POLYSORBATE 20

POLYSORBATE 20

CAS No. : 9005-64-5
EC No. : 500-019-9

Synonyms:
Polyoxyethylene (20) sorbitan monooleate; Montanox 80; Alkest TW 80; Tween 80; PS 80; Polysorbate 20; Polysorbate 40; Polysorbate 60; Polysorbate 65; Scattics; Canarcel; Poegasorb 80; Montanox 20; Polysorbate 20; PEG(20)sorbitan monolaurate; Alkest TW 20; Tween 20; Polyoxyethylene (20) sorbitan monolaurate; Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate); Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate); Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate); Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); 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; 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; POE(6) Sorbitan Monooleate; POE (5) sorbitan monooleate; Sorethytan (20) mono-oleate; POE (20) sorbitan monooleate; Sorbitan mono-oleate polyoxyethylene; Polyethylene oxi de sorbitan mono-oleate; Polysorbate 80 [USAN:BAN:INN:JAN]; 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; Sorbitan, mono-(9Z)-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivs; 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; Polysorbate 20; Tween 20; 9005-64-5; Polyoxyethylene (20) sorbitan monolaurate; POLYOXYETHYLENE SORBITAN MONOLAURATE; Polyoxyethylenesorbitan monolaurate; Polysorbate (INN); 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl dodecanoate; 2-{2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]- 2-(2-hydroxyethoxy)ethoxy}ethyl dodecanoate; 2-(2-(3,4-Bis(2-hydroxyethoxy)tetrahydrofuran-2-yl)- 2-(2-hydroxyethoxy)ethoxy)ethyl dodecanoate; 2-[2-[3,4-bis(2-hydroxyethoxy)tetrahydrofuran-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl dodecanoate; 9005-66-7; Alkest TW 20; Polysorbate 20 (NF); Polysorbate 40 (NF); Polysorbate 60 (NF); Tween(R) 20; tween (R) 20; Tween 20 (TN); Tween 40 (TN); Tween 60 (TN); SCHEMBL118527; POE (6) sorbitol monolaurate; POE(20) sorbitan monolaurate; CHEMBL371631; Ethoxylated Sorbitan monolaurate; POE (20) sorbitan monolaurate; E432; Polyoxyethylene Sorbitan Monolaurate Kosher; Polyoxyethylene Sorbitan Monolaurate 20 NF; 3,6-Anhydro-1-O-[2-(dodecanoyloxy)ethyl]-2,4,5-tris-O-(2-hydroxyethyl)hexitol

Polysorbate 20

Polysorbate 20 (common commercial brand names include Scattics, Alkest TW 20 and Tween 20) is a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan before the addition of lauric acid. Its stability and relative nontoxicity allows it to be used as a detergent and emulsifier in a number of domestic, scientific, and pharmacological applications. As the name implies the ethoxylation process leaves the molecule with 20 repeat units of polyethylene glycol; in practice these are distributed across 4 different chains, leading to a commercial product containing a range of chemical species.

Properties
Chemical formula    C58H114O26
Molar mass    1227.54 g/mol
Appearance    Clear, yellow to yellow-green viscous liquid.
Density    1.1 g/mL (approximate)
Boiling point    > 100 °C (212 °F; 373 K)
Surface tension:
CMC    8.04×10−5 M at 21 °C[1]
HLB    16.7

Chemistry
Polysorbate 20 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 20 are:
Polyoxyethylene (20) sorbitan monooleate
(x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl)
The critical micelle concentration of Polysorbate 20 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 20 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 20 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 20 may have more impurities than the food grade.[6]

Medical use
Polysorbate 20 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 20 per dose.[8] Polysorbate 20 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.
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 20 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]

On RODAC agar plates used in microbiological control, Polysorbate 20 counteracts any disinfectants often found on sampled surfaces, thereby allowing the microbes found on these surfaces to grow.

Polysorbate 20 (common commercial brand names include Scattics, Alkest TW 80 and Tween 80) is a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan before the addition of lauric acid. Its stability and relative nontoxicity allows it to be used as a detergent and emulsifier in a number of domestic, scientific, and pharmacological applications. As the name implies the ethoxylation process leaves the molecule with 80 repeat units of polyethylene glycol; in practice these are distributed across 4 different chains, leading to a commercial product containing a range of chemical species.

Food applications
Polysorbate 20 is used as a wetting agent in flavored mouth drops such as Ice Drops, helping to provide a spreading feeling to other ingredients like SD alcohol and mint flavor.
The World Health Organization has suggested acceptable daily intake limits of 0–25 mg of polyoxyethylene sorbitan esters per kg body weight.[3]

Biotechnical applications
In biological techniques and sciences, Polysorbate 20 has a broad range of applications. For example, it is used:

as a washing agent in immunoassays, such as Western blots and ELISAs. It helps to prevent non-specific antibody binding. In this major application, it is dissolved in Tris-buffered saline or phosphate buffered saline at dilutions of 0.05% to 0.5% v/v. These buffers are used for washes between each immunoreaction, to remove unbound immunologicals, and eventually for incubating solutions of immunoreagents (labeled antibodies) to reduce nonspecific background.
to saturate binding sites on surfaces (i.e., to coat polystyrene microplates, generally combined with proteins such as BSA).
to stabilize proteins purified protein derivative (PPD) solution used in skin testing for tuberculosis exposure
as a solubilizing agent of membrane proteins
for lysing mammalian cells, at a concentration of 0.05% to 0.5% v/v, generally combined with other detergents, salts and additives.
Pharmaceutical applications
Polysorbate 20 is used as an excipient in pharmaceutical applications to stabilize emulsions and suspensions.

Industrial and domestic applications
Polysorbate 20 is used by philatelists to remove stamps from envelopes and to remove residues from stamps, without harming the stamp itself.

Polysorbate 20 is also used as wetting agent in rubber balers in the elastomer industry.
Polysorbate 20 has been used as a shape directing agent to synthesize spheroidal magnetite nanoassemblies.

