tacrolimus and ethyl-cellulose

We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG).. Extended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG.. Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study.. We successfully developed the formulation exhibiting a significant reduction in C

Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Cellulose; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Humans; Hypromellose Derivatives; Immunosuppressive Agents; Lactose; Male; Middle Aged; Solvents; Tacrolimus; Young Adult

A novel once-a-day sustained-release (SR) system of tacrolimus (FK506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (EC) polymer as release retardant. Drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. Subsequently, the drug-layered pellets were recoated with EC polymer (0.5-1.5 mg) using a fluid bed granulator. Drug release from the reservoir-type pellets was markedly impeded by the outer EC-based coating layer (EC 1 mg), displaying about 60% of drug release after 8 h, regardless of the acidity of the media. In an in vivo pharmacokinetic study in fasted Cynomolgus monkeys, the drug level in blood was gradually increased over 4.7 h and high drug concentration was maintained until 24 h, with an elimination half-life of 16.6 h. There were no statistical differences between the novel SR pellets and the recently marketed SR capsule (Advagraf

Topics: Animals; Cellulose; Delayed-Action Preparations; Drug Carriers; Macaca fascicularis; Male; Tacrolimus

The present study was to develop a stable and sustained-release delivery system of tacrolimus (TCM). TCM is a macrolide antibiotic used as an immunosuppressant. It is formulated as a microsponge, which is a safe and effective delivery system with reduced side effects.. The method used to prepare ethyl cellulose (EC) and xanthan gum (XG)-facilitated EC-based microsponges employed emulsification and modified double emulsification techniques. TCM-containing microsponges were prepared using varying concentrations followed by evaluation of micromeritics, compatibility of drug and excipients, production yield, drug content and entrapment efficiency, zeta potential, size distribution and drug release.. The results showed excellent flow properties with adequate entrapment efficiency of the system and satisfactory release of active pharmaceutical ingredient. In vitro dissolution studies, which were conducted to determine the amount of drug released, illustrated a pronounced sustained effect up to 8 h. Zeta size and zeta potential analysis of microsponges confirmed the existence of micro-sized (1.99-3.09 µm) and stable particles (-15.33 to -3.38 mV), respectively.. Conclusively, the applied technique and selected combination of ingredients were found suitable for the preparation of TCM-containing sustained-release microsponges.

Topics: Cellulose; Drug Compounding; Drug Delivery Systems; Drug Liberation; Emulsions; Kinetics; Models, Theoretical; Polysaccharides, Bacterial; Spectroscopy, Fourier Transform Infrared; Static Electricity; Surface Properties; Tacrolimus; X-Ray Diffraction

Tacrolimus is a poorly water-soluble compound that is used to prevent allograft rejection. We aimed to prepare an extended release formulation of tacrolimus to achieve both an extended release profile and improved solubility of tacrolimus.. Extended release granules (ERG) of tacrolimus were prepared with lactose, ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) via the solvent evaporation method.. In an in vitro release study, ERG had an extended release profile, and the release rate of tacrolimus was regulated by the quantity of lactose, EC and HPMC in the formulation. HPMC-containing ERG successfully enhanced and maintained supersaturation of tacrolimus even after 24 h in a supersaturated release study. In contrast, the extent of supersaturation rapidly decreased after 4 h and the concentration nearly reached the same level as that of crystalline tacrolimus at 24 h for ERG without HPMC. In vivo absorption characteristics were compared between ERGs and immediate release (IR) formulation of tacrolimus. Successful and sustained absorption of tacrolimus without reducing bioavailability compared with IR formulation was observed for ERG.. These results suggest the feasibility of combining an EC-based formulation with solid dispersion utilizing HPMC for the extended release of oral formulations and sustained absorption of tacrolimus.

Topics: Administration, Oral; Animals; Biological Availability; Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Hypromellose Derivatives; Lactose; Macaca fascicularis; Male; Solubility; Solvents; Tacrolimus; Water