Polysorbate parenteral preparations

Surfactants such as polysorbates may be used as solubilising agents. Polysorbate 80 has been associated with the E-Ferol syndrome (thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis) in low-birthweight infants when used as a solubiliser aid in parenteral preparations. 

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. 

Polysorbates 60, 65, and 80 are GRAS listed. Polysorbates 20, 40, 60, 65, and 80 are accepted as food additives in Europe. Polysorbates 20, 40, 60, and 80 are included in the FDA Inactive Ingredients Guide (IM, IV, oral, rectal, topical, and vaginal preparations). Polysorbates are included in parenteral and nonparenteral medicines licensed in the UK. Polysorbates 20, 21, 40, 60, 61, 65, 80, 81, 85, and 120 are included in the Canadian List of Acceptable Non-medicinal Ingredients. 

Polysorbates are widely used in cosmetics, food products, and oral, parenteral, and topical pharmaceutical formulations and are generally regarded as nontoxic and nonirritant materials. There have, however, been occasional reports of hypersensitivity to polysorbates following their topical and intramuscular use. Polysorbates have also been associated with serious adverse effects, including some deaths, in low-birthweight infants intravenously administered a vitamin E preparation containing a mixture of polysorbates 20 and 80. When heated to decomposition, the polysorbates emit acrid smoke and irritating fumes. 

The use of surfactants in parenteral products is limited by their potent side-effects. All surfactants, especially those that are ionic may cause hemolysis. Anaphylactoid reactions have been noted, particularly in association with the destruction of lymphocytes, resulting in histamine release. Phospholipids are generally well-tolerated, and are frequently used in the preparation of emulsions. Nonionic surfactants such as Cremophor EL and polysorbate 80 (Tween 80) are known to cause hypersensitivity reactions (Eschalier et al., 1988 Mounier et al., 1995 Theis et al., 1995 Munoz et al., 1998 Volcheck and Van Dellen, 1998), including hypotension, largely via histamine release mechanisms. Because of potential side-effects, it is now traditional to pretreat the patient with an antihistamine and possibly a corticosteroid (e.g., prednisone) before administration of formulations that contain Cremophor EL. 

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. 

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