CN112129842A - 一种评价药用辅料羟丙甲纤维素(hpmc)缓控释效果的关键方法 - Google Patents
一种评价药用辅料羟丙甲纤维素(hpmc)缓控释效果的关键方法 Download PDFInfo
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Abstract
本发明公开了一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，制备缓释片：称取适量硝苯地平原料药，然后将其加入无水乙醇进行溶解后，再加入适量PVP，超声5min后将无水乙醇挥干，干燥后研磨过筛，分别加入A、B、C、D不同厂家处方量的HPMC、按相同方法制粒压片，得四种不同硝苯地平缓释片(a、b、c、d)，本发明通过对四组不同厂家HPMC红外吸收、结晶度、黏度、热重分析、粒径分布、扫描电镜等方面的检测，得出相同规格的HPMC，其形态为片状、粒径在150μm‑600μm之间、且大小均匀更能很好地控制药物释放速度，故该结论为选择HPMC作为缓控释药用辅料时提供一定的量化指标和方法。
Description
技术领域
本发明涉及医药技术领域，具体为一种评价药用辅料羟丙甲纤维素(HPMC) 缓控释效果的关键方法。
背景技术
仿制药是世界贸易组织公认的一项巨大的社会公共财富，与原研药相比，所需投资少、周期短，具有价格较低的优势。在仿制药物的研究、生产过程中，药用辅料种类与质量对仿制药物疗效的影响已经受到广泛关注，辅料问题得不到有效解决，将继续成为影响和制约我国仿制药质量提高的“瓶颈”，药用辅料的功能性是影响我国仿制药一致性评价的重要因素。因此探讨药用辅料关键性指标与仿制药质量一致性之间的关系对提高仿制药的质量具有十分重要的意义。
羟丙甲纤维素(Hydroxypropyl Methylcellulose，简称HPMC)是一个优良的缓控释药用辅料，广泛应用在硝苯地平、布洛芬、克拉霉素等缓控释制剂中。目前，国内HPMC应用在缓控释制剂时一直达不到质量要求，以至于国内大部分企业采用昂贵的进口HPMC，使得制药成本居高不下，究其原因是HPMC 起缓控释作用的关键性指标尚未明确。
发明内容
本发明的目的在于提供一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，通过对四组不同厂家相同规格的药用辅料羟丙甲纤维素，按相同配方工艺制备硝苯地平缓释片，并进行了体外释放度的测定，且对不同厂家HPMC红外吸收、结晶度、黏度、热重分析、粒径分布等方面检测，可以有效解决背景技术中的问题。
为实现上述目的，本发明提供如下技术方案：一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，包括如下步骤：
S1、试药：羟丙甲纤维素(来源于A、B、C、D四个不同厂家)、硝苯地平原料药、硝苯地平对照品、原研制剂、吐温-80、无水乙醇、盐酸、结晶乙酸钠、无水磷酸氢二钠、磷酸二氢钾、冰乙酸、磷酸；
S2、制备缓释片：称取适量硝苯地平原料药，然后将其加入无水乙醇进行溶解后，再加入适量PVP，超声5min后将无水乙醇挥干，干燥后研磨过筛，分别加入A、B、C、D不同厂家加入处方量的HPMC、按相同方法制粒压片，得四种不同硝苯地平缓释片(a、b、c、d)；
S3、建立色谱方法并绘制标准曲线：
色谱条件：谱柱Agilent C18(150mm×4.6mm,5μm)，流动相：甲醇- 水60:40；流速：1.0mL·min-1，柱温：40℃，检测波长：230nm，进样量： 20μL；在上述色谱条件下，理论板数按硝苯地平峰计算应不低于4000，拖尾因子应不大于1.5进行试验；
标准曲线绘制：
(1)、精密称取经105℃干燥1小时的硝苯地平对照品10.85mg，置50 mL棕色容量瓶中，加无水乙醇溶解并稀释至刻度，摇匀，作为贮备液；
(2)、分别精密量取贮备液1mL，2.5mL，3mL，4mL，5mL置50mL 棕色容量瓶中，加0.3％吐温-80稀释至刻度，摇匀，配制成每1mL含硝苯地平4.34μg，10.85μg，13.02μg，17.36μg，21.70μg的系列溶液；
