PRODUCTS

POLYSORBATE 80

Polysorbate 80 is derived from polyethoxylated sorbitan and oleic acid. The hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide. In the nomenclature of polysorbates, the numeric designation following polysorbate refers to the lipophilic group, in this case, the oleic acid (see polysorbate for more detail).

CAS No.: 9005-65-6
EC No.: 500-019-9

Synonyms:
POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Montanox 80; Alkest TW 80; Tween 80; PS 80; POE (20) sorbitan monooleate; Polyethylene glycol sorbitan monooleate; Polyoxyethylenesorbitan monooleate; Polysorbate 80; Polysorbatum 80; TWEEN® 80; Polysorbate 80 (glycol); Polyoxyethylene 20 sorbitan monooleate; Inhibited ethylene glycol, antifreeze; 2-hydroxyethyl 2-deoxy-3,5-bis-O-(2-hydroxyethyl)-6-O-{2-[(9E)-octadec-9-enoyloxy]ethyl}hexofuranoside; sorbate80; EG Coolant 1; EG Coolant 2; EG Coolant 3; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; glycosperse 0-20; Tween™ 80; glycosperse 0-20x; liposorb 0-20; glycospers e 0-20; Polyoxyethylene (20); glycosperse 0-20 veg; Tween(R) 80; Inhibited ethylene glycol; polysorb ate 80 b.p.c; Polysorbate 80 B.P.C; DSSTox_CID_1175; Polysorbate 80, U.S.P; DSSTox_RID_75992; DSSTox_GSID_21175; POE(6) Sorbitan Monooleate; SCHEMBL15879; POE (5) sorbitan monooleate; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorethytan (20) mono-oleate; POE (20) sorbitan monooleate; Sorbitan mono-oleate polyoxyethylene; Tox21_303472; LS-2298; Polyethylene oxi de sorbitan mono-oleate; Polysorbate 80 [USAN:BAN:INN:JAN]; NCGC00257261-01; 2-[2-[3,5-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate; Sorbitan, monooleate polyoxyethylene deriv; CAS-9005-65-6; POLYOXYETHYLENESORBITAN MONOOLEATE (TWEEN 80); (x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivs; Sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorbitan, mono-(9Z)-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorbitan, mono-9-octadecanoate, poly(oxy-1,2-ethanediyl) derivs., (Z)-; 2-hydroxyethyl 2-deoxy-3,5-bis-O-(2-hydroxyethyl)-6-O-[2-(oleoyloxy)ethyl]hexofuranoside; PEG-3 Sorbitan oleate; PEG-6 Sorbitan oleate; Polyethylene glycol (3) sorbitan monooleate; Polyethylene glycol 300 sorbitan monooleate; Polyoxyethylene (20) sorbitan monooleate; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Polyoxyethylene (3) sorbitan monooleate; Polyoxyethylene (5) sorbitan monooleate; Polysorbate 80; Polysorbate 80 [USAN:INN:BAN:JAN:NF]; Polysorbate 81; Sorbimacrogol oleate 300; Sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs.; Akamuls PSMO 20; Alkamuls T 80; Armotan pmo-20; Atlox 1087; Atlox 8916TF; Avitears; Capmul poe-O; CCRIS 700; Cemerol T 80; Cemesol TW 1020; Crill 10; Crill 11; Crill S 10; Crillet 4; Crillet 4 Super; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Crillet 41; Disponil SMO 120; Drewmulse poe-smo; Durfax 80; EC 500-019-9; Ecoteric T 80; Emasol O 105R; Emsorb 6900; Emulson 100M; Ethoxylated sorbitan monooleate; Eumulgin SMO 20; FEMA No. 2917; Flo Mo SMO 20; Glycols, polyethylene, ether with sorbitan monooleate; Glycosperse O 20; Glycosperse O 5; Glycosperse O-20; Glycosperse O-20 VEG; Glycosperse O-20X; Hodag SVO 9; HSDB 4359; MO 55F; Monitan; Montanox 80; Myvatex MSPS; NCI-C60286; Nikkol TO; Nikkol TO 10; Nikkol TO 10M; Nissan Nonion OT 221; Nonion OT 221; Olothorb; Peg sorbitan oleate; Peg-20 sorbitan oleate; Polisorbac 60; Polyethylene oxide sorbitan mono-oleate; Polyoxyethylene 20 sorbitan monooleate; Polyoxyethylene sorbitan monooleate; Polyoxyethylene sorbitan oleate; Polyoxyethylene(20) sorbitan monooleate; Polysorban 80; Polysorbate 80; Polysorbate 80 B.P.C.; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Polysorbate 80 BPC; Polysorbate 80, U.S.P.; Polysorbate 80, USP; Polysorbate 81; Protasorb O-20; Romulgin O; Sorbimacrogol oleate; Sorbimacrogol oleate 300; Sorbital 0 20; Sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivatives; Sorbitan, monooleate, polyoxyethylene derivs; Sorbon T 80; Sorethytan (20) monooleate; Sorethytan oleate; Sorlate; SVO 9; TO 10; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Tween 80; Tween 80 A; Tween 81; UNII-2MSF640LWM; UNII-58O7V09UCI; UNII-6OZP39ZG8H; Polyoxyethylene sorbitan monooleate; Sorbitan monooleate, ethoxylated; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorbitan, mono-(9Z)-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs.; Sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs., (Z)-; Sorbitan, monooleate