Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing.

PURPOSE

Solid dispersions containing various stabilizers and tacrolimus (TAC) prepared by an Ultra-rapid Freezing (URF) process were investigated to determine the effect on their ability to form supersaturated solutions in aqueous media and on enhancing transport across biological membranes.

MATERIALS AND METHODS

The stabilizers included poly(vinyl alcohol; PVA), poloxamer 407 (P407), and sodium dodecyl sulfate (SDS). In vivo absorption enhancement in rats was also investigated. Dissolution studies were conducted at supersaturated conditions in both acidic media for 24 h and at delayed release (enteric) conditions to simulate intestinal transit.

RESULTS

The rank order of C/Ceq(max) in the dissolution studies at acidic conditions was URF-P407 > URF-SDS > Prograf (PRO) > URF-PVA:P407. For C/Ceq(max) under enteric conditions, the order was URF-SDS > PRO > URF-PVA:P407 > URF-P407, and for the extent of supersaturation (AUC) in acidic and pH shift conditions it was URF-SDS>PRO>URF-PVA:P407>URF-P407. The pharmacokinetic data suggests URF-P407 had the greatest absorption having higher C (max) with a 1.5-fold increase in AUC compared to PRO. All URF compositions had a shorter T (max) compared to PRO.

CONCLUSIONS

The nanostructured powders containing various stabilizing polymers formed by the URF process offer enhanced supersaturation characteristics leading to increased oral absorption of TAC.