(3)、精密量取上述系列溶液各20μL注入高效液相色谱仪，按拟订色谱条件分别进样测定，记录色谱图。以硝苯地平质量浓度(x，μg/mL)为横坐标、峰面积(y)为纵坐标进行线性回归，得回归方程y＝44.039x-18.43， R2＝0.9993(n＝5)。结果表明，硝苯地平对照品溶液质量浓度在4.34μ g/mL～21.70μg/mL范围内与峰面积线性关系良好；
S4、样品释放度的测定：
(1)、取样品6片，避光操作。分别测定四种不同硝苯地平缓释片
(a、b、c、d)在pH 1.2溶出介质、pH 4.0醋酸盐溶出介质、pH 6.8 磷酸盐溶出介质及0.3％的吐温-80水溶液中的释放度；
(2)、照2015版《中国药典》溶出度测定法(桨板法)，即转速为75r ·min-1，温度37℃，溶出介质体积为900ml，依法操作，分别在进样后0.25 h、0.5h、1h、1.5h、2h、3h、4h、6h、8h、12h取样10ml，经0.45 μm微孔滤膜过滤，并及时补充10ml相同温度的溶出介质，取续滤液作为供试品溶液。用高效液相色谱法进行测定，计算各个时间点的释放度，并分别绘制四种不同硝苯地平缓释片(a、b、c、d)在4种溶出介质中的体外释放曲线图。
S5、羟丙甲纤维素性能参数测定：对羟丙甲纤维素进行红外吸收光谱测定、结晶度测定、黏度测定、热重分析和粒径分布、扫描电镜等测试。
优选的，所述缓控释制剂为硝苯地平缓释片。
优选的，建立硝苯地平缓释体外释放曲线测定方法以评价其缓释效果。
本发明提供了一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，具备以下有益效果：
本发明通过对四组不同厂家相同规格的药用辅料羟丙甲纤维素，按相同配方工艺制备硝苯地平缓释片，并进行了体外释放度的测定，且对不同厂家 HPMC红外吸收、结晶度、黏度、热重分析、粒径分布、扫描电镜等方面检测，得出HPMC粒径大小、均匀度及形态均是影响缓控释作用的关键性指标，相同规格的HPMC，其形态为片状、粒径在150μm-600μm之间、且大小均匀更能很好地控制药物释放速度，故该结论为选择HPMC作为缓控释药用辅料时提供一定的量化指标和方法。
附图说明
图1为本发明的样品a、b、c和d体外释放曲线图；
图2为本发明的样品A热重曲线图；
图3为本发明的样品B热重曲线图；
图4为本发明的样品C热重曲线图；
图5为本发明的样品D热重曲线图；
图6为本发明的样品A、B、C、D粒径分布图；
图7为本发明的样品A、B、C、D电镜扫描图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述。
实施例1：
缓释片的制备方法：称取适量硝苯地平原料药，然后将其加入无水乙醇进行溶解后，再加入适量PVP，超声5min后将无水乙醇挥干，干燥后研磨过筛，分别加入A、B、C、D不同厂家加入处方量的HPMC、按相同方法制粒压片，得四种不同硝苯地平缓释片(a、b、c、d)。
实施例2：
对实施例1所制的四组不同硝苯地平缓释片(a、b、c、d)进行体外释放度测定。
分别取四种不同硝苯地平缓释片(a、b、c、d)6片，避光操作。测定其在水溶液、pH1.2、pH4.0、pH6.8等四种不同溶出介质中的释放度。照2015 版《中国药典》溶出度测定法(桨板法)，即转速为75r·min-1，温度37℃，溶出介质体积为900ml，依法操作，分别在进样后0.25h、0.5h、1h、1.5 h、2h、3h、4h、6h、8h、12h取样10ml，经0.45μm微孔滤膜过滤，并及时补充10ml相同温度的溶出介质，取续滤液作为供试品溶液。采用高效液相色谱法进行测定。色谱条件为：色谱柱：CompassC18(250mm×4.6mm, 5μm)、流动相：甲醇-水(60:40)、流速：1.0ml·min-1、检测波长：230nm；柱温：30℃、进样量：20μl。
采用高效液相色谱法进行测定，计算各个时间点的释放度，绘制了四种不同硝苯地平缓释片(a、b、c、d)在4种溶出介质中的释放度表格，且绘制了不同硝苯地平缓释片(a、b、c、d)的体外释放曲线图(见附图)。
表1a组硝苯地平缓释片的释放度
表2b组硝苯地平缓释片的释放度
表3c组硝苯地平缓释片的释放度
表4d组硝苯地平缓释片的释放度
由表1-4可知A、B厂家羟丙甲纤维素制备的a、b组硝苯地平缓释片缓释效果较好，C、D厂家羟丙甲纤维素制备的c、d组硝苯地平缓释片在四种溶出介质中前2小时的释放度均达70％以上，甚至近100％，释放过快，缓释效果不好。
