Nanocarriers for oral delivery of biologics: small carriers for big payloads

Biologics have gained immense popularity in the past two decades as new and personalized medicines. Yet, the majority of the approved biologics are administered via the parenteral route (i.e., via injections).Biologics therapy is usually costly as they require administration by a healthcare professional, cold storage, and pose high risk of injection-site infection, leading to low patient compliance.Orally administrable biologics hold tremendous potential for making these therapeutics more accessible to the broader patient population and reducing cost, whilst boosting patient compliance.Nanocarrier-based oral biologics hold a strong promise in achieving efficient systemic uptake of these complex therapeutics, which is generally hindered by barriers such as harsh pH (stomach), digestive enzymes, mucus, and cellular barriers of the gastrointestinal tract.The lightning-paced development of a range of organic and inorganic nanocarriers for oral biologics delivery has pushed a handful of nanocarrier-based oral biologics to various stages of clinical trials, showing a promising future for nanocarriers in this field. Macromolecular therapeutics of biological origin, also known as biologics, have become one of the fastest-growing classes of drugs for management of a range of chronic and acute conditions. The majority of approved biologics are administered via the parenteral route and are thus expensive, have low patient compliance, and have high systemic toxicity. Therefore, tremendous efforts have been devoted to the development of carriers for oral delivery of biologics. This review evaluates key chemical (e.g. pH and enzymes) and physiological challenges to oral biologics delivery. We review the conventional formulation strategies and their limitations, followed by a detailed account of the progress on the use of nanocarriers used for oral biologics delivery, covering organic and inorganic nanocarriers. Lastly, we discuss limitations and opportunities presented by these emerging nanomaterials in oral biologics delivery. Macromolecular therapeutics of biological origin, also known as biologics, have become one of the fastest-growing classes of drugs for management of a range of chronic and acute conditions. The majority of approved biologics are administered via the parenteral route and are thus expensive, have low patient compliance, and have high systemic toxicity. Therefore, tremendous efforts have been devoted to the development of carriers for oral delivery of biologics. This review evaluates key chemical (e.g. pH and enzymes) and physiological challenges to oral biologics delivery. We review the conventional formulation strategies and their limitations, followed by a detailed account of the progress on the use of nanocarriers used for oral biologics delivery, covering organic and inorganic nanocarriers. Lastly, we discuss limitations and opportunities presented by these emerging nanomaterials in oral biologics delivery. Why oral biologics?Biologics (see Glossary) were originally defined as ‘pharmaceutical products consisting of proteins and/or nucleic acids’ [1.Durán-Lobato M. et al.Oral delivery of biologics for precision medicine.Adv. Mater. 2020; 32: 1901935Crossref Scopus (79) Google Scholar] (Figure 1A ). They have revolutionized the therapeutic landscape with their target specificity, becoming the fastest-growing classes of therapeutics. A steep increase in the number of biologics (~20% of the total drug approval in 2020) being approved by the US FDA and other regulatory bodies is an indication of the continuing market appetite for biologics [2.Midlam C. Status of biologic drugs in modern therapeutics-targeted therapies vs. small molecule drugs.in: Ramzan I. Biologics, Biosimilars, and Biobetters: An Introduction for Pharmacists, Physicians, and Other Health Practitioners. Wiley, 2020: 31-46Crossref Scopus (1) Google Scholar]. Biologics surpassed a market value of US$209 billion and eight biologics were reported to be amongst the top ten bestselling pharmaceuticals worldwide in 2020i [3.Brown D.G. Wobst H.J. A decade of FDA-approved drugs (2010–2019): trends and future directions.J. Med. Chem. 2021; 64: 2312-2338Crossref PubMed Scopus (43) Google Scholar]. Human recombinant insulin developed in the 1980s is one of the first examples and most widely used biologics for diabetes management. Since then, monoclonal antibodies against tumor necrosis factor (TNF), interleukin-1β, Janus kinase (JAK), and interleukin-6, have come to the market for the treatment of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD) [4.Choy E.H. et al.Translating IL-6 biology into effective treatments.Nat. Rev. Rheumatol. 