Info

Mean AUC/dose [(^g-hr/mL)/(mg/kg)]

2.7 ± 0.4

6.8 ± 4.0

Mean Cmax ± SD (^g/mL)

14.1 ± 4

33.9 ± 19

Absolute oral F% ± SD

21 ± 3

53 ± 31

Note: The two pre-dispersed emulsions differing in droplet size were obtained from the same lot of the SEDDS formulation wherein a portion of the lot was processed with the microfluidizer. Abbreviations: GDO, glycerol di-oleate; GMO, glycerol mono-oleate; PG, propylene glycol; SEDDS, self-emulsifying drug delivery systems.

Note: The two pre-dispersed emulsions differing in droplet size were obtained from the same lot of the SEDDS formulation wherein a portion of the lot was processed with the microfluidizer. Abbreviations: GDO, glycerol di-oleate; GMO, glycerol mono-oleate; PG, propylene glycol; SEDDS, self-emulsifying drug delivery systems.

diluted 50-fold with water and subjected to mild agitation. This was achieved by placing 1 g of the SEDDS formulation in 50 mL of water in a 100 mL cylindrical bottle and then gently rocking the container manually back and forth (~90°) about two times per second for a period of about 1 minute.

Dilution of the initial 300mg/g Drug X SEDDS formulation followed by agitation as described above, resulted in spontaneous generation of an emulsion with a mean droplet size of ~1000nm. Reduction of the droplet size was achieved by processing the formulation with a microfluidizer (Microfluidics, MFIC Corporation, Newton, Massachusetts, U.S.A.). A portion of the emulsion was passed through the microfluidizer twice with a setting of 3500 psi which reduced the mean droplet size of the emulsion to ~221 nm. The bioavailability of Drug X was determined in fasted rats administered either with the initial emulsion (droplet size of ~1000nm) or the microfluidizer-processed emulsion (~221 nm).

A summary of the pharmacokinetic parameters of this study is shown in Table 4. The Drug X bioavailability was 21% ± 3% for the crude emulsion and 53 ± 31% for the microfluidizer processed emulsion, which represents ~2.5-fold enhancement attributable to droplet size reduction.

Although variable, the data suggest an inverse correlation between Drug X bioavailability and the lipid droplet size of the emulsion formulations.

Development of a SEDDS formulation that could solubilize 300 mg of Drug X per gram of formulation and spontaneously microemulsify upon dilution was initially challenging because the high drug loading in the excipient matrix resulted in a poorly dispersed emulsion.

In another study, pharmaceutically acceptable amine, diethanolamine (DEA), was added to the SEDDS formulations, and this significantly reduced the lipid droplet size upon dilution with water. The molar ratio between Drug X and DEA investigated during formulation development ranged from 8:1 to 1:1 (0.25-5% total DEA content, respectively).

As shown in Figure 4, the population of the large droplets (> 1 ^m) upon approximate, 50-fold dilution in SGF was inversely correlated with the amount of DEA in the formulation. In the absence of DEA, a SEDDS formulation containing 300mg/g Drug X was very poorly dispersed, with greater than 90% of the droplets possessing a droplet size >1 ^m.

Addition of 0.8% (w/w) or greater amounts of DEA reduced the fraction of large droplets (> 1 ^m) to a negligible level. The effect of DEA on the dispersibility of the Drug X SEDDS formulations is rationalized as follows. Drug X is partially neutralized by DEA which, upon dilution of the SEDDS with water, results in a negative surface charge on the dispersed oil droplets, and reduced coalescence as a consequence of electrostatic repulsion.

As shown in Figure 5, the mean droplet size of the emulsions generated from the 300mg/g Drug X SEDDS formulations upon mixing with water showed a rapid reduction in droplet size as the percentage of DEA increased. The mean droplet size was significantly reduced from ~1000 nm when the amine was absent to ~150nm with the use of ~0.8% amine. In conclusion, the presence of a small

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