavailability (Crane and Luntz, 1968; Fonte et al., 2013; Singh et al., 2008; Ziv and Bendayan, 2000).”
Background
Fabrication of a PVA-Based Hydrogel Microneedle Patch
Oh, N. G., Hwang, S. Y., & Na, Y. H. (2022) · ACS Omega · doi:10.1021/acsomega.2c01993 · Cited by 98 · see citing works
Tissue engineering: Still facing a long way ahead
Hassanzadeh, P., Atyabi, F., & Dinarvand, R. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.04.024 · Cited by 95 · see citing works
Microneedle patch designs to increase dose administered to human subjects
Li, W., Li, S., Fan, X., & Prausnitz, M. R. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.09.036 · Cited by 90 · see citing works
Polyelectrolyte complexes as prospective carriers for the oral delivery of protein therapeutics
Bourganis, V., Karamanidou, T., Kammona, O., & Kiparissides, C. A. (2016) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2016.11.005 · Cited by 84 · see citing works
Chitosan Nanoparticle-Based System: A New Insight into the Promising Controlled Release System for Lung Cancer Treatment
Kuen, C. Y., & Masarudin, M. J. (2022) · Molecules · doi:10.3390/molecules27020473 · Cited by 84 · see citing works
“However, the therapeutic efficacy of these medications is often less desired as the drugs that are consumed, especially orally, need to go through many different paths such as the digestive tract, gastrointestinal tract, and liver to reach the target site, which may lead to the cleavage or degradation by the enzymes o…”
Background
In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery
Chen, B. Z., Ashfaq, M., Zhang, X. P., Zhang, J., & Guo, X. D. (2018) · Journal of drug targeting · doi:10.1080/1061186x.2018.1424859 · Cited by 82 · see citing works
“system is not suitable for genetic materials, proteins and other biotherapeutics due to the gastrointestinal drug metabolism [4].”
Background
Improving Oral Absorption Via Drug-Loaded Nanocarriers: Absorption Mechanisms, Intestinal Models and Rational Fabrication
Shahbazi, M., & Santos, H. A. (2012) · Current Drug Metabolism · doi:10.2174/138920013804545133 · Cited by 80 · see citing works
Smart Drug Delivery System
Sezer, A. D. (2016) · InTech eBooks · doi:10.5772/60475 · Cited by 77 · see citing works
Synthesis of well-defined protein–polymer conjugates for biomedicine
Zhao, W., Liu, F., Chen, Y., Bai, J., & Gao, W. (2015) · Polymer · doi:10.1016/j.polymer.2015.03.054 · Cited by 76 · see citing works
Nanoscale Particle Therapies for Wounds and Ulcers
Cortivo, R., Vindigni, V., Iacobellis, L., Abatangelo, G., Pinton, P., & Zavan, B. (2010) · Nanomedicine · doi:10.2217/nnm.10.32 · Cited by 74 · see citing works
Peptides as Drug Candidates: Limitations and Recent Development Perspectives
Haggag, Y. A. (2018) · Biomedical Journal of Scientific & Technical Research · doi:10.26717/bjstr.2018.08.001694 · Cited by 73 · see citing works
“Therapeutic peptides and proteins also tend to undergo denaturation, aggregation, and adsorption which limit their active concentration and proper function in vivo [15].”
Background
Enhancing the therapeutic use of biofilm-dispersing enzymes with smart drug delivery systems
Thorn, C. R., Howell, P. L., Wozniak, D. J., Prestidge, C. A., & Thomas, N. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113916 · Cited by 73 · see citing works
New synthesis method of HA/P(D,L)LA composites: study of fibronectin adsorption and their effects in osteoblastic behavior for bone tissue engineering
Yala, S., Boustta, M., Gallet, O., Hindié, M., Carreiras, F., Benachour, H., Sidane, D., & Khireddine, H. (2016) · Journal of Materials Science Materials in Medicine · doi:10.1007/s10856-016-5756-8 · Cited by 70 · see citing works
Films loaded with insulin-coated nanoparticles (ICNP) as potential platforms for peptide buccal delivery
Morales, J. O., Huang, S., Williams, R. O., & McConville, J. T. (2014) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2014.05.025 · Cited by 69 · see citing works
Improved Oral Bioavailability of Human Growth Hormone by a Combination of Liposomes Containing Bio-Enhancers and Tetraether Lipids and Omeprazole
Parmentier, J., Hofhaus, G., Thomas, S., Clusa, L., Gropp, F., Schröder, R. R., Hartmann, K., & Fricker, G. (2014) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24215 · Cited by 68 · see citing works
Protein-loaded PLGA–PEG–PLGA microspheres: A tool for cell therapy
Tran, V.-T., Karam, J., Garric, X., Coudane, J., Benoît, J., Montero‐Menei, C. N., & Venier‐Julienne, M. (2011) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2011.10.030 · Cited by 64 · see citing works
“, 2003) whereas non-toxic hydrophilic PEG is known for its stabilising effect on proteins (Kissel et al., 1996; Singh et al., 2008; Wade and Weller, 1994).”
