Study On The Scale-up Preparation Of Acyclovir-loaded Bioadhesive Microspheres

Since1990’s, studies on bioadhesive microparticles with controlled/sustained-release characteristics have become hot topics in pharmaceutical research. Bioadhesive microparticles showed promising potential in clinical application due to their large specific surface area which facilitate them to reach at the internal mucus layer easily and adhere to the mucous membrane more tightly. Unfortunately, not a product of bioadhesive microparticulate formulation has been brought to market because of some insurmountable barriers in scale-up manufacture.Compared to traditional formulations, the bioadhesive particulate preparations have more requirements for quality indicators. On one hand, due to the addition of adhesive polymers, the industrialized manufacturing process cannot take account of the characters of sustained release and bioadhesiveness simultaneously. On the other hand, the in-liquid drying method commonly used in laboratories has more influencing factors and harsh technological conditions. Furthermore, during the preparation process, large amount of organic solvents are often used which makes it even more difficult to meet with the quality requirements and an extra burden in reclaiming the solvents.To solve the problems, we carried on a deep investigation into the factors and the mechanism that influence the formation of bioadhesive particles using in-liquid drying method. Ethylcellulose (Ec,20cPs) and Carbopol (Cb,974P) were selected as matrix and bioadhesive polymer, respectively, and acyclovir as drug model. Lots of work on preformulation studies, such as micromeritics of raw materials and solvent properties has been implemented. Since then, we have gradually grasped a new preparation process which was rapid, simple and qualified. Meanwhile, according to the nature of solubility increase of acetone (the solvent of dispersed phase) in continuous phase consisted of liquid paraffin with certain ratio of the emulsifier, Span80, we put forward an idea to replace emulsification-evaporation techniques by emulsification-extraction techniques, which, as a result, overcame the problem of reclaiming the solvent of dispersed phase in traditional in-liquid drying method. In addition, the method of separation of Span80from liquid paraffin was also established using silica gel column chromatography, making the continuous phase liquid paraffin able to be recycled.Based on the above studies, we accomplished the scale-up preparation of acyclovir loaded bioadhesive microspheres (Acv-Cb-Ec ms) from1L to20L, and investigated the in vitro/in vivo properties of microspheres. The size of the microspheres ranges between450～900μm, the yield of microspheres was above85%. The drug release profile in pH3.6PBS was as follows:25%<Q0.5h<30%,60%<Q4h<70%,Q8h>85%. The results of in vitro and in vivo bioadhesive evaluation showed that Acv-Cb-Ec ms had a good bioadhesion property that they could retain in the gastrointestinal tract for an extended time. In pharmacokinetics study, relatively steady plasma drug concentrations were observed within8h after oral administration of Acv-Cb-Ec ms to rats. The AUC and mean residence time (MRT) of Acv-Cb-Ec ms were significantly higher than that of Acv suspension, which indicated that the bioavailability of acyclovir was greatly improved due to the prolonged retention of Acv-as-ms in gastrointestinal tract.