Development and Characterization of Tacrolimus Tablet Formulations for Sublingual Administration

Abstract

Objective: The study aimed to prepare and characterize inclusion complexes of tacrolimus with β-cyclodextrin to improve its solubility and to formulate them into sublingual fast disintegrating tablets with a view to bypass the first-pass metabolism. Methods: Tacrolimus: β-cyclodextrin inclusion complexes (1:1 and 1:2 molar proportions) were prepared using the kneading method. Their characterization was accomplished by determining the drug content, solubility, Attenuated Total Reflection-Infrared Spectroscopy (ATR-IR), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction analysis (pXRD). These were then formulated to fast disintegrating tablets and evaluated for precompression as well as post compressional characteristics. Results: SEM analysis showed the inclusion complexes as rough, non-porous, irregular surfaced aggregate particles. DSC and pXRD analyses confirm the crystallinity change and partial conversion to the amorphous form of the drug in the inclusion complexes. From the solubility studies, it was observed that both the inclusion complexes of 1:2 molar ratio (14.82±0.889 µg/ml) and 1:1 molar ratio (12.72±0.1004 µg/ml) improved the aqueous solubility to greater extents in comparison to that of the pure drug (3.05±0.121 µg/ml). All the tablet formulations showed good precompression and mechanical properties. The inclusion complex loaded tablets exhibited a superior drug release pattern when compared to tablets prepared with tacrolimus alone. The optimized formulation (TT3) showed an in vitro disintegration time of 34.33 s and a percent drug release of 97.87. Conclusion: The inclusion complex formulation combined with the sublingual route of administration can be expected to result in an improved bioavailability of tacrolimus by increasing its solubility and bypassing first-pass metabolism.

Pharmacokinetic Exploration of Sublingual Route for the Enhanced Bioavailability of Tacrolimus with Rabbit as Animal Model

“…The preparation and evaluation of tacrolimus-loaded fast-dissolving films and tablets had already been discussed in earlier publications by Mohanan J. and co-authors. 5,6 To brief, to enhance the solubility of the drug, firstly, inclusion complexes with β-cyclodextrin were developed and characterized followed by their formulation into fast-dissolving films and tablets for sublingual administration. The optimized formulations were further selected for their in vivo bioavailability study in rabbits.…”

Implementing Central Composite Design for the Development of Tacrolimus Film for Sublingual Administration

“…The slurry was kneaded thoroughly for around 40 min. After the evaporation of the solvents, the complexes were dried at room temperature for a period of 1 d [11]. FDF formulations loaded with β-cyclodextrin inclusion complex of tacrolimus monohydrate were formulated with HPMC E5 as the filmforming polymer, PEG 400 as the plasticizer, and CCS as the superdisintegrant [12].…”