项目来源

河北省科技计划

项目主持人

盖树常

项目受资助机构

河北龙海药业有限公司

项目编号

19272706D

立项年度

2019

立项时间

未公开

项目级别

省级

研究期限

未知 / 未知

受资助金额

未知

学科

生物技术与制药

学科代码

未公开

基金类别

重点研发计划

关键词

帕利哌酮 ; 制备工艺 ; 质量研究 ; Paliperidone ; Preparation process ; Quality research

参与者

未公开

参与机构

未公开

项目标书摘要：帕利哌酮渗透泵片由美国强生公司研发生产，是治疗精神分裂症的口服缓控释制剂。该剂型零级释药，不易受胃肠道可变因素的影响，提高了患者用药的依从性。原研工艺为三层片芯双孔释药，制备工艺复杂，设备要求高。本课题拟制备双层双释药孔渗透泵片，体外释放行为要与原研制剂一致。主药帕利哌酮是不溶于水的弱碱性药物，平均粒径D50为22.19 μm,参考双层渗透泵片处方信息确定辅料的种类和限度，原辅料相容性试验中，样品在高温、高湿、光照条件下，外观均无明显变化，含量稍有降低，相容性良好。采用湿法制粒工艺制备双层片芯，对片芯双层包衣。通过单因素实验考察包衣膜增重、促渗透聚合物用量、包衣液浓度等处方工艺因素对药物释放的影响。含药层处方:PEO 200K 92 mg,氯化钠(粉末)18.75 mg,PVP K29 7.3 mg,硬脂酸(粉末)0.75 mg,BHT 0.1 mg,黄氧化铁0.1 mg;推动层处方:PEO 7000K 96.65 mg,氯化钠(粉末)18.75 mg,PVP K29 7.5 mg,硬脂酸(粉末)0.75 mg,BHT 0.1 mg,红氧化铁1.25 mg。采用羟乙纤维素、PEG3350为包材制备内包衣层，包衣增重0.6%;采用CA、PEG3350为包材制备释药速度控制层，包衣工艺参数：进风温度30 ℃,物料温度27 ℃,雾化压力0.11~0.13 Mpa,包衣液浓度3%~4%,包衣增重20%。小试重复三批样品进行质量检测，含量均在95%~105%,杂质A含量小于1%,其他单一最大杂质小于0.2%,总杂小于1.2%,各个取样点对应的释放度均满足标准要求，释放曲线的f2值均大于50,水分含量为1.48%~1.52%(小于3%)。进行含量液相分析方法的方法学验证，结果表明,0.3~30 μg/mL浓度范围内标准曲线方程为y=436452.68388x-40054.79399,R2=0.99981>0.99,专属性，精密度，回收率等均符合要求。稳定性试验研究表明，帕利哌酮渗透泵片外观含量无显著变化，样品批间差异较小，杂质含量小于1%,总杂小于1.2%,质量稳定，需防潮、避光、密封保存。本课题的研究达到了预期目标。

Application Abstract: Paliperidone osmotic pump tablets are developed and produced by Johnson&Johnson in the United States.It is an oral sustained and controlled release preparation for the treatment of schizophrenia.The dosage form has zero-level drug release,is not easily affected by variable factors in the gastrointestinal tract,and improves the convenience of medication for patients.The original research formulation is a three-layer tablet core and two-hole drug release,the preparation process is complicated,and the equipment requirements are high.This subject intends to prepare a double-layer and dual-release drug pore osmotic pump tablet,and the in vitro release behavior should be consistent with the original formulation.The main drug,paliperidone,is a water-insoluble,weakly basic drug,with an average particle size D50 is 22.19 μm.Refered to the prescription information of double-layer osmotic pump tablets,determined the types and limits of excipients.The appearance of the sample under high temperature,high humidity,and light conditions has no obvious change,the content is slightly reduced,and the compatibility is good.A double-layer tablet core is prepared by a wet granulation process,and the tablet core is double-coated.Single-factor experiments were conducted to investigate the influence of the formulation process factors such as the weight gain of the coating film,the amount of penetration enhancing polymer,and the concentration of the coating solution on the drug release.Drug-containing layer prescription:PEO 200K 92 mg,sodium chloride(powder)18.75 mg,PVP K29 7.3 mg,stearic acid(powder)0.75 mg,BHT 0.1 mg,yellow iron oxide 0.1 mg;promotion layer prescription:PEO 7000K 96.65 mg,sodium chloride(powder)18.75 mg,PVP K29 7.5 mg,stearic acid(powder)0.75 mg,BHT 0.1 mg,red iron oxide 1.25 mg.Using hydroxyethylcellulose and PEG3350 as packaging materials to prepare the inner coating layer,the weight gain of the coating is 0.6%;using CA and PEG3350 as packaging materials to prepare the drug release rate control layer,the coating process parameters:inlet air temperature 30 ℃,material temperature 27 ℃,atomization pressure 0.11~0.13 Mpa,coating solution concentration 3%~4%,coating weight gain 20%.Three batches of samples were repeatedly tested for quality,and the content was 95%~105%,the content of impurity A was less than 1%,and other single maximum impurities were less than 0.2%,the total impurities are less than 1.2%,and the release degree corresponding to each sampling point meets the standard.It is required that the f2 value of the release curve is greater than 50,and the moisture content is 1.48%~1.52%(less than 3%).The methodological verification of the content liquid phase analysis method is carried out.The results showed that the standard curve equation in the concentration range of 0.3~30 μg/mL is y=436452.68388x-40054.79399,R2=0.99981>0.99,and the specificity,precision,recovery rate are all meet the requirements.Stability test studies have shown that the appearance content of paliperidone osmotic pump tablets has no significant change,the difference between samples is small,the impurity content is less than 1%,the total impurities are less than 1.2%,the quality is stable,and it needs to be protected from moisture,light,and sealed.The research of this subject has achieved the expected goal.

项目受资助省

河北省