Peptide Knowledge Center

Drug delivery system and obstacles of peptide and protein drugs

The absorption of protein and polypeptide drugs is obviously dependent on the route of administration. When taking orally, the protein will be destroyed by gastric acid and digestive enzymes, and it is also difficult to be absorbed by the gastrointestinal tract. Therefore, this method is only applicable to a few peptide drugs. In comparison, the following administration methods are more applicable to protein and peptide drugs. Mucosal drug delivery system is to use appropriate carriers to deliver drugs to human mucosa, such as nasal mucosa, oral mucosa, etc., and then enter the circulatory system for treatment. There are both mucous membranes and rich blood vessels in the nasal cavity, where the drug absorption efficiency is high, and it is less interfered by digestive juice and enzymes in the stomach and intestines, so it is an ideal drug delivery mode for proteins and peptides.

The permeability of oral mucosa is only inferior to that of nasal mucosa, which also has rich blood vessels, so the drug absorption rate is also high.

Subcutaneous injection and transdermal absorption can both avoid the damage of digestive fluid to protein, and also avoid the first effect of intestinal tract and liver on drugs. However, due to the existence of subcutaneous protease, these two methods of drug administration also face the problem of degradation fmoc-osu. In addition, the transdermal absorption efficiency of protein and peptide drugs is low, which is also a major problem to be solved.

After administration by the above method, the drug will enter the circulatory exenatide impurities system and circulate to the whole body along with the blood. Intravenous injection is to directly inject the drug into the circulatory system to avoid the aforementioned obstacles. However, proteolytic enzymes exist everywhere in the human body, and the drug may be damaged in the blood, liver and other organs. In addition, a variety of proteins (such as albumin, various antibodies, etc.) in the blood may also combine with drugs to make them lose their efficacy. Macrophages in the blood may also recognize protein drugs as invaders, so as to clear them and finally expel them from the kidney. This series of factors will reduce the concentration of protein peptide drugs in the blood and their half-life.

To solve these problems, researchers have designed a variety of systems, the most common of which are the following three ways or approaches:

1. PEG

PEG (polyethylene glycol) is a hydrophilic neutral molecule, which can covalently combine with some amino acids around the protein structure to form a hydrophilic barrier on the surface of the protein to prevent the degradation of protease, and also prevent the protein from binding with antibodies to produce immune reaction, so as to improve and prolong the efficacy. At present, there are many PEG based protein drugs on the market, such as PEG based L-asparaginase (Oncaspar of Enzon Company), PEG based interferon A-2b (IFNA-2b) (PEGIntron of Schering Company), PEG based interferon A-2a (IFNA-2a) (Pegasys of Roche Company), and PEG based granulocytes.Colony stimulating factor (GCSF) (Neulasta of Amgen Company), etc.

2. Fatty acid modification

Fatty acid modification is beneficial to improve the affinity between protein peptide drugs and cells, and promote the absorption of drugs by cells. The fatty acid modified on the protein can also mask the enzyme binding site of protein polypeptide molecules, delay or inhibit the destruction of hydrolase on drugs, and prolong the action time of drugs in vivo. Fatty acids can also combine reversibly with plasma albumin in vivo. The size of the combined complex is too large, which is limited in the transport through the vascular wall, so that the drug concentration in the blood can be maintained at a high level for a long time.

Hashizume et al. modified the insulin molecule with palmitic acid to obtain palmitic acylated insulin with higher lipophilicity. The results showed that the blood concentration of dipalmitic acid derivatives was significantly higher than that of unmodified insulin, while the single palmitic acid derivatives were between the two.

Huang Tao and others modified insulin with stearic acid, oleic acid and linoleic acid respectively, and compared the destructive effect of trypsin on insulin. It was found that the stearic acid modified insulin had the highest stability and the unmodified insulin had the lowest activity when trypsin was used in vitro. This result shows that the fatty acid modification of protein polypeptide drugs can improve the anti enzymolysis ability of protein polypeptide molecules, make them stable for a longer time and extend their half-life, and this ability to prevent enzymatic degradation increases with the increase of the unsaturation of fatty acid molecules.

Li et al. modified insulin with fatty acid to increase its combination with HSA. On the other hand, the side chain of fatty acid can also promote the formation of hexamer of insulin, thus delaying the diffusion and distribution of insulin from circulating blood to peripheral target organs, and significantly prolonging its half-life.

3. Nanohydrogel as drug carrier

Nanohydrogel refers to micro gel structure with particle size of 10~100nm. It has weak interaction with protein, can isolate protein from the external environment, and avoid enzyme degradation, so it is often used for drug loading. Zhang Lin et al. designed a nano gel which was obtained by physical crosslinking of alginate. Sodium alginate is a polyanion. After adding Ca2+, it will cross link to form gel. Nano gel can be obtained by adjusting the concentration and speed of adding Ca2+. This kind of hydrogel has low toxicity, and can form gel in situ to wrap biological macromolecules such as proteins and peptides, so as to effectively achieve the purpose of slow release.

Sundy et al. used CHPMA nano gel with particle size of 14~17nm as cross-linking agent to form hybrid hydrogel with 2-methacryloyloxyethyl phosphate choline (MPC), and tested its absorption and release of protein. The results showed that the proteins in the gel were mainly distributed in the inner CHPMA nano gel region. Soak gel in methyl- β- After cyclodextrin, protein is released from it.

Summary and outlook

Compared with traditional drugs, polypeptide and protein drugs have the advantages of specificity and efficiency, but they are easy to be degraded by protease, have poor stability, and have short drug efficacy. They need to be administered frequently in clinical applications, which brings huge physiological and psychological burden to patients. Therefore, it is essential to improve the stability of protein and peptide drugs in vivo. This article introduces the common administration methods at present, analyzes the reasons for low stability and short half-life of protein drugs, and introduces several common improvement methods. In addition to PEG modification and fatty acid modification, in recent years, researchers have also tried to modify protein drugs with polyamino acids; In terms of drug delivery system, in addition to nano gel as drug carrier, liposomes, micelles, etc. are also used for the delivery of protein and peptide drugs. With the continuous deepening of research, it is believed that new methods that can effectively improve the stability of peptide and protein drugs will be obtained in the future.