枸櫞酸西地那非分散片的制備及質(zhì)量控制
發(fā)布時(shí)間：2018-11-08 17:35
【摘要】：目的:肺動(dòng)脈高壓是一個(gè)復(fù)雜的血流動(dòng)力學(xué)的和病理生理狀態(tài),它以肺血管的痙攣及重構(gòu)和肺動(dòng)脈的內(nèi)膜加厚為主要特性,從而導(dǎo)致了肺血管阻力逐漸性地增長(zhǎng),終極造成右心的衰竭和死亡。在過去,我們主要采用吸氧、強(qiáng)心藥物、抗凝藥、利尿藥和非特異性的血管舒張藥來治療肺動(dòng)脈高壓,在病程的不同階段施展了重要的作用。然則,患者的癥狀僅僅在一定水平上得到了改善,對(duì)于病情的惡化仍舊束手無策,治療效果沒有很好的預(yù)后水平。隨著社會(huì)的進(jìn)步,肺動(dòng)脈高壓的藥物治療已經(jīng)從過去的傳統(tǒng)藥物發(fā)展到現(xiàn)在的靶向藥物,從單藥治療到多藥聯(lián)合和綜合治療,極大地改善了患者的癥狀及預(yù)后。而西地那非主要是通過抑制轉(zhuǎn)化環(huán)磷酸鳥苷(cGMP)的PDE-5酶(在肺血管中大量表達(dá))的活性,增加NO的舒張血管效應(yīng)而發(fā)揮療效。目前,國內(nèi)外常用的是枸櫞酸西地那非的薄膜衣片和注射劑,而枸櫞酸西地那非的分散片未見報(bào)道。本試驗(yàn)旨在制備出可以快速崩解的枸櫞酸西地那非分散片,加快其起效速度,可以用于臨床急救,達(dá)到快速降低患者的肺動(dòng)脈壓力的目的。同時(shí),利用星點(diǎn)設(shè)計(jì)-效應(yīng)面優(yōu)化法(Central composite desi gn-R esponse surface methodology)篩選出最佳的分散片的處方,并結(jié)合紫外分光光度法(UV)和高效液相色譜法(HPLC)建立準(zhǔn)確可靠的質(zhì)控方法來對(duì)自制的分散片進(jìn)行質(zhì)控及穩(wěn)定性的檢測(cè)。方法:本實(shí)驗(yàn)應(yīng)用星點(diǎn)設(shè)計(jì)-效應(yīng)面優(yōu)化法聯(lián)合單因素考察的方式來為分散片優(yōu)化出最佳的處方。首先,通過單因素考察大約了解分散片處方中一些輔料的種類和用量,并聯(lián)合星點(diǎn)設(shè)計(jì)-效應(yīng)面優(yōu)化法,全面地考察相應(yīng)的因素對(duì)分散片處方的影響。其次,以分散均勻性和15 m in累計(jì)溶出百分率作為考察指標(biāo),用星點(diǎn)設(shè)計(jì)-效應(yīng)面優(yōu)化法優(yōu)化各輔料的用量。同時(shí)為枸櫞酸西地那非分散片建立準(zhǔn)確、可靠的質(zhì)量控制方法。選用UV和HPLC方法來對(duì)自制的分散片劑進(jìn)行含測(cè)。參照《化學(xué)藥物穩(wěn)定性研究技術(shù)指導(dǎo)原則》并參考枸櫞酸西地那非的特性實(shí)施強(qiáng)酸、強(qiáng)堿、強(qiáng)氧化的破壞,并根據(jù)其最佳處方依次進(jìn)行影響因素、加速和長(zhǎng)期試驗(yàn),為處方的篩選、工藝的改良、質(zhì)量的控制、包裝運(yùn)輸及貯存條件等提供相應(yīng)的數(shù)據(jù)資料。結(jié)果:本試驗(yàn)確定了該分散片處方為:枸櫞酸西地那非為70.24 mg,顆粒內(nèi)加MCC為110 mg,乳糖為95 mg,CaHPO4·2H2O為50 mg,CCNa為30 mg,外加C CNa為40 mg,硬脂酸鎂為4.76 mg。試驗(yàn)表明,選用UV和HP LC方法所建立的含測(cè)方法準(zhǔn)確可靠,可以確定測(cè)定枸櫞酸西地那非含量的色譜條件為:選用反向硅膠KromasilC18色譜柱(200mm×4.6 mm,5μm);檢測(cè)波長(zhǎng)設(shè)定為290 nm,流速設(shè)定為1.0 mL/mi n,柱溫控制在35℃左右,流動(dòng)相為0.05 mol/L的磷酸三乙胺溶液(量取7 ml的三乙胺用水稀釋至1000 ml,用磷酸調(diào)節(jié)pH至3.0)-甲醇-乙腈=50:30:20。上述色譜條件下,枸櫞酸西地那非在5.25~42μg/mL的范圍內(nèi)線性優(yōu)良,準(zhǔn)確度高,精密度好。結(jié)果表明,該方法準(zhǔn)確、特異,可用于樣品含量的測(cè)定。枸櫞酸西地那非原料藥及分散片在強(qiáng)酸和強(qiáng)堿破壞性試驗(yàn)研究中都表現(xiàn)出其穩(wěn)定性,但其在強(qiáng)氧化環(huán)境中不穩(wěn)定。影響因素試驗(yàn)結(jié)果表明:高溫、高濕的環(huán)境都會(huì)對(duì)枸櫞酸西地那非分散片的穩(wěn)定性產(chǎn)生相應(yīng)的影響。所以應(yīng)該在陰涼干燥處存放該分散片;在歷經(jīng)12個(gè)月的長(zhǎng)期試驗(yàn)期間,該分散片的各項(xiàng)考察指標(biāo)都符合相應(yīng)的要求。分散片的有效期需要進(jìn)一步的試驗(yàn)來確定。結(jié)論:本試驗(yàn)篩選出了枸櫞酸西地那非分散片的最佳制備方法,自制的分散片外觀性狀優(yōu)良,含量均勻,與市售的枸櫞酸西地那非片劑相比,溶出行為顯著提高。確定的HPLC法專屬性好,使用方便,可用來檢測(cè)枸櫞酸西地那非的含量。
[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，
本文編號(hào)：2319201
[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，
本文編號(hào)：2319201
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