Studies On Solid Self-Microemulsifying Drug Delivery Systems

In recent years, increasing attention has been focused on self-microemulsifying drug delivery system (SMEDDS), which has shown a great success in improving oral bioavailability of poorly soluble drugs and becomes a potential drug delivery system. Conventionally, SMEDDS is prepared as liquid dosage forms that can be encapsulated in hard or soft gelatin capsules, which has some shortcomings especially in the manufacturing process, leading to high production costs. Moreover, these dosage forms may be prone to leakage during shelf-life, and incompatibility problems with the shells of the soft gelatin are usual. In order to overcome the shortcomings of liquid formulations and to combine the advantages of SMEDDS with those of solid dosage forms, studies on solid self-microemulsifying drug delivery system (S-SMEDDS) have begun.Solid carriers, preparation method, microstructure, drug release mechanism and in vivo absorption are important aspects of S-SMEDDS. It is the key issue that whether S-SMEDDS could maintain the in vitro and in vivo characteristics of L-SMEDDS. In this dissertation, S-SMEDDS with various drug release patterns were prepared by spray-drying or ion gelation, using water soluble excipients as solid carriers.(1) L-SMEDDS was prepared and characterized using nimodipine as a model drug. The effects of various water soluble carriers on internal microstructure and solubilization of L-SMEDDS were investigated by conductivity and in vitro dispersion. The results showed that water soluble carriers did not seem to have a remarkable effect on microstructure of L-SMEDDS. However, the water soluble carriers had increased solubilization of nimodipine in the self-microemulsifying system and decreased drug precipitation when dispersed in aqueous media.(2) S-SMEDDS of nimodipine were prepared by spray drying with water-soluble solid carriers. The effects of various water soluble carriers on the properties of S-SMEDDS were investigated by TEM, SEM, DSC, PXRD and in vitro dissolution. The results shown that solid carriers, especially the molecular weight of carrier, had an obvious influence on the surface morphologies of S-SMEDDS, reconstitution of microemulsion and the physical state of nimodipine in S-SMEDDS. The S-SMEDDS with dextran 40 as solid carrier, consisted of well-separated spherical particles and could form microemulsion with droplet size less than 50nm followed by dilution in water. Nimodipine in the S-SMEDDS was in the amorphous or molecular dispersion state. The S-SMEDDS had a faster in vitro release rate than the conventional tablet.(3) A comparative bioavailability study was performed in rabbits with the solid SMEDDS, the liquid SMEDDS and a conventional tablet of nimodipine. In fasted and fed conditions, the areas under the curves (AUC0→12h) for the S-SMEDDS were 2.5 and 2.6 times greater, respectively, and the mean values of Cmax for the S-SMEDDS were 6.6 and 5.5 times greater, respectively, compared to the conventional tablet. However, both AUC0→12h and Cmax for the S-SMEDDS and L-SMEDDS were not statistically different (p > 0.05). It suggested that the S-SMEDDS maintained the absorption characteristics of the L-SMEDDS.(4) HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system. TEM micrograph revealed that the reconstituted microemulsions with droplet size less than 100nm were released from the S-SMEDDS when exposed to aqueous media. Based on investigation by TEM, SEM, DSC and X-ray powder diffraction, differences were found in the particle structure between both types of formulations and potential structures were supposed. Dissolution data of both formulations were fitted to various mathematical models in order to describe the release kinetics. It was found that diffusion was the comparatively important drug release mechanism of the controlled release S-SMEDDS, differed from the controlled release formulation without self-microemulsifying ingredients. The differences in the particle structure could be an explanation for the difference in drug release mechanism.(5) Self-microemulsifying enteric gel beads (SMEGB) were prepared by ion gelation, using indomethacin as a model drug. Reconstitution test results showed that the reconstituted microemulsion with droplet size less than 150nm was released from SMEGB when exposed to aqueous media. SEM micrographs illustrated that the gel bead showed a regular spherical shape, with more compact surface and looser internal structure. Indomethacin in the SMEGB was in the amorphous or molecular dispersion state. The influence factors and drug release mechanisms were preliminarily investigated by the similarity factor and model fitting. It was found that the main influence factors were the mass ratio of L-SMEDDS/sodium alginate and the concentration of sodium alginate. It was possible that erosion of carrier was the main drug release mechanisms of SMEGB.In present work, S-SMEDDS with various drug release patterns were successfully prepared, maintaining the in vitro and in vivo characteristics of L-SMEDDS. Effects of water soluble carriers, changes of microstructure, drug release mechanisms and in vivo absorptions of S-SMEDDS were also preliminarily investigated. In the future, further investigations are necessary to establish new model of drug release and in vitro and in vivo correlation, providing an important base on S-SMEDDS formulation strategy and in vitro and in vivo assessment.