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Materials for Oral Delivery of Proteins and Peptides REVIEWS Materials for oral delivery of proteins and peptides Tyler D. Brown 1,2, Kathryn A. Whitehead 3,4 and Samir Mitragotri 1,2* Abstract | Throughout history , oral administration has been regarded as the most convenient mode of drug delivery , as it requires minimal expertise and invasiveness. Although oral delivery works well for small-molecule drugs, oral delivery of macromolecules (particularly proteins and peptides) has been limited by acidic conditions in the stomach and low permeability across the intestinal epithelium. Accordingly , the large numbers of biologic drugs that have become available in the past 10 years typically require administration by injection or infusion. As such, a renewed emphasis has been placed on the development of novel materials that overcome the physiological challenges of oral delivery for macromolecular agents. This Review provides an overview of physiological barriers to the oral delivery of biologics and highlights the advances made in materials across various length scales, from small molecules to macroscopic devices. This Review also describes the current status of materials for oral delivery of protein and peptide drugs. The past decade has seen an increase in the number route13. Unfortunately, barring some very small pep­ of new drugs approved by the US Food and Drug Admin­ tides such as ciclosporin, oral delivery is not a currently istration (FDA), leading to an all­ time record number available option for protein and antibody drugs14. These of 59 novel drug approvals in 2018. Drugs for oral use macro molecular agents have prohibitively low oral bio­ continue to dominate the therapeutic landscape, encom­ availability due to several features of the gastrointestinal passing over 50% of these approvals1. Over one­ third of tract, including the proteolytic environment of the stom­ the remaining approvals relate to biologic agents admin­ ach and limited absorption in the intestine15,16. A clear, istered via parenteral routes, such as subcutaneous, unmet need exists for the design of new materials to intravenous or intramuscular injections1. enable oral protein delivery, beyond commonly used Parenteral drug delivery achieves high bioavailability excipients or already FDA­approved inactive ingredients. (~100% for infusions)2,3. Nonetheless, parenteral admin­ In this Review, we discuss key physiological barriers istration is associated with considerable disadvantages, to the oral delivery of biologic therapies and describe including pain or discomfort4, severe reactions at the state­of ­the­art, materials­based approaches for improv­ injection site5,6, scarring7, local allergic reactions8 and ing their bioavailability. This Review also details the 9 1John A. Paulson School of cutaneous infections . Furthermore, intravenous injec­ current clinical translational landscape of materials Engineering and Applied tions require administration by a skilled health­care pro­ for oral protein delivery, arranged by the characteristic Sciences, Harvard University, fessional, and self­administered injections are associated length scale — from small molecules to macromolecular Cambridge, MA, USA. with social stigmatization of patients10. Taken together, devices. Our selection of this organizational structure 2Wyss Institute for these deleterious effects can result in poor compliance reflects the fact that some materials possess multiple Biologically Inspired of patients with their prescribed treatments (BOx 1), mechanisms of action, whereas others do not have an Engineering, Harvard University, Boston, MA, USA. especially among individuals with chronic diseases that established mechanism of action. 11,12 3Department of Chemical require long­ term monitoring and repeat dosing . Engineering, Carnegie Mellon Historically, oral administration has offered a con­ Barriers to oral delivery University, Pittsburgh, venient, familiar and painless alternative to injections. The gastrointestinal tract is designed to digest carbo­ PA, USA. Alchemists and researchers alike have been delivering hydrates, proteins and other nutrients into their con­ 4Department of Biomedical herbal remedies and drugs by the oral route dating as far stitutive subunits of amino acids and simple sugars. Engineering, Carnegie Mellon back as 1550 BCE (Fig. 1). Throughout history, techno­ Simultaneously, it also prevents the entry of pathogens. University, Pittsburgh, PA, USA. logical advances, including the mass manufacture of We should not be surprised, therefore, that the oral bio­ *e- mail: mitragotri@ tablets and capsules, have continued to drive the field availability of intact peptides and proteins is <1% and 17,18 seas.harvard.edu of oral drug delivery forward. Today, an estimated 70% of sometimes