基于渗透泵机理的一种口服时辰给药系统研究

【作者】 毕岳琦；

【导师】 侯世祥；

【作者基本信息】 四川大学 ， 药剂学， 2007， 博士

【摘要】 哮喘和高血压具有明显昼夜节律，最高呼气流量（PEF）是评价呼吸道通气功能的一项客观指标，哮喘在PEF值降低时症状加剧，在午夜至清晨间哮喘患者PEF值降至谷底，此段时间哮喘最容易发作；清晨血压升高过快容易诱发中风。对哮喘和高血压采取时辰治疗的研究已有大量报导，但目前专门用于时辰治疗的时辰给药系统尚不多见。本文以分别以茶碱和盐酸维拉帕米为模型药物，研究制备了具有“慢速—快速”双相释药特征的时辰给药系统，用于哮喘及高血压的夜间治疗并考察了其体外释药行为及释药机理。两种给药系统在夜间服用后有具有如下特点：即先慢速释药以维持一定的治疗浓度，在午夜至清晨间释药加快以达到高血药浓度，使药物的血药浓度同哮喘患者PEF或高血压患者的血压的变化曲线相协调。该给药系统较普通剂型更符合时辰治疗的需要。两种时辰给药系统均采用双层片芯包衣的方法制备，通过体外试验考察了片芯处方、包衣膜处方和厚度对两种给药系统中药物释药行为的影响，确定了最佳处方工艺。茶碱时辰给药系统片芯内外层渗透推动剂分别为磷酸钠和氯化钠，盐酸维拉帕米时辰给药系统片芯内外层渗透推动剂为甘露醇，外层加入HPMCE5作为释放阻滞剂。茶碱、盐酸维拉帕米两种时辰给药系统的优选包衣膜处方分别为CA-PEG400-DEP（54.5％-36.4％-9.1％，w／w）和CA-PEG1500-DEP（54.5％-36.4％-9.1％，w／w），最佳包衣增重分别为16mg／片～22mg／片及19mg／片～23mg／片。两种时辰给药系统体外释药规律的考察结果表明：释放介质pH值和搅拌速度对脉冲片的释药行为无显著影响，随释放介质渗透压升高，两种给药系统的释药速率降低，累积释放量减少。测定了茶碱和两种渗透推动剂从茶碱时辰给药系统中的释放曲线、释药过程中时辰给药系统内部渗透压和pH值的变化规律以及茶碱溶解度随pH值的变化规律，根据普通渗透泵片的释药速率方程为基础建立了其释药速率方程组，并推测系统的双相释药机理，其中茶碱在系统内溶解度的变化是系统双相释药的主要成因。另考察了体外释药过程中盐酸维拉帕米时辰给药系统内部渗透压的变化并估测其双相释药机理，其中片芯外层HPMC的逐步溶解释放导致系统内溶液粘度的变化是系统双相释药的主要成因。为了探讨两种时辰给药系统能否推广用于其他药物，参照茶碱时辰给药系统的制备工艺，制备了氨茶碱和盐酸维拉帕米的时辰给药系统；参照盐酸维拉帕米时辰给药系统的制备工艺，制备了茶碱和磷酸川芎嗪的时辰给药系统。体外释放结果表明茶碱时辰给药系统适用于类似茶碱和氨茶碱的在碱性条件下溶解度增大的药物，盐酸维拉帕米时辰给药系统适用于类似茶碱和盐酸维拉帕米的溶解速度及溶解度均不是很大的药物。以Beagle犬为试验对象进行了两种给药系统的药物动力学研究。建立了高效液相-紫外检测法测定血浆中茶碱及盐酸维拉帕米的浓度。通过考察包衣增重对给药系统体内药物释放的影响，发现包衣增重增大，系统体内的释药减少。包衣增重6mg／片时，茶碱时辰给药系统的相对生物利用度约为100％，盐酸维拉帕米时辰给药系统的相对生物利用度约为70％。试验组分别给予包衣增重6mg／片的茶碱及盐酸维拉帕米时辰给药系统，对照组分别给予茶碱缓释片及盐酸维拉帕米普通片。试验结果表明，茶碱试验组和对照组的AUC_0→8分别为57.7h·mg·L^-1和54.7h·mg·L^-1；Cmax分别为2.9mg·L^-1和3.8mg·L^-1。经方差分析和双单侧t检验，二者AUC_0→8无显著差异，Cmax有显著差异。茶碱试验组和对照组的Tmax分别为7.0h和4.5h，经符号秩检验，两组的Tmax有显著差异。盐酸维拉帕米试验组和对照组的AUC_0→8分别为2844h·ug·L^-1和4425h·ug·L^-1；Cmax分别为435ng·L^-1和1011ng·L^-1。经方差分析和双单侧t检验，二者AUC AUC_0→8和Cmax有显著差异。盐酸维拉帕米试验组和对照组的Tmax分别为7.0h和2.0h，经符号秩检验，两组的Tmax有显著差异。两种时辰给药系统的体外释药和体内吸收具有一定相关性，但盐酸维拉帕米时辰给药系统的体内释药不完全，与普通片相比其相对生物利用度为64％。体内试验表明，两种时辰给药系统的Tmax均为7h左右，睡前服用后Cmax出现在清晨，且在Cmax出现前体内均可维持相当的血药浓度，符合本课题的设计目的，可以满足哮喘及高血压时辰治疗的要求。本文针对哮喘和高血压的时间节律，尝试设计了专门用于该两种疾病的夜间治疗的时辰给药系统。较普通制剂或缓释制剂，时辰给药系统的达峰时间推迟，给药8h后血药浓度更高，更符合对哮喘和高血压进行时辰治疗的需求。另本文首次将渗透泵技术用于药物的双相释放，扩展的渗透泵技术的应用范围。更多还原

