The pharmacokinetics of water‐in‐oil‐in‐water‐type multiple emulsion of a new tacrolimus formulation

Abstract

We developed a water-in-oil-in-water-type (W/O/W)-type multiple emulsion of a new tacrolimus formulation. A potential approach to avoid the complications of systemic immunosuppression and simultaneously enhance immunosuppressive efficacy is to deliver immunosuppressive agents locally to the site of the target organs. The W/O/W emulsion is dispersed oil drops containing smaller water droplets that allow the delivery of drugs preferentially to the reticuloendothelial systems (RES). Since the liver and the spleen are primary components of the RES, and the brain and the kidney have a poor RES, we hypothesized that a W/O/W emulsion of tacrolimus would possess the pharmacokinetic benefits of local immunosuppression. We evaluated this hypothesis in a rat model. The tacrolimus levels of whole blood, the liver, spleen, brain, and kidney in rats given intravenous emulsions of tacrolimus (W/O/W group) were compared with a group administered tacrolimus alone (T group). There were no significant differences between the pharmacokinetic parameters of W/O/W group and T group based on whole blood data. However, the W/O/W group had significantly decreased tacrolimus levels in the brain and kidney, and significantly increased levels in the liver and spleen compared with the T group. These data suggest that the W/O/W emulsion is applicable as an intravenous drug carrier for local immunosuppression.

Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres

“…TLBM revealed a continuous flat concentration profile for 10 days after a single subcutaneous administration in the current study. This stable sustained release of TLBM was much longer than that of liposomal FK11 or tacrolimus emulsion 12, 13. Whole‐blood tacrolimus concentration profiles of TLBM after a single subcutaneous administration were similar to those of tacrolimus after the continuous infusion.…”

Tacrolimus in the Treatment of Ocular Diseases

“…The poor water solubility of tacrolimus means that aqueous solutions at clinically useful concentrations are likely to be unstable. Attempts to overcome this have led to ophthalmic tacrolimus prepared in castor oil, [104] olive oil, [105] and dextrin. [106] However, burning, redness, itching, and epithelial keratitis limit the use of such oil vehicles.…”

Application of Biodegradable Nanoparticles in Liver Targeting of Tacrolimus

“…They were intravenously injected through the tail vein with either the free, unencapsulated TAC or PLA-TAC-NP. Both groups received a dose equivalent to 1mg/kg TAC (Uno et al, 1997(Uno et al, , 1999. Four time points were assigned for sampling following drug administration, 5min, 15min, 1hr and 4hrs.…”

“…PLA-TAC-NP increased TAC concentrations in the liver by 24 fold and by 1.94 fold in the spleen and decreased concentrations of TAC in the kidneys by 7.12 fold. Uno et al (Uno et al, 1997) prepared W/O/W TAC emulsion that was able to increase TAC in liver by 3.85 fold and to the spleen by 1.52 fold whereas TAC levels in the kidney decreased by 1.24 fold. The enhanced targeting efficiency exhibited by the PLA-TAC-NP can be attributed to their smaller particle size (mean diameter 255 ± 4.58nm) compared to the droplets of the W/O/W (mean diameter 3.21 ± 0.10μm), since particles that lie within the lower sub-micron range, more precisely (100-300nm) are considered optimum for uptake by cells of the RES, and therefore are more likely to redistribute in RES rich organs, namely liver and spleen and less likely to end up in RES poor organs such as the kidneys.…”