Tocopheryl Polyethylene Glycol 1000 Succinate TPGS

Another lipid-based excipient useful for preparing solid dispersion formulations is d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS; Vitamin E TPGS, Eastman Chemical, Tennessee, U.S.A.). This excipient, which is listed in the United States Pharmacopoeia, is a water-soluble, surface-active, and self-emulsifying derivative of vitamin E that is capable of solubilizing many poorly water-soluble drugs. Because of its relatively low melting point (~40°C), molten TPGS formulations are suitable for filling into both soft and hard gelatin capsules; however, hard gelatin capsules require band-sealing in order to prevent leakage of the contents. Koo et al. (48) compared the bioavailability of solid dispersions of the antimalarial drug, halofantrine, formulated in PEG600, TPGS, Gelucire 44/14, or a 1:1 mixture of TPGS and Gelucire 44/14. The drug was dissolved in a molten excipient at 70°C to 80°C, and the solution was either poured into precooled suppository molds or filled directly into hard gelatin capsules and allowed to solidify. Each dosage unit contained 100 mg of halofantrine and 600 mg of an excipient. When administered to fasted beagle dogs, the solid dispersion formulations produced a uniform, five- to seven-fold improvement in halofantrine bioavailability relative to the commercial tablet formulation. In vitro dissolution studies in aqueous media revealed that both TPGS and Gelucire 44/14 formulations dispersed the drug in the solubilized state, whereas the PEG600 formulation dispersed the drug in the solid state. However, in this instance, no significant difference in oral bioavailability was observed among these three formulations, leading the investigators to conclude that optimal halofantrine bioavail-ability could be achieved either by full solubilization in the formulation or by particle size reduction.

In another study conducted in rats, the bioavailability of paclitaxel was improved four- to six-fold by coadministration with TPGS due to its effect on the solubility and permeability of the drug (49). Other investigators have studied the role of TPGS in enhancing the absorption of drugs, which are both poorly soluble and poorly permeable (50,51). Sokol et al. (52) reported enhanced absorption of cyclosporine from vitamin E TPGS formulations administered to pediatric patients, as compared to formulations without vitamin E TPGS. Formulations including TPGS allowed a 40% to 72% reduction in the cyclosporine dosage required to maintain therapeutic plasma drug concentrations. Similarly, Chang et al. (53) reported a significant increase in cyclosporine bioavailabilty in healthy volunteers when administered with TPGS. In both of these instances, the authors suggested not only drug solubilization, but also inhibition of the intestinal P-glycoprotein transporter as a contributing factor to the enhanced cyclosporine bioavailability.

TPGS is the primary excipient used in the soft gelatin capsule formulation of aprenavir (Agenerase®, GSK, North Carolina, U.S.A.), which was also shown to improve the drug bioavailability through a combination of increased solubility and permeability enhancement due to excipient-mediated P-glycoprotein efflux inhibition (54).

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