The Development Of Polypeptide Drugs And The Difficulties In Preparation

In recent years, with the gradual maturity of peptide synthesis technology and the continuous improvement of pharmaceutical preparation technology, peptide drugs have attracted extensive attention from domestic and foreign researchers, and related research and development work has been carried out one after another. In clinical medicine, polypeptide drugs are mainly used to treat various complex diseases such as tumors, diabetes, and osteoporosis, and have high application value. When people pay more and more attention to the concept of health, it is very necessary to find out the current development status of peptide drugs, and to explore the problems exposed in pharmaceuticals. This is the focus of this article. The prospect of research on pharmaceutical preparations, the viewpoints put forward, and the strategies elaborated are for reference only.

With the current development and progress of biotechnology, major breakthroughs have been made in the research and application of peptide drugs, and great achievements have been made, which has reshaped my country’s modern pharmaceutical industry and clinical treatment mechanism, and has attracted much attention in the field of pharmacy. Peptide drugs are easy to be synthesized and optimized, and their own characteristics make them of high medicinal value. Peptide drugs generally have a short half-life, unstable structure and properties, but compared with macromolecular proteins or antibody drugs, polypeptide drugs are more stable at room temperature and have higher unit activity. The size, polarity, hydrophilicity, and charge of polypeptide molecules are not as good as those of traditional small molecules, so it is difficult for polypeptide drugs to cross physiological barriers, so they cannot be taken orally. Therefore, it is necessary to deeply understand and understand its development status, and it is necessary to resolve the difficulties in pharmacy to help colleagues engaged in related research.

Part 1 Definition And Development Status Of Peptide Drugs

1.1 Definition Of Peptide Drugs

Amino acid is the basic unit of protein. Polypeptide is a kind of amino acid, which is converted into a compound through separation technology with peptide bonds to form polypeptide drugs. Polypeptide drugs are often formed by separating and purifying 10-100 amino acid molecules after dehydration. More than 100 amino acids can form proteins. The main difference between polypeptides and proteins lies in the length of the peptide chain. At the same time, peptides are more stable because there are no factors in the peptide synthesis that affect protein stability [1]. Peptides are biologically active substances that affect the functions of various cells in the body. They are indispensable in life activities and involve various fields such as cell growth, hormones, and nerves. They have specific therapeutic effects in clinical practice, and polypeptide drugs are widely found in biological systems. Among the signaling molecules, transmission molecules and digestive molecules in the body; peptides with multiple functions are widely used and can be used in cardiovascular, blood, muscle, bone and other systems, so they occupy an important position in the medical industry. Although polypeptide drugs Its development history is relatively short, but its rapid development has become the focus of pharmacy.

Research and clinical application status of peptide drugs: At present, most peptide drugs have the characteristics of ineffective oral administration, short biological half-life, and long treatment cycle, so their development and application are current hot spots, and their development prospects are unlimited. In the 1990s, an average of 9.7 peptide drugs entered the clinical development stage each year, which increased to 19.5 from 2000 to 2010, and the number is still increasing [2]. At present, peptide drugs have been widely used clinically. Due to its high safety and outstanding efficacy, it has been recognized by more and more doctors and patients, and its status in clinical treatment has been continuously improved. important supporting force.

Part 2 Difficulties And Countermeasures In Peptide Drug Formulation

2.1 Difficulties In Preparation Of Peptide Drugs

The research on peptide drugs in the field of pharmacy has attracted a lot of attention, and more attention has been paid to the field of non-injection drugs. The research mainly focuses on three aspects: nasal administration, pulmonary administration and oral administration. The difficulties in formulation of polypeptide drugs are mainly manifested in poor stability, short half-life in vivo, difficulty in passing through biomembranes, and poor antigenicity. The reasons are as follows.

First, the deamidation reaction. Asn/Gln residues are hydrolyzed to form Asp/Glu; the non-enzyme-catalyzed deamidation reaction is affected by the environment and the structure of the polypeptide, and increasing the pH value and temperature will facilitate the reaction.