2020; 16: 335-345Crossref PubMed Scopus (188) Google Scholar,5.Salas A. et al.JAK–STAT pathway targeting for the treatment of inflammatory bowel disease.Nat. Rev. Gastroenterol. Hepatol. 2020; 17: 323-337Crossref PubMed Scopus (170) Google Scholar].Despite their unprecedented success, almost all the biologics are administered via the parenteral route due to their structural complexity. Intravenous, intramuscular, and subcutaneous routes are typically used for the administration of biologics to maintain their bioavailability and avoid the first-pass metabolism [6.Ibeanu N. et al.Injectables and depots to prolong drug action of proteins and peptides.Pharmaceutics. 2020; 12: 999Crossref Scopus (14) Google Scholar]. Injection-associated pain, fear of needles, and injection site infection are responsible for dose skipping by patients, especially in the case of diabetes where daily insulin needs to be administered subcutaneously [6.Ibeanu N. et al.Injectables and depots to prolong drug action of proteins and peptides.Pharmaceutics. 2020; 12: 999Crossref Scopus (14) Google Scholar]. This can result in risk of relapse, prompting enormous efforts from pharmaceutical scientists across the world on delivery of biologics via oral, topical, buccal, and other routes [2.Midlam C. Status of biologic drugs in modern therapeutics-targeted therapies vs. small molecule drugs.in: Ramzan I. Biologics, Biosimilars, and Biobetters: An Introduction for Pharmacists, Physicians, and Other Health Practitioners. Wiley, 2020: 31-46Crossref Scopus (1) Google Scholar].Oral delivery is the most desired, noninvasive route, which offers high patient compliance [7.Alqahtani M.S. Advances in oral drug delivery.Front. Pharmacol. 2021; 12: 62Crossref Scopus (65) Google Scholar]. Many efforts have focused on the use of conventional excipient-based strategies to overcome the challenging barriers in the gastrointestinal tract (GIT) faced by oral biologics. These barriers include harsh gastric pH, digestive enzymes, gut microbiome, gut mucosa, and epithelium that not only destroy the tertiary/quaternary structure of the biologics but also prevent their uptake into the systemic circulation (Figure 1B) [2.Midlam C. Status of biologic drugs in modern therapeutics-targeted therapies vs. small molecule drugs.in: Ramzan I. Biologics, Biosimilars, and Biobetters: An Introduction for Pharmacists, Physicians, and Other Health Practitioners. Wiley, 2020: 31-46Crossref Scopus (1) Google Scholar]. An elaborate description of the key challenges faced by biologics at each stage of their transit through the GIT is provided in Box 1. To overcome these barriers, nano-sized carriers have emerged as a potential solution to enhance the systemic uptake of biologics (Figure 1C).Box 1Chemical and physiological challenges to oral delivery of biologicsHarsh pH environmentVarious sections of the GIT exhibit vastly different pH values, ranging from highly acidic in the stomach (pH 1–3) to neutral in the duodenum and jejunum (pH 6–7), and slightly to highly alkaline in the ileum and colon (pH 6–8.5), as summarized in Figure I [10.Homayun B. et al.Challenges and recent progress in oral drug delivery systems for biopharmaceuticals.Pharmaceutics. 2019; 11: 129Crossref Scopus (302) Google Scholar,93.Hua S. et al.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: 1117-1132Crossref PubMed Scopus (320) Google Scholar]. These abrupt changes in the pH, and mainly the highly acidic pH in the stomach, are well-known to degrade or decrease the activity of therapeutic biologics by causing oxidation, deamidation, or hydrolysis [94.Pridgen E.M. et al.Polymeric nanoparticle technologies for oral drug delivery.Clin. Gastroenterol. Hepatol. 