Percent Polysorbate 80 ww

Figure 8 Phase behavior of PEG 8000 and polysorbate 80 mixtures. Mixtures of PEG 8000 containing up to 90% of polysorbate 80 remain in the solid state at room temperature. Abbreviation: PEG, polyethylene glycol. Source: From Ref. 41.

Joshi et al.(42) prepared solid dispersions of a poorly water-soluble and weakly basic drug (pKa~ 5.5) in neat Gelucire 44/14 and in a 1:3-mixture of polysorbate 80 and PEG3350. The highest drug solubility (100 ^g/mL) was observed at pH 1.5; the solubility dropped to <1 ^g/mL between pH 3.5 and 5.5, and the drug was practically insoluble (<0.02 ^g/mL) at pH > 5.5. The solid dispersion formulations were prepared by dissolving the drug in the molten excipients at 65°C, which was filled into size 0 hard gelatin capsules and allowed to congeal, with each capsule containing either 25 mg or 50 mg of the drug in a total fill weight of 600 mg. The dissolution profiles of the two formulations were similar and, based on dissolution rate and other formulation physicochemical considerations, such as the higher melting point of the PEG-polysorbate mixture compared to Gelucire 44/14, the solid dispersion containing the mixture of polysorbate 80 and PEG3350 was selected for in vivo evaluation. The absolute bioavailability of the drug in dogs from the PEG-polysorbate 80 solid dispersion was 21-fold higher than that of a capsule containing micronized bulk drug blended with lactose and microcrystalline cellulose. It was hypothesized that polysorbate 80 ensured complete release of drug from the solid dispersion in a finely divided metastable amorphous (oily) state, which led to an increase in the drug dissolution rate.

Using in silico modeling with GastroPlus software, Dannenfelser et al. (16) predicted that the bioavailability of a highly permeable, poorly water-soluble (aqueous solubility ~0.17 ^g/mL at 25°C), neutral compound would be dependent on its apparent solubility in the GI fluids and on the drug particle size. Three different formulations of the drug were prepared: (i) a solution in a solvent-surfactant mixture, (ii) a solid dispersion in a 1:3-mixture of polysorbate 80 and PEG3350, and (iii) a dry blend of micronized drug with microcrystalline cellulose filled in hard gelatin capsules. The solid dispersion was prepared by dissolving the drug in the melted

PEG3350 at 65°C ± 5°C and filling (as the molten mixture) into hard gelatin capsules; the formulation congealed at room temperature, forming solid plugs in the capsules. The extents of absorption of the solid dispersion and the micronized drug, relative to the solution formulation, were 99% and 10%, respectively; absolute bioavailability could not be determined since a parenteral reference formulation was not available. Once again, this study demonstrated the utility of surfactant-containing solid dispersion formulation for enhancing the bioavailability of a poorly soluble drug and, in this instance, the solid dispersion formulation was selected for testing in Phase I clinical studies.

Other investigators have also reported enhanced dissolution (43) and bioavailability (44) of drugs from PEG-polysorbate mixtures. PEG solid dispersions containing varying amounts of the ionic and nonionic surfactants, sodium dodecyl sulfate (SDS), and polysorbate 80, respectively, were described by Sjokvist et al. (45). In this instance, instead of directly filling the molten formulations into hard gelatin capsules, the congealed formulation was first pulverized and then filled into capsules as the waxy, solid material. In another study, Owuso-Ababio et al. (46) prepared solid dispersions of mefenamic acid in neat PEG3350 or in a mixture of PEG3350 and polysorbate 20. Relative to the neat PEG solid dispersion, an increase in the dissolution rate of mefenamic acid was seen, when polysorbate 20 was incorporated.

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