Background
M cell targeting engineered biomaterials for effective vaccination
Islam, M. A., Firdous, J., Badruddoza, A. Z. M., Reesor, E., Azad, M. A., Hasan, A., Lim, M., Cao, W., Guillemette, S. R., & Cho, C. S. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.10.041 · Cited by 64 · see citing works
Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses
Ameri, M., Kadkhodayan, M., Nguyen, J., Bravo, J., Su, R., Chan, K., Samiee, A., & Daddona, P. E. (2014) · Pharmaceutics · doi:10.3390/pharmaceutics6020220 · Cited by 63 · see citing works
“Oral delivery is not a viable delivery method for therapeutic proteins due to poor absorption and degradation in the gastrointestinal tract and liver [1,2].”
Background
Lipid-Based Nanocarriers for the Oral Administration of Biopharmaceutics
Karamanidou, T., Bourganis, V., Kammona, O., & Kiparissides, C. A. (2016) · Nanomedicine · doi:10.2217/nnm-2016-0265 · Cited by 59 · see citing works
Alternative routes of administration for systemic delivery of protein pharmaceuticals
Moeller, E. H., & Jørgensen, L. (2008) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2008.11.005 · Cited by 57 · see citing works
Novel engineered systems for oral, mucosal and transdermal drug delivery
Li, H., Yu, Y., Dana, S. F., Li, B., Lee, C., & Kang, L. (2013) · Journal of drug targeting · doi:10.3109/1061186x.2013.805335 · Cited by 57 · see citing works
Formulation, in vitro and in vivo evaluation of celecoxib nanosponge hydrogels for topical application
Gangadharappa, H. V., Prasad, S. M. C., & Singh, R. P. (2017) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2017.09.004 · Cited by 57 · see citing works
Self-citation
Physicochemical study of ascorbic acid 2-glucoside loaded hyaluronic acid dissolving microneedles irradiated by electron beam and gamma ray
Kim, S., Lee, J., Shayan, F. L., Kim, S., Huh, I., Ma, Y., Yang, H., Kang, G., & Jung, H. (2017) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2017.10.044 · Cited by 53 · see citing works
Improved insulin loading in poly(lactic-co-glycolic) acid (PLGA) nanoparticles upon self-assembly with lipids
García-Díaz, M., Foged, C., & Nielsen, H. M. (2014) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2014.11.047 · Cited by 51 · see citing works
“To overcome these delivery limitations, there has been continuous efforts towards developing formulations that can protect and release the molecules at the epithelial surface of the GI tract, as well as enhancing the intestinal permeability (Li et al., 2012; Singh et al., 2008).”
Background
Attuning hydroxypropyl methylcellulose phthalate to oral delivery vehicle for effective and selective delivery of protein vaccine in ileum
Singh, B., Maharjan, S., Jiang, T., Kang, S., Choi, Y.-J., & Cho, C. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.04.017 · Cited by 49 · see citing works
“Both synthetic and natural polymers including enteric coating polymers are currently being evaluated as vehicles to deliver the proteins to the GI tract [3,4].”
