This study focused on identifying a precipitation inhibitor that could inhibit or reduce drug precipitation from Labrasol
formulations. Pluronic F127 was a potent agent for inhibiting precipitation of the tested compounds out of Labrasol formulations.
Combinations of Pluronic F127 with Labrasol inhibited drug precipitation to a greater extent than Pluronic F127 did alone.
This synergistic inhibitory effect was demonstrated with two poorly water-soluble compounds. In place of the complicated,
multiple-component emulsion systems reported in the literature, Pluronic F127 can be added as the precipitation inhibitor
and mixed with Labrasol. The Pluronic F127–Labrasol formulation is simple, easy to process and manufacture, and has advantages
for scale-up and cost because it uses existing formulation processes and commercially available facilities. Adding Pluronic
F127 into Labrasol formulations can improve them by inhibiting drug precipitation upon dilution.
Pyrene was used to explore the underlying mechanism for inhibiting drug precipitation by Pluronic F127 in Labrasol formulations
in this study. Pyrene has been widely used to probe the microenvironment of particles, such as micelles, microparticles, nanoparticles,
and proteins. The I333/I338 ratio in the vibrational emission spectrum of pyrene indicated the particles' micropolarity. Low I333/I338 values represent more hydrophobic microenvironments than higher values do (18–20). The pyrene study results suggested that
adding Pluronic F127 into Labrasol reduced the I1/I3 value significantly (see Table II), thus indicating the formation of an increasingly hydrophobic microenvironment. The increasingly
hydrophobic microenvironment could be attributed to hydrophobic interaction between surfactants or to the hydrogen binding
observed in other mixed micelles (18, 21, 22). This increasingly hydrophobic microenvironment enhances the hydrophobic interaction
of drugs with hydrophobic cores of mixed surfactants, as reported previously (23, 24). The microenvironment therefore holds
the drug more tightly and inhibits drug precipitation upon dilution. In contrast, when Pluronic F127 was added into PEG 400
or NMP, the I333/I338 value of these mixtures did not decrease (see Table 2). No hydrophobic microenvironment was formed because PEG 400 and NMP
are highly hydrophilic solvents.
Table II: I333/I338 value of the vibrational-emission spectrum of pyrene.
The results agreed with previous findings that the selected surfactant mixtures can result in more hydrophobic cores than
individual mixtures (18, 20, 22, 25, 26). The synergistic results of Pluronic F127 with Labrasol in this study were also consistent
with an increasingly hydrophobic microenvironment when Pluronic F127 was mixed with other surfactants. For example, the mixture
of Pluronic F127 with D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) became more hydrophobic than
Pluronic F127 or Vitamin E TPGS alone. Corresponding to this enhanced hydrophobicity, the mixture of Pluronic F127 and Vitamin
E TPGS inhibited drug precipitation more than either individual component in a strongly synergistic effect (27).
If Pluronic F127 is combined with micelle-forming surfactants, it will interact with the surfactants, which increases the
hydrophobicity of the mixed micelles, and thus strongly inhibits drug precipitation, as observed in the mixture of Pluronic
F127 with Labrasol or Vitamin E TPGS (see Figure 4) (27). More studies are needed to further confirm this hypothesis using
a large number of drugs and various surfactants. In addition to testing combinations of Pluronic F127 with various surfactants,
it would be interesting to investigate how types and amounts of Pluronics affect the inhibition of drug precipitation. In
the case of the Pluronic and Vitamin E TPGS mixture, Pluronic F127 and Pluronic F108, but not Pluronic F68, inhibited the
compound precipitation in SIF. Pluronic F127 was the most potent drug-precipitation inhibitor (27). It would be interesting
to analyze whether this finding proves true for other surfactants.
The addition of Pluronic F127 into the Labrasol formulations inhibited the precipitation of the tested compound upon dilution,
and a synergistic effect on inhibiting drug precipitation was observed. The study results suggest that Pluronic F127 could
be a potent inhibitor of drug precipitation for Labrasol formulations.
Wei-Guo Dai* is a fellow at Johnson & Johnson Pharmaceutical Research and Development, 145 King of Prussia Rd., Radnor, PA 19087. Liang C. Dong is chief scientific officer at ADDS Pharmaceuticals, and Abla A. Creasey is executive director of advanced technologies and regenerative medicine at Johnson & Johnson.
*To whom all correspondence should be addressed.
Submitted: Dec. 10, 2010. Accepted: Feb. 3, 2011.