PEG in Pharmaceutical Preparations (II): Stabilizers, Plasticizers and Modification Materials

Polyethylene glycol (PEG) has been used as a pharmaceutical excipient for hundreds of years. Due to its low toxicity and good water solubility, PEG has long been favored by pharmaceutical workers and is used in various pharmaceutical dosage forms such as injections, topical preparations, ophthalmic preparations, oral and rectal preparations, etc. In the past 20 years, new PEG technologies have developed rapidly, such as six PEG-modified drugs entering the market one after another, research on biodegradable PLA-PEG block copolymers, etc. There is reason to believe that PEG is still an important excipient in the pharmaceutical field. With the development of pharmaceutical excipients, more high-quality PEG products will enter the market.

PEG for Stabilizers

At present, the main problem of protein drug preparations is poor drug stability. For liquid dosage forms of protein drugs, the properties can be changed to increase stability by adding excipients (stabilizers) such as polyethylene glycol, sugars, salts, surfactants, etc. High concentrations of PEG are often used as cryoprotectants and precipitation/crystallization agents for proteins, and they can interact with the hydrophobic chains of proteins. Studies have shown that PEG with different molecular weights has different effects. For example, PEG 300 with a mass fraction of 0.5% or 2% can inhibit the aggregation of rhKGF (recombinant human keratinocyte growth factor); PEG 200, PEG 400, PEG 600 and PEG 1000 can stabilize BSA and lysozyme; PEG 4000 with different mass fractions (up to 15% mass fraction) can inhibit the thermal aggregation of low molecular weight urokinase.

PEG for Plasticizers and Porogens

PEG is a hydrophilic polymer substance that can be used as a plasticizer to change the physical and mechanical properties of the polymer to make it more flexible and plastic. For example, in order to make gelatin microcapsules have good plasticity, non-adhesion and good dispersion, plasticizers such as polyethylene glycol, sorbitol, propylene glycol, glycerin, etc. are often added. Studies have shown that when preparing gelatin microcapsules by the single coagulation method, adding plasticizer can reduce the aggregation of microcapsules and reduce the thickness of the capsule wall, and there is a negative correlation between the amount of plasticizer added and the half-life of drug release.

PEG is also widely used as a plasticizer in film coating materials. PEG contains hydroxyl groups and can be used as a plasticizer for some cellulose clothing materials. For example, a single-chamber single-layer osmotic pump (upper and lower) for the poorly soluble drug naproxen prepared using cellulose acetate as the membrane material, PEG 400 as the plasticizer, and gum arabic as the osmotic active substance and suspending agent. There are drug release holes on all surfaces) and the drug is released at a zero-order rate. The cumulative drug release rate in 12 hours can reach 81%. In addition, PEG is also used as a plasticizer in films and coatings. PEG is a polymer molecule that is miscible with water, so PEG can be used as a porogen for membrane-controlled sustained-release drugs. Porogens such as PEG can quickly dissolve in the medium to form larger pores. As the pores increase, external solvents can easily diffuse through the controlled-release membrane, accelerating drug release.

PEG for Modification Materials

PEG modifiers are pH-neutral, non-toxic, water-soluble polymers that are highly hydrophilic, have good biocompatibility and blood compatibility, and are non-immunogenic. Therefore, structural modification using PEG can improve the following properties of drugs:

• Increasing stability and reduce enzyme degradation;
• Improving pharmacokinetic properties, such as extending plasma half-life, reducing maximum plasma concentration, reducing fluctuations in plasma concentration, etc.;
• Reducing immunogenicity and antigenicity;
• Reducing toxicity and improve activity in vivo;
• Improving drug distribution in the body and enhance targeting;
• Reducing medication frequency and improve patient compliance.

PEG for Liposome Modification

Traditional liposomes and immunoliposomes are easily recognized and taken up by cells of the reticuloendothelial system (RES), resulting in a very short blood circulation half-life (usually less than 30 minutes) and are cleared before reaching the target organ, so their application is very limited. If the hydrophilic polymer molecule PEG is introduced on the surface of the liposome membrane, a layer of hydration film can be formed on the surface of the liposome to cover the hydrophobic binding site on the surface of the liposome, preventing the plasma component from approaching the liposome, thereby reducing the recognition and uptake of the liposome by RES and prolonging the blood circulation time of the liposome. PEG-modified liposomes can slowly accumulate at diseased sites (such as tumors, infections, myocardial infarction, etc.) through the so-called "passive targeting" or compensatory filtration mechanism, and promote drug transport in these areas. For example, PEG-modified liposomes of doxorubicin have achieved remarkable results in animal experiments and human clinical trials, and a long-acting liposome of doxorubicin (Doxil) has been launched. In addition, compared with traditional doxorubicin liposomes, PEG-modified doxorubicin liposomes have significantly changed pharmacokinetic characteristics, significantly enhanced anti-tumor activity, and reduced toxicity. This indicates that PEG-modified liposomes are a promising drug delivery system.

