Immunosuppression

Tacrolimus is an immunosuppressive drug primarily indicated for the reduction of immune response following organ transplantation to reduce the risk of rejection. The solubility of tacrolimus in water is 1-2 mg/mL (61), and thus has shown low oral bioavailability (62). Solid dispersion systems for improved oral bioavailability of tacrolimus have recently been explored by Yamashita et al. (63). These researchers evaluated solid dispersion systems of tacrolimus with PEG 6000, PVP, and HPMC in order to identify the optimum carrier. Initially, the solid dispersion formulations were produced by dissolving tacrolimus and each polymer carrier in a cosolvent system consisting of dichloromethane and ethanol, and then removing the solvent in a vacuum dryer at 40°C. Solid dispersions produced by this process contained tacrolimus in an amorphous state as determined by DSC and XRD. Dissolution testing was conducted in pH 1.2 medium with tacrolimus in excess of the saturation solubility to determine which carrier polymer would yield the greatest extent of supersaturation. The results of this dissolution testing revealed that although each solid dispersion formulation showed equivalent peak supersaturation concentrations that were 25-times that of saturation (50 mg/mL), the HPMC formulation was the only solid dispersion that was able to maintain these elevated concentrations for 24 h. This result demonstrated that HPMC can effectively prevent the precipitation of supersaturated tacrolimus which presumably would provide enhanced in vivo absorption, and thus the tacrolimus-HPMC formulation was selected for oral bioavailability evaluation.

The initial bioavailability study was conducted in beagle dogs with the crystalline powder and the solid dispersion formulation dosed as a suspension. The blood concentration profiles of the crystalline drug powder and the solid dispersion formulation is shown in Figure 10. This study clearly indicated that the ability of the tacrolimus-HPMC formulation to

Figure 10 Blood concentration of tacrolimus after oral administration of SDF with HPMC to beagle dogs. (•) SDF of tacrolimus with HPMC; (O) tacrolimus crystalline powders. Values are expressed as the mean with a vertical bar showing SE of six animals. Each dosage form was administered at the dose of 1 mg as tacrolimus.

Figure 10 Blood concentration of tacrolimus after oral administration of SDF with HPMC to beagle dogs. (•) SDF of tacrolimus with HPMC; (O) tacrolimus crystalline powders. Values are expressed as the mean with a vertical bar showing SE of six animals. Each dosage form was administered at the dose of 1 mg as tacrolimus.

produce and maintain supersaturated drug levels during dissolution testing correlated well to in vivo drug absorption as the solid dispersion exhibited Cmax and AUC values that were ten-fold higher than the crystalline powder.

Based on this result, the authors sought to optimize the solvent evaporation method by eliminating dichloromethane from the cosolvent system due to the health and environmental hazards associated with this solvent. HPMC is not soluble in ethanol, but is swellable. Therefore, by the new production method, tacrolimus was dissolved in ethanol, and this ethanolic solution was then used to swell the HPMC carrier. The solvent was then removed by the use of a vacuum oven at 40°C to form the dried solid dispersion. By the use of scanning electron microscopy, DSC, and XRD it was determined that tacrolimus was present in the HPMC carrier in an amorphous state. Dissolution testing and in vivo studies in monkeys revealed that the tacrolimus-HPMC solid dispersion prepared by the new method was equivalent to the solid dispersion prepared with the original cosolvent formulation. Therefore, in this study the authors demonstrated a solid dispersion formulation for tacrolimus that extensively supersaturated aqueous media and correspondingly improved oral absorption. By eliminating dichloromethane from the solvent system, the solvent evaporation method used to produce this tacrolimus solid dispersion was made considerably more feasible for commercial production. Therefore, this solid dispersion formulation of tacrolimus has substantial potential for improving immunosuppressive drug treatment and thereby decreasing the frequency of transplantation rejection.

Cyclosporin is another immunosuppressive agent that exhibits poor and variable absorption from the GI tract owing in part to its poor water solubility (7.3 mg/mL) (64). The leading solid oral dosage form for cyclosporin in the US is Neoral®, a microemulsion filled soft gelatin capsule formulation marketed by Novartis. As soft gelatin capsule dosage forms are relatively expensive, complicated to manufacture, and often have stability related issues (45,65); there would substantial benefit to replacing these dosage forms with conventional tablets or capsules that are bioequivalent. Toward this aim, Liu et al. evaluated a solid dispersion system of cyclosporin A in polyoxyethylene stearate (S40) as potential solid alternative to the liquid filled capsule (66). The solid dispersion formulation was prepared by a solvent-melt method in which cyclosporin A was dissolved in anhydrous ethanol, added to molten S40 at 65°C, and stirred until a majority of the solvent was evaporated. The molten mixture was then cooled at — 18°C, dried under vacuum at 25°C for 24 h, and then pulverized. The results of XRD and DSC studies demonstrated that cyclosporine A was present in the dispersion formulation in an amorphous state. Dissolution testing in water showed substantial improvement in the rate and extent of cyclosporine release form the solid dispersion formulation over that of the crystalline drug powder and the physical mixture.

A bioavailability study conducted in rats showed very similar drug absorption with the solid dispersion formulation as with the Neoral soft gelatin capsule formulation. The pharmacokinetic parameters from this study are shown in Table 6. Statistical analysis of these results revealed no significant differences in the pharmacokinetic parameters between these formulations. Relative to the Neoral formulation, the bioavailability of the solid dispersion system was found to be 98.1%. This study therefore demonstrated the apparent bioequivalence of the solid dispersion formulation to the Neoral soft gelatin capsule. Considering the manufacturing cost of soft gelatin capsules and the associated stability issues (45,65), the solid dispersion system may be a more attractive alternative for the oral delivery of cyclosporine.

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