Pharmaceutical companies backed off of developing oral peptide formulations after the 1990s' early excitement was followed by clinical failure. Specific oral peptides are now showing promise in cutting-edge clinical research. But what exactly may this area of study accomplish?
The biopharma industry and patients would benefit significantly from developing non-injectable versions of approved peptides and proteins. Over 100 injectable peptides were in pharma's clinical pipelines in 2013 - with a market anticipated at $23.5 billion by 2020. This finding is based on using insulin as the upper limit of the molecular definition of a peptide (roughly 6000 Da and 50 amino acids).
Compared to conventional organic small molecules, therapeutic peptides are more selective in their cellular surface target engagement, more powerful, and have fewer adverse effects. However, the majority of the available medicines need an injection. Why? After years of expensive but fruitless research in the 1990s, it seems as though few companies are willing to take the scientific and financial risk involved in developing a new peptide and a non-injected route of delivery at the same time. Pharmaceutical companies are more likely to develop a non-injectable variant of a peptide or protein already on the market. Because of this strategy, researchers working on oral peptide formulations have been restricted to a few commercially available peptides, all developed by medicinal chemists for intravenous administration. Type 2 diabetes may be treated using insulin and glucagon-like peptide-1 (GLP-1) analogs. This place is not a great place to begin since it fails to use innovative chemistry to pick peptides with the express goal of oral distribution. You can buy oral peptides on Biotech Peptides if you are a researcher.
Getting around obstacles in oral delivery
The upper digestive system has specialized in breaking down and absorbing peptides and proteins. The primary difficulties lie in controlling the pancreatic and brush-border enzymes (proteases), as well as the permeability of the intestinal epithelial layer so that the peptide can make it safely past the stomach using enteric-coated tablets or capsules. One way to accomplish these two aims is to construct a dosage form that includes the peptide of interest, enzyme inhibitor(s), and a permeation enhancer. The goal is to produce steep concentration gradients at the absorption site by simultaneously releasing all three components near the intestinal wall. More than a dozen technologies are now in clinical testing, all using composite formulations.
To get the peptide of interest near the absorptive epithelium, one may use a nanoparticle-based design in which the peptide is encapsulated and stabilized with a hydrophilic neutral or negatively charged (anionic) coating to pass through the mucus covering the epithelium. A pill or capsule with a polymeric coating is one method of administering nanoparticles. Nanocarrier systems may include well-established permeation enhancers, such as stable cell-permeating peptides; however, there is currently no agreement on whether the peptide should be released before or after absorption by epithelial cells. There is also debate about how much absorption of nanoparticles occurs through the small intestine in vivo. While the nanoparticle technique has a lot of potentials, it is still quite complicated, and most constructions are not even ready for clinical assessment.
There are other significant obstacles to the safe and effective oral delivery of peptides, such as the fact that each patient is unique not only in terms of their underlying disease conditions but also in terms of gastric emptying, dilution, and intestinal transit time, etc.
The problems above are exacerbated by the fact that pharmaceutical firms, at least according to their published research, tend to confine oral peptide investigations to a narrow range of proven formulation components. This process is logical, given the current regulatory frameworks. As a result, it's tempting to use formulation components that are already considered safe for consumption since they are excipients or have a food-grade classification. Aversion to producing new chemical entities (NCEs) may be why well-established peptides are employed. The chemical structures of peptides are not often altered for an oral program, despite advancements in peptide synthesis and design technology. Additional clinical trial and regulatory expenditures are only worth the risk in circumstances where the investment would likely pay off economically (such as for long-acting injectable insulins or GLP-1 analogs). Although they have not yet been licensed as injectables, newer, more lipophilic, and stable peptide analogs with longer half-lives are beginning to make their way into the oral programs. In February 2015, researchers reported that one GLP-1 analog, combined with a well-established permeability enhancer, yielded promising Phase II evidence.