Solid Carrier Self Micro-emulsifying Drug Delivery Systems

Self-microemulsifying drug delivery system (SMEDDS) has shown a great success in improving oral bioavailability of poorly water soluble drugs. Conventionally, SMEDDS is prepared as liquid dosage forms which have some shortcomings as follows:First of all, SMEDDS were encapsulated in hard or soft gelatin capsules which have some problems especially in the complicated manufacturing process and inconvenience application. In the meanwhile, these dosage forms may be easy to compatible with the shells of the soft gelatin, and transpiration during long-term storage is usual. Secondly, it is hard to use for some drugs such as the poor water soluble drugs which administer frequently because of single dosage forms and shortage of prolonged action preparations. It is also different to use for the drugs which excitation or instability in the stomach because entero-soluble forms are deficiency. Eventually, after oral administration, SMEDDS was dispersed in the stomach and then digested by the intestinal lipase and mixed micellar solutions. The process may lead to drug precipitation from the systems and is not benefit to absorption.In order to overcome the shortcomings of SMEDDS, studies on solid microemulsifying drug delivery system(S-SMEDDS) have begun. S-SMEDDS have combined the advantages of SMEDDS with solid dosage forms. S-SMEDDS can be achieved by adding various kinds of solid excipients, or by the application of coating techniques, and which abundant dosages forms. Furthermore, the eligible solid carriers had increased solubilization and decreased drug precipitation in the gastro-intestinal tract.Solid carriers had important effects on the properties of S-SMEDDS. How to choose solid carries is the key issue that whether S-SMEDDS could maintain the absorption characteristics of SMEDDS, including influence on the solubilization capacity and on digestion from the gastro-intestinal tract. In this dissertation, SMEDDS were prepared by using indomethacin as the model drug. And, the influences of several solid carries on SMEDDS were studied as follows:(1) Hydroxypropylmethylcellulose (HPMC) was a water-soluble carrier material used widely for oral formulations. The molecular structure of HPMC was made of lipophilic and hydrophilic groups, which benefit to emulsification and surface activity. SMEDDS was made by using indomethacin. The dispersion experiment and an in vitro lipolysis model were used to determine the influences of HPMC of three viscosity grades (K4M, K15M and K100M) and different concentrations of HPMC K100M upon SMEDDS digestion from gastrointestinal tract. The results showed all three kind of HPMC could inhibit drug precipitation from gastro-intestinal tract. With the increasing of viscosity of HPMC, the solubilization capacities of SMEDDS increased. With the increasing of viscosity and concentration, the drug concentration in aqueous phase after intestinal lipolysis both increased. S-SMEDDS were prepared by spray-drying, using different grade of HPMC. The results of release showed drug was released slower with the increasing of viscosity of HPMC. The release mechanism were backbone corrosion(2) Silica was good at biocompatibility, stability and hydrophilicity. In order to make the basis for the further development of S-SMEDDS, the influences of silica on absorption of S-SMEDDS were investigated. An in vitro lipolysis model was used to evaluation the influences of silica on SMEDDS digestion from intestinal tract. S-SMEDDS containing silica with different concentrations were prepared by extrusion/spheronization. The drug release and absorption were investigated. The results showed that the lipolysis rate and the drug concentration in aqueous phase after intestinal lipolysis both increased by adding silica, which was benefit to drug absorption. And while silica was not benefit to absorption for slowing drug release. Consistently, there was no significance influence of silica on intestinal absorption.(3)β-cyclodextrin could improve bioavailability of enclosed molecule for having the holes structure. The influences ofβ-cyclodextrin on the solubilization capacity and digestion from intestinal tract were studied. The results showed thatβ-cyclodextrin could improve the drug concentration in aqueous phase after intestinal lipolysis. S-SMEDDS were prepared by spray-drying, usingβ-cyclodextrin as the solid carries. It was obviously that the SMEDDS had a faster in vitro release rate than the conventional pellet. The absorption of SMEDDS and S-SMEDDS were better than the conventional pellet, but there was no significant difference between the SMEDDS and S-SMEDDS.In present work, the influences of three solid carries on SMEDDS were investigated by using in vitro experiments, in vivo experiments investigations should be necessary, which should not only be use for evaluating influences of solid carries on oral bioavailability preferably but also be benefit for revealing rules of solid vehicles on oral absorption, making the basis on formulation strategy of solid SMEDDS and providing an significant base on in vitro and in vivo assessment.