【Abstract】 Asthma and hypertension are two kinds of diseases with significant circadian rhythms. Peak expiratory flow （PEF） is a valuable criteria to evaluate the ventilation function of respiratory tract, and the symptom of asthma will exaggerate when PEF descend. The PEF of asthma patients always reaches its lowest point between midnight and early morning, and asthma is at a high risk to attack during the same time. Too fast elevation of blood pressure during early morning is easy to induce apoplexy to hypertension patients. A lot of reports have been published concerning the chronotherapy of asthma and hypertension, but drug delivery systems devised especially for chronotherapy were seldom studied.Theophylline and verapamil hydrochloride were selected as model drugs, and two chronopharmaceutical drug delivery systems with a "slow-fast" release pattern of drug for the nocturnal therapy of asthma and hypertension were developed in this paper. In vitro release rules and mechanism of the biphasic release of the two drug delivery systems were studied in this article.After oral administration at bedtime, the two drug delivery systems would first release their effective components at a relatively low speed, drug released during this period was supposed to maintain an effective blood concentration in vivo. Between midnight and early morning, drug release from the administered drug delivery systems was accelerated and the drug in blood would reach a higher concentration. Thus, the variation of drug blood concentration could synchronize with the change of PEF of asthma patients or the blood pressure of hypertension patients. This chronopharmaceutical drug delivery system may fit the requirements of chronotherapy better than conventional dosage forms.A tablet-in-tablet （TNT） core was applied in both of the developed drug delivery systems. Influences of composition of the TNT core, composition of the coating membrane and weight gain of the coating membrane on the release characteristics of the developed systems were studied. The most suitable formula and technology of the two systems were set by above experiments. The results of in vitro experiments showed that pH value and agitation intensity of dissolution media do not influence drug release from the two developed drug delivery systems significantly. Release rate and accumulative drug release from the systems decreased with the increase of osmotic pressure of dissolution medium. Percent drug release-time curve of theophylline and osmotic agents from chronopharmaceutical theophylline delivery systems, changes of microenviromental pH and microenviromental osmotic pressure in the system during dissolution and variation of the solubility of theophylline with pH value were studied. Base on the equation describing release rate of osmotic tablet, an equation group were setup and mechanisms of the biphasic release was estimated. The change of theophylline solubility with microenviromental pH of the developed system was supposed to be the main cause. Change of microenviromental osmotic pressure in chronopharmaceutical verapamil hydrochloride delivery systems during dissolution and mechanisms of its biphasic drug release were also studied. Change of microenviromental viscosity caused by gradual dissolution and release of HPMC in the system was possibly the main reason for its biphasic drug release.To investigate the possibility of extending the application of the two chronopharmaceutical drug delivery systems to other drugs, aminophylline and verapamil hydrochloride were applied to the chronopharmaceutical theophylline delivery system; and theophylline and ligustrazine phosphate were applied to the chronopharmaceutical verapamil hydrochloride delivery system. In vitro experiments showed that the use of chronopharmaceutical theophylline delivery system could be extended to drugs whose solubility can be elevated in alkaline solutions. The application of chronopharmaceutical verapamil hydrochloride delivery system could be expanded to such drugs whose solubility and dissolution rate were not too high in water as theophylline and verapamil hydrochloride.Beagle dog was selected as objects to study the Pharmacokinetics of developed drug delivery systems. Two HPLC methods using UV detector were set up to determine theophylline and verapamil hydrochloride in plasma. Test group were administered orally with chronopharmaceutical theophylline/ verapamil hydrochloride delivery system with a weight gain of 6mg per tablet, and reference were administered orally with sustained release tablets of theophylline and verapamil hydrochloride tablet.The results of in vivo experiments showed that the AUC_（0→8） of test group and reference group of theophylline were 57.7h·mg·L^-1 and 54.7h·mg·L^-1, and Cmax of the two groups were 2.9mg·L^-1 and 3.8mg·L^-1 respectively. Variance analysis and two-sided test indicated that AUC_（0→8） of the two groups had no significant difference, but their Cmax were quite different. Tmax of test group and reference group of theophylline were 7.0h and 4.5h, signed rank test showed that there was an obvious difference between the Tmax of the two group. AUC_（0→8） of test group and reference group of verapamil hydrochloride were 2844h·ug·L^-1 and 4425h·ug·L^-1 Cmax of the two groups were 435ng·L^-1 and 1011ng·L^-1 and Tmax of the two group were 7.0h and 2.0h respectively. Variance analysis and two-sided test indicated that AUC_（0→8） and Cmax of the two groups had significant difference, signed rank test showed that there was a obvious difference between the Tmax of the test and reference group.There were certain correlations between in vitro release and in vivo absorption of the two chronopharmaceutical drug delivery systems. In vivo release of chronopharmaceutical verapamil hydrochloride delivery system was not complete, its relative bioavailability was 64% compared with conventional tablet. Tmax of the two chronopharmaceutical drug delivery systems were about 7h. After bed time administration of the two systems, blood concentration of theophylline or verapamil hydrochloride continuously increased before Cmax appeared around early morning, and their drug blood concentration-time curve could meet the requirements of chronotherapy of asthma and hypertension. The purpose of this study was achieved by the developed systems.更多还原