盐酸文拉法辛微孔渗透泵型控释片的研究
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摘要
盐酸文拉法辛(Venlafaxine Hydrochloride,简称VH),是一种新型结构的苯乙胺类抗抑郁药,通过阻断5-羟色胺(5-HT)和去甲肾上腺素(NE)双重再摄取而发挥作用。本文以VH为主药,在考察了药物和各种辅料性质的基础上,以MCC、乳糖、氯化钠、HPMCK_(4M)为片芯材料;以醋酸纤维素、PEG-400、DBP的丙酮溶液为包衣液;喷雾速率为5 mL·min~(-1),包衣温度30℃,包衣锅转速30 rpm,制备了VH微孔渗透泵型(Micro-Porous Osmotic Pump,简称MPOP)控释片。
本文对VH的理化特性和游离膜的性质进行了研究:37℃时,水中溶解度为558.64 mg·mL~(-1);在正辛醇-水体系中的表观油水分配系数为0.1198。通过考察溶解度参数、玻璃转化温度、透湿性以及电镜扫描,确定了丙酮、DBP和PEG-400分别为CA游离膜的良溶剂、增塑剂和致孔剂。
本文采用了大鼠在体单向灌流法研究了VH在大鼠肠道内的吸收情况。大鼠在体肠吸收动力学试验结果表明:VH在整个肠道内均有较好的吸收,无特定吸收部位,适宜制备成长效缓、控释制剂,各个肠段间的K_a和P_(app)无显著性差异(P＞0.05);肠灌流液中的不同药物质量浓度对VH的K_a和P_(app)无显著性影响(P＞0.05);随灌流速度加快,经过小肠的灌流药量增加,K_a和P_(app)呈线性增大(r=0.9995),药物吸收增加,说明药物在大鼠体内的吸收机制为被动扩散,不存在饱和吸收。
本文考察了各种因素对VH MPOP体外释药行为的影响。结果表明,VH MPOP的体外释药行为符合零级释放规律;渗透压促进剂的种类和用量、致孔剂的用量、包衣液浓度、包衣增重以及释放介质的离子强度,对药物释放均有显著性的影响;而熟化时间和温度、释放介质的pH值、溶出方法和转速,对药物释放均无显著性的影响。用正交试验设计,优化筛选出最佳包衣液处方。MPOP片的释药动力主要为衣膜内外的渗透压差。稳定性试验结果显示,VH MPOP除对高湿条件敏感外,在光照、高温、留样及加速试验中均表现出了良好的稳定性。
本文建立了高效液相色谱法测定家犬血浆中药物浓度。采用双周期双交叉试验设计,以市售盐酸文拉法辛普通胶囊为参比制剂,测定了VH MPOP片在家犬体内的相对生物利用度和药代动力学,采用DAS2.0软件对血药浓度数据进行处理。结果表明,VH MPOP片与VH普通胶囊的AUC_(0-t)分别为(142±3.58)和(153±8.20)μg·h·mL~(-1);T_(max)分别为11.7h和6h;C_(max)分别为10.2μg·mL~(-1)和15.9μg·mL~(-1);MRT分别为14.1h和10.6h;t_(1/2)分别为(5.55±0.261)和(5.44±0.839)h,自制VH MPOP片相对于市售普通胶囊的生物利用度为92.6%。MPOP片具有出峰时间晚、峰值低、血药浓度平稳的缓控释特征。MPOP片的体外释药特性与体内吸收有良好的相关性。
Venlafaxine hydrochloride is one of new structure phenylethylamine class anti-despondent medicine,which through blocks 5-hydroxy tryptamine and goes to the armor adrenalin dually to absorb again plays the role.In this paper,micro-porous osmotic pumps(MPOP)controlled release tablets are prepared,taking VH as the model drug.Based on the comprehensive pre-formulation research,MCC,lactose,sodium chloride and HPMCK_(4M)are used to make the tablet core.Take cellulose acetate(CA),Polyethylene glycol400(PEG-400),Dibutyl phthalate(DBP)and acetone as the coating solution.Tablets are coated by pan-spray method,and the coating process is described as the spray speed is 5mL·min~(-1),coating temperature 30℃and the coating pan rotational speed 30 rpm.
