Some people say that the 21st century is the century of polypeptide drugs, and the fate of this substance between macromolecular proteins and small molecular compounds must be extraordinary.
Polypeptides are a class of compounds composed of amino acids linked by peptide bonds, and are chemically active substances ubiquitous in living organisms.
According to the classification method commonly used in the international pharmaceutical industry, drugs with more than 100 amino acid molecules belong to protein drugs, while drugs with less than 100 amino acid molecules belong to polypeptide drugs.
At present, tens of thousands of polypeptides have been found in organisms, and most of them have physiological activities, involving hormones, nerves, cell growth and reproduction and other fields.
The first step is to obtain crystals of the polypeptide to determine its secondary and tertiary structures.
Then, by alanine substitution, structure-activity relationship (SAR) and other analytical methods, essential amino acids and possible substitution sites are identified. During this process, especially when preparing liquid formulations, it is extremely important to identify labile amino acids and avoid isomerization, glycosylation, or oxidation.
Another important aspect of rational peptide drug design is to improve the physicochemical properties of natural peptides, because natural peptides tend to agglomerate and have low water solubility. Perishable hydrophobic groups should be avoided in chemical design, which can be achieved by substitution or N-methylation of specific amino acids. If the peptide drug has solubility problems, attention should be paid to the charge distribution of the peptide, the isoelectric point, and the pH of the formulation.
Other methods can also improve the stability of polypeptides, such as the introduction of stabilized alpha helices, the formation of salt bridges, or other chemical modifications, such as lactam bridges.
In general, the circulating plasma half-life of native polypeptides is short, therefore, several techniques to prolong the half-life have been developed. One technique is to restrict the degradation of enzymes, replacing the sites in the polypeptide that are easily cleaved by enzymes with other amino acids. Protected enzyme cleavage sites can also be obtained by enhancing the secondary structure of the polypeptide, such as insertion of probes or formation of cyclic peptides.
The second method is to combine polypeptides with albumin, which can prolong the half-life of polypeptide drugs and reduce the frequency of drug use. Liraglutide using this method is a successful example. The third method is to modify peptides. The technology of polyethylene glycol (PEG) modification of peptides is very mature, and many protein and peptide drugs have been successfully marketed after modification, such as PEG-modified interferon. However, due to safety and tolerability considerations, polyethylene glycol has not been the primary choice for injections.
The use of implantable devices to deliver drugs into the body has been proposed, and the use of osmotic pump drug delivery systems could allow patients to administer the drug once a year. This approach opens up an entirely new avenue for the release of peptide drugs, which can address patient convenience and compliance.
Due to the physical and chemical properties of polypeptides, most of them are injections in application, especially intravenous injection or intravenous drip, and the main preparation type is lyophilized powder.
In recent years, in addition to the classic subcutaneous, intramuscular and intravenous administration, other routes of administration have gradually developed, including mucosal administration (nasal, pulmonary or sublingual), oral administration (gastrointestinal tract) penetration enhancers, protease inhibitors or carriers) and transdermal routes of administration. In addition to various drug delivery systems, the application of excipients also helps peptide drugs enter drug development.
Studies have found that using trehalose, sucrose, maltose, glucose and other substances as excipients will increase the solubility and in vivo stability of polypeptides. The surfactant, sodium n-dodecyl sulfate (SDS), was shown to enhance the transmembrane ability of the polypeptide. Nanotechnology as a promising technology will play a role in peptide drug formulation, for example, nanoparticles, liposomes and micelles can better protect drugs from degradation. At the same time, some nano-targeted preparations can also reduce the side effects of drugs.