Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

Polysorbates (PSs) are synthetic nonionic surfactants consisting of polyethoxy sorbitan fatty acid esters. PSs have been widely employed as emulsifiers and stabilizers in various drug formulations and food additives. Recently, various PS-based formulations have been developed for safe and efficient drug delivery. This review introduces the general features of PSs and PS-based drug carriers, summarizes recent progress in the development of PS-based drug formulations, and discusses the physicochemical properties, biological safety, P-glycoprotein inhibitory properties, and therapeutic applications of PS-based drug formulations. Additionally, recent advances in brain-targeted drug delivery using PS-based drug formulations have been highlighted. This review will help researchers understand the potential of PSs as effective drug formulation agents.

Effect of Temperature on the Critical Micelle Concentration and Micellization Thermodynamic of Nonionic Surfactants: Polyoxyethylene Sorbitan Fatty Acid Esters

In this study, non-ionic surfactants, polyoxyethylene sorbitan fatty acid esters (polysorbate) are chosen to examine the temperature effect on the CMC over a wide temperature range. The enthalpy and entropy of micelle formation are evaluated according to the phase separation model. The surface tension of solutions was determined by means of Du Nöuys ring. The CMC values were taken from the sharp breaks in the surface tension vs. logarithms of surfactant concentration plots. As the surfactants' chain length increases the CMC at a constant temperature decreases, which is directly related to the decrease of hydrophilicity of the molecules. For each surfactant, as the system temperature increases, the CMC initially decreases and then increases, owing to the smaller probability of hydrogen bond formation at higher temperatures. The onset of micellization tends to occur at higher concentrations as the temperature increases. To evaluate the enthalpy of micellization, the CMCs are first correlated by a polynomial equation. It is found that ∆Gºmdecreases monotonically as the temperature increases over the whole temperature range. Both ∆Hºmand ∆Sºmappear to be decrease monotonically with an increase in temperature. The compensation temperature was found to be 42 ºC by linear regression over the whole temperature range and for all three surfactant systems together.

Final Report on the Safety Assessment of Sorbitan Caprylate, Sorbitan Cocoate, Sorbitan Diisostearate, Sorbitan Dioleate, Sorbitan Distearate, Sorbitan Isostearate, Sorbitan Olivate, Sorbitan Sesquiisostearate, Sorbitan Sesquistearate, and Sorbitan Triisostearate

Sorbitan fatty acid esters are mono-, di-, and triesters of fatty acids and sorbitol-derived hexitol anhydrides. They function as surfactants in cosmetic formulations. Previously, the Cosmetic Ingredient Review (CIR) Expert Panel had reviewed the safety of several of these sorbitan fatty acid esters (Sorbitan Laurate, Sorbitan Oleate, Sorbitan Palmitate, Sorbitan Sesquioleate, Sorbitan Stearate, Sorbitan Trioleate, and Sorbitan Tristearate). This safety assessment is an addendum to that report that includes Sorbitan Caprylate, Sorbitan Cocoate, Sorbitan Diisostearate, Sorbitan Dioleate, Sorbitan Distearate, Sorbitan Isostearate, Sorbitan Olivate, Sorbitan Sesquiisostearate, Sorbitan Sesquistearate, and Sorbitan Triisostearate. Although concentrations of these ingredients up to 25% have been reported to be used, most commonly they are used at less than 10%. These esters may be hydrolyzed to the fatty acid and anhydrides of Sorbitol. Fatty Acids are absorbed and metabolized. Sorbitan fatty acid esters were relatively nontoxic via ingestion in acute and long-term studies. They were generally minimal to mild skin irritants in animal studies, except that Sorbitan Isostearate applied to the skin was a moderate irritant in one rabbit study and when injected intradermally caused mild to severe irritation in guinea pigs. Sorbitan fatty acid esters did not sensitize guinea pigs. The fatty acid component, tested alone, typically caused only slight irritation and sensitization, and was not photosensitizing. Sorbitan fatty acid esters were not ocular irritants. Fatty acids are normal components of diet for which no data were available concerning reproductive or developmental toxicity, but Sorbitol had no adverse effects on the reproduction of CD rats during a multigeneration feeding study and was not a reproductive toxin at doses of 3000 to 7000 mg/kg/day for 2 years. Overall these esters and their corresponding fatty acids were not mutagenic, but Sorbitan Oleate was reported to reduce DNA repair following ultraviolet radiation exposure in human lymphocytes in culture. Sorbitan Laurate and Sorbitan Trioleate were cocarcinogens in one mouse study, but Sorbitan Trioleate and Sorbitan Oleate were not tumor promoters in another study. In clinical tests, Sorbitan fatty acid esters were generally minimal to mild skin irritants and were nonsensitizing, but Sorbitan Sesquioleate did produce an allergic reaction in fewer than 1% of patients with suspected contact dermatitis and addition of Sorbitan Sesquioleate to the components of a fragrance mix used in patch testing increased both irritant and allergic reactions to the fragrance mix. Careful consideration was made of the data on the cocarcinogenesis of Sorbitan Laurate and Sorbitan Trioleate, but the high exposure levels, high frequency of exposure, and absence of a dose-response led to the conclusion that there was not a cocarcinogenesis risk with the use of these ingredients in cosmetic formulations. Accordingly, these ingredients were considered safe for use in cosmetic formulations under the present practices of use.

Improved Gas Chromatographic Determination of Sorbitan Fatty Acid Esters in Confectionery Products

A method is described for gas chromatographic (GC) determination of sorbitan fatty acid esters in confectionery products as sorbitan monostearate. A sample is homogenized with chloroform, filtered, dried, and saponified with 0.1N NaOH in ethanol 1 h at 80°C. The saponification mixture is acidified, washed with hexane, and dried. Isosorbide, 1,4-sorbitan, and D-sorbitol are each derivatized at 70°C with pyridine, hexamethyldisilazane, and trimethylchlorosilane. GC separation of the polyols as TMS (trimethylsilyl) derivatives was performed on a 2% Dexsil 300 column temperature-programmed from 120 to 250°C at 107 min. The sorbitan monostearate content of the sample was calculated from the polyols, using the appropriate conversion factor. The procedure was applied to ice creams, cakes, and other confectionery products. Average recoveries from samples spiked with 1.0% Span 60 (sorbitan monostearate) were 91-96% for isosorbide, 83-99% for 1,4-sorbitan, and 82-98% for D-sorbitol. The detection limit was approximately 0.01%.