Second, oxidation. Polypeptide solution is easy to oxidize. One is that there are oxides in the solution to promote the oxidation of polypeptide, and the other is the spontaneous oxidation of polypeptide. The most easily oxidized amino acid residues are Trp, Tyr, Cys and Met. Oxidation will be affected by temperature, oxygen partial pressure, buffer solution.

Third, hydrolysis. Peptide bonds are easily broken by hydrolysis, and peptide bonds formed by Asp are more likely to be broken, especially Asp-Pro and Asp-Gly peptide bonds.

Fourth, wrong disulfide bonds are formed. Due to the exchange of disulfide bonds with each other or with sulfhydryl groups, the tertiary structure is changed and the activity is lost.

Fifth, racemization. All amino acid residues except Gly are susceptible to base-catalyzed racemization, especially Asp residues.

Sixth, denaturation, adsorption, aggregation or precipitation. Denaturation is mostly related to the destruction of the tertiary structure and secondary structure. In the denatured state, the polypeptide is prone to chemical reactions, and its activity recovery is difficult. During the denaturation process of peptides, intermediates will be formed first. These intermediates are easy to aggregate due to their low solubility, and the precipitates formed in the solution are visible to the naked eye.

2.2 Coping Strategies For The Difficulties In The Preparation Of Peptide Drugs

One, site-directed mutation. The stability of the polypeptide will be effectively improved by replacing the residues that cause the instability of the polypeptide by genetic engineering means, or adding residues that are conducive to the stability of the polypeptide.

Second, chemical modification. Polypeptides can be modified in various ways, and PEG is commonly used. PEG is a water-soluble polymer compound, non-toxic and degradable in the body. It can bind to peptides and improve their thermal stability, resist protease degradation, reduce antigenicity and prolong their in vivo half-life. Careful selection of modification methods or control of the degree of modification can improve and maintain its original biological activity.

Third, additives. Adding polyols, gelatin, sugars, amino acids and other additives or some special salts can improve the stability of the polypeptide. Among them, sugars and polyols can make more water molecules surround the protein at a lower concentration, which can significantly improve the stability of the polypeptide. In freeze-drying, the above substances can replace water and form hydrogen bonds with polypeptides, achieve the purpose of improving the stability of polypeptides, and also help to increase the glass transition temperature of freeze-dried products. In order to avoid adsorption, aggregation and precipitation on the surface of the polypeptide, surfactants such as SDS and Teeen can be used.

Fourth, freeze-drying. A series of reactions of peptides require water to participate, including hydrolysis, deamidation and other reactions. Water is the mobile phase of the reactant, and without water, peptides cannot react. At the same time, the reduction of water content will increase the denaturation temperature of the peptide, so lyophilization can be used to improve the stability of the peptide. This method is more feasible.

Part 3 Preparation Research And Prospect Of Peptide Drugs

3.1 Research On Sustained-Release Formulations Of Peptide Drugs

In clinical applications, oral administration is the most popular, but oral administration of peptide drugs will cause most drugs to be unable to be absorbed, because peptides cannot pass through physiological barriers. Because of its short half-life in the blood, intravenous administration will be rapidly eliminated and degraded, and the desired therapeutic effect cannot be achieved. In order to achieve the purpose of reducing the pain of patients with a small amount of drugs, slow-release and controlled-release technologies are mainly used at present: first, in the process of injecting drugs, high molecular polymers, such as hyaluronic acid, are added to improve the adhesion of drugs and reduce their diffusion. Speed; Second, use liposome encapsulation or solid particle encapsulation to allow polypeptide drugs to slowly seep out.

