枸橼酸西地那非分散片的制备及质量控制

发布时间：2018-11-08 17:35

【摘要】：目的:肺动脉高压是一个复杂的血流动力学的和病理生理状态,它以肺血管的痉挛及重构和肺动脉的内膜加厚为主要特性,从而导致了肺血管阻力逐渐性地增长,终极造成右心的衰竭和死亡。在过去,我们主要采用吸氧、强心药物、抗凝药、利尿药和非特异性的血管舒张药来治疗肺动脉高压,在病程的不同阶段施展了重要的作用。然则,患者的症状仅仅在一定水平上得到了改善,对于病情的恶化仍旧束手无策,治疗效果没有很好的预后水平。随着社会的进步,肺动脉高压的药物治疗已经从过去的传统药物发展到现在的靶向药物,从单药治疗到多药联合和综合治疗,极大地改善了患者的症状及预后。而西地那非主要是通过抑制转化环磷酸鸟苷(cGMP)的PDE-5酶(在肺血管中大量表达)的活性,增加NO的舒张血管效应而发挥疗效。目前,国内外常用的是枸橼酸西地那非的薄膜衣片和注射剂,而枸橼酸西地那非的分散片未见报道。本试验旨在制备出可以快速崩解的枸橼酸西地那非分散片,加快其起效速度,可以用于临床急救,达到快速降低患者的肺动脉压力的目的。同时,利用星点设计-效应面优化法(Central composite desi gn-R esponse surface methodology)筛选出最佳的分散片的处方,并结合紫外分光光度法(UV)和高效液相色谱法(HPLC)建立准确可靠的质控方法来对自制的分散片进行质控及稳定性的检测。方法:本实验应用星点设计-效应面优化法联合单因素考察的方式来为分散片优化出最佳的处方。首先,通过单因素考察大约了解分散片处方中一些辅料的种类和用量,并联合星点设计-效应面优化法,全面地考察相应的因素对分散片处方的影响。其次,以分散均匀性和15 m in累计溶出百分率作为考察指标,用星点设计-效应面优化法优化各辅料的用量。同时为枸橼酸西地那非分散片建立准确、可靠的质量控制方法。选用UV和HPLC方法来对自制的分散片剂进行含测。参照《化学药物稳定性研究技术指导原则》并参考枸橼酸西地那非的特性实施强酸、强碱、强氧化的破坏,并根据其最佳处方依次进行影响因素、加速和长期试验,为处方的筛选、工艺的改良、质量的控制、包装运输及贮存条件等提供相应的数据资料。结果:本试验确定了该分散片处方为:枸橼酸西地那非为70.24 mg,颗粒内加MCC为110 mg,乳糖为95 mg,CaHPO4·2H2O为50 mg,CCNa为30 mg,外加C CNa为40 mg,硬脂酸镁为4.76 mg。试验表明,选用UV和HP LC方法所建立的含测方法准确可靠,可以确定测定枸橼酸西地那非含量的色谱条件为:选用反向硅胶KromasilC18色谱柱(200mm×4.6 mm,5μm);检测波长设定为290 nm,流速设定为1.0 mL/mi n,柱温控制在35℃左右,流动相为0.05 mol/L的磷酸三乙胺溶液(量取7 ml的三乙胺用水稀释至1000 ml,用磷酸调节pH至3.0)-甲醇-乙腈=50:30:20。上述色谱条件下,枸橼酸西地那非在5.25~42μg/mL的范围内线性优良,准确度高,精密度好。结果表明,该方法准确、特异,可用于样品含量的测定。枸橼酸西地那非原料药及分散片在强酸和强碱破坏性试验研究中都表现出其稳定性,但其在强氧化环境中不稳定。影响因素试验结果表明:高温、高湿的环境都会对枸橼酸西地那非分散片的稳定性产生相应的影响。所以应该在阴凉干燥处存放该分散片;在历经12个月的长期试验期间,该分散片的各项考察指标都符合相应的要求。分散片的有效期需要进一步的试验来确定。结论:本试验筛选出了枸橼酸西地那非分散片的最佳制备方法,自制的分散片外观性状优良,含量均匀,与市售的枸橼酸西地那非片剂相比,溶出行为显著提高。确定的HPLC法专属性好,使用方便,可用来检测枸橼酸西地那非的含量。
[Abstract]:Objective: Pulmonary hypertension is a complex hemodynamic and pathophysiological state. It is characterized by the spasm and remodeling of the pulmonary vessels and the thickening of the inner membrane of the pulmonary artery, which leads to the gradual increase of the resistance of the pulmonary vessel and the failure and death of the right heart. In the past, we mainly used oxygen, cardiotonic, anti-coagulation, diuretics and non-specific vasodilators to treat pulmonary hypertension and play an important role in different stages of the course of the disease. then, the symptoms of the patient are improved only at a certain level, and the treatment effect does not have good prognosis level for the deterioration of the condition of the patient. With the progress of the society, the drug treatment of pulmonary hypertension has been developed from the past traditional medicine to the present targeted medicine, and the combination and the comprehensive treatment of the multi-drug are treated from the single medicine, and the symptoms and the prognosis of the patients are greatly improved. Sildenafil has a therapeutic effect mainly by inhibiting the activity of PDE-5 (in a large amount of expression in the lung vessel) of the conversion-cyclophospho-phosphate (cGMP) and increasing the vasodilation effect of NO. At present, a film-coated tablet and an injection of Sildenafil, which are commonly used at home and abroad, are not reported in the dispersible tablets of Sildenafil. The purpose of the test is to prepare a rapidly-disintegrable Sildenafil dispersible tablet, to accelerate the speed of action, and can be used for clinical first aid, and the purpose of rapidly reducing the pulmonary artery pressure of a patient is achieved. At the same time, the prescription of the best dispersible tablet is selected by using the star-point design-effect surface optimization method. and an accurate and reliable quality control method is established in combination with ultraviolet spectrophotometry (UV) and high-performance liquid chromatography (HPLC) to carry out quality control and stability detection on the self-made dispersible tablets. Methods: The optimal prescription of the dispersible tablets was optimized by using the method of star-point design-effect surface optimization and single-factor investigation. First of all, the influence of the corresponding factors on the formulation of the dispersible tablets was investigated by single factor study about the types and dosage of some of the excipients in the prescription of the dispersible tablets and the combination of the star-point design-effect surface optimization. Secondly, the content of each auxiliary material was optimized by using the star-point design-effect surface optimization method. and a accurate and reliable quality control method is established for the Sildenafil dispersible tablet. The self-made dispersible tablets were tested using UV and HPLC methods. With reference to the Technical Guidelines for the Study of the Stability of Chemical Drugs, and with reference to the characteristics of Sildenafil, strong acid, strong base and strong oxidation are carried out, and the influencing factors, acceleration and long-term test are sequentially carried out according to the optimal prescription, and the screening and process of the prescription are improved. The quality control, packaging transportation and storage conditions shall provide corresponding data. Results: The prescription of this dispersible tablet was as follows: Sildenafil was 70. 24 mg, MCC was 110 mg, lactose was 95 mg, CaHPO4 路 2H2O was 50 mg, CCNa was 30 mg, and C was 40 mg, and magnesium stearate was 4.76 mg. The test results show that the method established by the method of UV and HP LC is accurate and reliable, and the chromatographic conditions for determining the content of Sildenafil in the method can be determined as follows: the reverse silica gel Kromasil C18 column (200mm-4.6mm, 5. mu.m) is selected; the detection wavelength is set to 290 nm, and the flow rate is set to 1.0 mL/ mi n, The column temperature was controlled at about 35 鈩，

本文编号：2319201