polyoxyethylene deriv.; Glycol; Poly(20)oxyethylene sorbitan monooleate; Polyoxyethylene sorbitan monooleate; Polysorbate 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Montanox 80; Alkest TW 80; Tween 80; PS 80; POE (20) sorbitan monooleate; Polyethylene glycol sorbitan monooleate; Polyoxyethylenesorbitan monooleate; Polysorbate 80; Polysorbatum 80; TWEEN® 80; Polysorbate 80 (glycol); Polyoxyethylene 20 sorbitan monooleate; Inhibited ethylene glycol, antifreeze; 2-hydroxyethyl 2-deoxy-3,5-bis-O-(2-hydroxyethyl)-6-O-{2-[(9E)-octadec-9-enoyloxy]ethyl}hexofuranoside; sorbate80; EG Coolant 1; EG Coolant 2; EG Coolant 3; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; glycosperse 0-20; Tween™ 80; glycosperse 0-20x; liposorb 0-20; glycospers e 0-20; Polyoxyethylene (20); glycosperse 0-20 veg; Tween(R) 80; Inhibited ethylene glycol; polysorb ate 80 b.p.c; Polysorbate 80 B.P.C; DSSTox_CID_1175; Polysorbate 80, U.S.P; DSSTox_RID_75992; DSSTox_GSID_21175; POE(6) Sorbitan Monooleate; SCHEMBL15879; POE (5) sorbitan monooleate; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorethytan (20) mono-oleate; POE (20) sorbitan monooleate; Sorbitan mono-oleate polyoxyethylene; Tox21_303472; LS-2298; Polyethylene oxi de sorbitan mono-oleate; Polysorbate 80 [USAN:BAN:INN:JAN]; NCGC00257261-01; 2-[2-[3,5-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate; Sorbitan, monooleate polyoxyethylene deriv; CAS-9005-65-6; POLYOXYETHYLENESORBITAN MONOOLEATE (TWEEN 80); (x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivs; Sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorbitan, mono-(9Z)-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorbitan, mono-9-octadecanoate, poly(oxy-1,2-ethanediyl) derivs., (Z)-; 2-hydroxyethyl 2-deoxy-3,5-bis-O-(2-hydroxyethyl)-6-O-[2-(oleoyloxy)ethyl]hexofuranoside; PEG-3 Sorbitan oleate; PEG-6 Sorbitan oleate; Polyethylene glycol (3) sorbitan monooleate; Polyethylene glycol 300 sorbitan monooleate; Polyoxyethylene (20) sorbitan monooleate; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Polyoxyethylene (3) sorbitan monooleate; Polyoxyethylene (5) sorbitan monooleate; Polysorbate 80; Polysorbate 80 [USAN:INN:BAN:JAN:NF]; Polysorbate 81; Sorbimacrogol oleate 300; Sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs.; Akamuls PSMO 20; Alkamuls T 80; Armotan pmo-20; Atlox 1087; Atlox 8916TF; Avitears; Capmul poe-O; CCRIS 700; Cemerol T 80; Cemesol TW 1020; Crill 10; Crill 11; Crill S 10; Crillet 4; Crillet 4 Super; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Crillet 41; Disponil SMO 120; Drewmulse poe-smo; Durfax 80; EC 500-019-9; Ecoteric T 80; Emasol O 105R; Emsorb 6900; Emulson 100M; Ethoxylated sorbitan monooleate; Eumulgin SMO 20; FEMA No. 2917; Flo Mo SMO 20; Glycols, polyethylene, ether with sorbitan monooleate; Glycosperse O 20; Glycosperse O 5; Glycosperse O-20; Glycosperse O-20 VEG; Glycosperse O-20X; Hodag SVO 9; HSDB 4359; MO 55F; Monitan; Montanox 80; Myvatex MSPS; NCI-C60286; Nikkol TO; Nikkol TO 10; Nikkol TO 10M; Nissan Nonion OT 221; Nonion OT 221; Olothorb; Peg sorbitan oleate; Peg-20 sorbitan oleate; Polisorbac 60; Polyethylene oxide sorbitan mono-oleate; Polyoxyethylene 20 sorbitan monooleate; Polyoxyethylene sorbitan monooleate; Polyoxyethylene sorbitan oleate; Polyoxyethylene(20) sorbitan monooleate; Polysorban 80; Polysorbate 80; Polysorbate 80 B.P.C.; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Polysorbate 80 BPC; Polysorbate 80, U.S.P.; Polysorbate 80, USP; Polysorbate 81; Protasorb O-20; Romulgin O; Sorbimacrogol oleate; Sorbimacrogol oleate 300; Sorbital 0 20; Sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivatives; Sorbitan, monooleate, polyoxyethylene derivs; Sorbon T 80; Sorethytan (20) monooleate; Sorethytan oleate; Sorlate; SVO 9; TO 10; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Tween 80; Tween 80 A; Tween 81; UNII-2MSF640LWM; UNII-58O7V09UCI; UNII-6OZP39ZG8H; Polyoxyethylene sorbitan monooleate; Sorbitan monooleate, ethoxylated; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80; Sorbitan, mono-(9Z)-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs.; Sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs., (Z)-; Sorbitan, monooleate polyoxyethylene deriv.; Glycol; Poly(20)oxyethylene sorbitan monooleate; Polyoxyethylene sorbitan monooleate; Polysorbate 80; POLYSORBATE 80; Polysorbate 80; POLİSORBAT 80; Polisorbat 80

