Enhanced intestinal lymphatic absorption of saquinavir through supersaturated self-microemulsifying drug delivery systems

The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus(HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated selfmicroemulsifying drug delivery system(S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS.Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper selfmicroemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS.Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for silybin

To enhance the oral absorption of the poorly water-soluble drug silybin, a self-microemulsifying drug delivery system （SMEDDS） composed of ethyl linoleate, Cremophor EL and PEG 400 for oral administration of silybin was formulated, and its physicochemical properties and bioavailability of silybin were evaluated. The in vitro release of silybin from microemulsion and dispersion of silybin from SMEDDS were significantly faster than those from the commercial silybin hard capsule, respectively. The area under the drug concentration-time curve （AUC） and the mean maximum plasma level （Cmax） of the SMEDDS were remarkably greater than those of the hard capsule after oral administration to rats. The absorption of silybin formulated in SMEDDS exhibited a 2.3-fold increase in bioavailability as compared with the hard capsule. These results demonstrated that SMESDDS might be a useful drug delivery system for the oral delivery of the poorly water-soluble drug silybin.

Effect of mesopores on solidification of sirolimus self-microemulsifying drug delivery system

To investigate the influence of mesopores towards the solidification of self-microemulsifying drug delivery system(SMEDDS), mesoporous silica nanospheres(MSNs) and Santa Barbara Amorphous-15(SBA-15) were compared. The MSNs had hydrodynamic size of 195.35 ± 5.82 nm, and pore diameter of 2.70 nm. The SBA-15 had hydrodynamic size of 2312.19 ± 106.93 nm, and pore diameter of 10.91 nm. The MSNs and SBA-15 showed similar loading efficiency of SMEDDS containing sirolimus(SRL). However,MSNs had higher drug dissolution and in vivo absorption, with relative bioavailability of 174.62%. Thus,the length of mesopores played a more important role in solidification of SMEDDS as compared with the pore diameter. This study suggests that the SMEDDS-MSNs can be a potential candidate for oral administration of hydrophobic drugs.

Inhibitive Effect of Cremophor RH40 or Tween 80-based Self-microemulsiflying Drug Delivery System on Cytochrome P450 3A Enzymes in Murine Hepatocytes

This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate.The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium.In vitro release was detected by a dialysis method in reverse.The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes.The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique.The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting.Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500.The MDZ was completely released in 10 h.A significant decrease in the formation of 1’-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed.A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250.This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.

Enhancement of solubility and therapeutic potential of poorly soluble lovastatin by SMEDDS formulation adsorbed on directly compressed spray dried magnesium aluminometasilicate liquid loadable tablets: A study in diet induced hyperlipidemic rabbits

The aim of present study was to formulate and evaluate a self-microemulsifying drug delivery systems(SMEDDS)containing lovastatin and to further explore the ability of porous Neusilin■ US2 tablet as a solid carrier for SMEDDS.SMEDDS formulations of varying proportions of peceol,cremophor RH 40 and transcutol-P were selected and subjected to invitro evaluation,including dispersibility studies,droplet size,zeta potential measurement and release studies.The results indicated that the drug release profile of lovastatin from SMEDDS formulations was statistically significantly higher(p-value<0.05)than the plain lovastatin powder.Thermodynamic stability studies also confirmed the stability of the prepared SMEDDS formulations.The optimized formulation,which consists of 12% of peceol,44% of cremophor RH 40,and 44% of transcutol-P was loaded into directly compressed liquid loadable tablet of Neusilin■ US2 by simple adsorption method.In order to determine the ability of Neusilin®US2 as a suitable carrier pharmacodynamics study were also carried out in healthy diet induced hyperlipidemic rabbits.Animals were administered with both liquid SMEDDS and solid SMEDDS as well.From the results obtained,Neusilin■ was found to be a suitable carrier for SMEDDS and was equally effective in reducing the elevated lipid profile.In conclusion,liquid loadable tablet(LLT)is predicted to be a promising technique to deliver a liquid formulation in solid state.

Enhanced stability of nano-emulsified paclitaxel

The main goal of this work was to develop an optimal self-microemulsifying paclitaxel prepared with PLGA and solubilizer such as tetraglycol, Cremophor ELP, and Labrasol. The prepared PTx-loaded SMES showed the size of the range of 80–130 nm by dy-namic light scattering and a spherical shape by atomic force microscopy. In experiment of storage stability in deionized water (DW) or blood condition, PTx-loaded SMES showed good stability in DW and comparable stability in blood condition at 37oC for 7 days. In addition, PTx-loaded SMES showed a sig-nificant inhibitory effect on B16F10 melanoma proli-feration. In conclusion, we confirmed that the for-mulations tried in this study could be used as admin-istration form for animal trials of PTx.