Polyethylene Glycol in Pharmacy

Polyethylene glycol (PEG) is a versatile polymer that has found widespread applications in various fields, particularly in pharmaceuticals. Due to its excellent solubility, biocompatibility, and low toxicity, PEG has been approved by the FDA for use in injectable formulations and other pharmaceutical products. It can be tailored into a variety of forms and functions based on its molecular weight and structure, making it a critical component in drug formulation and delivery. This article explores the diverse applications of PEG in the pharmaceutical industry, including its use as a solvent, excipient, plasticizer, pore-forming agent, drug carrier, modifier, and penetration enhancer.

What is Polyethylene Glycol?

Polyethylene glycol is a versatile polymer composed of repeating units of ethylene oxide. It is widely recognized for its unique properties, including water solubility, biocompatibility, and low toxicity. These characteristics make PEG an essential material in various industries, particularly in pharmaceuticals, cosmetics, and biotechnology. PEG can exist in different physical forms: liquid, semi-solid, or solid, depending on its molecular weight, which typically ranges from 200 to 40,000 g/mol.

Fig. 1. Polyethylene glycol structure.

In the pharmaceutical field, PEG serves multiple roles, such as a solvent, stabilizer, and excipient. It is used in drug formulations to enhance solubility and bioavailability, and it can act as a carrier for active pharmaceutical ingredients (APIs). Additionally, PEG is employed in the process known as PEGylation, where it is conjugated to drugs or therapeutic proteins to improve their stability, prolong circulation time, and reduce immunogenicity. Beyond pharmaceuticals, PEG is used in cosmetics as a moisturizer and emulsifier, and in biotechnology for cell culture and protein purification. Its chemical versatility, non-toxicity, and ease of modification make PEG a fundamental component in many commercial and industrial applications.

Polyethylene Glycols from BOC Sciences

Polyethylene Glycol Classification

Polyethylene glycol is classified based on its molecular weight, structure, and end-group functionality. This classification helps determine its suitability for various applications, from pharmaceuticals to industrial processes. The table below outlines the key classifications of PEG:

What is Polyethylene Glycol Used for Pharmacy?

1. Polyethylene Glycol as a Drug Solvent

• Injectable Preparations

PEG 200-600 water solutions at various concentrations serve as excellent solvents, capable of increasing the solubility of poorly soluble drugs and stabilizing drugs that are unstable in water, thus making them suitable for use as solvents in injectable preparations.

• Eye Drops

PEG 400 can be used as a solvent to formulate indomethacin eye drops, with PEG 400-based formulations showing better performance than those with Span 80. Additionally, PEG can act as a thickening agent in eye drops, increasing viscosity, prolonging the retention time of the drug in the eye, enhancing therapeutic efficacy, and reducing irritation.

2. Polyethylene Glycol as an Additive or Excipient

• Cosolvent

Polyethylene glycol can form cosolvents with water in liquid excipients, enhancing the solubility of poorly soluble drugs.

• Binder and Lubricant

PEG 4000 and PEG 6000 are commonly used as water-soluble binders and lubricants in tablet formulations. Granules produced using PEG as a binder have good formability, and the tablets remain non-hardening, suitable for granulation of both water-soluble and insoluble materials.

• Stabilizer

For example, adding polyethylene glycol to liquid protein drug formulations can modify the protein properties, increasing stability. High concentrations of PEG are often used as cryoprotectants and precipitating/crystallizing agents for proteins, interacting with the hydrophobic chains of proteins. Studies show that PEGs of different molecular weights have varying effects; for instance, 0.5% or 2% PEG 300 can inhibit the aggregation of recombinant human keratinocyte growth factor, while PEG 200, 400, 600, and 1000 can stabilize BSA and lysozyme.

3. Polyethylene Glycol as a Plasticizer and Porogen

Plasticizers are additives that increase the flexibility of materials. The choice of plasticizer greatly affects the drug release rate and properties of the coating. Polyethylene glycol is a commonly used plasticizer. Porogens, also known as release rate modifiers, are often water-soluble substances such as PEG, PVP, sucrose, and salts. For example, polyethylene glycol rapidly dissolves in water, forming diffusion channels for drug release, transforming the initial membrane into a porous one, enhancing membrane permeability, and improving drug release rate. Thus, PEG can be used as a porogen in membrane-controlled release formulations.

4. Polyethylene Glycol as a Drug Carrier

• Base Material

A suitable mixture of PEGs (such as equal parts of PEG 300 and PEG 500) provides a certain paste-like consistency with good water solubility and drug compatibility, making it an excellent water-soluble base material for ointments. Its advantages include non-irritation to the skin, stability without degradation, and no interference with sweating when applied to the skin. Since PEG is non-electrolytic, its pH can be adjusted to meet any required value for human use. Additionally, PEG can be used as a base material for suppositories. Due to its crystalline nature and water solubility, PEG is commonly used as a carrier for poorly soluble drugs, and suppositories formulated with PEG bases are less irritating than those using traditional fat bases.

