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Medical Use Polyethylene Glycol

Medical Use Polyethylene Glycol

It is a translation based on the content of corporate PR magazine “Sanyo Chemical News” issued in August 2016.

Useful performance chemicals by Sanyo Chemical Industries’ Group

Medical Use Seiji Horie Chief, Functional Materials Research Dept. Biotechnology & Medical Division

Medicines include those for number-average molecular weight Features of internal use, external use for skin and (Mn). We have PEG products whose mucous membranes, and direct Mn ranges between about 200 and (1) Appearance and Properties injections into blood vessels. 20,000. PEG products are liquid, MACROGOL is liquid, paste or Depending on the use and purpose, paste or solid depending on the solid (flake or powder) depending on there are various forms of molecular weight. They features are the molecular weight (Fig. 3). including powder, tablets, cream and [1] low toxicity, [2] high lubricity, [3] Different grades of MACROGOL liquid. Compounds other than the capability of mixing with other PEG each having different properties e.g. active pharmaceutical ingredients in products of different molecular vapor pressure (Table 2). They can be medicines are called weight and [4] high solubility with mixed together to produce medicines (additives). They are intentionally and many types of organic having desired hardness and . formulated in order to assure stability, solvent. Taking advantage of these (2) Solubility into solvent safety and uniformity depending on favorable features, they have been Table 3 shows solubility of the characteristics of the medicines. used for various fields including MACROGOL. At low temperatures, They play specific functional roles in medicines, medical excipients, hair the higher molecular weight of the facilitating dissolving or sustained care and skincare products, , MACROGOL, it shows the lower release as required. Our polyethylene pigment dispersant, lubricant and solubility into polar solvents. glycol (PEG) for medical use, binder. However, at 50°C, a high solubility is MACROGOL products are one of We have six different types of obtained regardless of the molecular pharmaceutical . medical use PEG products MACROGOL as shown in Table 1. Polyethylene Glycol They are listed by the Japanese Pharmacopoeia or Japanese In 1960, our company developed, Fig. 1 Molecular formula of Pharmaceutical Excipients. To ensure polyethylene glycol first in Japan, PEG products. They the safety and quality of the PEG have been used for various uses. products, they are manufactured Among many of our PEG products, under strict management system those used as medical ingredients or which is complying with standard for excipients are called MACROGOL. Good Manufacturing Practice [GMP] PEG is presented generally by the applicable for manufacturing and molecular formula as shown in Fig. 1. quality control in conformity with the It is a and has a molecular self-imposed standard for weight distribution. A molecular pharmaceutical excipient GMP (Fig. Fig. 2 GMP-compliant plant weight distribution is defined by a 2).

Sanyo Chemical Industries’ News 1 Winter 2019, No. 512 Figure 4 shows change of pH value with time for MACROGOL 1500. At higher storage temperature, the change proceeds faster. Therefore, to retard the change, they should be MACROGOL 400 MACROGOL 1500 MACROGOL 6000 stored in a cool, dark place.

Liquid Paste Solid (flake) Solid (powder) MACROGOL is hygroscopic. They

Small Large should therefore be kept away from moisture. MACROGOL of a larger Average molecular weight molecular weight shows a lower Fig. 3 Appearance and average molecular weight of MACROGOL hygroscopicity. weight. MACROGOL hardly solves According to the Japanese Applications of MACROGOL into nonpolar solvents even at high Pharmacopoeia or the Japanese temperatures. Pharmaceutical Excipients, (1) Pharmaceutical Excipients (3) Safety (toxicity) MACROGOL’s pH value ranges There are about 70 different kinds MACROGOL has lower toxicity widely between 4.0 and 7.0. This is of pharmaceutical excipients 1) (in terms of LD50 [Acute Oral because polyether compounds such as including diluents and binders. Toxicity]) (Table 4). MACROGOL MACROGOL are subject to oxidative The pharmaceutical excipients not of a larger molecular weight shows a degradation. It is attributable to merely are additives for making lower toxicity. oxygen radicals, which can lead to pharmaceutical preparation according (4) Change over time decrease in pH value with time. to the desired effects, but also

Table 1 Physical-chemical characteristics of MACROGOL listed by the Japanese Pharmaceutical Excipients or the Japanese Pharmacopoeia

MACROGOL Product name MACROGOL 200 MACROGOL 400 MACROGOL 1500 MACROGOL 4000 MACROGOL 20000 6000

Japanese Applicable official Japanese Japanese Japanese Japanese Japanese Pharmaceutical standard (list) Pharmacopoeia Pharmacopoeia Pharmacopoeia Pharmacopoeia Pharmacopoeia Excipients

Colorless, Colorless, Powder or flake in Form transparent viscous transparent viscous Paste in white Powder in white Powder in white white liquid liquid