Polysorbate 20 are a class of emulsifiers used in some pharmaceuticals and food preparation. They are often used in cosmetics to solubilize essential oils into water-based products. Polysorbates are oily liquids derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Common brand names for polysorbates include Scattics, Alkest, Canarcel.

What Is Polysorbate? – Polysorbate 20 vs. 60 vs. 80 Uses

What Is Polysorbate and What Is Polysorbate Derived from?
Oxiteno’s ALKEST TW line of polysorbates are mild, non-ionic surfactants comprised of polyethoxylated esters of 3,6-sorbitan. Being derived mainly from natural materials, many of these versatile surfactants are water-soluble products that are used as emulsifiers, solubilizers, wetting agents, and dispersants throughout the food, cosmetics, and personal care industries.

These surfactants consist primarily of partial fatty acid esters (oleate, stearate or laurate) of sorbitol-derived cyclic ethers (sorbitans and sorbides) polymerized with approximately 20 molecules of ethylene oxide per molecule of polysorbate.

The estimated bio-based carbon content of these products ranges from 31-38%, making them a renewable option for the environment.c Oxiteno offers a variety of options to meet your polysorbate needs, many of which are Kosher/Halal, meet the NF and FCC requirements, and are made from non-GMO/RSPO certified materials.

Polysorbate 20 vs. 60 vs. 80
As the only US Gulf polysorbate manufacturer, Oxiteno offers an array of options that can be sourced from non-GMO and RSPO certified materials, including oleic acid (Polysorbate-80), lauric acid (Polysorbate-20), and stearic acid (Polysorbate-60).

The assortment of options offered by Oxiteno allows formulators to choose from a unique set of properties to achieve stable, well-dispersed products. The physical state of these various polysorbates range from semi-solid (Polysorbate-60) to viscous liquids (Polysorbate-80 and -20), which allows the chemist variability during the formulation process.

Other distinctions between these products include their unique hydrophilic-lipophilic balances (HLB) which range from 14.9-to-16.7 (Polysorbate 60 and 20, respectively).  This HLB value can be a critical tool to begin preliminary assessments for an oil-in-water emulsification.  However, when used in combination with Oxiteno’s line of compatible and low-HLB sorbitan esters (ALKEST SP series), a vast assortment of formulation possibilities is now achievable, ranging from water-in-oil to oil-in-water emulsifications.

What is Polysorbate 20?
Polysorbate 20 is an oleic acid with an approximate hydrophilic-lipophilic balance of 15.

Polysorbate 20 uses
Due to the unique properties and safety of Polysorbate-80, this product (ALKEST TW 80) is commonly used in the food industry to emulsify salad dressings and chocolates, as well as the pharmacological industry to disperse active ingredients in pharmaceuticals.
In addition, ALKEST TW 80 is used alongside other personal care chemicals throughout the cosmetics industry to help prepare facial cleansers, skin and hair care products.

What is Polysorbate 60?
Polysorbate 60 is a stearic acid with an approximate hydrophilic-lipophilic balance of 14.9.

Polysorbate 60 uses
Because Oxiteno’s ALKEST TW 60 (Polysorbate-60) is currently listed on the CleanGredients database (cleangredients.org), it has been approved by the Environmental Protection Agency (EPA) for use in Safer Choice products.

ALKEST TW 60 is commonly used in a variety of industries, including cosmetics and food.  Polysorbate-60 can be used as an emulsifier and thickening agent in personal care formulations and finds itself as a dispersant in oral care.  This product is also commonly used as an indirect food additive by agrochemical companies to solubilize flavors and emulsify fats.

In addition, ALKEST TW 60 is listed on the US EPA’s Inert Ingredients List under 40.CFR.180.910 and 40.CFR.180.930.  ALKEST TW 60 is offered in a variety of options, including Kosher/Halal (K) and free of genetically modification (FMG K).

What is Polysorbate 20?
Polysorbate 20 is a lauric acid with an approximate hydrophilic-lipophilic balance of 16.7.

Polysorbate 20 uses
Similar to Polysorbate-60, Oxiteno’s ALKESTTW 20 (Polysorbate-20) is also listed on the CleanGredients database (cleangredients.org). ALKEST TW 20 is currently used in the cosmetic and personal care industries.  This product can be used as a solubilizing agent in oil-in-water emulsifications as well as a humectant in skin care products. In addition, polysorbate-20 is frequently used as an indirect additive for food emulsification.

Is Polysorbate safe?
Since Oxiteno’s ALKEST TW series is derived mainly from natural materials, they are inherently biodegradable products that exhibit a minimal impact to the environment.  In addition, they are considered safe for human consumption, as thorough studies have shown no carcinogenicity and genotoxicity related to polysorbates.a

The Food and Drug Administration (FDA) allows polysorbates to be directly added to food as adjuvants and emulsifiers for flavoring agents.  The FDA also includes Oxiteno’s line of polysorbates on its list of indirect food additives as surface active agents and these products are also safe for use in over-the-counter ophthalmic drug products. In addition, the safety of polysorbates has been assessed by the Cosmetic Ingredient Review (CIR) Expert Panel. The CIR expert panel evaluated the scientific data and concluded that polysorbates 20, 21, 40, 60, 61, 65, 80, 81 and 85 were safe as cosmetic ingredients.

Sorbitan Fatty Acid Esters
Polyoxyethylene sorbitan esters are synthesized by the addition, via polymerization, of ethylene oxide to sorbitan fatty acid esters. These nonionic hydrophilic emulsifiers are very effective antistaling agents and, thus, are used in a wide variety of bakery products. These emulsifiers are much more widely known as the polysorbates, e.g., polysorbate 20, 60, and 80 (Figure 7). Polysorbate 20, 60, and 80 utilize lauric, stearate, and oleate, respectively, for the fatty acid portion of the molecule. Polysorbate 60 is a monostearate, whereas polysorbate 65 is a tristearate.