POLYSORBATE 80

Polysorbate 80
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Polysorbate 80[1]
Polysorbate 80.png
Names
IUPAC name
Polyoxyethylene (20) sorbitan monooleate
Other names
Montanox 80
Alkest TW 80
Tween 80
PS 80
Identifiers
CAS Number
9005-65-6 check
ChEMBL
ChEMBL1697847 ☒
ChemSpider
none
ECHA InfoCard   100.105.529 Edit this at Wikidata
E number   E433 (thickeners, ...)
RTECS number
WG2932500
UNII
6OZP39ZG8H ☒
CompTox Dashboard (EPA)
DTXSID0021175 Edit this at Wikidata
Properties
Chemical formula   C64H124O26
Molar mass   1310 g/mol
Appearance   Amber colored liquid
Density   1.102 g/mL, oily liquid
Boiling point   > 100°C
Solubility in water   100 mL/L[2]
Solubility in other solvents   soluble in ethanol, cottonseed oil, corn oil, ethyl acetate, methanol, toluene
Viscosity   300–500 centistokes (@25°C)
Hazards
Main hazards   Irritant
NFPA 704 (fire diamond)
NFPA 704 four-colored diamond
110
Flash point   113 °C (235 °F; 386 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒ verify (what is check☒ ?)
Infobox references
Polysorbate 80 is a nonionic surfactant and emulsifier often used in foods and cosmetics. This synthetic compound is a viscous, water-soluble yellow liquid.