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PEG for Emulsion Modification

Long-circulating emulsions refer to emulsions that properly modify the surface of fat emulsions for intravenous injection to avoid phagocytosis of mononuclear phagocyte system (MPS) and prolong systemic circulation time. The surface of the emulsion droplets is covered with flexible and hydrophilic PEG chains, which enhances the hydrophilicity, reduces the chance of plasma proteins interacting with it, and reduces the possibility of being engulfed by MPS. Using dipalmitoyl phosphatidylcholine as emulsifier, Tween80 as co-emulsifier, triolein as oil phase, and adding an appropriate amount of PEG-modified distearoyl phosphatidylethanolamine (DSPE-PEG), a microemulsion with a particle size of 44nm was prepared. After intravenous injection, the clearance rate in blood was significantly lower than that of unmodified microemulsion, and t1/2 was significantly prolonged. Fluibprofen has extremely low solubility, and only its derivative, fluibprofen ester emulsion, is commercially available. Park et al. prepared fluprofen microemulsion using ethyl oleate as the oil phase, lecithin as the emulsifier, and DSPE-PEG as the co-emulsifier. Compared with the former, t1/2, AUC, and MRT were significantly increased, while the phagocytosis of MPS could be reduced. In addition, according to literature reports, arubicin microemulsions modified with PEG and folic acid have significant targeting properties to cancer cells.

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PEG for Nanoparticle and Microsphere Modification

Biodegradable polymer nanoparticles have many advantages as drug delivery carriers, such as controlled release, targeting, and low toxicity. However, polymer nanoparticles cannot be widely used because they are cleared by RES within seconds or minutes after intravenous administration. To overcome this shortcoming, the hydrophilic polymer PEG can be introduced to modify the polymer. Studies have shown that when hydrophilic PEG-modified nanoparticles are used for intravenous administration, blood clearance and RES uptake are significantly reduced. Moreover, the introduction of PEG will affect the biodegradation behavior of the nanoparticles and adjust the drug release mode.

PEG for Peptide and Protein Modification

The alcoholic hydroxyl group at the end of PEG is chemically inactive. In order to ensure a suitable reaction rate between it and the drug active group, the alcoholic hydroxyl group needs to be activated to facilitate the reaction with the α- and ε-amino groups of the protein. According to the type of bond formed between PEG and protein amino groups, activated PEG can be divided into the following two categories:

• Alkylated PEG, such as aldehyde PEG, PEG-trifluoroethylsulfonate (PEG-T), etc.
• Acylated PEG, such as PEG succinimidyl succinate (PEG-SS), PEG succinimidyl carbonate (PEG-SC), etc.

Protein and peptide drugs mainly include proteins with special functions such as enzymes and cytokines. The modification of PEG is to chemically couple activated PEG to proteins and peptides. PEG-modified protein drugs can extend the half-life of the drug, reduce immunogenicity and toxic side effects, while maximizing its biological activity.

PEG for Penetration Enhancers

Osmotic enhancers are chemicals that can reversibly change the barrier function of the skin stratum corneum without damaging any active cells. The ideal penetration enhancer should have no pharmacological activity, non-toxic, no irritation, no sensitization, and good compatibility with drugs, matrix and skin.

Common penetration enhancers include sulfoxides, surfactants, polyols, pyrrolidone, etc. Polyol compounds include ethanol, propylene glycol, polyethylene glycol, isopropyl alcohol and glycerin. Research shows that PEG is no less effective than oleic acid in transdermal absorption formulations. However, according to research reports, because PEG contains a large number of ether oxygen atoms, it is highly likely to form hydrogen bonds with the drug, which will inevitably reduce the thermodynamic activity of the drug. At the same time, due to the high viscosity of PEG itself, it will increase the viscosity of the carrier microenvironment, which not only inhibits the hydration of the stratum corneum, but also causes dehydration of the stratum corneum due to its hypertonic effect, and the penetration-promoting effect is not ideal. Therefore, PEG should be used in combination with penetration enhancers such as oleic acid, azone, and propylene glycol.

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