Construction And Evaluation Of A Novel Drug Delivery System Of Long-Term Nanosuspension

Nowadays, many new chemical entities occurred with the rapid development of science and technology. But most of them were either poorly water-soluble or with poor stability, which leads to a short half life or low bioavailability. Therefore, it was particularly important to discover a new drug delivery system, in order to achieve a long and efficient effect. There are a lot of methods to achieve this purpose, and one of them is to reduce particle sizes of poorly water-soluble drugs to nano-scale. The intramuscular route could extend the drug release time, at the same time. To achieve this, the novel drug delivery system of long-term nanosuspension was constructed. Firstly, the particle sizes were reduced by wet milling method. Secondly, the long-lasting effect was achieved via intramuscular injection. This delivery system was evaluated according to the particle size, crystalline state, re-dispersibility, sedimentation ratio, sterilization stability, pharmacokinetics and muscular stimulation. In this research, andrographolide and curcumin were selected as the model drugs and they were prepared into nanosuspension, respectively. The characterizations of the nanosuspension were evaluated. The specific contents were as follows:1. The establishment of HPLC method for in vitro analysis. HPLC methods for the determination of andrographolide and curcumin were established, respectively. Andrographolide showed good linear relationship between concentration and peak area, among the concentration of 0.2 ~ 40 μg/ml. And this method was with good specificity, high precision and good accuracy. Curcumin also showed good linear relationship between concentration and peak area, among the concentration of 0.2 ~ 40 μg/ml. And this method was with good specificity, high precision and good accuracy. 2. The quality evaluation system of the drug delivery system of long-term nanosuspension was established. It contains particle size, crystalline state, re-dispersibility, sedimentation ratio, sterilization stability, in vitro dissolution, as well as the analysis method of pharmacokinetics and muscular stimulation.3. Andrographolide was selected as the model drug, and andrographolide nanosuspension was prepared. The characterizations were also evaluated. The optimized formulation was as follows. 0.3 g Tween 80 was dispersed into 100 m L distilled water under magnetic stirring. Then 10 g andrographolide was dispersed into the mixture. The suspension was transferred to the milling bowl. The speed was 3000 rpm and milling time was 30 min. The particle size, crystalline state, re-dispersibility, and sedimentation ratio were evaluated. 4. Curcumin was selected as the model drug, and curcumin nanosuspension was prepared. The characterizations were also evaluated. The optimized formulation was as follows. 1.25 g Tween 80 was dispersed into 250 m L distilled water under magnetic stirring. Then 20 g curcumin was dispersed into the mixture. The suspension was transferred to the milling bowl. The speed was 3000 rpm and milling time was 30 min. The particle size, crystalline state, re-dispersibility, and sedimentation ratio were evaluated. 5. The research of in vivo pharmacokinetics and muscular irritation in rats. Rats were chosen as the experiment animals. The in vivo properties of andrographolide and curcumin nanosuspension in rats were researched, and muscular irritation was investigated, respectively. Results showed that, after intramuscularly administrating andrographolide nanosuspension, it presented sustained release and can enhance the absorption amount compared with oral way, which could lead to a long effect; after intramuscularly administrating curcumin nanosuspension, the relative bioavailability can be enhanced up to 55 times and a long effect was achieved. The muscular irritation experiments showed that the two drugs have no obvious irritation to muscle. This drug delivery system could enhance the drug absorption amount and achieve a long effect.