Among the above methods, the encapsulation of solid particles is the most widely used, and the materials that can be used to prepare particles include polycaprolactone, polyamino acid, polylactic acid, polyorthoester, etc. Polyester materials are mostly used for polypeptide microcapsules, especially PLGA. The typical curve of protein release from PLGA particles is divided into three phases, which are initial detonation release phase, diffusion controlled release phase, and decomposition controlled release phase[3]. The first phase means that the protein located on or near the surface of the particle can be released rapidly within a few hours; the second phase means that the protein can be diffused and released through the pores in the particle. In order to achieve continuous release, it needs to be overlapped with decomposition and controlled release; The three phases mainly decompose the polymer, and then form gaps to allow the continuous release of the encapsulated protein. The difficulty in practical application lies in reducing the initial burst release and increasing the drug loading. The polypeptide and polypeptide microparticle formulations prepared by this method include LHRH, GH, IFN, EPO and the like. The microparticle preparation of the LHRH analogue leuprolide can control drug release for up to one month. This product was first launched in France in 1988, and has since been launched in more than 40 countries in Europe and America. The drug was introduced in my country in 1993.

3.2 Research On Non-Injection Route Of Administration

The main characteristics of peptide drugs are large molecular weight, poor fat solubility, and difficulty passing through the physiological barriers of organisms. In order to obtain the best drug effect, it is necessary to use the form of injection, but frequent injections are very painful. In order to alleviate the pain of patients and the pain of medication, people have launched research on the non-injection form of polypeptide drugs. A study of relevant domestic literature found that the most researched areas are nasal cavity and pulmonary medication.

Nasal administration: The mucosal area of the nasal cavity is about 200 cm2, the epithelial cell space is large and closely connected with capillaries, the lymphatic tissue is abundant, the blood flow rate is about 40 mL/min, and the medication conditions are good. Through nasal inhalation, the drug can directly enter the blood system of the whole body, reduce the possibility of degradation by large proteins and denaturation of aerosol particles, promote drug absorption, and achieve a good therapeutic effect. At present, there are mainly two methods of medication, spray and nasal drops, and the bioavailability of nasal drops is higher.

Pulmonary drug administration: The adsorption surface area of the human lung is 140m2, which is much larger than that of the nasal cavity, and the lungs are rich in capillaries, with large gaps between epithelial cells and stronger permeability during the medication process. Some animal experiments also show that when peptide drugs are administered to the lungs, the bioavailability is about 20% to 50%, but some peptide drugs will be degraded by lung proteins, or interact with aerosols in the process of reaching lung tissue. The combination of microparticles leads to denaturation. As for which peptide drug is suitable for pulmonary administration, further analysis is required.

In the process of pulmonary drug delivery, the appropriate drug delivery method is very critical, which will have a direct impact on the drug release effect in the lungs. Powdered medicaments are currently the main way to use specific inhalation devices to directly reach the lungs, and can achieve the best therapeutic effect. An ideal powdered drug needs to meet the following conditions: It can also be rapidly disaggregated in large quantities at low flow rates and low pressures, and can reach the lungs directly. Pulmonary powder delivery is still under investigation.

Oral administration: Oral administration is not too painful and convenient, and it is quite popular in clinical practice, but polypeptide drugs are not easily absorbed by the gastrointestinal tract, so oral administration has serious limitations, mainly because it inhibits the development of the disease and relieves the pain of patients The process requires taking a large amount of drugs, and peptide drugs are easily degraded by a large number of peptidases and proteolytic enzymes due to their unstable chemical structure and properties and difficulty passing through physiological barriers. At the same time, some drugs will be eliminated by the liver even after absorption. It is difficult to realize oral administration of polypeptide drugs. At present, researches are mostly focused on improving the ability of peptide drugs to pass through physiological barriers and resist protein degradation [4]. In terms of promoting polypeptide drugs to pass through physiological barriers, the use of accelerators is the main means. Common accelerators include fatty acids, bile salts, and chelating agents. Inhibitors etc.

Part 4 Conclusion

To sum up, peptide drugs are suitable for the treatment of various diseases, so they have attracted more people’s attention, and related research has been put on the agenda. At present, it is necessary to have an in-depth understanding of the development status of polypeptide drugs, and it is necessary to dig out and solve the difficulties in the formulation of polypeptide drugs, especially the difficulty of instability. The development of preparations will provide assistance, and then new achievements will be made in research and development, which will ultimately benefit the majority of patients!