Oral administration is convenient, simple and easy to be accepted by patients, but there are the following limitations in the oral administration of polypeptide drugs: ① gastrointestinal degradation; ② large relative molecular weight, poor permeability of gastrointestinal mucosa; ③ formation of polymer; ④ first pass metabolism of liver. Generally, the oral absorption rate of polypeptide drugs is less than 2%, and the bioavailability is very low, which makes oral administration become the most difficult route of biotechnological drugs. At present, the focus of the research on the oral preparation of protein peptide drugs is mainly on the aspects of seeking to promote absorption and improve the bioavailability. The commonly used methods to promote absorption and improve bioavailability are as follows:

(1) Improve the permeability of absorption barrier: add the accelerating absorbent.

(2) Reduce the activity of peptidase in absorption pathway and absorption site: add aprotinin, bacilli enzyme, etc.

(3) Molecular structure modification: prevent degradation.

(4) Prolonging the action time: for example, the bioadhesion technology is used to prolong the retention of the drug preparation at the absorption site.

Injection system

PEG modification

PEG modification refers to the covalent combination of PEG and the nonessential group of peptide molecules to modify drugs. Increase the solubility and stability of drugs in water, change the biological distribution behavior in vivo, increase the relative molecular weight, create a space barrier, reduce the enzymolysis of drugs, avoid the metabolism and elimination of drugs in the kidney, and prevent drugs from being recognized by immune system cells, thus prolonging the circulation time of drugs [7].

Microsphere for injection

The main purpose of developing microspheres for injection is to achieve sustained-release effect. In 1986, Ipsen biotechnology company of France launched the market of intramuscular injection of triptoreline polyglycolide monoglycolide microspheres, and then successively produced leuprorelin acetate, buhuirelin and meterelin intramuscular injection microspheres, which are used to treat some hormone dependent diseases, such as prostate cancer, hysteromyoma, breast cancer, endometriosis, etc. One injection of leuprorelin (75mg) microsphere once a month is equivalent to 1mg solution every day. The effect of different durations can be obtained by changing the proportion or molecular weight of the copolymer.

Liposomes for intravenous injection

It has been reported that all kinds of cytokines, such as GM-CSF, IFN-r, IL-1, IL-2, IL-6, are embedded in liposomes, which can be sterilized by r-ray irradiation and stored at low temperature for more than 3 months. Intravenous injection can achieve slow-release effect, and change the distribution and accumulation characteristics of IL-2 in vivo, which makes it easier to enter cells to play a role and improve receptor sensitivity. Similarly, TNF-a coated with liposomes also increased its cytotoxic activity, and it was also active to non sensitive resistant cells, indicating that liposomes had sensitizing effect on target cells. The preparation method of immunoliposomes is also applied to biotechnological drugs.

Vaccine controlled release preparation

It is one of the main goals of the WHO vaccine development plan to vaccinate once to achieve complete immunization, improve the type of vaccination and reduce the cost of vaccination. The controlled-release vaccine preparations studied are mainly microspheres or other microparticles. Through the selection of materials and the degree of encapsulation, the release rate of vaccine can be controlled, such as rapid release and constant release, pulse release, etc. The vaccines studied include toxoid vaccines such as diphtheria, tetanus, gas gangrene and cholera, virus vaccines such as hepatitis B vaccine, nucleic acid vaccine and synthetic vaccine.

Other dosing systems

Other routes of administration of polypeptide drugs include nasal mucosa, lung, rectum, oral mucosa, skin, etc.

## 2、 The development of peptide drugs

Peptide drugs are mainly used in the treatment of cancer, metabolic disorders related major diseases, which have a very important global market. At present, there are about 60-70 kinds of polypeptide drugs in the global drug market, such as somatroline, Copaxone, Zoladex, sandostatin, secretin, leuprolide, indicator, ceruletide, bivalirudin, vasopressin and vapreotide There are 200-300 kinds of peptide drugs in clinical trials, 500-600 kinds in preclinical trials, and more peptide drugs in laboratory research stage.

It can be predicted that more and more peptide drugs will be approved by FDA to enter the drug market in the future. Some existing peptide drugs have a considerable market. Some drugs, such as gratiret and octreotide, have global sales of more than $1 billion a year. The annual sales of terpatide (Forteo) for osteoporosis and exenatide for diabetes are also close to 1 billion US dollars. In spite of this, the market share of peptide drugs is still very small in the global drug market of nearly US$1 trillion. The annual market share is less than US \$20 billion, accounting for less than 2% of the global drug market. On the other hand, it just shows that peptide drugs have a wide space to rise [4].