• Solid Dispersion Material

PEG, with its good water solubility and ability to dissolve in various organic solvents, can disperse certain drugs at the molecular level, preventing drug aggregation. In solid dispersion materials, PEG acts as a water-soluble carrier material, increasing drug dissolution rates. PEG can also serve as a carrier material in sustained-release solid dispersions; for example, in the melting method, the drug is dissolved in molten PEG, filled into hard capsules, solidified at room temperature, and released slowly according to a dissolution mechanism. Different PEG contents can form various types of solid dispersions.

• Polymeric Nanomicelles

Research on polymer micelles mainly involves homopolymer and copolymer micelles. PEG can constitute the hydrophilic segment of amphiphilic block copolymers, forming various diblock or triblock copolymers with hydrophobic materials. These copolymers expand the range of drug carriers. For instance, copolymerization of PCL and PEG increases the hydrophilicity of PCL particles, forming amphiphilic copolymers that improve the micelle formation properties of polymers. Amphiphilic copolymers loaded with drugs form nanomicelles, where hydrophobic segments enhance the loading capacity for oil-soluble drugs like paclitaxel, while hydrophilic segments increase the water solubility of the drugs.

5. Modification Material

As a modification material, polyethylene glycol can modify drugs to alter their properties or modify drug carriers to improve their performance. PEG modifications can improve drug properties as follows: (1) increase stability and reduce enzymatic degradation; (2) improve pharmacokinetic properties, such as extending plasma half-life, reducing peak plasma concentration, and decreasing blood concentration fluctuations; (3) reduce immunogenicity and antigenicity; (4) reduce toxicity and enhance in vivo activity; (5) improve in vivo distribution and enhance targeting; (6) reduce dosing frequency and increase patient compliance.

• Protein Drug Modification

Polyethylene glycol can chemically modify proteins through covalent bonding. PEGylation of proteins changes their biochemical characteristics, including size, hydrophobicity, and charge, thereby increasing protein solubility and stability. Additionally, PEGylation reduces protein immunogenicity and enhances drug efficacy and safety. PEG can be conjugated to amino, thiol, or carboxyl groups on proteins.

• Drug Carrier Modification

Preparation and in vitro drug release studies of PEG-modified polyamide-amine (PAMAM)-methotrexate (MTX) molecular complexes involve connecting functionalized PEG to PAMAM surface amino groups via amide bonds. The hemolytic toxicity of PEGylated PAMAM is investigated, and PAMAM-PEG/MTX complexes are prepared to determine their maximum complexation and study their in vitro drug release behavior in different buffer solutions and plasma under various storage conditions. Compared to PAMAM, PEGylated PAMAM shows significantly reduced hemolytic toxicity and has a certain sustained-release effect, making it a promising new drug delivery carrier material.

• Small Molecule Drug Modification

In addition to modifying proteins and carriers, polyethylene glycol is increasingly used to modify small-molecule drugs. For instance, PEG can modify small-molecule drugs using thionyl chloride as a coupling agent. After chlorocarbonylation, the drug is linked to PEG via degradable ester bonds. This method improves the yield of the target modification and enhances the water solubility of PEG-modified nicotinic acid.

6. Polyethylene Glycol as a Penetration Enhancer

Penetration enhancers are substances that can improve or accelerate the penetration of drugs through the skin. Ideal penetration enhancers should be non-damaging and non-irritating to the skin, pharmacologically inactive, non-allergenic, stable in physical and chemical properties, compatible with drugs and excipients, fast-acting, and long-lasting. Polyols, such as polyethylene glycol, isopropanol, and glycerol, are common penetration enhancers. The mechanism of action of polyols is to solvate proteins, occupy protein hydrogen-bond binding sites, reduce drug-tissue binding, and increase the distribution of other co-administered penetration enhancers in the stratum corneum.

Other Uses of Polyethylene Glycol

Beyond its extensive use in pharmaceutics, polyethylene glycol plays a significant role in various biomedical fields:

1. Contact lens solution. The viscosity of polyethylene glycol aqueous solution is sensitive to shear rate, and bacteria are less likely to grow on polyethylene glycol.
2. Synthetic lubricating drugs. Epoxy ethane and water condensation polymers. Used as an ointment substrate for preparing water-soluble drugs and as a solvent for poorly water-soluble drugs like aspirin, caffeine, nimodipine, etc., for injection preparation.
3. Carrier for drug sustained release and enzyme immobilization. Applying polyethylene glycol aqueous solution to the outer layer of pills can control the diffusion of the drug within the body to enhance efficacy.
4. Surface modification of medical polymer materials. Using amphiphilic copolymers containing polyethylene glycol to adsorb, trap, and graft onto medical polymer material surfaces can improve the biocompatibility of medical polymer materials in contact with blood.
5. Production of alkyl alcohol contraceptive membranes.
6. Production of hydrophilic anticoagulant polyurethane.
7. Polyethylene glycol 4000 is an osmotic laxative. It can increase osmotic pressure in the intestinal cavity, absorb water, soften feces, increase their volume, and promote bowel movement.
8. Denture adhesives. Using the non-toxic and gel-forming properties of polyethylene glycol as a component of denture adhesives.
9. PEG 4000 and PEG 6000 are often used to promote cell fusion or protoplast fusion and help organisms (such as yeast) intake DNA during transformation. PEG can absorb water from solutions, hence used to concentrate solutions.
10. In experiments studying protein molecules, PEG can simulate crowded intracellular environments to verify the effects of crowded environments on protein structure.

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