| Compared to other formulations, Long-acting injectionscan maintain the drug concentration between the minimum effective concentration(MEC) and the minimum toxic concentration(MTC), extend the exposure time, reduce side effects and improve the drug compliance due to the lower frequency.ZL004 can increase leukocyte count which belongs to dithiolopyrrolones,and is poorly soluble in water. This paper chose ZL004 as the model drug to study the preformulation and prepare the long-acting injections including microspheres and suspensions.Firstly, in this paper, the preformulation of ZL004 was performed which mainly included the solubility in different organic solvents, dissolution medium and different p H buffer solution, dissolution rate and inherent dissolution rate in the dissolution medium, oil-water partition coefficients, polymorphism, stability studies and solvent residue.Secondly, a HPLC method for determination of ZL004 content and a analysis method of microspheres in vitro drug release were established. These methods are simple and good specificity, high precision and good accuracy. And ZL004 suspension agent particle size measurement method was also established. By this method, the determination of samples possessed good stability, high precision and good durability.Finally, in this paper we use o/w emulsification method to prepare the microspheres. In vitro evaluation, we found that it can’t maintain constant release rate. In addition, ZL004 suspension was prepared, and eventually optimal process and prescription parameters are as follows. Prescription included CMC-Na, glycerol as suspending agent, Poloxamer188 as the wetting agent, water as dispersion medium. Process parameters were as follow. The number of grinding beads was 30.The rotating speed was 600 rpm and grinding time was 60 minutes. The ZL004 suspension prepared by this method had similar particle size distributions with paliperidone palmitate injection and good physical stability within 30 days. |
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