Preparation of 0.05% FK506 suspension eyedrops and its pharmacokinetics after topical ocular administration.

Purpose: To investigate the stability of FK506 eye suspension and its pharmacokinetics in rabbit aqueous humor, as well as its distribution in eye tissues.

Methods: Sedimentation rate, flocculation value, redispersion time, rheological study, and accelerated experiment were determined for evaluating the stability of FK506 suspension. In a single-dose pharmacokinetic study, six rabbits were instilled a 25-microL drop of 0.05% FK506 suspension and aqueous humor samples were collected at different intervals after administration. In a multiple-dose pharmacokinetic study, a 25-microL drop of FK506 suspension was instilled into the right eye of six rabbits four times a day for 7 days. On the eighth day, aqueous humor samples were collected before the administration of the first, second, third dose, and at different checkpoints after the third dose. For tissue distribution study, six eyes per time points (18 rabbits in total) were treated with single dose of FK506 suspension, and the eyes were enucleated at 60, 100, and 240 min after treatment, then eye tissues were collected. The concentrations of FK506 in all samples were determined by LC-MS/MS.

Results: The preliminary results indicated that the stability of FK506 suspension was in accord with the standards of Chinese pharmacopoeia. The maximum concentrations of aqueous humor after single dose and multiple dose administrations were 31.40 +/- 9.32 ng/mL and 37.73 +/- 11.25 ng/mL, respectively. The concentration of FK506 in cornea at 60, 100, and 240 min after a single dose were 402.0 +/- 96.8 ng/g, 363.8 +/- 84.5 ng/g, and 220 +/- 62.3 ng/g, respectively. Determination of pharmacokinetic parameters of single-dose and multiple-dose administration, as well as the FK506 concentrations in eye tissues, showed that the FK506 formulation and the dosing regimen ensured the therapeutic concentration of FK506 for treating corneal allograft rejection.

Conclusions: Based on the stability, single-dose and multiple-dose pharmacokinetics, and tissue distribution, FK506 suspension eyedrops may be a suitable candidate for clinical application in ophthalmology.