Contents
1   Chemistry
2   Other names
3   Uses
3.1   Food use
3.2   Health and beauty use
3.3   Medical use
3.4   Laboratory use
4   See also
5   References
Chemistry
Polysorbate 80 is derived from polyethoxylated sorbitan and oleic acid. The hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide. In the nomenclature of polysorbates, the numeric designation following polysorbate refers to the lipophilic group, in this case, the oleic acid (see polysorbate for more detail).

The full chemical names for polysorbate 80 are:

Polyoxyethylene (20) sorbitan monooleate
(x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl)
The critical micelle concentration of polysorbate 80 in pure water is reported as 0.012 mM.[3]

Other names
E number: E433

Brand names:

Alkest TW 80
Scattics
Canarcel
Poegasorb 80
Montanox 80 – Montanox is a registered trademark of Seppic
Tween 80 – Tween is a registered trademark of Croda Americas, Inc.[4]
Uses
Food use
Polysorbate 80 is used as an emulsifier in foods.

For example, in ice cream, polysorbate is added up to 0.5% (v/v) concentration to make the ice cream smoother and easier to handle, as well as increasing its resistance to melting.[5] Adding this substance prevents milk proteins from completely coating the fat droplets. This allows them to join together in chains and nets, which hold air in the mixture, and provide a firmer texture that holds its shape as the ice cream melts.

Health and beauty use
Polysorbate 80 is also used as a surfactant in soaps and cosmetics (including eyedrops), or a solubilizer such as in a mouthwash. The cosmetic grade of polysorbate 80 may have more impurities than the food grade.[6]

Medical use
Polysorbate 80 is an excipient that is used to stabilize aqueous formulations of medications for parenteral administration, and used as an emulsifier in the making of the popular antiarrhythmic amiodarone.[7] It is also used as an excipient in some European and Canadian influenza vaccines.[8] Influenza vaccines contain 2.5 μg of polysorbate 80 per dose.[8] Polysorbate 80 is found in many vaccines used in the United States.[9] It is also used in the culture of Mycobacterium tuberculosis in Middlebrook 7H9 broth. It is also used as an emulsifier in the estrogen-regulating drug Estrasorb.[10]

Also used in granulation for stabilization of drug and excipients while doing IPA binding

Laboratory use
Some mycobacteria contain a type of lipase (enzyme that breaks up lipid molecules); when these species are added to a mixture of polysorbate 80 and phenol red, they cause the solution to change color, so this is used as a test to identify the phenotype of a strain or isolate.[citation needed]

Name
Polysorbate 80
Accession Number
DB11063
Description
Polysorbate, a substance formulated by the reaction of sorbitan fatty acid ester (a nonionic surfactant) with ethylene oxide, is used in many foreign countries, including the U.S. and the EU, where it acts as an emulsifier, a solubilizer in many foods, including bread, cake mix, salad dressing, shortening oil and chocolate 18.

Polysorbate 80 is a hydrophilic nonionic surfactant. It is utilized as a surfactant in soaps and cosmetics and also as a lubricant in eye drops. In food or pharmaceutical products, it can act as an emulsifier. Polysorbate 80 is an excipient that is used to stabilize aqueous formulations of medications for parenteral administration or vaccinations.15

A solubilizing agent acts as a surfactant and increases the solubility of one agent in another. A substance that would not normally dissolve in a particular solution is able to dissolve with the use of a solubilizing agent.15

It is also known as an emulsifier, which helps ingredients mix together and prevent separation, and water-containing small amounts of salts, and is included in several vaccines licensed in the USA.9
On RODAC agar plates used in microbiological control, polysorbate 80 counteracts any disinfectants often found on sampled surfaces, thereby allowing the microbes found on these surfaces to grow.
What is Polysorbate 80?
Polysorbate 80 is an oleic acid with an approximate hydrophilic-lipophilic balance of 15.
Polysorbate 80 uses

