Enhanced dissolution and oral absorption of tacrolimus by supersaturable self-emulsifying drug delivery system

Abstract

A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different ( P >0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients.

Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design

“… 36 Hydrophobic moieties interact with hydrophobic tails of drug-loaded colloid, rigidifying hydrocarbon layer of the interface, resulting in the action of supersaturation. 37 Meanwhile, hydrophilic moieties shield the surface of the micelle, generating hydrophilic barrier which hamper the aggregation and/or destruction of the colloid. 37 P407 also spontaneously forms micelle and solubilizes water-insoluble drugs, thereby contributing to supersaturation.…”

“… 37 Meanwhile, hydrophilic moieties shield the surface of the micelle, generating hydrophilic barrier which hamper the aggregation and/or destruction of the colloid. 37 P407 also spontaneously forms micelle and solubilizes water-insoluble drugs, thereby contributing to supersaturation. 38 Thus, P407 was selected as a supersaturating agent for SuM formulation.…”

Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

“…The CL/F of tacrolimus increased non-linearly as the daily dose increased, which is consistent with previous findings in kidney and lung transplant recipients. 8 , 51 , 52 This phenomenon can be explained by the poor water solubility of tacrolimus and its low transmembrane permeability in the intestine, which may result in its low and variable oral bioavailability and limited absorption rate in the gastrointestinal tract. 2 The non-linear kinetics of tacrolimus warrant further investigation with a larger sample size.…”

3D Printed Tacrolimus Rectal Formulations Ameliorate Colitis in an Experimental Animal Model of Inflammatory Bowel Disease

“…This approach is especially useful for enhancing drug solubility of poorly water-soluble drugs, which are solubilized in the small drops of oil [33]. The low oral bioavailability of tacrolimus and its poor water solubility made it a suitable candidate for inclusion in a 3D printed lipid-based suppository [34].…”