2014; 12: 1605-1610Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar].Enzymatic degradationNumerous digestive enzymes are present in various sections of the GIT that tend to degrade biologics and reduce their efficacy (Figure I). For example, insulin is rapidly degraded by pepsin, trypsin, and α-chymotrypsin in the stomach and intestine [95.Ismail R. Csoka I. Novel strategies in the oral delivery of antidiabetic peptide drugs–Insulin, GLP 1 and its analogs.Eur. J. Pharm. Biopharm. 2017; 115: 257-267Crossref PubMed Scopus (64) Google Scholar]. It is worth mentioning that the stomach and duodenum host the highest proteolytic activity, and thus most nanocarriers, for oral biologics delivery aim to specifically release their cargos in either the ileum or colon to avoid exposure to these enzymes.Mucus barrierMucus is another major challenge for oral delivery of biologics, especially the biologics that require systemic uptake for their desired therapeutic action. Mucin domains are established by a protein core that is rich in proline, serine, and threonine (PST sequences) [96.Allen A. The structure and function of gastrointestinal mucus.in: Boedeker E.C. Attachment of Organisms to the Gut Mucosa. CRC Press, 2018: 3-12Crossref Google Scholar]. Generally, there are two types of mucins, cell surface mucins and gel-forming mucins. The cell surface mucins are usually anchored at the apical side of epithelial cells, while the gel-forming mucins are the major component of the mucus layer [97.Johansson M.E. et al.The gastrointestinal mucus system in health and disease.Nat. Rev. Gastroenterol. Hepatol. 2013; 10: 352Crossref PubMed Scopus (767) Google Scholar]. The dynamic viscoelastic and shear-thinning nature of the mucus layer is one of the main reasons for negatively influencing oral bioavailability [98.Joubert R. et al.In vitro oral drug permeation models: the importance of taking physiological and physico-chemical factors into consideration.Expert Opin. Drug Deliv. 2017; 14: 179-187Crossref PubMed Scopus (8) Google Scholar].Epithelial barrierIntestinal epithelium presents one of the most severe barriers for oral biologics that are systemically active. In the small intestine, 90% of epithelial cells are absorptive cells [99.Gehart H. Clevers H. Tales from the crypt: new insights into intestinal stem cells.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 19-34Crossref PubMed Scopus (324) Google Scholar] and the tight junctions between epithelial cells are designed to only allow translocation of small molecules, thus making permeability of the macromolecular drugs almost impossible. Nanocarriers have been shown to interact with the epithelial cell surfaces and can traverse tight junctions (i.e., paracellular transport) when decorated with suitable surface charge or targeting moieties. Other nanocarriers interact with specific receptors and traverse the epithelium through the cells, known as transcellular transport [9.Brown T.D. et al.Materials for oral delivery of proteins and peptides.Nat. Rev. Mater. 2020; 5: 127-148Crossref Scopus (152) Google Scholar].Gastrointestinal microbiotaFigure IBarriers associated with oral delivery of biologics.Show full captionThe stomach has a highly acidic environment (pH 1–3), which is detrimental to sensitive biologics. The small intestine contains a large amount of various enzymes, which digest the biologics. Similarly, the colon also has enzymes associated with the degradation of biologics. Other major barriers to systemic uptake of biologics are the mucus and epithelial barriers that physically prevent biologics from penetrating and reaching the bloodstream. Furthermore, the colon has two mucus layers, which make it more difficult for biologics to penetrate and reach the epithelium. Created with BioRender.com.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Conventional excipient-based formulations for oral delivery of biologicsExcipients improve efficacy and palatability of drugs including biologics [8.Darji M.A. et al.Excipient stability in oral solid dosage forms: a review.AAPS PharmSciTech. 