Abstract
Polysorbate 80 is a synthetic nonionic surfactant used as an excipient in drug formulation. Various products formulated with polysorbate 80 are used in the oncology setting for chemotherapy, supportive care, or prevention, including docetaxel, epoetin/darbepoetin, and fosaprepitant. However, polysorbate 80, like some other surfactants, is not an inert compound and has been implicated in a number of systemic and injection- and infusion-site adverse events (ISAEs). The current formulation of intravenous fosaprepitant has been associated with an increased risk of hypersensitivity systemic reactions (HSRs). Factors that have been associated with an increased risk of fosaprepitant-related ISAEs include the site of administration (peripheral vs. central venous), coadministration of anthracycline-based chemotherapy, number of chemotherapy cycles or fosaprepitant doses, and concentration of fosaprepitant administered. Recently, two polysorbate 80-free agents have been approved: intravenous rolapitant, which is a neurokinin 1 (NK-1) receptor antagonist formulated with the synthetic surfactant polyoxyl 15 hydroxystearate, and intravenous HTX-019, which is a novel NK-1 receptor antagonist free of synthetic surfactants. Alternative formulations will obviate the polysorbate 80-associated ISAEs and HSRs and should improve overall management of chemotherapy-induced nausea and vomiting.

Funding Heron Therapeutics, Inc.

Keywords: Fosaprepitant, Injection-site adverse events, Oncology, Polysorbate 80, Safety
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Introduction
Polysorbate 80, also known as Tween 80, is a synthetic nonionic surfactant commonly used in food, cosmetics, and drug formulations as a solubilizer, stabilizer, or emulsifier [1–3]. Polysorbate 20 and 60 (Tween 20 and 60) are also included in this family of surfactants [1, 4]. It has also been used to prevent protein adsorption and/or aggregation [2]. A wide range of pharmaceutical agents are available in formulations that contain polysorbate 80, including amiodarone [5], vitamin K [6], etoposide [3], docetaxel [7], various vaccines [8], protein biotherapeutics [2], erythropoietin-stimulating agents [9, 10], and fosaprepitant [11]. Recent data have indicated that polysorbate 80 is a biologically and possibly pharmacologically active compound and consequently may alter the pharmacologic properties of the drug it is formulated with or may itself directly mediate adverse events [3, 12]. Consequently, polysorbate 80 has been implicated in some of the adverse reactions associated with drugs formulated with this vehicle.

This review covers the safety of polysorbate 80 in the oncology setting, focusing on polysorbate 80-associated adverse events that may have occurred with the use of docetaxel, darbepoetin alfa, epoetin alfa, and fosaprepitant.

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

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Overview of Polysorbate 80
Chemistry of Polysorbate 80
Polysorbate 80 is a synthetic surfactant composed of fatty acid esters of polyoxyethylene sorbitan [1, 2]. The fatty acid composition is primarily oleic acid, but other fatty acids, such as palmitic or linoleic acid, may be included (Fig. 1). Therefore, polysorbate 80 is usually available as a chemically diverse mixture of different fatty acid esters with the oleic acid comprising > 58% of the mix [1]. However, the main component of polysorbate 80 is polyoxyethylene-20-sorbitan monooleate, structurally similar to polyethylene glycols. Polysorbate 80 has a molecular weight of 1309.7 Da and a density of 1.064 g/ml [3].

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Fig. 1
Chemical structure of the primary constituents of polysorbate 80