Surface functionality of NPs, as can be speculated, also influences the interaction with the biologic medium. Hydrophilic surfactants such as Polysorbate 20, poloxamer 188, and other pegylated polysorbates are used to coat the nanocarrier surface to render them transportable through the BBB. Efflux transporters, which are known to be located in the BBB, are responsible for poor penetration of certain CNS drugs into the brain. These surfactants are believed to inhibit the efflux and solubilize lipid membranes of BMEC due to their typical surfactant activity, thus enhancing the penetration of drugs inside the brain. These compounds also adsorb or mimic low-density lipoproteins and enter the brain via receptor-mediated endocytosis. Thus, this surface modification strategy is expected to affect the mechanism of nanocarrier uptake by cells.

Partial immersion
Commier and colleagues coated titanium MNs via partial immersion [145]. The hexagonally patterned MNs (Macroflux) measured 2 cm2 with 321 microneedles/cm2 [145]. The coating solutions were loaded with 0.2 wt.% polysorbate and 24 or 40 wt.% desmopressin [145]. The researchers carried out the coating under room conditions (22°C, 45% relative humidity) using a device that restricts the drug to MN tips. The MN tips were then coated with desmopressin and administered to hairless guinea pig skin for 5 or 15 min [145]. Therapeutic concentrations of the drug were obtained after 5 min and the bioavailability went up to 85% [145].

Vaccine stability
Vaccine manufacturers in the United States and elsewhere have ongoing programs to assess the stability of all vaccine products. Stability of a product is influenced by the specific formulation of the product, the addition of stabilizing compounds (such as gelatin or Polysorbate 20), the compatibility of the product with the intended container and closure and the preparative treatments needed to reduce adsorption or chemical interaction of the vaccine components with the container, and the vaccine's specific temperature limits. Stability assessment programs usually also examine sterility, pH, and the measurable content of preservatives and other chemical ingredients.

Coating effect
Nanoparticles are generally coated with polymers like polyethylene glycol (PEG), polyethylene oxide, dextran, Polysorbate 20, and starch and small molecules like citrate (Alexis et al., 2008; Zhang et al., 2009; Almeida et al., 2011; Ernsting et al., 2013). Scientific studies reveal that the coating of such materials generally enhances the biodistribution (Hsu et al., 2014). PEG and Polysorbate 20 are the widely employed coating materials used to enhance the circulation time of nanoparticles (Gaucher et al., 2009). It has been reported that apolipoprotein E substantially binds to the Polysorbate 20 of the coated nanoparticles and is involved in the transport of polysorbate-coated nanocarriers. Additionally, Polysorbate 20 is a Pgp inhibitor, and its coating on nanocarriers loaded with drugs like doxorubicin is beneficial (Alexis et al., 2008; Bartlett et al., 2007). PEG of mass range 10 kDa is believed to be a better coating material, out of a variety of PEGs, due to lower protein adsorption tendencies (Ernsting et al., 2013).

Chemical, protein and colloidal enhancers
Chemical penetration enhancers under consideration as skin adjuvants, alone or in conjunction with iontophoresis, ultrasound, or electroporation methods, include oleic and retinoic acids,255 dimethylsulfoxide (DMSO), ethanol, limonene, Polysorbate 20, and others. Flagellin, a bacterial surface component protein, was engineered to express influenza nucleoprotein epitope and applied to the bare skin of mice, inducing virus-specific interferon-gamma T cells.244 Certain colloids may serve as antigen carriers.33 Deformable lipid vesicles (“transfersomes”) containing tetanus toxoid applied to animal skin yielded comparable immune responses with alum-adjuvanted tetanus toxoid given by the IM route.

The polysorbates are used in pharmaceuticals for various reasons, including the modification of an active ingredient's absorption. ... Polysorbates 20 and 80 are listed as welling or clarifying agents in ophthalmic products and as cleaning, wetting, or solvent agents for contact lenses in concentrations not to exceed 1.0 percent. Polysorbate 20 is classified as an "inactive ingredient or pharmaceutical necessity" in topical analgesic, antirheumatic, otic, burn, and sunburn treatment/prevention products.

Polysorbates 20 and 80 (Tween 20 and Tween 80) are used in the formulation of biotherapeutic products for both preventing surface adsorption and as stabilizers against protein aggregation. The polysorbates are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan being polyoxyethylene sorbitan monolaurate for polysorbate 20 and polyoxyethylene sorbitan monooleate for Polysorbate 20. The polysorbates used in the formulation of biopharmaceuticals are mixtures of different fatty acid esters with the monolaurate fraction of polysorbate 20 making up only 40-60% of the mixture and the monooleate fraction of Polysorbate 20 making up >58% of the mixture. The polysorbates undergo autooxidation, cleavage at the ethylene oxide subunits and hydrolysis of the fatty acid ester bond. Autooxidation results in hydroperoxide formation, side-chain cleavage and eventually formation of short chain acids such as formic acid all of which could influence the stability of a biopharmaceutical product.

/Experimental Therapy/ /Investigators/ studied the effects of Polysorbates 20 and 80 in 13 patients with bile salt-deficient steatorrhea, 8 of whom received Polysorbate 20 and 5 Polysorbate 20. When 2 g were administered three times a day, the Polysorbates increased micellization of ingested fat and improved fat absorption. Therapy reduced steatorrhea in 10 of the 13 patients.
The metabolism of Polysorbate 20 in rats has been studied in detail with 14C-label tracer techniques. When administered orally, the ester link of the Polysorbate 20 molecule is hydrolyzed by pancreatic lipase, and the fatty acid moiety is released to be absorbed and metabolized as any other dietary fatty acid.

The intravenous infusion of 5 mL of Polysorbate 20 at a rate of 0.2 mL/15 sec into 14 intact and 8 splenectomized dogs evoked anaphylactic-like symptoms that may have been mediated by endogenous histamine release. Histamine release was indicated by skin changes, tachyphylaxis, and protection by antihistamines. Other changes included decreased arterial pressure, heart rate, and plasma volume and increased respiratory rate, lymph flow, and hematocrit. The Polysorbate 20 have been shown to be nonspecific histamine releasers, and their hemodynamic effects are entirely compatible with histamine release. The later response of decreased output, hypotension, and tachycardia is almost indistinguishable from that found in endotoxic or hemorrhagic shock.

