The Effect Of Precipitation Inhibitor On The Behavior Of Self-microemulsifying Drug Delivery System In Gastrointestinal Tract

The supersaturatable self-emulsifying drug delivery system (S-SEDDS) can improve bioavailability of poorly water soluble drugs. It can enhance the absorption of drugs when compared with the formulations of self-emulsifying drug delivery system (SEDDS). Precipitation inhibitor (PI) was used to generate and maintain the supersatursted state to effectively improve absorption of drug. But the impact of PI on S-SEDDS and behavior of S-SEDDS in gastrointestinal tract were unclear. The dosage forms of S-SEDDS were only soft capsule and solid powder by spray drying, which unbenefit for enlarging the applicability.This study showed the effect of PI on the behavior of SMEDDS in simulative environment of gastrointestinal tract. Furthermore, the mechanism was discussed. This study also developed a new solid S-SEDDS dosage form——self-microemulsifying mouth dissolving film (SMDF) and the properties both in vitro and in vivo had been examined.(1) Using indomethacin (IMC) as the model drug to prepare SMEDDS. The effects of various PI, including hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), Sodium alginate L120 and Gelatine on solubilization of SMEDDS by in vitro dispersion were discussed. (The HPMC and PVP with different types, involving HPMC E3、E5、E50、K4M、K15M、K100M and PVP K30、K90). The study of the crystallization kinetics indicated the regularities of inhibiting IMC crystallization under the impact of PI. The results showed that HPMC with lower molecular weight or higher substitution ratio of methyl and hydroxypropyl groups have stronger ability of inhibiting IMC crystallization.(2) The effect of PI on SMEDDS lipolysis investigated by in vitro lipolysis model. The effects of various HPMC (HPMC E3、E5、E50、K4M、K15M、K100M) on rate of lipolysis, solubilization of IMC after lipolysis and distribution of IMC molecules across the aqueous phase were studied. The results showed that HPMC with lower viscosity bring more benefits for drug solubilization and drug distribution in aqueous phase. These might be the result of retiform aggregation patterns formed by various grades of HPMC.(3) The SMEDDS mouth dissolving films (SMDF) containing IMC has been developed. A three factor, three-level Box-Behnken design was used for optimizing formulation, investigated the effect of amounts of microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hypromellose on properties of SMDF. Optimized SMDF could release 40% of drug in 1 min and release completely at 5min. The surface of SMDF showed tight and the surface encapsulated by self-microemulsifying ingredients completely.The results of differential scanning calorimetry (DSC) and X-ray diffraction (XRD) showed the internal physical state of IMC in the SMDF was amorphous. In vivo absorption study showed SMDF significantly increased oral bioavailability of IMC compared to the mouth dissolving film (MDF) and enteric tablets.In present study, the effects of various PI on SMEDDS were investigated and interaction mechanisms were analysed. The SMDF has broad application prospects, good compliance, strong tensile and can rapidly release drug through fast self-microemulsifying.