Freezing point (°C) -35 or below 6 40 55 58 60

Specific gravity 1.120 1.120 - - - - (20/20°C)

pH*1 5.5 6 5.5 7 7 7

Mn*2 200 400 550*3 3,100 8,600 20,000

Water content (%) 1.0 or below 1.0 or below 1.0 or below 1.0 or below 1.0 or below 1.0 or below

Ignition residue (%) 0.10 or below 0.10 or below 0.10 or below 0.25 or below 0.25 or below 0.25 or below *1 Measured with a sample of 5 g diluted with 100 mL water *2 Mn average molecular weight calculated based on the hydroxyl value measured according to JIS K1557 *3 Mixture of two different HOCH2(CH2OCH2)nCH2OH compounds whose “n” value is 5-6 and 28-36 respectively The numbers that follow the word MACROGOL represent the average molecular weight. However, for MACROGOL 1500, 4000 and 6000 only, note that they do not represent the average molecular weight. To use or handle our products, contact our sales office. Before use, read through the latest version of the safety data sheet (SDS). Users shall be responsible for determining suitability and safety of the product that they will use in each individual application.

Table 2 Properties of MACROGOL

MACROGOL MACROGOL Product name MACROGOL 200 MACROGOL 400 MACROGOL 1500 MACROGOL 6000 4000 20000 Mn*1 200 400 550*3 3,100 8,600 20,000 Kinematic viscosity 4.1 7.1 16 80 800 14000 (mm2/s [210°F]) Vapor pressure 1.3 1.2×10-2 - <2.7×10-10 <2.7×10-10 <2.7×10-10 (Pa [100°C]) Specific heat 2.2*2 2.2*2 2.3*3 2.3*3 2.3*3 2.5*3 (kJkg-1K-1) Fusion heat (kJkg-1) - 150 160 180 190 190 Surface tension 44.5 44.5 - - - - (mN/m [25°C]) *1 Mn average molecular weight calculated based on the hydroxyl value measured according to JIS K1557 *2 Average value at temperature between 30 and 60°C *3 Average value at temperature between the freezing point and 100°C

Sanyo Chemical Industries’ News 2 Winter 2019, No. 512

Table 3 Solubility of MACROGOL Table 4 Toxicity of MACROGOL

Measuring LD *1 Product name Water Diethyl Product name 50 temperature (g/kg [oral, rat]) 20°C A A A*1 D MACROGOL 200 28 MACROGOL 200 50°C A A A*1 D MACROGOL 400 30 *2 MACROGOL 20°C A A D D MACROGOL 1500 44 1500 50°C A A A*1 D MACROGOL 4000 50 *2 MACROGOL 20°C B C D D MACROGOL 6000 50 4000 50°C A A A*1 D * 1 Registry of Toxic Effects of Chemical substances, Feb. 2003 (NIOSH) MACROGOL 20°C C C D*2 D 20000

*1 95% ethanol *2 99.5% ethanol Legend A: Dissolve ≥100 g with a solvent of 100 mL B: Dissolve 50 to <100 g with a solvent of 100 mL C: Dissolve 1 to <50 g with a solvent of 100 mL D: Dissolve <1 g with a solvent of 100 mL lend [1] easy use (in handling and like pasty material, can be used for colonic cleansing is necessary. taking the drug), [2] stable quality making an ointment of desired Inadequate bowel preparation can (prevention of deterioration), [3] viscosity so that it can be spread lead to poor colonic visualization, higher usefulness (helping the uniformly over the affected part. missed lesions, or other risks of active ingredient to reach the MACROGOL in flake or powder, anastomotic failure or infectious target area; adjusting the paraffin-like solid material, has a diseases. Intestinal lavage is manifestation of the medicinal moldability, so that it can be used therefore essential. Colon cleansing effect) and [4] higher safety (e.g. for preparing . It can agents are required to be [1] capable reduction of side effects) to the be used also as a coating of facilitating quick, easy and drug. agent to increase the tablet’s surface efficient cleaning, [2] non-digestible (2) Examples of applications smoothness. It can harden the and non-absorbable, and capable of Features such as lower toxicity , surface of tablets to improve their passing out through the bowel easily, higher versatility and various forms friability and flowability. Among and [3] minimal patient’s of MACROGOL, make it useful as many of MACROGOL application discomfort (easy to take). PEG medical additive for various areas, here describes its use as a formulation as colon cleansing applications (Table 5). colon cleansing agent and agent is osmotically balanced for MACROGOL in liquid can be used precipitant for blood plasma the kinds and concentration of the as a , stabilizer for fractionation as well that has not while acting as an agent liquids for external use, and been much introduced to date. for retaining water in the bowel. solubilizing agent for lipophilic (3) Colon cleansing agent The water and electrolytes drugs. It helps the drug permeating Before inspection or for concentrations in body fluids can be into the affected part effectively. or other colonic kept well balanced. Feces can be MACROGOL in paste, Vaseline- diseases, bowel preparation for softened and discharged easily. PEG is non-digestible and non- absorbable so that it is directly discharged out of the body.2) PEG based agents do not induce

Storage substantial shifts in fluid and temperature: 5°C level or poor patient compliance, so that they have now Storage temperature: 25°C been used most widely among other types of colon cleansing agents. pH (5 mass% aqueous solution) solution) aqueous mass% (5 pH

Storage (4) Precipitant for plasma temperature: 40°C fractionation An adult’s blood volume is about Storage started Elapse (month) 80 mL per 1 kg of body weight.

