Hongtao Song

Sirolimus solid self-microemulsifying pellets: formulation development, characterization and bioavailability evaluation.

To enhance the dissolution and oral absorption of water insoluble drug sirolimus (SRL), self-microemulsifying pellets of SRL were developed and evaluated. Solubility test, self-emulsifying grading test, ternary phase diagrams and central composite design were adopted to screen and optimize the composition of liquid SRL-SMEDDS. The selected liquid SRL-SMEDDS formulations were prepared into pellets by extrusion-spheronization method and the optimal formulation of 1mg SRL-SMEDDS pellets capsule (1.0, 22.4, 38.4, 19.2, 121.6, 30.4 and 8.0 mg of SRL, Labrafil M1944CS, Cremophor EL, Transcutol P, MCC, Lactose and CMS-Na, respectively) was finally determinated by the feasibility of the preparing process and redispersibility. The optimal SRL-SMEDDS pellets showed a significant quicker redispersion rate than the dissolution rate of commercial SRL tablets Rapamune in water. The droplet size and polydispersity index of the reconstituted microemulsion was almost unchanged after solidification, and pellet size and friability were all qualified. Visual observation and scanning electron microscopic analysis confirmed good appearance of the solid pellets. DSC, XRPD, and IR analysis confirmed that there was no crystalline sirolimus in the pellets. Pharmacokinetic study in beagle dogs showed the oral relative bioavailability of SRL-SMEDDS pellets to the commercial SRL tablets Rapamune was about 136.9%. In conclusion, the solid SMEDDS pellets might be an encouraging strategy to improve the oral absorption of SRL and the extrusion-spheronization method was a feasible technology for the solidification of liquid SMEDDS.

Development of solidified self-microemulsifying delivery systems with enhanced stability of sirolimus and extended release

The application of sirolimus (SRL) as immunosuppressive agent is hampered by its poor water solubility and narrow therapeutic range. The self-microemulsifying drug delivery system (SMEDDS) succeeded in improving the solubility of SRL in our previous work. In this study, the formulation of the SMEDDS was further optimized by investigating the influence of the excipients including the media, antioxidant and organic acid. It was demonstrated that addition of 0.20% of citric acid in SMEDDS most efficiently promoted the stability of SRL under high temperature (40±2°C), high humidity (relative humidity 90±5%) or strong light irradiation (4500±500lx). SMEDDS absorbed by microcrystalline cellulose (MCC) was mixed with hydroxypropyl methylcellulose (HPMC) to prepare tablets. The optimal formulation composed of 15% of HPMC 100 LV with hardness of 120N, which had a sustained release of 12h. Results of X-ray powder diffraction and differential scanning calorimetry demonstrated that SRL in the tablets was in amorphous or molecularly dispersed state. The SMEDDS-tablets presented as promising substrates for water insoluble drugs with enhanced stability and extended release.

CYP3A4∗18B and CYP3A5∗3 polymorphisms contribute to pharmacokinetic variability of cyclosporine among healthy Chinese subjects.

AIM Cyclosporine is an immunosuppressant drug used to prevent allograft rejection. It is metabolized by CYP3A4 and CYP3A5, has a narrow therapeutic index, and variable pharmacokinetics. Here, we investigated whether CYP3A5∗3 and CYP3A4∗18B polymorphisms contribute to inter-individual pharmacokinetic variability in healthy subjects. PATIENTS AND METHODS Fifty-six healthy Chinese subjects were enrolled in the study after signing a written consent. The subjects received 5mgkg(-1) of cyclosporine orally and were genotyped for CYP3A5∗3 and CYP3A4∗18B using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Blood concentrations of cyclosporine were measured by high-performance liquid chromatography for up to 30h post-dose. RESULTS The mean cyclosporine AUC0→30 and AUC0→∞ in the male group was significantly higher than that in the female group (P=0.037 and 0.035); the CL/F in the male group was significantly lower than that in the female group (P=0.033). The Cmax of cyclosporine in CYP3A4∗1/∗1 was significantly greater than that in CYP3A4∗1/∗18B in the male group (P=0.023), but not the female group. In addition, the Cmax in CYP3A5∗1/∗3 was significantly lower than that in CYP3A5∗3/∗3 in the male group (P=0.01). CONCLUSIONS The results indicate that gender and polymorphism in CYP3A4∗18B and CYP3A5∗3 significantly affect cyclosporine pharmacokinetics in healthy subjects.