The hemolytic action of Polysorbates 20, 40, 60, and 80 on human erythrocytes was measured and correlated with the physical properties of the surfactants. The hemolytic power depended on the mutual effect of the hydrophobic and hydrophilic fragments of the Polysorbate 20 molecule and did not depend on the hydrophile-lipophile balance as such. It was suggested that the role of the polyoxyethylene moiety in the action of the Polysorbate 20 on membranes lies with its effect on the relative lipophilicity of the compound. The polyoxyethylene fragment may have also interacted with surface components when the molecule was adsorbed onto the membrane. It was concluded that the lysis of erythrocytes by the Polysorbate 20 was caused not by the destruction of the membrane but by some rearrangement of the membrane structure accompanying adsorption of the surfactant.

The effects of the Polysorbate 20 on mitochondrial respiration seem to reflect a direct action on the ferrocytochrome C step in the electron transport chain of oxidative phosphorylation. The addition of Polysorbate 20 to suspensions of liver mitochondria from normal and tumor-bearing rats led to an increase in the activity of succinate-cytochrome C reductase in one study and an increase in the activity of cytochrome C oxidase in another. The activation of cytochrome C oxidase by the Polysorbate 20 is well documented. They have been shown to reversibly convert cytochrome oxidase from an inactive to an active coupling state by providing a suitable environment for the most active conformational state. This effect was pH independent when demonstrated with purified cytochrome oxidase.

The synthesis, the physicochemical characterization and the biological evaluation of three novel pH-sensitive systems prepared derivatizing Polysorbate 20 (Tween 80) with glycine, N-methyl-glycine and N,N-dimethyl-glycine (TW80-GLY, TW80-MMG and TW80-DMG) /is described/. These derivatives form pH-sensitive vesicles and translocate small molecules into cells. The reported systems are efficient drug delivery systems for human hepatoblastoma cells.

/Investigators/ found that the labeled lauric acid moiety of Polysorbate 20 was rapidly absorbed and oxidized by rats. After 24 hours, some 75 percent of the lauric acid was oxidized and expired as CO2. 4 percent was not absorbed from the alimentary tract.

The polyoxyethylene sorbitan moiety left after hydrolysis of the ester is poorly absorbed from the rat's gastrointestinal tract. In one study with a radioactive carbon label in the polyoxyethylene portion of Polysorbate 20, 90 percent was excreted in the feces and 8 percent in the urine. No radioactivity was found in the liver, carcass, or expired C02.
After intravenous injection of Polysorbate 20 into rats, the distribution of the labeled lauric acid moiety was: expired CO2, 68 percent; carcass, 22 percent; urine, 5 percent; feces and gastrointestinal contents, 2.5 percent; and liver 0.7 percent. The distribution of the labeled polyoxyethylene moiety was: urine, 83 percent; feces, 11 percent; carcass, 2 percent; liver, 0.15 percent; and expired CO2 nil.

After intravenous injection into rats, the ester bond is hydrolyzed by blood lipases. When Polysorbate 20 was injected into rats, the labeled lauric acid moiety was metabolized and appeared mostly as expired CO2. The polyoxyethylene moiety was not catabolized, since no radioactivity was recovered as CO2 when this portion of the molecule was labeled. Most of the labeled polyoxyethylene appeared in the urine, but some was present in the feces, indicating biliary excretion.

The polysorbates find almost ubiquitous use in the food industry and have been approved by the FDA as direct and indirect food additives for human consumption with certain restrictions. ... Polysorbates 20, 60, and 80 are approved for direct use in all food types as synthetic flavorings (21 CFR 172.515). ... Polysorbates 20, 40, 60, and 80 are approved for indirect addition to all food types as components of adhesives (21 CFR 175.105). Polysorbates 20, 40, 60, 65, 80, and 85 are approved for indirect addition to all food types as emulsifiers and/or surfactants (21 CFR 178.340).

Since the fatty acids used in the production of cosmetic ingredients frequently contain fatty acids other than the principal acid named, each of the Polysorbates may contain a complex fatty acid moiety. In a study on Polysorbates 20, 40, 60, and 80, 15 different fatty acids were detected.
Aqueous solutions of Polysorbate 20 undergo autoxidation on storage at room temperature, with changes in the peroxide number, pH, surface tension, and cloud point. Autoxidation is accelerated by light, elevated temperature, and copper sulfate. Hydrolysis of Polysorbate 20 also occurs at room temperature, whereas the oxyethylene moieties undergo chain shortening at temperatures above 40 °C.

Polysorbate 20 is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and 2) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part.
Polysorbate 20 is an indirect food additive for use only as a component of adhesives.

The substances listed in paragraph (c) of this section may be safely used as emulsifiers and/or surface-active agents in the manufacture of articles or components of articles intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food, subject to the provisions of this section. Polysorbate 20 (polyoxyethylene (80) sorbitan monolaurate) meeting the following specifications: Saponification number 40-50, acid number 0-2, hydroxyl number 60-108, oxyethylene content 70-74 percent is included on this list.

The Polysorbate 20 are a series of general purpose, hydrophilic, nonionic surfactants supplied by the manufacturers at 100 percent concentration. Various terms used to describe their roles in cosmetics include oil/water emulsifier, detergent, dispersing agent, solubilizer, and stabilizer.

The Polysorbate 20 exhibit high hydrophile-lipophile balance (HLB) values, indicating they will function to disperse oil in water as opposed to water in oil. HLB values for most emulsifiers fall in the range of 1.8 to 18.6, with the Polysorbate 20 in the range 9.6 to 16.7. Because of their nonionic nature, the Polysorbate 20 are comparatively insensitive to hard water and electrolytes and may be used in both acidic and basic formulations.
The Polysorbate 20 find numerous uses in industry, research, pharmacy, and food production. They are used in the textile industry as antistatic agents, fiber lubricants, and finish emulsifiers. In biological research, they find uses in membrane protein extraction, virus deactivation, and growth culture preparation.

