Abstract
In order to improve the aqueous solubility and dissolution of Tacrolimus (TAC), amorphous solid dispersions of TAC were prepared by hot melt extrusion with three hydrophilic polymers, Polyvinylpyrrolidone vinyl acetate (PVP VA64), Soluplus® and Hydroxypropyl Cellulose (HPC), at a drug loading of 10% w/w. Molecular modeling was used to determine the miscibility of the drug with the carrier polymers by calculating the Hansen Solubility Parameters. Powder X-ray diffraction and differential scanning calorimetry (DSC) studies of powdered solid dispersions revealed the conversion of crystalline TAC to amorphous form. Fourier transform Infrared (FTIR) spectroscopy results indicated formation of hydrogen bond between TAC and polymers leading to stabilization of TAC in amorphous form. The extrudates were found to be stable under accelerated storage conditions for 3 months with no re-crystallization, indicating that hot melt extrusion is suitable for producing stable amorphous solid dispersions of TAC in PVP VA64, Soluplus® and HPC. Stable solid dispersions of amorphous TAC exhibited higher dissolution rate, with the solid dispersions releasing more than 80% drug in 15 min compared to the crystalline drug giving 5% drug release in two hours. These stable solid dispersions were incorporated into orally-disintegrating tablets in which the solid dispersion retained its solubility, dissolution and stability advantage.
Highlights
Tacrolimus (TAC) is a potent immunosuppressive drug widely used to prevent organ rejection of liver and kidney transplants and less frequently in heart, lung and heart lung transplants
The solubility parameter of TAC was calculated using molecular dynamic simulation using the method reported by Gupta and coworkers [29]
After cooling at 50 ◦C/min to −50 ◦C, and reheating at 10 ◦C/min, the melting endotherm of the drug disappeared and glass transition temperature (Tg) was observed at 78.8 ◦C confirming conversion of crystalline TAC to amorphous form by melting and rapid cooling in the differential scanning calorimetry (DSC). These results show that TAC can be converted to its amorphous form by melting and rapid cooling [21,33]
Summary
Tacrolimus (TAC) is a potent immunosuppressive drug widely used to prevent organ rejection of liver and kidney transplants and less frequently in heart, lung and heart lung transplants. TAC is marketed as a capsule (Prograf®) containing solid dispersion of drug with hydroxypropyl methylcellulose in order to improve dissolution and bioavailability [4,7] and extended release tablet (Envarsus XR®) prepared by melt agglomeration technology [8]. It exhibits low bioavailability (10–25%) and significantly variable pharmacokinetics due to its poor aqueous solubility, extensive metabolism by intestinal and hepatic cytochrome P450 3A4 enzyme [9] along with the effects of P glycoprotein efflux in the intestine [5,10,11]. TAC has a narrow therapeutic window (5–20 ng/mL) and overexposure increases the risk of nephrotoxicity and neurotoxicity [12,13] whereas low level can lead to graft rejection
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