In this paper,physics-chemistry characteristic of VH and dissociation membrane nature were studied.Equilibrium solubility of VH in water was 558.64 mg·mL~(-1)under 37℃;Apparent n-octanol/water partition coefficient was 0.1198.Acetonl,DBP and PEG-400 were good solvent,good plasticizer and good pore forme for CA by investigating solubility parameter(δ),T_g,water permeability and canning electronic micrographs.
To investigate the absorption characters of VH in the intestine,the absorption kinetics and the absorption sites were studied by utilizing the rat intestinal absorption single pass perfusion model in situ.The results of perfused rat intestinal model showed that VH could be well absorbed at all segments of intestine in rats,where there was no special absorption site and was a good candidate for a sustained-release system.The concentration of drug had no evident influence on the absorption rate constants.Increasing perfusion flow rate produced increased values of K_a and P_(app).It was showed that the absorption of VH was the passive diffusion mechanism.
Studies were made about the various effect factors on the drug release of VH MPOP. The release behavior in vitro of the VH MPOP complied with zero order release rule.The results suggested that osmotic pressure promoting agent,pore former and coating weight had marked effect on the drug release,whereas the type of dissolution medium,dissolution method,rotation speed and pressure of the tablet core had less effect.Meanwhile,the effect of coating technique on the drug release was studied.By orthogonal experimental design, the best coating material were optimized.Investigation about the drug release mechanism proved that the release kinetic derives from the difference of the osmotic pressure across the membrance.The stability test results showed that VH MPOP is unstable under high humidity,whereas good stability was found under light,high temperature,the accelerating test and room temperature.
HPLC with UV method was preformed to detect the concentration of VH in plasma of dogs.using commercial conventional capsules as the reference and by the two periods cross-over design for determining the pharmacokinetics and bioavailability in six healthy dogs.For controlled-release tablets and capsules,AUC_(0-t)was(142±3.58)and(153±8.20)μg·h·mL~(-1);T_(max)was 11.7h and 6h;C_(max)was10.2μg·mL~(-1)and 15.9μg·mL~(-1);t_(1/2)was (5.55±0.261)and(5.44±0.839)h respectively.MRT was 14.1h and 10.6h.The relative bioavailability was 92.6.%.MPOP tablets had the controlled-release characteristics of delayed T_(max),lower C_(max)and smoother plasma concentration.Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.
本文对VH的理化特性和游离膜的性质进行了研究:37℃时,水中溶解度为558.64 mg·mL~(-1);在正辛醇-水体系中的表观油水分配系数为0.1198。通过考察溶解度参数、玻璃转化温度、透湿性以及电镜扫描,确定了丙酮、DBP和PEG-400分别为CA游离膜的良溶剂、增塑剂和致孔剂。
本文采用了大鼠在体单向灌流法研究了VH在大鼠肠道内的吸收情况。大鼠在体肠吸收动力学试验结果表明:VH在整个肠道内均有较好的吸收,无特定吸收部位,适宜制备成长效缓、控释制剂,各个肠段间的K_a和P_(app)无显著性差异(P＞0.05);肠灌流液中的不同药物质量浓度对VH的K_a和P_(app)无显著性影响(P＞0.05);随灌流速度加快,经过小肠的灌流药量增加,K_a和P_(app)呈线性增大(r=0.9995),药物吸收增加,说明药物在大鼠体内的吸收机制为被动扩散,不存在饱和吸收。
本文考察了各种因素对VH MPOP体外释药行为的影响。结果表明,VH MPOP的体外释药行为符合零级释放规律;渗透压促进剂的种类和用量、致孔剂的用量、包衣液浓度、包衣增重以及释放介质的离子强度,对药物释放均有显著性的影响;而熟化时间和温度、释放介质的pH值、溶出方法和转速,对药物释放均无显著性的影响。用正交试验设计,优化筛选出最佳包衣液处方。MPOP片的释药动力主要为衣膜内外的渗透压差。稳定性试验结果显示,VH MPOP除对高湿条件敏感外,在光照、高温、留样及加速试验中均表现出了良好的稳定性。
本文建立了高效液相色谱法测定家犬血浆中药物浓度。采用双周期双交叉试验设计,以市售盐酸文拉法辛普通胶囊为参比制剂,测定了VH MPOP片在家犬体内的相对生物利用度和药代动力学,采用DAS2.0软件对血药浓度数据进行处理。结果表明,VH MPOP片与VH普通胶囊的AUC_(0-t)分别为(142±3.58)和(153±8.20)μg·h·mL~(-1);T_(max)分别为11.7h和6h;C_(max)分别为10.2μg·mL~(-1)和15.9μg·mL~(-1);MRT分别为14.1h和10.6h;t_(1/2)分别为(5.55±0.261)和(5.44±0.839)h,自制VH MPOP片相对于市售普通胶囊的生物利用度为92.6%。MPOP片具有出峰时间晚、峰值低、血药浓度平稳的缓控释特征。MPOP片的体外释药特性与体内吸收有良好的相关性。