2018; 19: 12-26Crossref PubMed Scopus (42) Google Scholar]. A comprehensive list of conventional excipients used for the preparation of oral biologics formulations is provided in Table 1. In general, excipients for delivery of oral biologics can be classified into: (i) protective excipients and (ii) permeation enhancers.Table 1Protective excipients and permeation-enhancing excipients in improving delivery of oral biologicsExcipientsChemicalsAdvantagesDrawbacksRefsProtective excipientsEnzyme inhibitorAprotininSoybean trypsin inhibitorOvomucoidPancreatic endopeptidases•Protect biologics from enzyme degradation•A large amount of enzyme inhibitor required may cause intestinal mucosal damage or disturb gastrointestinal microbiota species[11.Deb P.K. et al.Protein/peptide drug delivery systems: practical considerations in pharmaceutical product development.in: Takade R. Basic Fundamentals of Drug Delivery. Elsevier, 2019: 651-684Crossref Scopus (28) Google Scholar]pH modifiersCitric acidsHydrochloric acidSodium hydroxide•Protect degradation of biologics by reducing the activity of pH-sensitive enzymes in the GIT•Increase paracellular transport of biologics via chelation•May alter protein structure by changing pH•Change local pH environment and effect enteric-coated formulations[9.Brown T.D. et al.Materials for oral delivery of proteins and peptides.Nat. Rev. Mater. 2020; 5: 127-148Crossref Scopus (152) Google Scholar]Permeation-enhancing excipientsAbsorption enhancerDetergents, surfactantsFatty acidsCa2+-chelating agentsBile saltsSodium caprylateSalcaprozate sodium (SNAC)Piperazine derivatives•Enhance transcellular transport•Open the tight junctions•Opening of tight junctions can lead to nonselective transportation across the GIT, which can introduce undesirable substances into the systemic circulation•Chelating agents can cause nutritional deficiencies, as trace elements can bind to them instead of being absorbed in the GIT•Bile salts can be irritating to the GIT[13.Liu C. et al.Strategies and industrial perspectives to improve oral absorption of biological macromolecules.Expert Opin. Drug Deliv. 2018; 15: 223-233Crossref PubMed Scopus (56) Google Scholar]Mucoadhesive polymerChitosanHydroxypropylcellulose•Prolong the biologics residence time at the desired drug absorption site•Intestine mucus turnover might limit its effect[19.Mumuni M.A. et al.Insulin-loaded mucoadhesive nanoparticles based on mucin-chitosan complexes for oral delivery and diabetes treatment.Carbohydr. Polym. 2020; 229: 115506Crossref PubMed Scopus (50) Google Scholar]Solubility enhancerPolyethylene glycol (PEG)Ionic liquids•PEGylation can impart hydrophilicity to the biologics, which increases circulation half-life and prevents protein degradation•Ionic liquids can protect biologics from enzyme degradation and increase solubility•PEGylation can lead to the development of anti-PEG antibodies and hypersensitivity•Ionic liquids can reduce protein stability by influencing the intermolecular interaction[20.Vargason A.M. et al.The evolution of commercial drug delivery technologies.Nat. Biomed. Eng. 2021; 1–17Google Scholar] Open table in a new tab Protective excipientsProtective excipients include pH modifiers and enzyme inhibitors that can be used to improve delivery of oral biologics. pH modifiers such as citric acid lower the local pH in the intestine during drug release and reduce the activity of proteases to prevent degradation of biologics. However, pH modifiers may hamper the pharmacological activity of biologics, hence they are not widely preferred [9.Brown T.D. et al.Materials for oral delivery of proteins and peptides.Nat. Rev. Mater. 2020; 5: 127-148Crossref Scopus (152) Google Scholar]. Various peptides and polypeptides inactivate the proteolytic luminal enzymes in the intestine and are referred to as sacrificial enzyme inhibitors. These peptides and polypeptides degrade faster than biologics due to their low molecular weight [10.Homayun B. et al.Challenges and recent progress in oral drug delivery systems for biopharmaceuticals.Pharmaceutics. 