Polysorbate 80 has both hydrophobic and hydrophilic moieties [1, 2]. The hydrophobic moieties drive an interaction with the air-water interface or a solid-water interface, such as that found in vials, syringes, and other glass and plastic containers [2]. The hydrophobic moieties of polysorbate 80 also result in the formation of micelles at concentrations above the critical micelle concentration of 0.01% (weight/volume) in protein-free aqueous solution [3]. This formation of micelles may play a critical role in the mechanism of action of polysorbate 80. Enzyme-linked immunosorbent assays have shown that polysorbate 80 could activate the complement system, a multiprotein immune mechanism. Activating the complement system may lead to phagocytosis, stimulation, and recruitment of white blood cells, or perforation of plasma membranes, possibly leading to immunologic side effects such as acute hypersensitivity and systemic immune reactions [13]. This possibility has been tested in a zebrafish model, where oxidized fatty acid residues in polysorbate 80 samples caused anaphylactoid reactions at the highest tested concentrations [14]. Polysorbate 80 substituted for human serum albumin in an epoetin alfa preparation in Europe is thought to have played a role in the development of neutralizing antibodies and pure red blood cell aplasia [15]. However, it is not yet known which specific parts of the chemical structure of polysorbate 80 are responsible for adverse events such as systemic and administration-site reactions.

Aqueous solutions of polysorbate 80, as well as the undiluted liquid, undergo auto-oxidation over time, with changes being catalyzed by light, increased temperature, and copper sulfate [16]. Auto-oxidation leads to the formation of a variety of hydroperoxides, peroxides, and carbonyl compounds that may readily degrade proteins [16]. During the initial stages of propagation, the peroxide formation is usually faster than its decomposition; eventually, the rates of formation and decomposition equalize, and then decomposition occurs faster than formation [16]. Parameters such as surface tension and cloud point properties may be used to establish degradation in the hydrophilic chains [16].

Pharmacokinetic Properties of Polysorbate 80
In both animal [17] and clinical studies [18, 19], polysorbate 80 is rapidly removed from systemic circulation. The polysorbate 80 plasma concentration-time curve (AUC) in a patient administered an intravenous (IV) infusion of docetaxel 35 mg/m2 (polysorbate 80 1.75 g) showed a polysorbate 80 peak concentration of 304 μg/ml [18]. The AUC for polysorbate 80 was 321.7 mg h/ml, with a short disposition half-life of 1.07 h and a total plasma clearance of 5.44 l/h. The volume of distribution of polysorbate 80 at steady state was similar to the total blood volume (4.16 l), suggesting that polysorbate 80 circulates as large micelles and does not significantly distribute outside the central compartment [18]. In vitro studies suggest that polysorbate 80 is metabolized by rapid carboxylesterase-mediated hydrolysis [17].

Polysorbate 80 may potentially have an effect on the distribution and elimination of some IV-administered drugs with which it has been formulated (Table 1) [20–25]. This effect may lead to increased systemic exposure and decreased clearance of the drug [3]. For example, polysorbate 80 may influence the binding of docetaxel in a concentration-dependent manner [25]. A potential explanation of this effect may be that polysorbate 80 forms micellar complexes with proteins, so that the binding of docetaxel becomes saturated on single sites and the fraction of unbound drug increases [3, 25]. An alternative explanation is that the metabolism of polysorbate 80 and the subsequent displacement of oleic acid-mediated protein-binding sites may cause an increase in the fraction of unbound drug [3].

Table 1
Pharmacokinetic effects of drugs formulated with polysorbate 80

Drug   Effect of polysorbate 80
Preclinical studies
Doxorubicin [20]   Increased concentration in plasma
Methotrexate [21]   Increased uptake in brain
Increased absorption
Increased excretion into bile
Etoposide [22]   Increased AUC and decreased elimination
Clinical studies
Doxorubicin [23]   Increased volume of distribution up to 3-fold
Decreased AUC up to 2-fold
Increased clearance up to 2-fold
Paclitaxel [24]   Increased concentration in brain
Docetaxel [25]   Increased fraction unbound in plasma
AUC area under the plasma concentration-time curve

Pharmacodynamic Properties of Polysorbate 80
Polysorbate 80 has demonstrated several pharmacodynamic properties, including altering membrane fluidity and increasing membrane permeability [26]. An in vitro study indicated that polysorbate 80 potentiated the effect of antibiotics in resistant cell lines, which was thought to be due to the effect of polysorbate 80 on cell membrane permeability [27]. In vitro, polysorbate 80 increases the susceptibility of cells to oxidative stress [28]. In animal tumor models, it appears to have cytotoxic effects [3]. Cytotoxicity and antitumor activity associated with polysorbate 80 may be linked to the release of oleic acid, known to interfere with cell proliferation through the formation of peroxides [29–32].