Polysorbate 20 containing 80 units of oxyethylene are hydrophilic nonionic surfactants that are used widely as emulsifying agents in the preparation of stable oil-in-water pharmaceutical emulsions. They may also be used as solubilizing agents for a variety of substances including essential oils and oil-soluble vitamins, and as wetting agents in the formation of oral and parenteral suspensions. They have been found useful in improving the oral bioavailablity of drug molecules that are substrates for P-glycoprotein. Polysorbate 20 are also widely used in cosmetics and food products.
Polysorbate 20 are prepared from sorbitol in a three-step process. Water is initially removed from the sorbitol to form a sorbitan (a cyclic sorbitol anhydride). The sorbitan is then partially esterified with a fatty acid, such as oleic or stearic acid, to yield a hexitan ester. Finally, ethylene oxide is chemically added in the presence of a catalyst to yield the polysorbate.

Nonionic surfactants are commonly used as excipients in pharmaceutical formulation, but recent studies demonstrate that the ingredients affect the pharmacokinetics of the active drugs. However, the mechanisms are largely unknown. Here, ... the effects of four common nonionic surfactants Polysorbate 20, polyoxyl 35 castor oil, polyoxyl 40 stearate and poloxamer 188, on cytochrome P450 3A /were examined/ in vitro and in vivo using midazolam as a probe. ... The effects of these surfactants on the 1'-hydroxylation of midazolam /were examined/ in isolated rat liver and intestinal microsomes. All the surfactants tested inhibited midazolam 1'-hydroxylation in a concentration-dependent manner and presented a mixed competitive inhibitory model with decreased V(max) and increased K(m) values in vitro. Among the tested nonionic surfactants, Polysorbate 20 was the most potent inhibitor of midazolam 1'-hydroxylation with an IC(50) of 2.06 and 0.39mg/mL in the liver and intestinal microsomes, respectively. These surfactants were also tested in vivo ... on the pharmacokinetics of midazolam in rats. These four surfactants displayed different inhibitory patterns in terms of the AUC of midazolam and 1'-hydroxymidazolam. Polysorbate 20 significantly increased both AUC(0-4 hr) and AUC(0-infinity) of midazolam and decreased the AUC(0-4 hr) of 1'-hydroxymidazolam to about 40% (p<0.05) in both single- and multiple-treated rats, along with a significant decrease of the metabolic ratio of 1'-hydroxymidazolam/midazolam to 25%. Polyoxyl 35 castor oil, polyoxyl 40 stearate and poloxamer 188 displayed complicated inhibition on the 1'-hydroxylation of midazolam dependent on the administration formula. These results confirmed that effects of these surfactants would have potential inhibitory effects on cytochrome P450 3A and altered midazolam bioavailability. Therefore, caution is needed when selecting nonionic surfactants in drug formulation.

Several product formulations containing the polysorbates have been tested for human skin sensitization on a total of 3481 subjects using a variety of testing methods. These studies included: four Schwartz-Peck prophetic patch tests on product formulations containing 0.3 to 2.4 percent Polysorbates 20, 60, or 80; four controlled-use tests on product formulations containing Polysorbate 85 at 1.0 percent or Polysorbates 60 and 80 at 2.5 percent each; 15 Draize-Shelanski repeated insult patch tests on product formulations containing 0.084 to 6.0 percent Polysorbates 20, 40, 60, or 80; and one Kligman maximization test on a product formulation containing 6.0 percent Polysorbate 20. Of the 3481 subjects reported, there were no reactions indicative of sensitization to any of the polysorbates.

The effect of Polysorbate 20 on corneal permeability to fluorescein was investigated in human subjects in an effort to find safe and effective agents that increase permeability to drugs. Subjects were normal volunteers of both sexes, aged 20 to 46 years. Single drops of Polysorbate 20 at various concentrations in saline were administered to one eye; the other eye served as a control. Polysorbate 20 caused no adverse effects on the eye at concentrations up to 40 percent.

Several product formulations containing Polysorbate 20, 40, 60, 80, or 85 at concentrations of 1.0 to 8.5 percent have also been tested in the Draize rabbit eye irritation test with scores indicative of minimal to mild irritation. A bubble bath formulation produced severe irritation when instilled into rabbit eyes as evidenced by damage to the conjuctiva, iris, and cornea. A subsequent test with the same formulation diluted to 0.5 percent in water showed minimal transient eye irritation.

The Magnusson-Kligman guinea pig maximization test was used to determine the sensitization potential of Polysorbate 20; five assays were completed on three different batches of the material. The procedure consisted of an induction phase of intradermal injection and topical application followed by a series of two or three topical challenges. Animals were injected intradermally with 0.1 mL of 50 percent complete Freund's adjuvant in saline, a 0.1 mL of an irritant concentration of Polysorbate 20 in paraffin oil (5.0 to 7.5 percent), and 0.1 mL of the test material in 50 percent complete Freund's adjuvant in saline. One week following the injections, undiluted Polysorbate 20 was applied topically under occlusion for 24 hours to a site pretreated with 10 percent sodium lauryl sulfate. After a 2-week rest period, undiluted Polysorbate 20 was again applied topically for 24 hours under occlusion. Second and, in one case, third challenge applications were made at 1 week intervals. Four of the five assays evoked responses at challenge indicative of moderate sensitization; one batch of Polysorbate 20 produced strong sensitization under the conditions of the test.

Polysorbate 20 produced no inflammation when applied to the cheek pouch mucosa of hamsters at an unspecified volume and concentration, and 10 percent aqueous Polysorbate 40 produced neither inflammation nor toxic effects when infused into the urinary bladder of guinea pigs.

