"Peg drug" of innovative drug structure design

notes preceding the text of a book or following the title of an article At first, I knew that polyethylene glycol (PEG) was a substance originated from the undergraduate course "pharmaceutical preparations" In the book, I learned that PEG participated in the research and development of pharmaceutical preparations in various roles Later, I really contacted peg in practice, which originated from a two-phase reaction during graduate school Because the reaction effect was not good, I used the phase transfer catalyst PEG-400, although it was not obtained The ideal result, but that bottle of sticky stuff impresses me.. Now, to talk about peg, it is based on the in-depth study of innovative drugs, and found that it is not only used in preparation, synthesis and other practical operations, but also can be directly connected to drug molecules, thus changing the properties of drugs Therefore, this paper briefly summarizes its application in pharmacy, and hopes to be able to on this basis More "good things" that can modify drugs are found Peg is a kind of ethylene glycol polymer with a relative molecular weight of 200-8000 or more It is composed of repeated oxyethylene group It is not only water-soluble, but also soluble in DCM, DMF, benzene, acetonitrile, ethanol and other organic solvents Peg has two terminal hydroxyl groups, with linear (molecular weight 5000-30000) or branched (molecular weight 40000-60000) chain structure The molecular formula of linear peg is H - (o-ch2-ch2) N-OH Peg200, peg300, PEG400, peg600, peg1000, PEG2000, PEG4000, PEG6000, peg10000 and so on are commonly used Peg with a relative molecular weight of 200-600 at room temperature is liquid, and peg with a relative molecular weight of 1000 or above is solid 2 Peg has been used as pharmaceutical excipients for hundreds of years Because of its low toxicity and good water solubility, PEG has been widely used in injection, local preparation, eye preparation, oral and rectal preparation and other pharmaceutical formulations Peg has good solubility in water and good solubility with drugs and other solvents Liquid peg with small relative molecular weight can be used as solvent in the preparation Solid peg with large relative molecular strength can be made into solid dispersion with insoluble drugs to promote the dissolution of drugs Peg200, peg300, PEG400 and peg600 are colorless and slightly odorous viscous liquids with stable chemical properties, safety and low toxicity, so they are often used as solvents for drugs PEG4000 and PEG6000 are the typical representatives of water-soluble lubricants in tablets The tablets can be directly added with proper amount of PEG to complete the tablets They can also be granulated with alcohol solution, suspension or emulsion first, and the lubrication effect remains unchanged The disintegration and dissolution of the tablet made from peg are not affected, which can improve the solubility of the main drug in the stomach and ultimately help to increase the bioavailability In addition to being used as a lubricant, PEG can also be used as an adhesive, of which PEG4000 is the most commonly used, especially for the heat unstable drugs If PEG4000 is used as the adhesive, the powder can be directly pressed in the dry state, and the effect is ideal In addition, PEG can also be used as a plasticizer to change the physical and mechanical properties of the polymer to make it more flexible and plastic; as a porogen of membrane controlled slow and controlled release drugs; as a penetration promoter to make keratin solvate, occupy the hydrogen bond binding site of protein, reduce the combination of drugs and tissues, and increase the distribution of other penetration promoters in the cuticle 3 The use of PEG in synthesis Peg has a long history in chemical synthesis It has been widely used in combinatorial chemistry and organic chemistry It can provide homogeneous reaction conditions and has the advantages of easy purification and analysis Therefore, as a solvent and catalyst, peg is increasingly used in laboratory research and industrial production
As a solvent, the research in recent years tends to be "green" of PEG With its characteristics of viscosity, low toxicity, thermal stability, low price, non volatilization, biodegradation and environmental friendliness at room temperature and high temperature, PEG has attracted more and more attention in Synthesis Chemistry and heterogeneous catalysis, such as heck reaction, Suzuki coupling reaction, oxidation reaction and reduction reaction Addition reaction and asymmetric Aldo reaction And peg has different solubility at different temperatures, and it can be mutually soluble with water, dichloromethane, alcohol, acetone and other solvents However, peg is insoluble in ether, n-hexane and other solvents, so it can be used to precipitate peg, so peg and solute can be separated At present, a large number of articles have reported that peg is a reusable solvent In the aspect of catalysis, because PEG chain structure can be folded into holes of different sizes, and the chain links can be folded into spiral and free sliding chains, forming the shape similar to crown ether, it can coordinate with metal ions of different sizes for phase transfer catalysis Although the reaction effect is not good in liquid-liquid phase, it has a good catalytic effect on the reaction of sodium, potassium and other metal salts Peg400-1000 is a commonly used catalyst for the reactions involving different salts The research shows that PEG400 is more suitable for the reactions involving Na + and K + due to its moderate molecular weight, especially the relative proportion of two polar terminal hydroxyl groups; because of its strong water solubility, the catalyst and salt by-products can be washed away with