对乙酰氨基酚温敏凝胶的制备与质量评价研究

发布时间：2018-04-25 19:04

本文选题：温敏凝胶 + 泊洛沙姆　；参考：《山东中医药大学》2014年硕士论文

【摘要】：旧的]将小儿退热药对乙酰氨基酚(APAP)制备成外用温敏凝胶制剂,通过经皮吸收,避免胃肠首过效应,增加儿童用药的顺应性,从而开发一种针对小儿退热新剂型。 [方法] 1.APAP凝胶制剂适用性研究：参照药典有关标准,用紫外分光光度法对APAP含量进行测定；在设计处方前对药物的基本物理性质、化学性质和制剂性质进行考察；对APAP的油水分配系数进行研究,测定其在水中的溶解度；考察APAP在实验所需的pH环境中的稳定性,用以指导下一步制剂处方和工艺的研究。 2. APAP凝胶基质的筛选：以天然高分子为主要原料,在查找文献和预实验的基础上,优选适合外用的温敏性水凝胶的基质组合,制备作为释药载体,选择壳聚糖(CS)/聚乙烯醇(PVA)/甘油磷酸钠(β-GP),泊洛沙姆407(F127)/泊洛沙姆188(F68)/聚乙烯醇(PVA)两组凝胶基质,以凝胶温度、粘度、凝胶强度和脱水性为指标,采用正交设计优化凝胶处方,并对凝胶黏度热稳定性进行考察。 3. APAP凝胶制剂制备工艺及质量标准的研究：按照2010版中国药典标准的要求对APAP凝胶的质量进行了详细考察,建立APAP凝胶剂的检测方法,并进行方法学验证,拟定了APAP凝胶的质量标准。 4. APAP凝胶剂生物粘附性和体外释放研究：考察了凝胶的生物粘附性、载药量；用Franze吸收池用新鲜兔皮进行体外渗透实验,考察凝胶的累积释放量。 5. APAP温敏凝胶剂皮肤刺激性试验：参照“化学品急性皮肤刺激性/腐蚀性试验方法进行皮肤刺激性实验(GBT21604-2008),观察皮肤涂抹空白凝胶、加药凝胶后局部是否会引起可逆性炎症变化和不可逆性的组织损伤。采用自身对照,将凝胶基质一次(或多次)涂敷于新西兰白兔的皮肤上,在规定的时间间隔内,观察动物皮肤局部刺激作用的程度并进行评分,以评价受试物对皮肤的刺激作用。 [结果] 1.常温下对乙酰氨基酚在水中的溶解度为45.62g/L,说明该药在水中略溶,在pH5.0和PH7.0缓冲溶液中略溶。在37℃,PH=5～7的弱酸性环境中溶解度较高,均在50g/L以上。测定不同PH缓冲溶液下的PAPP值,可以看到各PH条件下的分配系数介于2.6～2.8之间,随着环境Ph的增大,分配系数逐渐减小,在Ph=5左右出现向上的拐点,但总体来说相差很小,证明对乙酰氨基酚在本实验所需的弱酸性环境中是稳定的,符合实验要求。 2.经过对凝胶热稳定性的研究,可以看出P407和PVA的浓度对黏度的敏感性不大,但仍然随温度的上升黏度有增大的趋势,且PVA浓度对黏度的影响对P407大；经过对各种附加剂对凝胶的IGT、凝胶黏度影响的研究,表明P188的加入使得胶凝温度升高,盐类对凝胶的形成影响较为显著,加入的盐类中,除CaCl之外,均可使溶液的粘度增大。在选用的阴离子中,对凝胶粘度和胶凝温度的影响次序为：SO42-PO43-Cl-,这些离子明显的增加了溶液的粘度,并降低了胶凝的温度,而阳离子Ca2+则使溶液的粘度降低,同时使凝胶的温度升高。两个基质组合分别进行三水平三因素正交实验,由于PVA/CS/GP最优组合的胶凝温度和黏度都不符合要求,排除,PVA/P407/P188组合各项指标均符合要求,优化处方为4.5%PVA、5.5%P188和23%P407,在34℃、30s内可发生凝胶化,PVA/P407/P188凝胶的制备工艺简单可行,具有温敏性,适合作为后期加药实验的基质。 3.在确定温敏凝胶基质最优组合的基础上完善整个制剂的处方,并将做成的成品按照2010版药典二部“凝胶剂”、“对乙酰氨基酚凝胶剂”等标准的方法,对APAP温敏凝胶剂进行质量考察,并拟定出对乙酰氨基酚温敏凝胶的质量标准,经考察,自行试制的三批制剂均符合要求。 4.以IGT为指标考察基质最大载药量,加入APAP确实显著的提升凝胶的IGT,当加药量大于0.1g时,凝胶出现不溶物,溶液逐渐变浑浊,胶凝时间逐渐变长,IGT超过37-C；当加药量为0.2g时,凝胶30min内无法形成凝胶；进行体外释药实验,以累积经皮释放量对时间曲线作图,可见APAP凝胶制剂经皮吸收量与时间具有一定的相关性,且释放速率较恒定,在1.5h后单位面积的渗透量释放加快,在6.0h后,释放量出现拐点,后面4个小时只释放了不到1mg,在10h内,药物生物膜通过共释放了90.55%的药量,尽管通过皮肤直接透过药物要通过若干皮层而难以大量吸收,但本实验仍能证明以泊洛沙姆为基质主要成分的温敏凝胶具有一定的体外释放性,并具有明显的缓释效果。 5.对乙酰氨基酚凝胶急性或多次经皮给药后对皮肤无刺激性,或轻度的皮肤刺激性,从而为对乙酰氨基酚凝胶的经皮给药的安全性提供了实验依据。结论：对乙酰氨基酚温敏凝胶制剂的主药对乙酰氨基酚临床退热疗效确切,已经上百年的检验,常规剂量非常安全；其合成工艺成熟,质量稳定,价格低廉；制剂给药方便,儿童顺应性好：可以避开肝肠首过效应；分计量准确,使用、储存方便,具有良好的释药性能和透皮效果;制剂本身对皮肤无任何副作用、刺激性,可以将其制成外用温敏制剂成为一种未来新型的治疗感冒的途径。
[Abstract]:The antipyretic antipyretic drug to acetaminophen (APAP) was prepared for external use of thermosensitive gel. Through the percutaneous absorption, it avoided the first over effect of the gastrointestinal tract and increased the compliance of the children. A new type of antipyretic dosage form for children was developed.