even <0.1% . Indeed, orally administered https://doi.org/10.1038/ Americans (~230 million individuals) take at least one drugs must overcome numerous biological hurdles prior s41578-019-0156-6 prescription drug each day, regardless of administration to their absorption, as detailed in the next sections (FIG. 2). NATURE REVIEWS | MATERIALS REVIEWS Biochemical barrier intestine, which is brimming with digestive enzymes Two major categories of biochemical barriers exist secreted by the pancreas. Common enzymes found here for proteins: enzymatic and pH. Proteases and other include trypsins, chymotrypsins, carboxypeptidases enzymes readily cleave proteins at specific cleavage sites and elastases. Enterocytes of the small intestine also and are located throughout the gastrointestinal tract. produce several aminopeptidases, carboxypeptidases, Likewise, drastic deviations from neutral pH can read­ endopeptidases and γ­glutamyl transpeptidases22. ily denature (unfold) proteins, rendering them inactive. The small intestine is divided into three distinct Digestion first begins in the mouth, where the slightly regions: duodenum, jejunum and ileum, each of which acidic (pH ~6.5) conditions and saliva rich in salivary possesses unique features that affect nutrient absorp­ amylases and lysozymes initiate degradation of carbo­ tion23. As partly digested food and other particulates hydrates and peptidoglycans, respectively19. However, transit through the gastrointestinal tract, they are sub­ the buccal cavity is not considered a prominent barrier to jected to a luminal pH that steadily increases from the oral drug delivery as the residence time of a pill or capsule stomach (pH 1.0–2.0) through the duodenum (pH 4–5.5.0), is minimal, and the drug exposure is correspondingly jejunum (pH 5.5–7.0) and ileum (pH 7.0–7.5), before minimal. transiting to the colon and rectum (pH 7.0–7.5)24,25. The stomach and intestine possess the most active This pH gradient, along with varying gastric emptying biochemical barriers to bioavailability of orally ingested rates and gastrointestinal motility, strongly influence proteins20 (Fig. 2a). Digestive fluids of the stomach, the pharmacokinetics of orally administered drugs26. secreted by gastric glands, are composed of hydro­ Inactivation and/or protection from these enzymes and chloric acid, the protein­ digesting enzyme pepsin and pH changes are essential for the effective oral delivery of mucus. Hydrochloric acid renders the stomach the protein­ based drugs. most acidic environment in the body (pH 1–2). In such highly acidic conditions, pepsin performs optimally. Mucus barrier. Mucus is a viscoelastic, hydrogel­ like Found at high concentrations in the stomach, pepsin substance lining the gastrointestinal tract that is secreted acts as a broad endopeptidase, hydrolysing peptide by goblet cells (Fig. 2b). Mucus is predominately com­ linkages of aromatic residues such as phenylalanine, posed of mucins, which are a heavily glycosylated class tryptophan and tyrosine 21. Hydrolysis of fats, oils and of glycoproteins with a propensity to form gels due to triglycerides also occurs in the stomach and is catalysed their charged, bottlebrush­like architecture27. Mucus also by lipase enzymes. Digestion continues in the small contains water, lipids, electrolytes, immunoglobulins, antimicrobial peptides, protease inhibitors and various other active proteins28. Mucus, therefore, provides a Box 1 | Challenges associated with adherence to treatment nutrient­ rich niche for commensal bacterial coloniza­ Patients might choose to forgo their medications for a variety of reasons, which could tion throughout the gastrointestinal tract, while serving 29 lead to a decreased quality of life and even death. Poor treatment compliance can be as a barrier to pathogenic bacteria . associated with one or more of the factors outlined below. One of the main functions of mucus is to facilitate Treatment- related factors the passage of food, chyme and faeces through the body. Mucus also acts as a physical barrier that limits the dif­ • Administration required by a skilled professional fusion of drugs and other molecules from the lumen to • Overly complex therapeutic regimen the underlying epithelium28,30. The pore size of mucus • Required monitoring of therapy has been estimated to be approximately 0.2 μm on aver­ • Extended duration of therapy age31,32. Pore size varies, however, depending on the • Frequent changes to the drug regimen location, dynamic responses to the presence of endo­ • Actual or perceived adverse effects of treatment genous and exogenous stimuli and the patient’s state 33 Disease- related factors of health . • Symptoms are non- existent or minimal Gastrointestinal mucus also has unique dynamic, physiochemical characteristics. The
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