Fig. 4 Change over time (MACROGOL 1500) Blood consists of cellular components of erythrocyte, Since pH value measurements shown here may not be the case depending on the storage conditions of the sample, they should be used for reference only.

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Table 5 Application of MACROGOL advantage of PEG is that it can

Use Properties of medical drugs and additives precipitate while minimizing the

Adjusts application concentration and viscosity of the ointment, keeps it applied uniformly over Base material for modification of protein molecules. the affected part, facilitates its sustainable permeation into the part, and absorbs body fluids ointment oozing out of the affected part. MACROGOL has been widely and Mixing different MACROGOL products together will produce base materials having a desired Base material for melting point and dissolution rate. MACROGOL of a higher average molecular weight shows a effectively used for manufacturing higher storage stability. medicines. Available as a smoothing agent, coating agent or binder for manufacturing tablets. Compared Tablet binder to sugar coating agents, it can shorten the coating time, and impart better aesthetics and harder surface to tablets. It can be used also as a solvent, stabilizer, plasticizer, , lubricant, cohesive agent, luster, binder, smoothing Prospects agent, moisturizer, emulsifier, pressure sensitive adhesive, adhesion enhancer, diluent, thickener, disintegrant, solubilizing agent, wetting agent, sugar coating agent, softener, wetting modifier, solubilizer, suspending agent, dispersant, desiccant and disintegrating agent, etc. At present, Japan has its own leucocyte and platelet, and liquid into individual components. Protein official medicines lists of the part called plasma. Cellular is a condensation polymer of 20 Japanese Pharmacopoeia and the components account for about 45% kinds of amino acids. It has a Japanese Pharmaceutical Excipients. of the entire constituents of blood different molecular characteristic However, responding to while the remainder is plasma. depending on the kinds and globalization of pharmaceutical Biological medicals produced configuration of the composed manufacturing businesses, Japan, from blood e.g. donated blood are amino acids. Moreover, plasma America and EU countries are generally called blood products. proteins show complicated cooperating each other to develop a They include blood component molecular characteristics because unified, international standard and products (erythrocyte, leucocyte and they exist in the form of couples list of medicines. Our company will platelet) intended for e.g. blood with sugar (glucose) chains and/or enhance the PEG product lineups transfusion, and plasma derivatives. (fats), Therefore, for ensuring that they comply with the They are produced by refining fractionation (to separate and refine) international quality standard so that proteins such as and plasma proteins, it is necessary to we can globally contribute to the blood clotting components. adjust processing parameters development of . MACROGOL can be used as a depending on many factors such as Moreover, along the recent precipitant when separating and molecular characteristics, molecular advancement in medicines, we shall refining (fractionating) proteins weight and forms. continue developing new, need- from blood. Fractionation processes include oriented and high quality Plasma consists of about 7 to 8% [1] PEG fractionation that uses PEG pharmaceutical excipients. of various types of proteins, about as a precipitant for proteins, [2]

90 to 91% of water, and the ethanol fractionation that adjusts References remainder of sugar and . five parameters of pH value, ionic 1) IJEC Japan, ed. “Iyakuhin tenkabutu ziten 2000 (Dictionary of Pharmaceutical additives 2000), Yakuji Plasma derivatives are obtained by strength, ethanol concentration, Nippo, Limited. physicochemically separating protein concentration and 2)Davis GR, Ana SCA, Morawaski SG et al: Gastroenterology 78; 991-995 (1980) important proteins such as albumin temperature to change the solubility 3)Hiroshi Morise “Kessyo bunkaku seizai-no seizou Excluded volume of proteins, and [3] chromatography houhou towa? (Wat is the method of manufacturing 3) plasma fractionation?), HP of Japan blood products fractionation. association (2018/11) http://www.ketsukyo.or.jp/study/vol02_04.html. PEG precipitates proteins by 4) Shunsuke Yoshizawa, Kentaro Shiraki “Seibutu Protein reducing the dielectric constant and kogaku (Biotechnology)” vol.93, No.5 (2015), 260- 263 using the excluded volume effect. Figure 5 shows its working [Contact (about the product)] mechanism. Osmotic pressures Sales & Marketing Dept., Biotechnology & Medical Division existing between the near-protein http://www.sanyo-chemical.co.jp/eng/ region where PEG cannot enter and

Osmotic the region in which PEG already pressure Proteins associate and precipitate exists move proteins so that they come closer to each other to achieve Fig. 5 PEG acting as a precipitant for plasma proteins 4) thermal stabilization. Another

Sanyo Chemical Industries’ News 4 Winter 2019, No. 512