Polysorbates toxicity

Pesce AJ, McKean DL. Toxic susceptibilities in the newborn with special consideration of polysorbate toxicity. Ann Clin Lab Sci 1989 19(l) 70-3. 

Surfactants. The use of surfactants is greatly restricted in formulating ophthalmic solutions. The order of surfactant toxicity is anionic > cationic >> nonionic. Several nonionic surfactants are used in relatively low concentrations to aid in dispersing steroids in suspensions and to achieve or to improve solution clarity. Those principally used are the sorbitan ether esters of oleic acid (Polysorbate or Tween 20 and 80), polymers of oxyethylated octyl phenol (Tyloxapol), and polyoxyl 40 stearate. The lowest concentration possible is used to perform the desired function. Their effect on preservative efficacy and their possible binding by macromolecules must be taken into account, as well as their effect on ocular irritation. The use of surfactants as cosolvents for an ophthalmic solution of chloramphenicol has been described [271]. This com-... 

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

Indeed, the selection of raw materials from the pharmaceutical perspective is severely restricted by toxicity concerns, and Attwood and Florence (1998) suggested that only a few nonionic surfactants such as polysorbates 80 and 20 may be suitable for oral administration, with the possibility of some phospholipids serving the same function. Since that time a small number of other nonionic surfactants (e.g., cremo-phores) have been evaluated. 

Olivier, J.C., et al. 1999. Indirect evidence that drug brain targeting using polysorbate 80-coated polybutylcyanoacrylate nanoparticles is related to toxicity. Pharm Res 16 1836. 

Lecithin-based o/w MEs for parenteral use were formulated using polysorbate 80, IPM (Isopropyl myristate), lecithin, and water at different lecithin-polysorbate 80 weight ratios [115]. The formulated systems were shown to be highly stable and of minimal toxicity when evaluated in vitro. Phospholipid-based ME formulations of all-trans retinoic acid (ATRA) for parenteral administration were prepared and tested in vitro [116]. ATRA is effective against acute promyelocytic leukemia with highly variable oral bioavailability. Parenteral ME of ATRA was prepared using pharmaceutically acceptable ingredients, namely phospholipids and soybean oil. The inhibitory effect of ATRA on two human cancer cell lines (HL-60 and MCF-7) was not affected by incorporation into a ME formulation. 

Polysorbate 20 moderate toxicity by IP and IV routes. Moderately toxic by ingestion. Human skin irritant. 

LD50 (mouse, IV) 1.42 g/kg LD50 (rat, oral) 37g/kg Polysorbate 21 moderately toxic by IV route. 

Polysorbate 60 LD50 (rat, IV) 1.22 g/kg. Moderately toxic by IV route. Experimental tumorigen reproductive effects. 

Polysorbate 80 moderately toxic by IV route. Mildly toxic by ingestion. Eye irritation. Experimental tumorigen, reproductive effects. Mutogenic data. 

Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics 1986 77 593—597. 

Surfactants may be included in an ophthalmic suspension to disperse the drug effectively during manufacture and in the product during use. Non-ionic surfactants are generally preferred because they tend to be less toxic. The level of surfactant included in the formulation should be carefully evaluated, as excessive amounts can lead to irritation in the eye, foaming during manufacture and upon shaking the product, or interactions with other excipients. The most likely interaction is with the preservative. For example, polysorbate 80 interacts with chlorobutanol, benzyl alcohol, parabens and phenyl ethanol and may result in a reduced preservative effectiveness in the product. 

Typical excipients used in parenteral suspensions include surfactants that are used to stabilise emulsions and suspensions as wetting agents (polysorbate 80, poloxamer), as micelle makers for the preparation of solubilisations and to influence the flocculation and deflocculation behaviour of a dispersed system (carmellose sodium, polyvidone). Paren-terally used surfactants in high concentrations are toxic and may cause venous irritation and occasional thrombophlebitis. However, these high concentrations are not necessary to formulate stable parenteral suspensions. 

Particularly by preparation of SLN from warm microemulsions, emulsifiers are used in high excess and are normally removed by an adequate purification process. Heydenreich et al. investigated different purification processes (ultrafiltration, ultracentrifugation, and dialysis) and studied the cytotoxicity of the purified cationic SLN dispersions beside particle size and zeta potential. The removal of excess polysorbate decreased the toxicity about 10-fold and dialysis was found to be the preferred method to remove the excess of polysorbate whereas particularly ultrafiltration was not as efficient. 

The hypothesis that the two excipients, benzyl alcohol and polysorbate 80, precipitated cardiogenic shock seems plausible, particularly because the plasma concentrations of amiodarone and desethylamiodarone never reached toxic concentrations. 

Theories of anaesthesia which depend on the assumption that the anaesthetic enters lipid membranes [108] may explain why the non-ionic C12E9 is a useful endo-anaesthetic. Polyoxyethylene ethers have, according to Bucher [109], a selective affinity for the myelin surrounding the afferent pathways of stretch and tactile receptors. In concentrations sufficient to cause disperse bacterial growth, polysorbate 80 and Triton A20 are completely innocuous to virulent tubercle bacilli however, the latter detergent has a marked toxic effect on avirulent strains... 

It might be that this difference between Triton X-100 and polysorbate 80 may be the reason why the former is more toxic than polysorbate. Sulphate conjugation of non-ionic detergents yields anionic derivatives which are probably intrinsically more toxic. Different tissues produce different sulphate products [152] in the liver (in vitro) the products of Triton X-100 sulphation have 5 to 11 oxyethylene units while in the adrenal cortex the products have a shorter chain length, of 2 to 5 ethylene oxide units. 

The high incidence of sarcomas induced by polysorbate 80, Sodium Patent Blue V and by Sodium Blue VRS is in accord with observations made on the relation between surface activity and the incidence of local sarcomas in long-term injection tests [179,180]. Surface-active food colourings and other additives had been found to produce sarcomas when administered over long periods in concentrated solutions, when the surface tension was below the critical lytic index below which surfactants produce irreversible damage to cells. The physicochemical nature of the toxic action of such surfactants is illustrated by experiments with Sodium Patent Blue V [181] (Fig. 10.22). At 2 % and 3 % levels there was a high incidence of sarcoma induction but at 1 % levels no sarcomas were produced. At 1 % levels the surface tension lowering produces no cell... 

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