Preliminary Study On Paliperidone Palmitate Nanosuspension For Injection

This paper aims to develop the drug delivery system of insoluble drugs—nanosuspension.Smaller particle size causes higher solubility and faster dissolution rate.Consequently, nanosuspension can improve the bioavailability of insoluble drugs.Paliperidone(PA) belongs to insoluble drugs and is clinically used for the treatment of schizophrenia. As a prodrug, Paliperidone palmitate(PP) was produced by esterification of paliperidone and palmitic acid.It has low solubility and big particle size.In this paper,grinding method and microfluidization method had been compared to choose a better approach for preparing the paliperidone palmitate nanosuspension(PP-NSP) which is used via intramuscular injection.After the formulation and preparative technique had been determined, the quality and in vivo study of PP-NSP were also evaluated.First of all, the HPLC analytical method for determination of PP cotent and related substances was established and validated. The results showed that this method is specific, sensitive, simple and accurate, which can be used for subsequent quality evaluations.Secondly,The grinding method was employed to prepare PP-NSP, 0.8mm in diameter of grinding medium was chosen according to the target particle size(D50)which was between 500 nm to 800 nm.The volume of grinding medium is 85% of that of the milling chamber. The optimised parameters of the production process were determined that concentration of tween-20 was 12mg/m L, spindle speed was 4000 rpm and grinding time was 20 mins. However, the final preparation had a high viscosity, it should be pretreated under 50% of intensity of ultrasonic power for 30 s, otherwise the D50 would be betweent 2~3μm instead of 730±10nm. It is found that PP-NSP prepared by grinding method had poor stability and it would cause particles agglomeration.Thirdly, the microfluidization method was applied to prepare PP-NSP. The parameters were as follows: concentration of tween-20 was 24mg/m L, homogenization pressure was 30000 psi and homogenizing frequency was 20 times. The preparation was more stable and the D50 was only 538±6nm.In order to further increase the stability ofthe PP-NSP, different kinds of physical stabilizer had been screened. The eventual concentration of polyethylene glycol-4000 was 300mg/m L, which had less impact on the particle size and in vitro release.The quality of the PP-NSP which was prepared by microfluidization method were reviewed.PP-NSP was milky white. It would stratify and form white precipitation when it stood for a long time.But the precipitation can be dispersed uniformly by gentle shake.Its p H value was 7.26±0.02 which meets the requirement of intramuscular preparations. The profile of release in vitro was investigated by using oar method with0.001mol/L hydrochloric acid solution containing 0.5% tween-20 as the medium.Results showed that the amount of burst release at 1.5min was 18.73±1.47% which was under 20%, and in vitro release rates were 61.44±0.38% in 20 min and 84.48±1.15% in45 min respectively. The in vitro release profiles were expressed by Ritger-Peppas equation.The preliminary stability tests in 30 days under the conditions of 25℃、40℃、 60℃ and strong light were carried out.The indexes such as particle size,content,related substances and appearance were all investigated.Results showed that there were no significant changes of PP-NSP when kept under 25℃ and strong light,but the particle size was bigger when kept at 60℃ for only 5 days. The related substances increased by 0.464% and content of API decreased by about 10% when kept at 60℃ for 30 days. What is more, the colour of the preparation turned from milky to faint yellow and the precipitation should be shaked strongly to be dispersed.After administration of PP, its in vivo hydrolysate PA will take effect.The pharmacokinetic behavior of PA was investigated by using HPLC-MS/MS method in SD rats.Results showed that PP-NSP had a sustained release behavior in vivo and the mean retention time(MRT) was 3.874±0.352 days.The AUC(0�'∞) compared with commercial preparation was 97.095±8.887%.As is known that the bigger the particle size is,the longer the MRT is. So the MTR of PP-NB was longer than PP-NA’s for half a day, and the AUC(0�'∞) compared with commercial preparations was just84.063±14.052%.