Scientists generate more and more proteins and peptides (PPs) to treat different illnesses as science advances. Because of their excellent selectivity and effectiveness and low toxicity, PPs have emerged as a viable alternative to tiny molecular medicines, piquing the pharmaceutical industry's attention.
Peptides are chains of amino acids joined together by peptide bonds to form polypeptides. Peptides are amino acid chains with less than fifty amino acids. More than fifteen amino acids may be found in polypeptides, larger than oligopeptides. At least fifty amino acids must be present to be considered a protein.
Administering medications via the proper channels ensures both therapeutic effectiveness and patient compliance. On the other hand, Peptides are frequently administered intravenously because of their low oral bioavailability. Pain, dislike of injections, needle aversion, and local irritation might make it difficult for patients to stick with long-term continuous injections. The oral route is the most appealing option owing to its increased safety and compliance; hence many research organizations have sought to create alternative delivery channels for peptides such as the oral route, nasal, ocular, buccal, and transdermal administration.
It is also possible to establish improved glucose homeostasis by administering insulin orally rather than injecting it subcutaneously (sc). Patients with some chronic diseases might benefit from better living circumstances due to using the oral route of administration.
Peptide absorption via the oral route also improves through academic research. Throughout the 1990s, the number of publications on oral peptide administration exploded. The main challenges in developing oral delivery methods for PPs include:
- The harsh conditions of the gastrointestinal (GI) tract.
- Large molecular size.
- High hydrophilicity.
- Low transmembrane permeability.
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Many factors hinder PPS oral absorption.
Pharmaceutical businesses and funding agencies have shown great interest in oral PPs; however, there are several obstacles to developing oral PPs due to the GI tract instability and low permeability across intestinal epithelia. Due to the intrinsic nature of the GI tract, which is not only the primary location of food digestion and nutrient uptake but also the first line of defense against toxins and infections, the physiological barriers are the main impediments to oral absorption of PPs. It is vital to understand the physiological and formulation aspects to overcome oral delivery hurdles.
The body's natural defenses
Most medications must first endure stomach acid and gastric secretions after oral delivery to reach the small intestine. However, the pH, enzymes, mucus, and even epithelial permeability of the stomach and intestines are entirely different, all of which impact the stability and uptake of PPs.
Factors that influence the formulation
For the development of marketable oral PPs medicines, the formulation is as vital as overcoming physiological hurdles. A formulation must consider PPs' chemical and physical stability to ensure their long-term viability in manufacture, transit, storage, and administration. Various outstanding publications have summarized the formulation parameters that affect stability for parenteral formulations. Hydrophobic and hydrophilic interactions, hydrogen bonding, and electrostatic interactions play a crucial role in the strength of PPs, unlike small-molecule medicines. The pH of a formulation might modify PPs by altering their surface charge, density, and dispersion. PPs' colloidal stability is likewise influenced by pH, affecting protein aggregation and breakdown rates. The physical stability of PPs in liquid is likewise influenced by ionic strength, just as by pH. Scientists may improve hydrophobic interactions between proteins by increasing the amount of salt in the solution. As a result, experts use solutions to stabilize PPs in solution formulation.
Excipients like arginine, histidine, and glycine are essential to the formulation of proteins to increase their solubility or prevent protein aggregation. Arginine can stabilize the structure of proteins by reducing the accumulation of proteins. Researchers may also stabilize proteins by applying polysorbate, a surfactant, which reduces molecular interactions on various surfaces. The chemical volatility of PPs affects all stages of the product lifecycle, from conception through disposal. PPs contain methionine residues, Tryptophan, Histidine, Cysteine, Phenylalanine, or Tyrosine, which antioxidants may prevent, such as methionine ascorbic acid most susceptible to oxidation. Aside from enzymatic decomposition, oral delivery presents the most significant problem in preserving PPs from GI conditions. Enteric coating, encapsulation, and enzyme inhibitors are the most common methods of protecting oral formulations from digestive enzymes. SNAC, bile salts, and nonionic surfactants are among the permeation enhancers used in oral formulations for this purpose.
PP oral absorption methods are currently in development.
It is possible to boost the absorption of oral PPs via stability, penetration of mucus or adhesion, and the addition of a permeation amplifier. Experts often combine these methods into a single delivery system.
The pH and digestive enzymes in the GI tract have the most significant impact on the stability of PPs following oral delivery, depending on physiological and formulation parameters. Furthermore, the composition of peptides has a substantial effect on their strength. Oral PP formulations have relied on various stabilizing techniques, which we will discuss in this section.
Systems that penetrate and adhere to mucus
Multiple hurdles to protein absorption are posed by the mucus lining of the intestinal membrane of the GIT, as previously described. In the design of medication delivery systems, mucus is a double-edged sword. Systems that penetrate mucus and adhere to it are two different methods to increase delivery efficacy. Mucus penetrating systems may quickly pass through the unstirred layer to access the intestinal epithelium. On the other hand, Mucoadhesive systems may extend medication absorption by preventing mucociliary clearance from the intestines. Mucoadhesive and mucus-penetrating systems have received several favorable evaluations.
Enhancement of absorption
PPs' low permeability through epithelial membranes owing to their considerable molecular weight and strong hydrophilicity is another major factor limiting oral bioavailability. To create oral products, it is essential to increase the intestinal permeability of PPs via chemical or medicinal techniques. In clinical or preclinical goods, absorption boosters may be the most often employed strategy to improve oral PP absorption thus far.
Results and future outlooks
Since the rise in market share over the previous decade, oral administration of PPs has become a more viable option for therapeutic research and development. This option is why PPs' stability and permeability experience an overcome using innovative methods to improve oral bioavailability. Enteric coating, enzyme inhibitors, permeability enhancers, and chemical alteration are technologies that researchers have effectively applied in PPs orally marketed products. For oral PPs formulation, nanotechnology-based techniques have demonstrated promising results. Furthermore, intestinal microdevices, such as intestinal microneedles, have been created for the oral delivery of PPs. A careful evaluation of these new technologies is essential to ensure safety, effective, and reliable preparation. A poor oral bioavailability for systemic distribution of PPs, even when adopting modern technologies to increase stability and permeability, still exists for specific products.
Numerous studies have shown that nanoparticles may aid in the passage of PPs through the digestive system. Instead, the primary focus should be a better knowledge of how these nanocarriers interact with PPs or the intestinal environment. Also essential is a better understanding of how PPs travel across the intestinal epithelium and how physiological variables affect PPs absorption. After oral delivery, nanoparticles and polypeptides must be characterized in vivo to design highly effective oral systems for PPs.