[method]
Study on the applicability of 1.APAP gel: the content of APAP was measured by UV Spectrophotometry with reference to the relevant standard of Pharmacopoeia; the basic physical properties, chemical properties and preparation properties of the drugs were investigated before the formulation of the prescription; the oil and water distribution coefficient of APAP was studied to determine the solubility in water; and APAP was investigated in the experiment. The stability required in the pH environment is used to guide the research on the formulation and technology of the next step.
2. APAP gel matrix screening: Based on natural polymers as the main raw material, based on searching for literature and pre experiment, the selection of substrate combination suitable for external use of thermosensitive hydrogels is prepared as a carrier of drug release, and the selection of chitosan (CS) / polyvinyl alcohol (PVA) / sodium glycerphosphate (beta -GP), poloxamer / poloxamer 188 (F68) / polyethylene (F68) / polyethylene The gel matrix was two groups of alcohol (PVA). The gel temperature, viscosity, gel strength and dehydration were used as the indexes. The gel formulation was optimized by orthogonal design, and the thermal stability of the gel viscosity was investigated.
Study on the preparation technology and quality standard of 3. APAP gel: according to the requirements of the standard of Chinese Pharmacopoeia of the 2010 edition, the quality of the APAP gel was investigated in detail, the detection method of APAP gel was established, and the method was verified, and the quality standard of the APAP gel was drawn up.
The bioadhesion and in vitro release of 4. APAP gels were studied. The bioadhesion and drug loading of the gel were investigated, and the in vitro infiltration experiment was carried out with fresh rabbit skin from the Franze absorption pool, and the cumulative release of the gel was investigated.
5. APAP thermosensitive gel skin irritation test: skin irritation test (GBT21604-2008) based on "chemical acute skin irritation / corrosive test" (chemical skin irritation test), observation of skin smear blank gel, and whether the local gel can cause reversible inflammatory changes and irreversible tissue damage. The matrix is applied to the skin of New Zealand white rabbits once or more, and the extent of local irritation of the animal skin is observed and scored in a specified time interval to evaluate the irritation of the subject to the skin.