In animal studies, polysorbate 80 has been associated with a profound and sustained decrease in blood pressure, which may be attributable to the negative inotropic properties of polysorbate 80 [33]. In clinical studies, amiodarone formulations devoid of polysorbate 80 and benzyl alcohol had a substantially reduced risk of hypotension [5].

Polysorbate 80 and Adverse Events
Polysorbate 80 has been associated with a number of adverse events. In food, small concentrations of undigested polysorbate 80 may enhance bacterial translocation across intestinal epithelia, a potential explanation for an observed increase in the incidence of Crohn’s disease [34]. In drug formulations, polysorbate 80 has been implicated in a number of systemic reactions (e.g., hypersensitivity, nonallergic anaphylaxis, rash) and injection- and infusion-site adverse events (ISAEs; e.g., pain, erythema, thrombophlebitis) [3, 35–37]. Polysorbate 80 has also been implicated in cases of renal and liver toxicity [38–40].

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Polysorbate 80 in the Oncology Setting
Various chemotherapeutic, supportive care, and preventative agents used in the oncology setting utilize polysorbate 80 in their formulations, including docetaxel (Taxotere®, Sanofi-Aventis US LLC), the biologicals epoetin alfa (Epogen®, Amgen Inc.; Procrit®, Amgen Inc.) and darbepoetin alfa (Aranesp®, Amgen Inc.), and the antiemetic fosaprepitant IV (Emend® IV, Merck, Sharp & Dohme). Certain adverse events (both systemic and ISAE) occur with these drugs, in which polysorbate 80 may be implicated. There are some challenges in evaluating the literature on this topic, as attribution of adverse events to polysorbate 80 is confounded by its administration with the pharmacologically active agent and by the heterogeneity of reporting of these adverse events in clinical trials. However, there is evidence to implicate polysorbate 80 in systemic and administration-site reactions.

Docetaxel
Docetaxel is a taxane that inhibits cell replication by stabilizing the microtubule cytoskeleton [7, 41]. To solubilize this agent for clinical use, it has been formulated using polysorbate 80. An injection concentrate (20 mg/ml) comprises 20 mg of docetaxel in 1 ml at a 50/50 (V/V) ratio of polysorbate 80/dehydrated alcohol. Currently, docetaxel is indicated for the treatment of several cancers, including locally advanced or metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer, hormone-refractory prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck [7].

Docetaxel has been associated with a number of ISAEs and systemic reactions [7, 42, 43], including hypersensitivity [3, 7], fluid retention [3, 7], cutaneous reactions [7, 44], gastrointestinal adverse events [7], and peripheral neuropathy [3, 7]. In clinical trials in patients with cancer, the incidence of ISAEs has been reported to be 3–4% [7].

The presence of polysorbate 80 in the IV formulation of docetaxel has been implicated in hypersensitivity systemic reactions (HSRs) that were observed in the early clinical studies [3, 45]. In those studies, the incidence of HSRs ranged from 5% to 40%, with most events being grade 2 in severity on the four-point scale of the National Cancer Institute common toxicity criteria [3]. Severe HSRs or, very rarely, fatal anaphylaxis have been reported in patients treated with docetaxel [7]. Polysorbate 80 and the oleic acid released by its metabolism have been implicated in the HSRs seen with docetaxel therapy [46]. Consequently, patients treated with the conventional formulation of docetaxel are premedicated with oral corticosteroids [7].

Developments in formulating docetaxel IV without polysorbate 80 include dendrimer (Dep) docetaxel [47, 48] and nanosomal docetaxel lipid suspension [22, 49]. In one study, the diminished potential for HSRs with the novel nanosomal docetaxel lipid suspension, compared with the conventional docetaxel formulation, reduced the requirement for premedication with corticosteroids [50].