Our daily lives see us exposed to toxins in many forms. We breathe them in thanks to polluted air, we unwittingly apply them to our skin, serve them up disguised in our foods, not to mention inhaling cigarette smoke, even as a by product of someone else’s life choices.

Our modern lifestyle is largely toxic, so much so that ‘detoxing’ is a term that we are used to seeing.
Unfortunately allergies and disease are also things we are used to seeing, and medical studies are beginning to make connections between some of these toxins and damage to our bodies.

But what of Polysorbate 20?
What is it?
This is a lesser known synthetic compound, also known as Tween 80.

It is an amber/golden-colored viscous liquid. It is made from polyethoxylated sorbitan (chemical compounds derived from the dehydration of sugar alcohol) and oleic acid, a fatty acid found in animal and vegetable fats.

What does it do?
Polysorbate 20 is used as an emulsifier or defoamer in foods, vitamins, medicines, and vaccines.

Why is it used in food?
It is used as a defoamer for the fermenting process of some wines, and also to bind some ice-creams and other ‘puddings’, to keep their creamy texture without separating. It is also used to bulk foods up and keep sauces smooth.

Why is it used in cosmetics?
It can also act as a surfactant in soaps and cosmetics, as well as a solubilizer – helping to dissolve ingredients so that they can more easily blend together. It is used as a solubilizer. It makes products look creamier and more attractive.

Polysorbate 20
Polysorbate 20
Why is it used in medicine?
It is used as an ingredient in some vaccines, as well as in some vitamins and supplements. Polysorbate 20 is used to improve the consistency of gel capsules and to make pills disperse in the stomach.

What products is it used in?
Polysorbate 20 is a versatile and useful ingredient, so it is present in quite a few products. Here is a short, generalized list of where it is most often found:
• Food shortening
• Chewing Gum
• Ice Cream
• Gelatin
• Vitamins
• Soap
• Shampoo
• Cosmetics
• Skin Creams
• Condiments
• Medicines
• Vaccines

Should we be worried?
Let’s see what the Material Safety Data Sheet for Polysorbate 20 has to say:
• Slightly flammable to flammable in presence of heat
• Slightly hazardous in case of skin contact (irritant), of eye contact (irritant), of ingestion, of inhalation.
• May cause adverse reproductive effects based on animal test data. No human data found.
• May cause cancer based on animal test data. No human data found.
• May affect genetic material (mutagenic)
However, it is also listed in the handbook of green chemicals.

Important
Not all Polysorbate 20 is created equal
Some cosmetic grade Polysorbate 20 may potentially contain ethylene oxide, 1,4-dioxane and mono- and diethylene glycol as impurities, although worryingly these carcinogenic contaminants have also been picked up in food additives.

The report on Skin Deep gives Polysorbate a moderate hazard, with a 3/10 rating, but the contaminants ethylene oxide and 1,4-dioxane have ratings as a high hazard (8/10 and 10/10).

Generally, the cosmetic grade Polysorbate 20 is more likely to contain these impurities. Some natural cosmetics manufacturers are very careful about the quality that they use, and stick to only the food grade Polysorbate 20.

What about scientific studies?
There are many published studies which analyze Polysorbate 20, but it is important to recognize their limitations before generalizations are made.
This study suggests a link between the ingredient and infertility in mice.
The relative weight of the uterus and ovaries was decreased relative to the untreated controls. ….. Ovaries were without corpora lutea, and had degenerative follicles.

It was seen to accelerate the maturation of female rats and resulted in deformities of the ovary. These effects were demonstrated in newborn mice which were injected with Polysorbate 20. It is certainly a concern when we consider that some vaccines may contain Polysorbate 20.
A separate study suggested that Polysorbate 20 could be a causative agent of a pregnant woman going into anaphylactic shock.
While this is also a worry, I would choose to be wary of this study as research was conducted on just one pregnant woman who had a severe allergic reaction to a multivitamin administered via IV. While doctors identified Polysorbate 20 as the cause, no other incidences of this type of reaction have been reported.

A recent study has shown a real connection between ingesting Polysorbate 20 and the development of bowel problems – it could be a real worry for those with a predisposition to Colitis.

So should we avoid Polysorbate 20?
The evidence suggests that this ingredient is potentially toxic, particularly the lower grade versions – which are typically used in cosmetics which list Polysorbate 20 in their ingredients lists.

It can be considered a concern to accept vaccines which contain the ingredient.
The choice is ultimately down to you, and while we are told that ingesting Polysorbate is not a high risk, there are certainly some worrying issues.
When reading labels, be aware that it can also go by Alkest, Canarcel and Tween.

Polysorbates, Biotherapeutics, and Anaphylaxis: A Review
Rapidly increasing use of monoclonal antibodies (MAbs) in the treatment of neoplastic, autoimmune, and inflammatory diseases has led to a dramatic increase in hypersensitivity reactions worldwide, complicating the use of MAbs as first-line therapies and limiting patient survival and quality of life (1). The origins of anaphylaxis are not well understood, though its mechanism is fairly straightforward (Figure 1). It is usually attributed to some undefined intrinsic property or properties of a biotherapeutic — despite the fact that biotherapeutic formulations are necessarily complex and include a host of functional excipients. Those help drug products meet the stringent challenges of shelf-life, stabilization, solubility, reconstitution following lyophilization, and the propensity of proteins to aggregate — especially at the high concentrations typically used to reduce MAb administration volume and time.

Approximately 70% of all MAb formulations contain either PS-20 or PS-80 (2). Polysorbate (PS) surfactants are one such family of excipients incorporated into many biotherapeutics to prevent protein aggregation and associated loss of efficacy. Although Polysorbate 20 are effective in that role, they contain ether linkages (within polyoxyethylene moieties) and unsaturated alkyl chains that spontaneously self-oxidize in aqueous solutions to form immunogenic and anaphylactogenic chemical species, including hydro- and alkyl-peroxides, epoxy acids, and reactive aldehydes such as formaldehyde and acetaldehyde. Polysorbate 20 also hydrolyze in aqueous solutions to release free fatty acids that can increase solution turbidity. Lot-to-lot variability exceeds an order of magnitude in the concentration of chemically reactive species such as peroxides (3).

