Peptide and protein therapeutics have grown dramatically in recent decades, but delivery has restricted their usage. Even though oral administration is preferable, most are now administered intravenously or subcutaneously due to the gastrointestinal system’s breakdown and poor absorption. Researchers are looking into absorption enhancers, enzyme inhibitors, carrier systems, and stability enhancers to make oral peptide distribution easier. Although transdermal peptide administration eliminates digestive system difficulties, it still has limits in absorption. A lack of changes makes it impossible for peptides to survive in the body unmodified. This review focuses on peptide medication delivery through oral and transdermal routes, emphasizing the challenges of absorption and stability. Systemic and site-specific delivery methods are also covered.
The therapeutic use of peptides and proteins is auspicious. It is estimated that the peptide and protein medicine industry now stands at more than $40 billion per year or 10 percent of the pharmaceutical business. Even though this market is developing at a far quicker rate than the market for small molecules, its share of the market will continue to rise. More than a hundred peptide-based medicines have been authorized so far, the majority consisting of less than 20 amino acids. Comparatively, peptides and proteins have several interaction sites with their target compared to traditional small-molecule medications, which now make up the bulk of the pharmaceutical industry. Reduced toxicity and adverse effects may be achieved by improved selectivity. In domains including cancer, immunology, infectious illness, and endocrinology, peptides may be tailored to target a wide variety of molecules.
These peptide and protein therapies’ poor bioavailability and metabolic liability are only two of their drawbacks. Protein bioavailability is restricted by the GI tract’s breakdown and their inability to pass the epithelial barrier when taken orally. Their absorption is hindered by considerable molecular weight, poor lipophilicity, and charged functional groups. Most orally given peptides have limited bioavailability (less than 2%) and short half-lives (less than 30 minutes). Because of other factors, such as systemic proteases, rapid metabolism, opsonization, conformational changes, dissociation of subunit proteins, non-covalent complexation with blood products, and destruction of labile side groups, peptide and protein therapeutics have limited bioavailability. These include intravenous or subcutaneous delivery methods that circumvent absorption problems.
It’s becoming more popular to design methods that allow for the oral administration of peptides and proteins since it enhances patient compliance. Noninvasive delivery strategies, including oral and transdermal distribution, have several challenges. These hurdles to delivery will also be examined in detail. Therapeutic targeting and systemic stability are the topics of the concluding section of this study.
Obstacles to oral transmission
Most researchers choose oral substance administration since it is the most convenient method of taking medication. Patients are more likely to take their prescriptions as directed when they take them orally because of how simple it is for them to do so. Many protein therapies are being developed, but oral administration remains a problem. Protease inhibitors, the epithelium barrier, and efflux pump reduce the oral bioavailability of protein- and peptide-based medications by up to 90 percent.
Proteases and peptidases break down proteins in the stomach and intestines using enzymes and hydrolysis in the acidic environment. There are at least 569 proteins in the human degradome, a complete list of proteases in human cells. Serine, cysteine, threonine, aspartic, and metalloproteinases are among the five major categories of proteases. In addition to their activities in DNA replication and transcription, these proteases have a role in cell proliferation, apoptosis, stem cell mobilization, hemostasis, senescence, and various other critical processes in the body’s cells. The pancreas releases trypsin, carboxypeptidase, and Chymotrypsin into the small intestine, where they are concentrated in the duodenum. Twenty percent of the enzymes responsible for breaking down the proteins and peptides eaten are found in this class of enzymes. The remaining 80% of the enzymatic breakdown is explained in the following paragraphs.
Oral protein therapeutic administration is hampered by peptide breakdown, but the small intestine’s epithelial barrier offers an even more significant difficulty. The lamina propria and muscularis mucosa support a single layer of columnar epithelial cells in this barrier. Molecules can pass through the epithelium in two different ways: transcellular or paracellularly. A thin layer of the Glycocalyx, a sulfated mucopolysaccharide, glycoproteins, enzymes, electrolytes, and water lies directly on the epithelial cell barrier. Additionally, mucins, which are high-MW, highly glycosylated proteins, cover most mucosal surfaces. There is a lack of bulk flow to the epithelial cells, resulting in an unmixed layer on the surface of the epithelium. This layer is shielded from convective mixing forces, reducing how the surrounding environment absorbs tiny molecules and ions. However, the unstirred layer may operate as an absorption enhancer by providing the additional particle time to be exposed to the epithelial barrier after it has passed the mucosal layer.
Peptide breakdown takes place mainly at the brush boundary membrane. In the small intestine, the brush border is the microvilli-covered surface of cells, and the microvilli are critical for digestion and absorption of nutrients. Transepithelial transport is regulated by TJs, which mediate the paracellular route of absorption in intact membranes and constitute the rate-limiting step. The multiprotein complex comprising trans-membrane proteins, peripheral membrane proteins, and regulatory molecules like kinases is necessary to construct TJs at adhesion junctions. Adhering junctions and desmosomes function together to maintain cellular closeness and intercellular communication by providing the required adhesive connections for intercellular adhesion. Perijunctional rings of actin and myosin support both adhering junctions and TJs. Several proteins are critical to the formation and maintenance of the tight junction (TJ).
Efflux pumps stand as the last obstacle to protein substance absorption. Multidrug resistance in humans is mediated by ATP-binding cassette superfamily proteins that lie on the apical edge of mature epithelial cells. In multidrug-resistant strains, the overexpression of 49 ATP-binding cassette proteins has been found. P-glycoprotein I, a particular efflux pump, is an example (PGP-I; also known as MDR1). PGP-I may return substances and peptides to the GI lumen after being absorbed in the GI. Cyclosporine is one of the PGP-I substrates, as are linear lipophilic and cyclic peptides. If you are a researcher you can buy peptides online, for research purposes only.