Preparation and comparison of tacrolimus-loaded solid dispersion and self-microemulsifying drug delivery system by in vitro/in vivo evaluation

Abstract This study aimed to compare the dissolution and the intestinal absorption of tacrolimus in self‐microemulsifying drug delivery system (SMEDDS) and solid dispersion (SD). Poloxamer 188 SD was prepared by the combination of the solvent evaporation method and the freeze drying method. Hydroxypropyl methylcellulose (HPMC) SD was prepared by the solvent evaporation method combined with the vacuum drying method. The formation of SD was confirmed by SEM images which showed new solid phases. The SMEDDS was composed of oil (Labrafil M1944 CS 28%), surfactant (Cremophor EL 48%) and co‐surfactant (Transcutol P 24%). The self microemulsion formed by the SMEDDS upon aqueous media had spherical droplets with a hydrodynamic size of 46.0 ± 3.2 nm. The dissolution of tacrolimus from SD and SMEDDS was performed in sink and non‐sink conditions with various pH. As revealed by the DSC and FT‐IR, the tacrolimus was molecularly or amorphously dispersed in the SMEDDS and SD. The in vivo intestinal absorption study in rats showed that both SMEDDS and SD improved the absorption of tacrolimus over the raw tacrolimus while the SMEDDS exhibited lower absorption rate constant (Ka) and apparent permeability coefficients (Papp) than the SD. The self‐prepared SD with poloxamer 188 or HPMC had comparable intestinal absorption as compared with Prograf®. The tacrolimus‐loaded SMEDDS and SD would be further compared by in vivo pharmacokinetic study. Graphical abstract Figure. No caption available.

Preparation and characterization of silymarin synchronized-release microporous osmotic pump tablets

The pharmacological activity of herbal medicine is an overall action of each component in accordance with their original proportion. An efficient, sustained, and controlled-release drug delivery system of herbal medicine should ensure the synchronized drug release of each active component during the entire release procedure. In this study, silymarin (SM), a poorly soluble herbal medicine, was selected as a model drug to develop a synchronized-release drug delivery system: an SM microporous osmotic pump (MPOP) tablet. The SM was conjugated with phospholipid (SM phytosome complex, SM-PC) to improve the solubility, and the difference in the apparent octanol–water partition coefficient between the two components was significantly reduced. The dissolution rate of SM-PC was significantly higher than SM active pharmaceutical ingredients and was the same as that of the commercial SM capsule. The SM-PC was used to generate the MPOP tablet. SM was mixed with poly(ethylene) oxide and sodium chloride (an osmotic agent) to form the MPOP core, followed by coating with cellulose acetate and poly(ethylene) oxide to generate the SM MPOP. The results demonstrated that SM MPOP could synchronically and sustainably release the five active components within 12 hours (the similar coefficient f2 between two components was >65), and the average cumulative release rate was 85%. Fitting of the drug-release curve showed a zero-order release profile for SM MPOP. Our study showed that the phytosome complex technique combined with the MPOP system will achieve synchronized release of the various active components of herbal medicine and have potential applications in developing sustained release preparations in herbal medicine.

Preparation and characterization of silymarin synchronized and sustained release dropping pill.

PURPOSE This study aimed to develop a synchronized and sustained-release silymarin dropping pill, and to evaluate its pharmacokinetic characteristics. METHOD Polyoxyethylene stearate, glyceryl monostearate, and stearic acid were used to prepare the dropping pills. X-ray powder diffraction, differential scanning calorimetry, and release were used to evaluate its physicochemical properties. The plasma concentration of silybin in beagle dogs after oral administration of silymarin dropping pills and silymarin capsule was determined by RP-HPLC. RESULTS Synchronized release was achieved with high similarity factor f2 values between every set of two of the five components. Mean plasma concentration-time curves of silymarin after oral administration of dropping pills in beagle dogs were in accordance with first-order absorption and open twocompartment model. The Tmax, Cmax, and AUC0-∞ of dropping pills in beagle dogs were 0.8750±0.13 h, 0.8183±0.07 μg·ml-1, and 2.274±0.90 μg·h·ml-1, respectively. Silymarin dropping pills prolonged in vivo exposure and reduced maximum in vivo concentration, achieving a stable level in the serum. CONCLUSION The combination of solid dispersion technique and dropping pill formulation allowed synchronized release of multiple components in herbal medicine, and has potential application in the development of sustained release in herbal medicine.