2019; 11: 129Crossref Scopus (302) Google Scholar]. Aprotinin and chicken ovomucid are the most commonly used enzyme inhibitors to block trypsin and chymotrypsin present in the small intestine [11.Deb P.K. et al.Protein/peptide drug delivery systems: practical considerations in pharmaceutical product development.in: Takade R. Basic Fundamentals of Drug Delivery. Elsevier, 2019: 651-684Crossref Scopus (28) Google Scholar]. However, large quantities of enzyme inhibitors are generally required, which increases the cost and efficacy of the formulations.Permeation enhancersPermeation enhancers for oral delivery of biologics include mucoadhesive molecules, absorption enhancers, and solubility enhancers. Mucoadhesive molecules are typically functional polymers that interact with intestinal mucus either electrostatically or through covalent bonding to prolong the gut residence time of the biologics [9.Brown T.D. et al.Materials for oral delivery of proteins and peptides.Nat. Rev. Mater. 2020; 5: 127-148Crossref Scopus (152) Google Scholar]. Currently, aminated polymers like chitosan have been established as the most effective mucoadhesive polymers [12.Maria S. et al.Synthesis and characterization of pre-activated thiolated chitosan nanoparticles for oral delivery of octreotide.J. Drug Deliv. Sci. Technol. 2020; 58: 101807Crossref Scopus (14) Google Scholar]. Absorption enhancers exploit many different mechanisms of action to improve oral delivery of biologics [13.Liu C. et al.Strategies and industrial perspectives to improve oral absorption of biological macromolecules.Expert Opin. Drug Deliv. 2018; 15: 223-233Crossref PubMed Scopus (56) Google Scholar]. In this regard, detergents and surfactants disrupt the lipid bilayer on the cell membrane to achieve transcellular transport, while fatty acids and Ca2+-chelating agents transiently open the tight junctions to improve paracellular biologics transport [14.Mandracchia D. et al.Design, synthesis and evaluation of biotin decorated inulin-based polymeric micelles as long-circulating nanocarriers for targeted drug delivery.Nanomed. Nanotechnol. Biol. Med. 2017; 13: 1245-1254Crossref PubMed Scopus (42) Google Scholar]. Other chemical permeation enhancers, like sodium caprate and salcaprozate sodium (SNAC), are extensively used in the clinic. In this regard, SNAC is a key component of the recently US FDA-approved oral semaglutide [15.Pearson S. et al.Oral semaglutide in the management of type 2 diabetes: a report on the evidence to date.Diabetes Metab Syndr Obes. 2019; 12: 2515-2529Crossref PubMed Scopus (13) Google Scholar]. More recently, piperazine derivatives have emerged as a potential permeation enhancer, especially 1-phenylpiperazine, which has low cytotoxic and improved permeability coefficients of mannitol 14 folds when crossing Caco-2 monolayer [16.Fein K.C. et al.Structure-function analysis of phenylpiperazine derivatives as intestinal permeation enhancers.Pharm. Res. 2017; 34: 1320Crossref PubMed Scopus (10) Google Scholar,17.Stuettgen V. Brayden D.J. Investigations of piperazine derivatives as intestinal permeation enhancers in isolated rat intestinal tissue mucosae.AAPS J. 2020; 22: 1-13Crossref Scopus (10) Google Scholar]. Although the solubility enhancer is primarily used for increasing the aqueous solubility of small molecule lipophilic compounds, some reports have used solubility enhancers to increase the bioavailability and prolong the half-life of biologics in the systemic circulation. Attachment of polyethylene glycol (PEGylation) is commonly used for this purpose, providing a stealth cover for the biologics to enable their longer systemic circulation [18.Suk J.S. et al.PEGylation as a strategy for improving nanoparticle-based drug and gene delivery.Adv. Drug Deliv. Rev. 2016; 99: 28-51Crossref PubMed Scopus (1921) Google Scholar]. Besides, ionic liquids have also been used for this application, with their unique loosely synchronized anions and cations that bind to mucus and enhance permeation [9.Brown T.D. et al.Materials for oral delivery of proteins and peptides.Nat. Rev. Mater. 