Venlafaxine hydrochloride is one of new structure phenylethylamine class anti-despondent medicine,which through blocks 5-hydroxy tryptamine and goes to the armor adrenalin dually to absorb again plays the role.In this paper,micro-porous osmotic pumps(MPOP)controlled release tablets are prepared,taking VH as the model drug.Based on the comprehensive pre-formulation research,MCC,lactose,sodium chloride and HPMCK_(4M)are used to make the tablet core.Take cellulose acetate(CA),Polyethylene glycol400(PEG-400),Dibutyl phthalate(DBP)and acetone as the coating solution.Tablets are coated by pan-spray method,and the coating process is described as the spray speed is 5mL·min~(-1),coating temperature 30℃and the coating pan rotational speed 30 rpm.
In this paper,physics-chemistry characteristic of VH and dissociation membrane nature were studied.Equilibrium solubility of VH in water was 558.64 mg·mL~(-1)under 37℃;Apparent n-octanol/water partition coefficient was 0.1198.Acetonl,DBP and PEG-400 were good solvent,good plasticizer and good pore forme for CA by investigating solubility parameter(δ),T_g,water permeability and canning electronic micrographs.
To investigate the absorption characters of VH in the intestine,the absorption kinetics and the absorption sites were studied by utilizing the rat intestinal absorption single pass perfusion model in situ.The results of perfused rat intestinal model showed that VH could be well absorbed at all segments of intestine in rats,where there was no special absorption site and was a good candidate for a sustained-release system.The concentration of drug had no evident influence on the absorption rate constants.Increasing perfusion flow rate produced increased values of K_a and P_(app).It was showed that the absorption of VH was the passive diffusion mechanism.
Studies were made about the various effect factors on the drug release of VH MPOP. The release behavior in vitro of the VH MPOP complied with zero order release rule.The results suggested that osmotic pressure promoting agent,pore former and coating weight had marked effect on the drug release,whereas the type of dissolution medium,dissolution method,rotation speed and pressure of the tablet core had less effect.Meanwhile,the effect of coating technique on the drug release was studied.By orthogonal experimental design, the best coating material were optimized.Investigation about the drug release mechanism proved that the release kinetic derives from the difference of the osmotic pressure across the membrance.The stability test results showed that VH MPOP is unstable under high humidity,whereas good stability was found under light,high temperature,the accelerating test and room temperature.
HPLC with UV method was preformed to detect the concentration of VH in plasma of dogs.using commercial conventional capsules as the reference and by the two periods cross-over design for determining the pharmacokinetics and bioavailability in six healthy dogs.For controlled-release tablets and capsules,AUC_(0-t)was(142±3.58)and(153±8.20)μg·h·mL~(-1);T_(max)was 11.7h and 6h;C_(max)was10.2μg·mL~(-1)and 15.9μg·mL~(-1);t_(1/2)was (5.55±0.261)and(5.44±0.839)h respectively.MRT was 14.1h and 10.6h.The relative bioavailability was 92.6.%.MPOP tablets had the controlled-release characteristics of delayed T_(max),lower C_(max)and smoother plasma concentration.Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.
引文
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