Immunogenicity of biotherapeutics is a serious and growing concern for the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). It will continue to have a significant and growing influence on the development and regulatory approval of both biosimilar and new innovator biotherapeutics (4).

Anaphylaxis, on the other hand, is an allergic reaction that, although serious, is generally overlooked and accepted as an unavoidable property of biotherapeutic proteins themselves. Few or no attempts have been made to differentiate and segregate out its actual source in biologics. Although unwanted polysorbate-induced immunogenicity is well documented, little attention has been paid to polysorbate-induced anaphylaxis (5–14). Regulatory authorities understandably focus heavily on comparable efficacy in evaluating biosimilars. But similar efficacy does not imply necessarily a similar safety profile between innovator and biosimilar products. Both unwanted immunogenicity and anaphylaxis should comprise major components of safety assessment of biotherapeutics.

Anaphylaxis typically is rapid in onset and manifests over minutes to hours. In some cases, it can cause death (15, 16). The underlying mechanism is a release of mediators from certain types of white blood cells that can be triggered by either immunologic or nonimmunologic mechanisms (16). The most common causes include insect bites, food allergies, and medications.

In the latter category, the commonly used polysorbate excipients PS-80 and PS-20 are found in over 70% of MAb and other protein biotherapeutics, and now they have been shown to cause anaphylaxis in patients receiving those drugs. Anaphylaxis symptoms occur over minutes to hours, with an average onset in 5–30 minutes if exposure is intravenous, affecting the skin, respiratory system, gastrointestinal tract, heart and vasculature, and central nervous system (15). Symptoms include hives, itchiness, flushing or swelling (angioedema); lingual, laryngeal, and pharyngeal edema; runny nose, and conjunctival edema. Possible respiratory symptoms include shortness of breath, bronchial spasm, and upper airway obstruction secondary to swelling (17–19). Coronary artery spasm can be associated with a drop in blood pressure or shock, sometimes leading to subsequent myocardial infarction, dysrhythmia, or cardiac arrest. Treatments for anaphylaxis include positioning a patient flat and administering antihistamines, steroids, intravenous fluids, and intramuscular epinephrine (17, 20).

Among biotherapeutics, drug hypersensitivity and anaphylaxis have been reported for a number of MAbs — rituximab, ofatumumab, obinutuzumab, trastuzumab, cetuximab, tocilizumab, infliximab, etanercept, adalimumab, abciximab, golimumab, certolizumab, brentuximab, bevacizumab, and omalizumab — all of which are formulated with polysorbate surfactants (1, 5, 21).

Chemical Nature of Polysorbate 20: Polysorbate 20 play a positive role in biotherapeutic formulations. They prevent aggregation — important because aggregated proteins are immunogenic and can induce a patient’s immune system to generate neutralizing antibodies, thus reducing or eliminating the effectiveness of an administered drug. However, a number of shortcomings associated with Polysorbate 20 need to be urgently addressed, especially now as biotherapeutics are increasing their role in treatment of a growing number of cancers and other major life-threatening diseases.

Polysorbate 20 are complex esters of structurally diverse and (in some cases) chemically reactive species. PS-20 and PS-80 (Tween 20 and Tween 80) are mixtures of structurally related fatty-acid esters of polyoxyethylene sorbitan and lauric acid or oleic acid, respectively. In PS-20, the monolaurate fraction comprises 40–60% of the alkyl chains, with alkyl groups of different chain lengths making up the remainder of the molecules. In PS-80, about 60% of the alkyl chains are derived from oleic acid, with the remainder of the esters derived from other fatty acids (22). All commercially available Polysorbate 20 also contain measurable amounts of polyoxyethylene, sorbitan polyoxyethylene, and isosorbide polyoxyethylene fatty-acid esters (22–24).

Polysorbate 20 undergo intrinsic self-oxidation yielding reactive hydro- and alkyl-peroxides (25–30) as well as reactive aldehydes such as formaldehyde and acetaldehyde (31), which induce immunogenicity of soluble proteins.

Polysorbate-Induced Anaphylaxis
Increasingly the anaphylactogenic properties of PS-80 are well documented in clinical literature. Identifying the precise mechanistic cause of polysorbate-induced anaphylaxis is complicated by the complex chemical nature of polysorbate surfactants. Preclinical animal studies have identified a number of specific molecular species that induce anaphylaxis.

As early as 1985, Masini et al. demonstrated polysorbate-induced histamine release in peripheral tissues and isolated mast cells as well as hemodynamic responses (32). In 1997, Bergh et al. reported that air exposure to aqueous solutions of PS-80 produced formaldehyde and acetaldehyde in amounts that could elicit allergic reactions in some individuals (33). The latter authors prophetically warned drug developers to take into consideration the possibility that allergenic compounds are formed during manufacture, storage, and handling of products containing polysorbate and chemically similar surfactants.

Coors et al. conducted a thorough examination of PS-80 as an inducer of severe anaphylactoid reactions (34). Their extensive complement of well accepted and sensitive detection methodologies included skin-prick testing, enzyme-linked immunosorbent assays (ELISAs), immunoglobulin E (IgE) immunoblotting, and flow-cytometric detection of basophil activation in control patients and others with a medical history of anaphylactic shock due to intravenous administration of a multivitamin product during pregnancy (a surrogate for intravenously administered drugs). Neither the ELISAs nor the immunoblots identified any polysorbate-specific IgE antibodies, confirming the nonimmunologic nature of the anaphylactoid reaction. This study demonstrated that PS-80 can cause severe nonimmunologic anaphylactoid reactions.