2020; 5: 127-148Crossref Scopus (152) Google Scholar].Oral biologics in the clinic and under clinical trialsWith unprecedented success in overcoming the challenges associated with delivering oral biologics, many biologics have now advanced to clinical trials. For example, Rybelsus® was approved in 2019 for the management of diabetes [21.Hedrington M.S. et al.Oral semaglutide for the treatment of type 2 diabetes.Expert. Opin. Pharmacother. 2019; 20: 133-141Crossref PubMed Scopus (26) Google Scholar], while MYCAPSSA™ was approved in 2020 for the treatment of acromegaly [22.Melmed S. et al.Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial.J. Clin. Endocrinol. Metab. 2015; 100: 1699-1708Crossref PubMed Scopus (122) Google Scholar]. It is worth noting that with over 400 million people suffering from diabetes worldwide and a global healthcare burden of over US$600 billion, oral delivery of insulin and other diabetes management biologics have received the highest research attention due to the high frequency of injections [23.Wu H. et al.Secular trends in all-cause and cause-specific mortality rates in people with diabetes in Hong Kong, 2001–2016: a retrospective cohort study.Diabetologia. 2020; 63: 757-766Crossref PubMed Scopus (58) Google Scholar,24.Saeedi P. et al.Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas.Diabetes Res. Clin. Pract. 2019; 157: 107843Abstract Full Text Full Text PDF PubMed Scopus (3270) Google Scholar].An important milestone in the delivery of oral biologics for diabetes management was attained in 2019. The first ever oral glucagon-like peptide 1 (GLP-1) receptor agonist, Rybelsus® (oral semaglutide), was approved by the US FDA and became available in the market for the management of type 2 diabetes. Rybelsus® relies on a specific mixture of several conventional excipients comprising of pH modifiers (to raise local pH in the stomach), enzyme inhibitors (to reduce the enzymatic digestion), and absorption enhancer for rapid gut absorption [21.Hedrington M.S. et al.Oral semaglutide for the treatment of type 2 diabetes.Expert. Opin. Pharmacother. 2019; 20: 133-141Crossref PubMed Scopus (26) Google Scholar]. To date, PIONEER 12 Phase III clinical trials [101.Rodbard H.W. et al.Efficacy of oral semaglutide: overview of the PIONEER clinical trial program and implications for managed care.Am. J. Manag. Care. 2020; 26: S335-S343Crossref PubMed Google Scholar] have been conducted for Rybelsus®, to investigate the efficacy and long-term safety of oral semaglutide. The results showed that Rybelsus®, significantly reduced glycated hemoglobin (HbA1c), as a measure of long-term blood glucose, when compared with placebo, empagliflozin, or sitagliptin, which are commercially available oral antidiabetic drugs. Another Phase III trial is testing the efficacy of Rybelsus® in children and teenagers with type 2 diabetes (NCT04596631). The results of these ongoing trials are greatly anticipated to determine the effective dosage, safety, and efficacy of oral semaglutide in both adult and younger generations.There are several other biologics for the management of diabetes at various stages of clinical trials based on both conventional excipients and nanomaterials. For example, Biocon Ltd. utilized the PEGylation strategy to improve the stability and permeation of insulin through transcellular transport. But their study is limited due to the lack of comparison with the approved formulation of insulin [25.Khedkar A. et al.Pharmacokinetics and pharmacodynamics of insulin tregopil in relation to premeal dosing time, between meal interval, and meal composition in patients with type 2 diabetes mellitus.Clin. Pharmacol. Drug Dev. 2020; 9: 74-86Crossref PubMed Scopus (15) Google Scholar]. Diasome Pharmaceuticals developed nano-sized hepatic-directed vesicle insulin (HDV-I) (<150 nm diameter) formulated with phospholipid for both type 1 and type 2 diabetes. HDV-I not only achieved increased absorption and reduced degradation but also targeted delivery of insulin to the hepatocytes for better and faster relief [26.Geho W.B. et al.Hepatic-directed vesicle insulin: a review of formulation development and preclinical evaluation.J. Diabetes Sci. Technol. 