[results]
The solubility of acetaminophen in water at 1. at normal temperature was 45.62g/L, indicating that the drug was slightly soluble in water and slightly dissolved in pH5.0 and PH7.0 buffer solutions. At 37, the solubility of the drug was higher in the weak acid environment of PH=5 ~ 7, all above 50g/L. The PAPP value under different PH buffer solutions could be measured in order to see that the distribution coefficient under each PH condition was between 2.6 and 2.8. In the meantime, with the increase of the environment Ph, the distribution coefficient gradually decreases and the inflection point is up around Ph=5, but the difference is very small in general. It is proved that acetaminophen is stable in the weak acid environment needed in this experiment, which meets the requirements of the experiment.
2. through the study of the thermal stability of the gel, it can be seen that the concentration of P407 and PVA is less sensitive to viscosity, but it still increases with the rising viscosity of the temperature, and the effect of PVA concentration on the viscosity is large to P407; after the study of the effect of various additives on the gelation of the gel and the viscosity of the gel, it is shown that the addition of P188 makes the gelation temperature. In addition, the viscosity of the gel and the gelation temperature in the selected anions are SO42-PO43-Cl-. These ions obviously increase the viscosity of the solution and reduce the temperature of the gelation, and the cationic Ca2+ is Ca2+. The viscosity of the solution was reduced and the temperature of the gel was increased. The two matrix combinations were three levels and three factors respectively. Because the gelation temperature and viscosity of the optimal combination of PVA/CS/GP were not conformed to the requirements, all the indexes of the PVA/P407/P188 combination were in conformity with the requirements. The optimum formulation was 4.5%PVA, 5.5%P188 and 23%P407, at 34, 30s. Gelation can take place. The preparation process of PVA/P407/P188 gel is simple and feasible, and has thermo sensitivity. It is suitable to be used as a substrate for later dosing experiments.
3. to improve the formulation of the whole preparation on the basis of determining the optimum combination of the temperature sensitive gel matrix, and the quality of the APAP Wen Min gel was investigated in accordance with the standard method of the 2010 edition of the Pharmacopoeia "gel" and "Paracetamol Gel", and the quality standard of the acetaminophen thermosensitive gel was drawn up. The three batches of preparations made by ourselves were all in accordance with the requirements.
4. take the IGT as the index to investigate the maximum drug loading of the matrix, adding APAP to improve the IGT of the gel. When the dosage is greater than 0.1g, the gel appears insoluble, the solution becomes turbid, the gelation time becomes longer, and the IGT exceeds the 37-C. When the dosage is 0.2g, the gel can not form the gel in 30min, and the release experiment in vitro is carried out to accumulate the skin in vitro. The release amount to the time curve, it can be seen that the APAP gel preparation has a certain correlation with the time, and the release rate is constant. The release rate of the unit area is quicker after 1.5h. After 6.0h, the release rate is inflection point, and the last 4 hours only release less than 1mg. In 10h, the drug biofilm is released by a total of 90.55%. Although the dosage is difficult to absorb through a number of cortex through the skin through the skin directly through the skin, this experiment still proves that the temperature sensitive gel with the main component of poloxamer has a certain release in vitro and has a significant slow release effect.
5. Paracetamol Gel has no irritation or mild skin irritation to the skin after acute or repeated percutaneous administration of the skin, which provides an experimental basis for the safety of Paracetamol Gel's percutaneous administration.
Conclusion: the main drug of acetaminophen thermosensitive gel has a definite effect on acetaminophen clinical antipyretic treatment. It has been tested for a hundred years, the routine dose is very safe, the synthetic process is mature, the quality is stable, the price is low, the preparation is convenient and the compliance of the children is good: it can avoid the head over effect of the liver intestines, accurate measurement, use and storage. It is convenient to save, and has good drug release and transdermal effects. The preparation itself has no side effects on the skin, irritating, and can be used as a foreign temperature sensitive preparation to become a new way to treat the cold in the future.

【学位授予单位】：山东中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【参考文献】