实施例3：红外吸收光谱测定
通过红外光谱仪对四种(A、B、C、D厂家)羟丙甲纤维素样品进行光谱采集，四种样品的红外光谱十分相似，均含有(-OH)(3400～3500cm-1)，(C-O-C) (1000～1100cm-1环状)(900～1000cm-1链状)，(C-O)(1100～1200cm-1)，(C-H) (2900～3000cm-1，1400～1500cm-1)，(-CH3)(1300～1400cm-1)等基团的特征吸收峰，故据此分析，四种HPMC样品在红外吸收上并无显著差异。
实施例4：结晶度测定
采用X-衍射仪进行结晶度测定，X射线源为Cu靶，镍滤波片，管压设置为40kV，管流30mA，广角测试条件：步长0.05°，扫描速度为5°/min，利用X-衍射仪对A、B、C、D四种样品进照射扫描，并采用采用D/teX Ultra 高速探测器接收衍射线,从而得出表5数据。
表5羟丙甲纤维素的结晶度
| 样品 | A | B | C | D |
| 结晶度 | 26.7％ | 28.4％ | 25.5％ | 28.4％ |
由表5可知，A、B、C、D四种样品的结晶度并无显著差异，故结晶度对羟丙甲纤维素的释放率影响较小。
实施例5：黏度测定
根据中国药典2015版通则0633第三法，测得A、B、C、D样品的黏度分别为6050、4080、4300、3990。再结合实施例2对采用A、B、C、D样品制作的硝苯地平缓释片进行的释放度检测，根据实施例2的表1-4的释放度结果进行分析可知，粘度在3000-6000范围内，HPMC缓释效果区别小。
实施例6：热重分析
对A、B、C、D四组样品进行热重分析，得到热重曲线，如图2-5所示；
由图可知，样品A在300℃之前对热稳定，从339.98℃起开始快速失重，在71.97℃的质量损失为4.76％，其中该部分质量损失是HPMC中的水分，可用于确定样品的水分含量，在300～400℃范围内质量损失主要是HPMC的降解，超过380℃后，样品碳化恒重；样品B、样品C和样品D的热重曲线表明，产物在300℃之前对热稳定，分别从347.11，343.77，346.99℃起开始快速失重。以上4组样品热重曲线并无明显差异，在300℃之前对热稳定，340℃左右开始快速失重。
实施例6：粒径分布
采用激光粒度分析仪，对A、B、C、D四组样品进测试，对A、B、C、D 四组样品分别进行3次取样，然后将测试结果取平均值，最后得到四组样品进中羟丙甲纤维素颗粒物粒径分布，其中羟丙甲纤维素颗粒物粒径分布体现的是颗粒物体积分布，即颗粒物的体积占比％，由测试结果得到A、B、C、D 四组样品的粒径分布曲线图，如图6。
由结果显示，A厂家粒径主要分布在150μm-350μm；B厂家粒径大多集中分布在200μm-600μm这个区间；C厂家粒径不仅在100μm-200μm有分布，在10μm-30μm处亦有分布；D厂家粒径除主要分布在50μm-150μm区间外，在15nm-30nm处亦有粒径分布。由结果可分析，且A、B厂家颗粒粒径相对较大(主要分布在150μm-600μm内)，且粒径分布较均匀，而C、D厂家颗粒粒径分布集中在150μm以内，粒径相对小且粒径分布不均匀。因此，可推断羟丙甲纤维素HPMC粒径大小在150μm-600μm范围且大小均匀能更好地控制药物释放速度。
实施例7：扫描电镜
将A、B、C、D四组样品分别置铜台双面胶带上，自然挥干后喷金，用扫描电子显微镜观察放大140倍，观察结果如图7。
由图可知，样品A、B与C、D形态有较大的差别。样品A、B形态相似，均呈片状；样品C形态呈绳状，样品D形态呈绳状及团状，由此可知，羟丙甲纤维素HPMC形态呈片状能更好地控制药物释放速度。
结论：通过对羟丙甲纤维素HPMC红外吸收光谱、结晶度、黏度、热重分析、粒径分布及扫描电镜等测试，以考察HPMC对硝苯地平缓释片释放度的的关键影响因素。结果显示，HPMC粒径大小、均匀度及形态均是影响缓控释作用的关键性指标，相同规格的HPMC，其形态为片状、粒径在200μm-600μm 之间、且大小均匀能更好地控制药物释放速度。
Claims (3)
1.一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，其特征在于，包括如下步骤：