2009; 3: 1451-1459Crossref PubMed Scopus (70) Google Scholar].Besides conventional excipients and nanomaterials, innovative oral delivery devices have become very popular. An example of this is RaniPillTM from Rani Therapeutics for oral delivery of octreotide to treat acromegaly, bleeding esophageal varices, and hypoglycemia [27.Ahmed M. et al.Functional, diagnostic and therapeutic aspects of gastrointestinal hormones.Gastroenterol. Res. 2019; 12: 233Crossref PubMed Google Scholar]. In this device, the outer enteric capsule degrades in the intestine, extending the packed microneedles. These microneedles penetrate the intestinal wall, providing a sustained systemic release of octreotide directly into the bloodstream [27.Ahmed M. et al.Functional, diagnostic and therapeutic aspects of gastrointestinal hormones.Gastroenterol. Res. 2019; 12: 233Crossref PubMed Google Scholar].Furthermore, there has been significant progress for testing oral formulations of octreotide: the MYCAPSSA™ capsule was approved by US FDA in 2020 after success in clinical trials (NCT01412424, NCT02685709, and NCT03252353)ii [28.Brayden D.J. Maher S. Transient Permeation Enhancer®(TPE®) technology for oral delivery of octreotide: a technological evaluation.Expert Opin. Drug Deliv. 2021; (Published online June 28, 2021)https://doi.org/10.1080/17425247.2021.1942838Crossref Scopus (11) Google Scholar]. MYCAPSSA™ used transient permeability enhancer (TPE®) technology, which uses absorption enhancer sodium caprylate to help drug penetration through mucus and epithelial barrier [29.Tuvia S. et al.A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms.Pharm. Res. 2014; 31: 2010-2021Crossref PubMed Scopus (91) Google Scholar]. The results from a pivotal Phase III trial of 151 patients with acromegaly showed that when compared with injected octreotide or lanreotide, the monotherapy with MYCAPSSA™ was equally effective and safe for the 13 months duration of the study (NCT01412424). Importantly, oral formulation of MYCAPSSA™ makes it efficient to achieve dosage titration when compared with conventional parenteral injection [22.Melmed S. et al.Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial.J. Clin. Endocrinol. Metab. 2015; 100: 1699-1708Crossref PubMed Scopus (122) Google Scholar].In addition, Nordic Bioscience developed an oral formulation of salmon calcitonin for the treatment of osteoarthritis. They used one of the Eligen® drug delivery agents to increase its lipophilicity and ability to cross the GIT [30.Bihlet A.R. et al.Clinical and biochemical factors associated with risk of total joint replacement and radiographic progression in osteoarthritis: data from two phase III clinical trials.Semin. Arthritis Rheum. 2020; 50: 1374-1381Crossref PubMed Scopus (10) Google Scholar]. The Phase I clinical trials (NCT00486317, NCT00486369) showed enhanced efficacy compared with nasal formulation [31.Henriksen K. et al.Oral salmon calcitonin–pharmacology in osteoporosis.Expert. Opin. Biol. Ther. 2010; 10: 1617-1629Crossref PubMed Scopus (38) Google Scholar]. Various oral biologics delivery systems that are currently approved for patient use and are under various phases of clinical trials are listed in Table S1 in the supplemental information online.Nanocarriers for oral delivery of biologicsIn recent years, nano-sized carriers have emerged as attractive platforms for the oral delivery of sensitive payloads, including biologics. The nano-sized carriers offer tremendous promise to overcome challenges for oral delivery of biologics by protecting the therapeutic payload, enabling targeted delivery, and enhancing intestinal permeation. Nanocarriers used for drug delivery can be broadly classified as organic or inorganic nanocarriers, with various subtypes of each. Figure 2 shows five of the most commonly used nanocarriers for oral biologics delivery, along with recent examples. Of these, as reported in Table S1 in the supplemental information online, only one liposome-based nano-formulation of HDV-I by Diasome Pharmaceuticals has progressed to clinical trial stages [26.Geho W.B. et al.Hepatic-directed vesicle insulin: a review of formulation development and preclinical evaluation.J. Diabetes Sci. Technol. 2009; 3: 1451-1459Crossref PubMed Scopus (70) Google Scholar]. In the following sections, we provide an up-t