Studies On Solid Self-Emulsifying Drug Delivery System Of Loratadine

As an antihistamine drug with tricyclic structure, loratadine is mainly used to relieve the symptoms caused by all kinds of allergic reactions as well as the treatment of chronic urticarial, itchy skin disease and other allergic skin diseases. As a result of extremely poor water-solubility, Loratadine has only an mass of 3.3μg?m L-1 in the water of 25℃, thus causing the problem of individual differences and low bioavailability with the oral formulations. Self-emulsifying drug delivery system has great advantage in improving both individual differences and bioavailability. However, the conventional self- emulsifying preparation is usually filled with the oil,surfactant and cosurfactant in soft capsules which containing large amount of surfactant leading to cause gastrointestinal irritation and the problem of leakage might occur in the long-term storage. All those problems can be solved when using the solid self-emulsifying drug delivery system(S-SEDDS). In this system, loratadine is dissolved in the appropriate oil phase and highly dispersed in the solid adsorption carrier. The preparation will form fine emulsion spontaneously when encountering water. The S-SEDDS not only can improve the bioavailability of loratadine in vivo, but also avoid the irritation of gastrointestinal arising from surfactant. S-SEDDS has the advantage of simple preparation, good stability and quality controllable.In the investigation of drug properties, the solubility of loratadine in 0.1mol·L-1 hydrochloric acid solution, water and p H6.8 phosphate buffer solution was determined. The results showed that the solubility of loratadine was p H-dependent that solubility decreased with p H increased; The oil-water partition coefficients of loratadine in octanol-water system was determined and log P was 2.25, showed that the drug was lipophilic. The solubility of loratadine in different oil phase and cosolvent was also investigated to select the higher solubility of oil phase and cosolvent.In prescription screening study, single factor experiment was carried out preliminarily. The influence of the oil absorption material and solid diluent on the preparation was examined. The results showed that the amount of the oil absorption carrier and the type of the solid diluents had significant effect. On the basis of single factor experiment, orthogonal designed experiments were used to optimize the prescription. The dissolution, fluidity of particles and emulsion particle size was evaluated and the optimized formulation was decided. The validation study of prescription showed that the preparation process was stable and controllable in quality which can meet the production demand.In the evaluation study in vitro, the morphology of solid self-emulsifying preparation was observed by means of X-ray diffraction experiment and the optical microscope, the particle size and distribution of emulsion when the solid self-emulsifying preparation in water were measured by the laser particle size analyzer. The results showed that no loratadine crystal was observed in the solid self-emulsifying preparation. Loratadine molecular was dissolved in the oil and adsorbed by the pore of the adsorption material. The emulsion particle size of the solid self-emulsifying preparation in water was about 2μm and the size distribution was uniform.The content determination method for loratadine was established by HPLC method. Loratadine concentration in 2~100μg?m L-1 had good linearity and the method had high accuracy and good precision. The examination method of related substances of loratadine was also studied with high detection sensitivity, good specificity and good reproducibility. At the same time, the dissolution method was established for determination of loratadine dissolution from S-SEDDS capsules. Compare to the commercial tablet of Clarityne, loratadine dissoluted from S-SEDDS capsule and tablet Clarityne were all above 80% in 45 min.In the study of stability, the results of influence factor tests showed that the related substances was slightly increased in the condition of strong light and the wet weight increased in the 92.5% humidity conditions. These were indicated that this product should be light-avoided and air tightened. The accelerated testing for 6 months and 6 months at room temperature showed that the appearance, emulsion particle size, content, dissolution and related substances had no significant changes.In vivo pharmacokinetic study, the relative bioavailability of solid self-emulsifying capsule in beagle dogs was investigated compare with the commercial tablet Clarityne. The results showed that compared to the commercial tablet, Cmax of solid self-emulsifying was significantly increased(Cmax=1146.54ng·L-1, and the tablet Clarityne Cmax = 299.62ng·L-1); the relative bioavailability of solid self-emulsifying capsule was 368%. The parameters of Cmax, t1/2, AUC(0-t) and AUC(0-∞), were analyzed statistically, Cmax, AUC(0-t) and AUC(0-∞)) had significant difference(P<0.05) between two groups, suggesting that S-SEDDS formulation can significantly improve the bioavailability of loratadine in vivo.In conclusion, the S-SEDDS preparation of loratadine was stable and controllable with feasible preparation process. In this study, the formulation contained appropriate solid excipient instead of liquid surfactants and also emulsified when dispersed into water. S-SEDDS cannot only enhance the bioavailability in vivo and also avoid gastrointestinal side effects which caused by surfactant. These studies manifested that the purpose of the experimental design was achieved.