water after the reaction, making the treatment process of the products large Great simplification PEG400 as a phase transfer catalyst has been widely used in many liquid-liquid, gas-liquid, gas-solid, solid-liquid two-phase organic chemical reactions because of its easy availability, low price, no toxicity of crown ether and no decomposition of quaternary ammonium salt Especially in the solvent-free solid-liquid reaction, PEG400 shows the advantages that other PTCs can't match In the 1970s, Davis et al First reported that PEG was used to modify proteins, and then carried out many studies on the covalent binding of PEG with proteins and small molecule drugs PEG modification of drugs is PEGylation, which is the chemical coupling of activated peg to proteins, peptides, small molecule organic drugs and liposomes PEG modification of drugs can be divided into two stages The first stage is limited to the application of monomethoxy PEG (20000) peg modifier with low molecular weight The second stage is characterized by stable linkage, site-specific modification and controlled-release Therefore, the modified drug has higher biological activity, better physical and thermal stability, higher product homogeneity and purity At this stage, PEG modification technology has not only been successfully applied to the research of protein and peptide drugs, but also made a breakthrough in the field of organic small molecule drugs and liposomes The connection between PEG and drug molecules can be divided into permanent bonding and non permanent bonding The former is the stable combination of PEG and drug molecules through chemical bonds, and drug molecules can still play an effective role; the latter is the unstable combination of PEG and drug molecules through chemical bonds, such compounds often need to be hydrolyzed and released under certain pH value or the existence of some specific enzymes to effectively play the efficacy In general, small molecule drugs are less directly connected with PEG, but are connected through various connecting arms Choosing the appropriate type of connecting arm can also achieve slow release, targeted release and increase drug loading Generally, there are four types of connecting arms: pH sensitive connecting arm, enzyme sensitive connecting arm, ortho promoting connecting arm and n-mannich base connecting arm
Compared with unmodified drugs, modified drugs often have the following outstanding advantages: (1) stronger biological activity; (2) stronger passive targeting effect of liposomes on tumors; (3) longer half-life; (4) lower maximum blood concentration; (5) less fluctuation of blood concentration; (6) less enzyme degradation; (7) less immunogenicity and antigenicity; (8) less toxicity; (9) better (10) decrease of medication frequency; (11) improve the compliance of patients, improve the quality of life, and reduce the cost of treatment Two PEG modified drugs with good sales volume, pegylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated PEGylated pegylated Pegylat Fegerstin, a rhG CSF produced by E.coli Expression, is a kind of leukocyte growth factor, which can regulate the production of bone marrow neutrophils and affect the increase and differentiation of neutrophil precursors It is used in the treatment of congenital neutropenia, periodic neutropenia, idiopathic neutropenia, bone marrow transplantation and chemotherapy related neutropenia Cytopenia Pegfiggistim is a long-acting form of pegfiggistim, which is covalently combined with N-terminal methylthioamino group of rhG CSF The increase of PEG in the molecular structure can reduce the renal clearance rate of rhG CSF, the uptake of drug molecules by cells, and the proteolysis The half-life of pegylated fegerstin is significantly longer than that of fegerstin Pegylated rhG CSF (trade name: Jin Youli) produced by Baike (Jinan) biopharmaceutical Co., Ltd of Shiyao group was approved by the State Food and Drug Administration of China in 2011 To reduce the incidence of infection caused by febrile neutropenia after chemotherapy In terms of sales, in 2014, the annual sales of pegylated fegetine was US $4.686 billion, ranking No 8 on the list, while in 2015, the sales was US $4.868 billion, ranking No 9 on the list Cetuzumab, an anti TNF - α monoclonal antibody of Fab fragment, consists of a light chain containing 214 amino acids and a heavy chain containing 229 amino acids, with a molecular weight of about 91kd Its combination with PEG (nearly 40kDa, peg2mal40k) prolonged the plasma elimination half-life of cetuzumab Cetuzumab does not contain Fc fragments, so it cannot anchor complement or cause antibody dependent cell-mediated cytotoxicity In vitro, it can not induce programmed cell death of monocytes or lymphocytes derived from human peripheral blood, nor can it induce neutrophil degranulation It has been shown that cetuzumab can inhibit the production of monocyte cytokines, especially the release of IL-1 β induced by LPS It was approved by FDA in April 2008, EMA in Europe in May 2008, PMDA in Japan in December 2012, and Yushi was responsible for sales in the United States, Europe and Japan The approved indications are Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis 6 what are the drugs modified by PEG? At present, many PEG modified protein drugs have been used in clinic, including peg recombinant coagulation factor Ⅷ, PEG recombinant human growth hormone, PEG interferon and other PEG modified macromolecular drugs have been listed successively; at the same time, more PEG modified protein drugs are in the stage of clinical research, but there is no PEG modified small molecule drug products 7 The key technology of PEG modification: the relative molecular weight of PEG should be selected by considering the biological activity and pharmacokinetics It has been proved that