S1、试药：羟丙甲纤维素(来源于A、B、C、D四个不同厂家）、硝苯地平原料药、硝苯地平对照品、原研制剂、吐温-80、无水乙醇、盐酸、结晶乙酸钠、无水磷酸氢二钠、磷酸二氢钾、冰乙酸、磷酸；
S2、制备缓释片：称取适量硝苯地平原料药，然后将其加入无水乙醇进行溶解后，再加入适量PVP，超声5min后将无水乙醇挥干，干燥后研磨过筛，分别加入A、B、C、D不同厂家加入处方量的HPMC、按相同方法制粒压片，得四种不同硝苯地平缓释片（a、b、c、d）；
S3、建立色谱方法并绘制标准曲线：
色谱条件：谱柱Agilent C18（150mm×4.6 mm,5μm），流动相：甲醇-水60:40；流速：1.0mL·min-1，柱温：40℃，检测波长：230nm，进样量：20μL；在上述色谱条件下，理论板数按硝苯地平峰计算应不低于4000，拖尾因子应不大于1.5进行试验；
标准曲线绘制：
（1）、精密称取经105 ℃干燥1小时的硝苯地平对照品10.85 mg，置50 mL棕色容量瓶中，加无水乙醇溶解并稀释至刻度，摇匀，作为贮备液；
（2）、分别精密量取贮备液1 mL，2.5 mL，3 mL，4 mL，5 mL置50 mL棕色容量瓶中，加0.3%吐温-80稀释至刻度，摇匀，配制成每1 mL含硝苯地平4.34μg，10.85μg，13.02μg，17.36μg，21.70μg的系列溶液；
（3）、精密量取上述系列溶液各20μL注入高效液相色谱仪，按拟订色谱条件分别进样测定，记录色谱图，以硝苯地平质量浓度（x，μg/mL）为横坐标、峰面积（y）为纵坐标进行线性回归，得回归方程y=44.039x-18.43，R2＝0.9993(n＝5），结果表明，硝苯地平对照品溶液质量浓度在4.34 μg/mL～21.70 μg/mL范围内与峰面积线性关系良好；
S4、样品释放度的测定：
（1）、取样品6片，避光操作，分别测定四种不同硝苯地平缓释片（a、b、c、d）在pH 1.2溶出介质、pH 4.0醋酸盐溶出介质、pH 6.8磷酸盐溶出介质及0.3%的吐温-80水溶液中的释放度；
（2）、照2015版《中国药典》溶出度测定法（桨板法），即转速为75 r•min-1，温度37℃，溶出介质体积为900 ml，依法操作，分别在进样后0.25 h、0.5 h、1 h、1.5 h、2 h、3 h、4 h、6h、8 h、12 h取样10 ml，经0.45 μm微孔滤膜过滤，并及时补充10 ml相同温度的溶出介质，取续滤液作为供试品溶液，用高效液相色谱法进行测定，计算各个时间点的释放度，并分别绘制四种不同硝苯地平缓释片（a、b、c、d）在4种溶出介质中的体外释放曲线图；
S5、羟丙甲纤维素性能参数测定：对羟丙甲纤维素进行红外吸收光谱测定、结晶度测定、黏度测定、热重分析和粒径分布、扫描电镜等测试。
2.根据权利要求1所述的一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，其特征在于：所述缓控释制剂为硝苯地平缓释片。
3.根据权利要求1所述的一种评价药用辅料羟丙甲纤维素(HPMC)缓控释效果的关键方法，其特征在于：建立硝苯地平缓释体外释放曲线测定方法以评价其缓释效果。
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| CN113267583A (zh) * | 2021-06-10 | 2021-08-17 | 北京亚宝生物药业有限公司 | 一种基于hplc的硝苯地平有关物质分析方法 |
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| CN112592311B (zh) * | 2021-01-03 | 2023-01-31 | 迪沙药业集团有限公司 | 一种硝苯地平a晶块状晶习及其控释片组合物 |
| CN113267583A (zh) * | 2021-06-10 | 2021-08-17 | 北京亚宝生物药业有限公司 | 一种基于hplc的硝苯地平有关物质分析方法 |
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Application publication date: 20201225 |