Background
Surface Coating Approach to Overcome Mucosal Entrapment of DNA Nanoparticles for Oral Gene Delivery of Glucagon-like Peptide 1
Nie, T., He, Z., Zhou, Y., Zhu, J., Chen, K., Liu, L., Leong, K. W., Mao, H., & Chen, Y. (2019) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.9b10294 · Cited by 47 · see citing works
Glucose sensitive konjac glucomannan/concanavalin A nanoparticles as oral insulin delivery system
Xu, M., Huang, J., Jiang, S., He, J., Wang, Z., Qin, H., & Guan, Y. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.01.048 · Cited by 47 · see citing works
Controlled-release systemic delivery - a new concept in cancer chemoprevention
Gupta, R. C., Bansal, S. S., Aqil, F., Jeyabalan, J., Cao, P., Kausar, H., Russell, G. K., MUNAGALA, R. S., Ravoori, S., & Vadhanam, M. V. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs209 · Cited by 45 · see citing works
Influence of polymer molecular weight on the in vitro cytotoxicity of poly (N-isopropylacrylamide)
Mellati, A., Kiamahalleh, M. V., Dai, S., Bi, J., Jin, B., & Zhang, H. (2015) · Materials Science and Engineering C · doi:10.1016/j.msec.2015.10.043 · Cited by 45 · see citing works
Protease-resistant single-domain antibodies inhibit Campylobacter jejuni motility
Hussack, G., Riazi, A., Ryan, S., van Faassen, H., MacKenzie, R., Tanha, J., & Arbabi‐Ghahroudi, M. (2014) · Protein Engineering Design and Selection · doi:10.1093/protein/gzu011 · Cited by 45 · see citing works
“Monoclonal antibodies and larger antibody fragments (i.e. Fabs, scFvs) have shown limited success in the GI tract (Reilly et al., 1997; Singh et al., 2008; Hussack et al., 2011).”
Background
Alginate-Loaded Liposomes Can Protect Encapsulated Alkaline Phosphatase Functionality When Exposed to Gastric pH
Smith, A. M., Jaime-Fonseca, M. R., Grover, L. M., & Bakalis, S. (2010) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf904466p · Cited by 44 · see citing works
Strategies for Enhanced Peptide and Protein Delivery
McCrudden, M., Singh, T. R. R., Migalska, K., & Donnelly, R. F. (2013) · Therapeutic Delivery · doi:10.4155/tde.13.31 · Cited by 43 · see citing works
Oral delivery of Bifidobacterium longum expressing α-melanocyte-stimulating hormone to combat ulcerative colitis
Wei, P., Yang, Y., Ding, Q., Li, X., Sun, H., Liu, Z., Huang, J., & Gong, Y. (2015) · Journal of Medical Microbiology · doi:10.1099/jmm.0.000197 · Cited by 42 · see citing works
“On the contrary, given that a-MSH is a typical peptide, oral delivery of this peptide results in an extremely low bioavailability because of its abundant and unfavourable degradation in the stomach and lack of stability in the luminal environment (Scheuch & Siekmeier, 2007; Singh et al., 2008; Fan et al., 2014).”
Background
Emerging Novel Approaches for the Enhanced Delivery of Natural Products for the Management of Neurodegenerative Diseases
Bandiwadekar, A., Jose, J., Khayatkashani, M., Habtemariam, S., Kashani, H. R. K., & Nabavi, S. M. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-021-01922-7 · Cited by 42 · see citing works
“However, it is not suitable for the delivery of drugs that undergo first-pass metabolism, in which degradation of the drug will occur (Singh et al. 2008).”
Background
Microneedles for drug delivery and monitoring
Singh, T. R. R., McMillan, H. L., Mooney, K. M., Alkilani, A. Z., & Donnelly, R. F. (2013) · Elsevier eBooks · doi:10.1533/9780857097040.2.185 · Cited by 41 · see citing works
Ovalbumin and cholera toxin delivery to buccal mucus for immunization using microneedles and comparison of immunological response to transmucosal delivery
Oh, Y., Cha, H., Hwang, S. J., Kim, D. S., Choi, Y.-J., Kim, Y., Shin, Y., Nguyen, T. T., Choi, S., Lee, J. M., et al. (2021) · Drug Delivery and Translational Research · doi:10.1007/s13346-021-00964-z · Cited by 41 · see citing works
Transdermal delivery of insulin across human skin in vitro with 3D printed hollow microneedles
Xenikakis, I., Tsongas, K., Tzimtzimis, E. K., Katsamenis, O. L., Demiri, E. C., Zacharis, C. K., Georgiou, D., Kalogianni, E. P., Tzetzis, D., & Fatouros, D. G. (2021) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2021.102891 · Cited by 41 · see citing works
Arginine end-functionalized poly(l-lysine) dendrigrafts for the stabilization and controlled release of insulin
Sideratou, Z., Sterioti, N., Tsiourvas, D., Tziveleka, L., Thanassoulas, A., Nounesis, G., & Paleos, C. M. (2010) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2010.07.072 · Cited by 41 · see citing works
Development of vertical SU-8 microtubes integrated with dissolvable tips for transdermal drug delivery
Xiang, Z., Wang, H., Pant, A., Pastorin, G., & Lee, C. (2013) · Biomicrofluidics · doi:10.1063/1.4798471 · Cited by 40 · see citing works
Exploring the fate of liposomes in the intestine by dynamic in vitro lipolysis
Parmentier, J., Thomas, N., Müllertz, A., Fricker, G., & Rades, T. (2012) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2012.08.018 · Cited by 40 · see citing works
“of BCS class III drugs, like proteins, by protecting them against degradation in the gastro-intestinal tract (GIT) and by improving their intestinal absorption (Patel and Ryman, 1976; Rowland and Woodley, 1981; Fricker and Drewe, 1996; Singh et al., 2008; Werle and Takeuchi, 2009).”