Sun et al. evaluated the sensitization effect of PS-80 from different manufacturing lots in dogs, observing different degrees of anaphylactoid reaction (35). Similarly, in assessing 10 batches of PS-80 solutions from different suppliers, Yang et al. found that spontaneously formed PS-80 impurities such as peroxides and oxidized fatty acid residues (present at varying levels in each tested batch) induced anaphylactoid reactions in an in vivo zebrafish model (36).

Qiu et al. demonstrated that Polysorbate 20 induces typical nonimmune anaphylactic reactions (pseudoallergy) in dogs — characterized by the release of histamine and unvaried IgE antibodies (37). PS-80 induced histamine release with a twofold increase in SC5b-9, a 2.5-fold increase in C4d, and 1.3-fold increase in Bb while IgE remained unchanged. PS-80 caused cardiopulmonary distress in dogs and activated their complement systems through classical and alternative pathways, as indicated for both in vivo and in vitro preparations.

With the growing importance and routine use of a growing number of biotherapeutics, clinical reports of polysorbate-induced anaphylaxis are increasing as well. For example, reactions occurred after administration in two patients receiving omalizumab (38). Intradermal testing produced significant wheal and flare reactions (hives and angioedema) to PS-20 that did not appear in negative control subjects. In vitro and in vivo immunologic data support the conclusion that adverse reactions experienced by the two patients after more than a year of successful omalizumab therapy were likely anaphylactoid in nature. The authors of an earlier report of unexplained omalizumab anaphylaxis had not considered the possible association with PS-20 (39).

Patients receiving the red-cell growth hormones darbepoietin and erythropoietin also have developed hypersensitivity reactions (40). Based on subsequent skin testing and observed clinical symptoms, investigators concluded that the cause of those reactions was the excipient PS-80. The authors also believe that might have contributed to a related incidence of pure red-cell aplasia.

In a study comparing etoposide formulations with and without PS-80 using the same premedication protocol, one patient exhibited a hypersensitivity reaction to the PS-80 containing formulation but none with the etoposide formulation not containing it (41). The authors concluded that the hypersensitivity reaction probably was due to PS-80 rather than etoposide itself.

Badiu et al. reported multiple cases of PS-80–induced anaphylaxis arising from administration of a number of vaccines (42). A 17-year-old girl experienced generalized urticaria, eyelid angioedema, rhinoconjunctivitis, dyspnea, and wheezing an hour after her third intramuscular administration of Gardasil quadrivalent human papilloma virus vaccine (Merck), which contains PS-80. Intradermal tests were positive with that product, whereas skin tests with the bivalent vaccine (not containing PS-80) were negative. Prick tests of PS-80 were positive in the patient and negative in 10 healthy controls. The CD203 basophil-activation test result was negative for PS-80 at all the tested dilutions, and no specific IgE was found. The authors also skin-tested two influenza vaccines: one containing PS-80 (Fluarix from GlaxoSmithKline), which resulted in a positive reaction, and another flu vaccine with no adjuvant or preservative (Vaxigrip from Sanofi Pasteur MSD), which gave negative results.

Limaye  et al. reported a case of an allergic reaction to erythropoietin in which a patient developed generalized pruritis, erythema, and orofacial angioedema (43). The Eprex erythropoietin formulation (Johnson & Johnson) contained recombinant human erythropoietin and PS-80 as an excipient (0.15 mg/mL). Skin-prick and sequential intradermal testing with increasing concentrations of that and Amgen’s Neupogen filgrastim (containing polysorbate at 0.04 mg/mL) gave positive reactions, whereas a polysorbate-free erythropoietin preparation yielded negative test results. Intradermal testing with pharmaceutical-grade polysorbate resulted in a positive local reaction followed by mild orofacial angioedema an hour later. No reaction was observed in a control subject (43). Purcell et al. also identified Polysorbate 20 as the likely cause of an immune response to erythropoietin when human albumin was replaced by Polysorbate 20 and glycine (44).

Drug hypersensitivity and anaphylaxis has been reported for Factor VIII, darbopoietin, erythropoietin, and a number of MAbs, all of which contain a polysorbate surfactant (1, 5, 21, 43). Urticariform lesions have been described in patients undergoing treatment with infliximab, adalimumab, etanercept, and ustekinumab — four MAb drugs containing Polysorbate 20 (45–47). In addition, polysorbate-induced anaphylactic responses have been reported in nonbiologic drug classes containing polysorbate: vitamin A (48), certain steroids (49–51), and the antiviral drug acyclovir (52).

Separating MAb-Induced from PS-Induced Anaphylaxis
Although it is clear that Polysorbate 20 can and do induce anaphylactic responses, it seems that no current clinical trials attempt to differentiate anaphylaxis induced by Polysorbate 20 from that induced by drug substances. To do so, separate vehicle studies would have to be conducted. Anaphylaxis occurs in just a small fraction of patients, all of whom have had different exposure histories to Polysorbate 20 from earlier treatments. So selecting multiple control cohorts (those with no previous polysorbate exposure and those with previous exposure over different timeframes) is prohibitively expensive and would add further costs to the already expensive process of clinical testing and regulatory approval. Substituting alternative nonionic surfactants such as alkylsaccharides in biosimilars, then comparing anaphylaxis rates in clinical trials might begin to answer this question (3, 4).

Preventing the Problem
Clinical and commercial incentives to replace Polysorbate 20 are clear. For innovator biotherapeutics, minimizing anaphylaxis would offer significant clinical and safety benefits to patients — possibly reducing the time and cost of pretreatment with antihistamines and steroids. With more than 900 biosimilars and more than 600 biobetters currently in development (53), concerns about the high development costs have led some industry experts to conclude that the price of biosimilars may be only 20% lower than that of corresponding innovator products.

That raises a barrier for physicians to justify switching patients away from well-characterized innovator products to newly introduced biosimilars without some clear and substantial clinical benefit on offer. Replacing Polysorbate 20 with surfactants that minimize anaphylaxis episodes without allowing progressive protein degradation or increased immunogenicity would meet a critical need while providing a substantial differentiating clinical benefit for all concerned: patients, physicians, and third-party payers.