Supportive Care: Epoetin Alfa, Darbepoetin Alfa
A number of subcutaneous and IV formulations of erythropoietin-stimulating agents (ESAs) contain polysorbate 80. Darbepoetin alfa [10] is formulated with polysorbate 80 in the US. Outside the US, epoetin alfa (Eprex®, Janssen-Cilag Ltd; Erypo®, Biocon Limited) [9] is formulated with polysorbate 80, instead of human serum albumin, to avoid potential contamination by human immunodeficiency virus and Creutzfeldt-Jakob disease-causing prions [51]. These ESAs are indicated for the treatment of anemia and to reduce transfusion requirements in patients receiving myelosuppressive chemotherapy for cancer [9, 10, 52]. They act by stimulating erythropoiesis by the same mechanism as endogenous erythropoietin.

Adverse events associated with darbepoetin alfa in patients with cancer include abdominal pain, edema, and thrombovascular events [10]. HSRs, including cases of rash, anaphylactic reactions, and angioneurotic edema, have been reported with epoetin alfa [9]. In particular, the inclusion of polysorbate 80 in one epoetin alfa formulation has been associated with antibody-mediated pure red cell aplasia (PRCA) in patients with chronic kidney disease [51].

Supportive Care: Fosaprepitant (Emend IV)
Aprepitant is a selective, high-affinity antagonist of human substance P/neurokinin 1 (NK-1) receptors that was first developed for oral administration [53, 54]. Aprepitant was approved in 2003 for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy [53]. Subsequently, an IV prodrug formulation (fosaprepitant; Emend IV) was approved in 2008; this formulation includes polysorbate 80 [11]. Because NK-1 antagonists target another important neurotransmitter/receptor involved in the emetogenic pathway, they complement 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists and enhance control of chemotherapy-induced nausea and vomiting [55, 56].

Polysorbate 80 is not a physiologically inert compound and may account for the increased risk of systemic adverse events and ISAEs associated with its use in drug formulations [3, 12]. Safety issues associated with polysorbate 80 have led to formulation changes for docetaxel within the oncology setting [22, 47–49].

In particular, fosaprepitant, which includes polysorbate 80 in its formulation, has been associated with an increased risk of HSRs and other systemic reactions including anaphylaxis; most recently, anaphylactic shock has been added per the 2017 label update. The update also includes symptoms such as hypotension and syncope [11], as well as increased ISAEs, compared with oral aprepitant. Factors that have been linked to the increased risk of fosaprepitant ISAEs include the site of administration (peripheral vs. central venous), co-administration of anthracycline-based chemotherapy, number of chemotherapy cycles or fosaprepitant doses, and concentration of the fosaprepitant administered.

There is a need for an IV formulation of an NK-1 receptor antagonist that does not use polysorbate 80 as a vehicle and that has a lower risk of HSRs and ISAEs. HTX-019 (Cinvanti®, Heron Therapeutics) is a novel formulation of the NK-1 receptor antagonist aprepitant, which is free of polysorbate 80 and other synthetic surfactants. HTX-019 was approved in November 2017 [68]

Conclusion
Polysorbate 80 is a nonionic surfactant commonly used as an excipient in drug formulations. Various agents used in the oncologic setting, such as docetaxel, epoetin/darbepoetin, and fosaprepitant, are formulated with polysorbate 80. Polysorbate 80 appears to be a pharmacologically active compound and has been implicated in a number of systemic adverse events and ISAEs. The current formulation of fosaprepitant has been associated with an increased risk of HSRs such as anaphylaxis and anaphylactic shock, as well as increased ISAEs, compared with oral aprepitant. Factors that have been associated with an increased risk of fosaprepitant ISAEs include the site of administration (peripheral vs. central venous), coadministration of anthracycline-based chemotherapy, number of chemotherapy cycles of fosaprepitant doses, and concentration of the fosaprepitant administered. The recent approvals of HTX-019, a novel IV formulation of the NK-1 receptor antagonist aprepitant that is free of polysorbate 80 and other synthetic surfactants, provides a new and effective therapeutic option for the prevention of chemotherapy-induced nausea and vomiting with a reduced risk of HSRs and ISAEs.