Background
Bioneedles as alternative delivery system for hepatitis B vaccine
Hirschberg, H. J. H. B., van de Wijdeven, G. G. P., Kraan, H., Amorij, J., & Kersten, G. F. A. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.06.028 · Cited by 40 · see citing works
Cracking the intestinal lymphatic system window utilizing oral delivery vehicles for precise therapy
Miao, Y., Xu, T., Gong, Y., Chen, A., Zou, L., Jiang, T., & Shi, Y. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-01991-3 · Cited by 43 · see citing works
“The unfolding of some proteins in gastric juices may cause them to lose their ability to function normally [65].”
Background
Nanocarrier possibilities for functional targeting of bioactive peptides and proteins:state-of-the-art
Moutinho, C. M. S. G., Matos, C. M., Teixeira, J. A., & Balcão, V. M. (2011) · Journal of drug targeting · doi:10.3109/1061186x.2011.628397 · Cited by 38 · see citing works
“Due to their intrinsic versatility for drug formulations, sustained-release properties, subcellular size and tissue and cell biocompatibility, nano-sized particles appear to be a highly promising solution for peptide and/or protein administration, and have consistently been receiving more attention than do liposomes b…”
Background
Nanoscale carriers for targeted delivery of drugs and therapeutic biomolecules
Kiparissides, C. A., & Kammona, O. (2012) · The Canadian Journal of Chemical Engineering · doi:10.1002/cjce.21685 · Cited by 35 · see citing works
Responsive polysaccharides and polysaccharides-based nanoparticles for drug delivery
Ngwuluka, N. C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-08-101997-9.00023-0 · Cited by 35 · see citing works
Emerging trends in pulmonary delivery of biopharmaceuticals
Kunde, S. S., Ghosh, R., & Wairkar, S. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.02.003 · Cited by 35 · see citing works
Biomaterial adjuvant effect is attenuated by anti-inflammatory drug delivery or material selection
Norton, L. W., Park, J., & Babensee, J. E. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.05.032 · Cited by 35 · see citing works
“These principles of engaging innate and adaptive immune responses towards foreign antigens are utilized in the pharmaceutical formulations for vaccine delivery using polymers, such as chitosan[5-9] and PLGA[5,6,10-13]; whereas, it would be detrimental to tissue engineered device function to engage adaptive immune resp…”
Background
Therapeutic potential of Camel Milk
Dubey, U. S., Lal, M., Mittal, A., & Kapur, S. (2015) · Emirates Journal of Food and Agriculture · doi:10.9755/ejfa.2015-04-122 · Cited by 34 · see citing works
“They play a vital role in preventing the degradation of protein drugs in the harsh environment of the GI tract (Okada et al., 1998; Singh et al., 2008; Behrens et al., 2002).”
Background
Daptomycin Proliposomes for Oral Delivery: Formulation, Characterization, and In Vivo Pharmacokinetics
Rueda, J., Kovvasu, S. P., & Betageri, G. V. (2018) · AAPS PharmSciTech · doi:10.1208/s12249-018-0989-0 · Cited by 32 · see citing works
Biomaterials for Protein Delivery: Opportunities and Challenges to Clinical Translation
Gorantla, A., Hall, J., Troidle, A., & Janjic, J. M. (2024) · Micromachines · doi:10.3390/mi15040533 · Cited by 31 · see citing works
“Furthermore, the intestinal wall represents a selectively permeable barrier that prevents larger macromolecules, such as proteins, from being absorbed [31,32].”
