Effect Of Dispersion On Bioavailability

Compared to simple oil solutions of the drug, only modest improvements in drug bioavailability were generally observed from self-emulsifying formulations (Table 1). However, it is important to note that these studies were conducted in different species, with different formulations and with different lipid and surfactant doses, which sometimes differed within an individual study. It should also be noted that only healthy test subjects, with fully functioning GI lipid handling pathways, were studied. As noted earlier in this chapter, self-emulsifying formulations appear to provide better absorption enhancement, when the normal physiological processes enabling lipid digestion and dispersion are compromised (15).

Julianto et al. (41) reported a two-fold increase in vitamin E bioavailability, when dosed to humans as a SMEDDS as compared to a marketed lipid solution formulation (Natopherol®). However, since a greater amount of lipid was dosed in the SMEDDS than in the Natopherol formulation, it is not possible to determine if the superior bioavailability provided by the SMEDDS formulation was a result of better dispersion or a greater amount of administered lipid, relative to the Natopherol formulation.

Hauss et al. (42) compared the bioavailability of the poorly soluble leokotriene B4 (LTB4) biosynthesis inhibitor, ontazolast, when administered to rats as four lipid-based formulations [soybean oil emulsion, two SEDDS, and a Peceol (Gattefosse, S.A.)] solution or a reference aqueous suspension formulation. The soybean oil emulsion and the SEDDS formulations all significantly increased ontazolast bioavailability to a similar degree relative to the suspension formulation. While the SEDDS formulations did not provide greater drug exposure than the crude soybean oil emulsion or Peceol solution, significant differences were noted in the absorption profiles, with the SEDDS providing more rapid and less variable absorption.

Studies conducted by Porter et al. (43) demonstrated a significant increase in the bioavailability of danazol, administered as either a LCT solution or a LC-SMEDDS formulation, relative to either a conventional solid dosage form or a MC-SEDDS formulation. The presence of a high concentration of surfactant in the SMEDDS containing long chain triglycerides (LC-SMEDDS) formulation did not improve danazol absorption over that seen from the simple LCT solution, which supported the findings of Grove et al. (31) who demonstrated similar bioavailability of seocalcitol, when administered to rats as simple MCT or LCT solutions or following addition of high concentrations of surfactant to yield MC-SMEDDS or LC-SMEDDS formulations, respectively. It should be noted that the

SMEDDS formulations of danazol described by Porter et al. (43) were not controlled for the ratio amounts of oil, surfactant, or cosurfactant, which makes it difficult to accurately assess the impact of dispersion on drug absorption.

Grove, et al. (31) reported similar bioavailability for seocalcitol, when administered to rats as either a solution in MCT oil or as a MCT-containing SMEDDS (MC-SMEDDS). In this study, similar volumes of the lipid were dosed in each formulation, which provided unequivocal evidence that the presumed, superior dispersion or resistance to precipitation provided by the MC-SMEDDS formulation was not contributing to seocalcitol absorption above and beyond that, which was due to solubilization in the lipid vehicle. However, when the study was repeated in minipigs, a tendency towards higher bioavailability was seen for the MC-SMEDDS formulation relative to the MCT oil solution formulation (44).

In the study by Porter et al. (43), danazol was administered to dogs as either a solution in LCT oil or as a LCT-containing SMEDDS (LC-SMEDDS). While greater bioavailability was seen with the LCT solution, a total of 3 g of LCT oil was administered in each dose as compared to the 1.8 g of LCT oil administered in the LC-SMEDDS formulation. Again, since the administered lipid volume was not controlled, it is not possible to assess the contribution of the presumed, superior dispersion or resistance to precipitation provided by the SMEDDS formulation on the absorption of danazol.

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