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J. Inoue, M. Yamaguchi, H. Sakaki, T. Kida, T. Tajika, K. Inada, A. Ohtori; Preclinical Pharmacokinetics of Difluprednate Emulsion. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2651.
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To evaluate the effect on pharmacokinetics by particle size of Difluprednate ophthalmic emulsion in rabbit models.
0.05% Difluprednate ophthalmic emulsion and 0.05% Difluprednate ophthalmic suspension were singly instilled to white male rabbits. Concentrations of deacetylated difluprednate (DFB), the major metabolite of Difluprednate, in the aqueous humor were measured with LC/MS/MS. Difluprednate ophthalmic emulsion with a different particle size suspension was also singly instilled to white male rabbits and concentrations of DFB in the aqueous humor were assessed 1 h post administration, when the concentration presumably reached the highest level.
After administration of 0.05% Difluprednate ophthalmic emulsion, Cmax of DFB was 43.996 ng/mL, and Tmax was 1.0 h in the aqueous humor. Thereafter, DFB concentrations in the aqueous humor decreased with time to attain 3.866 ng/mL 4 h post instillation. AUC-4h was 90.4 ng·h/mL. After administration of 0.05% Difluprednate ophthalmic suspension, Cmax of DFB in the aqueous humor was 31.062 ng/mL, and Tmax was 1.0 h. Thereafter, DFB concentrations in the aqueous humor decreased with time to reach 2.872 ng/mL 4 h post instillation. AUC-4h was 62.9 ng ·h/mL. Cmax and AUC-4h after instillation of the emulsion formulation were 1.4-fold higher compared with those of suspension, and this difference was statistically significant. 0.05% Difluprednate ophthalmic emulsion with a particle size in the lower limit of particle diameter specification (95 nm), was administered to male white rabbits, the DFB concentration in the aqueous humor 1 h post instillation was 34.019±7.651 ng/mL. A particle size in the upper limit (125 nm) yielded a DFB concentration in the aqueous humor of 29.069±4.130 ng/mL, and a particle size in the midrange (110 nm) resulted in values of 37.912±11.408 ng/mL.
Formulation types affected the transfer of Difluprednate, the emulsion formulation resulted in higher ocular bioavailability than the suspension. However, the transfer of difluprednate does not seem to be affected by the particle size of difluprednate at 0.05% as long as the mean value of the particle size of the emulsion is within the range of 90.3-129.3 nm (measured values pre-instillation).
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