Background
Characterization, Optimization, In Vitro and In Vivo Evaluation of Simvastatin Proliposomes, as a Drug Delivery
Rahamathulla, M., Gangadharappa, H. V., Veerapu, G., Hani, U., Alhamhoom, Y., Alqahtani, A., & Moin, A. (2020) · AAPS PharmSciTech · doi:10.1208/s12249-020-01666-4 · Cited by 31 · see citing works
Poly(amidoamine)-Cholesterol Conjugate Nanoparticles Obtained by Electrospraying as Novel Tamoxifen Delivery System
Cavalli, R., Bisazza, A., Bussano, R., Trotta, M., Civra, A., Lembo, D., Ranucci, E., & Ferruti, P. (2011) · Journal of Drug Delivery · doi:10.1155/2011/587604 · Cited by 31 · see citing works
In-situ mineralization of calcium carbonate in pectin based edible hydrogel for the delivery of protein at colon
Gautam, M., & Santhiya, D. (2019) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2019.101137 · Cited by 30 · see citing works
Optimization of PLGA formulation containing protein or peptide‐based antigen: Recent advances
Hajavi, J., Ebrahimian, M., Sankian, M., Khakzad, M. R., & Hashemi, M. (2018) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36423 · Cited by 30 · see citing works
“However, surfactant should be restricted to the minimum level required to avoid possible toxic and hypersensitivity reactions.(8,132) Poly vinyl alcohol (PVA) was historically used to stabilize proteins during emulsification and these remains until today, especially for stabilization of the secondary emulsion.”
Background
Evaluation of self-emulsifying drug delivery systems for oral insulin delivery using an in vitro model simulating the intestinal proteolysis
Liu, J., Hirschberg, C., Fanø, M., Mu, H., & Müllertz, A. (2020) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2020.105272 · Cited by 29 · see citing works
A Comprehensive Review of the Evolution of Insulin Development and Its Delivery Method
Sugumar, V., Ang, K. P., Al-Shanon, A. F., Sethi, G., Yong, P. V. C., Looi, C. Y., & Wong, W. F. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14071406 · Cited by 29 · see citing works
“Degradation by gastrointestinal enzymes is likely through this route [77,78].”
Background
Morphological and release characterization of nanoparticles formulated with poly (dl-lactide-co-glycolide) (PLGA) and lupeol: In vitro permeability and modulator effect on NF-κB in Caco-2 cell system stimulated with TNF-α
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Authors: Singh, R., Singh, S., & Lillard, J. W.
Affiliations: University of Louisville (US)
Corresponding author: Lillard, James W.
ORCID: Singh, Rajesh
Singh, Shailesh
Venue: Journal of Pharmaceutical Sciences
Publisher: Elsevier BV
Published: 2008-07
Volume: 97
Issue: 7
Pages: 2497-2523
ISSN: 0022-3549 (ISSN-L)
DOI: 10.1002/jps.21183
PMC: PMC4627499
OpenAlex: W1966939994
Cited by: 186
References: 184
Citations by year: 2026: 3 · 2025: 6 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 12 · 2020: 10 · 2019: 6 · 2018: 12 · 2017: 6 · 2016: 14 · 2015: 13 · 2014: 13 · 2013: 10 · 2012: 13
FWCI: 0.55
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Pharmaceutical Sciences (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5p60md000525-04)
National Cancer Institute (U54CA118638)
National Institute of Allergy and Infectious Diseases (AI 057808, R01AI057808)
National Institute of Diabetes and Digestive and Kidney Diseases (DK58967, R03DK058967)
National Center for Research Resources (RR 03034, G12RR003034)
National Institute on Minority Health and Health Disparities (MD00525, P60-MD000525)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Life Sciences › Agricultural and Biological Sciences › Food Science › Proteins in Food Systems
Keywords: oral drug delivery, therapeutic proteins, protein degradation, gastrointestinal tract, drug delivery systems, protein encapsulation, liposomes, mucosal barrier, serum half-life
MeSH terms: Absorption, Administration, Oral, Biocompatible Materials, Drug Carriers, Drug Stability, Liposomes, Particle Size, Polymers, Proteins, Technology, Pharmaceutical, Drug Delivery Systems, Nanoparticles

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