抗骨关节炎新药ML4000固体分散体及其片剂的制备与质量研究

发布时间：2018-03-14 14:38

本文选题：ML4000　切入点：固体分散体　出处：《河南大学》2016年硕士论文　论文类型：学位论文

【摘要】：骨关节炎(OA)属于临床常见的关节炎的一种,主要治疗药物为非甾体抗炎药(NSAIDs)。本文的模型药ML4000是在COX/5-LOX双重抑制剂ML3000的结构基础上连接NO释放基团,所制备的具有COX/5-LOX双重抑制作用的NO供体型新型非甾体抗炎药,ML4000抗炎活性强,同时还具有显著的NO释放活性,胃肠耐受性良好,无心血管不良反应。首先对ML4000进行了处方前理化性质研究,主要包括药物的外观性状、熔点、晶型、溶解度、引湿性。原料药为微黄色结晶性粉末,Tm=106.3~107.3℃;通过粉末X射线衍射与差示扫描量热技术对ML4000的晶型加以研究,结果表明ML4000为晶态化合物;ML4000在乙腈、二甲基甲酰胺、丙酮、氯仿和二氯甲烷等有机溶剂中溶解,在乙醚中略溶,在甲醇和无水乙醇中极微溶解,在水中不溶;在不同pH缓冲溶液中均为不溶或难溶;ML4000不具有吸湿性。ML4000在水中不溶,固体分散技术在改善难溶性药物溶解性能方面具有显著的优势。本文将ML4000制备成为固体分散体(Solid Dispersions,SD),并压制成片,旨在改善药物的体外溶出情况,提高体内生物利用度。建立了高效液相色谱法对ML4000原料药、SD及其片剂的含量、溶出度加以测定,并进行方法学验证,验证结果表明方法重现性好,准确度高。本研究还对SD及其片剂进行了质量评价与初步稳定性考察。分别以泊洛沙姆188、聚乙二醇4000(PEG4000)、聚乙二醇6000(PEG6000)、聚维酮(PVP K30,PVP K90)、共聚维酮Co-PVP和SOLUPLUS?为载体,采用各自适宜的制备方法(熔融法、溶剂-熔融法和溶剂蒸发法)制备SD,并通过对体外溶出情况的考察进行处方与制备工艺的筛选。结果发现以上几种载体所制备SD均可在一定程度上提高药物的溶出速率与溶出度,泊洛沙姆188、PEG4000和PEG6000与其他辅料相比所制备SD的增溶效果不明显。对以上三种方法加以比较,溶剂蒸发法的制备工艺以及所制备SD溶出效果明显优于其他两种。PVP K90与SOLUPLUS?在制备过程中,产品粘性过大,所制备SD难以刮出或处理。Co-PVP制备成固体分散体所需药辅比为1:5,所需载体量远大于PVP K30(1:2)。最终确定采用溶剂蒸发法,以PVP K30为载体,药辅比为1:2,二氯甲烷为溶剂,溶剂用量以1g ML4000加40ml二氯甲烷为优化处方。采用差示扫描量热技术(DSC)与傅里叶变换红外光谱扫描技术(FT-IR)对ML4000-PVP K30固体分散体加以表征,以判断药物在固体分散体中的存在状态及药物与辅料之间的相互作用。DSC图结果表明,ML4000具有一个明显的吸热峰,PVP K30空白辅料本身为无定型态,物理混合物中药物结晶峰减弱,但仍明显存在,SD(1:2,1:3)中的药物结晶峰基本消失,证明ML4000:PVP K30=1:2即可形成SD,且药物在SD中以无定型状态存在;FT-IR结果表明药物与载体材料之间可能存在氢键作用;SD中药物的质量分数与溶出重现性符合要求。固体分散体初步稳定性考察结果表明,ML4000固体分散体在高热与强光条件下较稳定,溶出度及药物质量分数无明显变化,但SD具有一定的吸湿性,因此需密闭干燥保存;长期留样实验表明,SD留样3个月稳定,可进一步制备成片剂。在固体分散体研究的基础上,采用粉末直压技术将固体分散体片粉压制成片。以片粉的流动性、可压性和片剂的外观、溶出情况为判定标准,对固体分散体片剂的处方及工艺因素进行单因素考察,筛选出崩解剂种类为PVPP,润滑剂种类为硬脂酸镁。在此基础上,选择崩解剂用量、润滑剂用量以及填充剂的种类三个因素,每个因素三个水平,应用L9(34)正交实验设计优化处方。根据优化处方制备3批样品,处方的均一性和重现性良好,对其进行质量研究及稳定性初步考察。结果表明,ML4000固体分散体片的含量均匀度、含量及溶出情况均符合要求,初步稳定性实验显示,样品在强光(4500lx±500lx)、高热(60℃)与高湿(RH75%±5%)条件下放置10d或加速试验条件放置1个月均稳定。
[Abstract]:Osteoarthritis (OA) is a common clinical arthritis, the main drugs for the treatment of non steroidal anti-inflammatory drugs (NSAIDs). The model of this paper is the connection of NO ML4000 drug release groups in the structural basis of COX/5-LOX dual inhibitor of ML3000, prepared with COX/5-LOX dual inhibition of NO donor type non model steroidal anti-inflammatory drugs, ML4000 strong anti-inflammatory activity, but also has a significant release of NO activity, good gastrointestinal tolerance, cardiovascular adverse reactions. First carried out on the ML4000 of properties before the prescription, including appearance, drug melting point, crystal type, solubility, hygroscopicity. Raw materials for micro yellow crystalline powder, Tm=106.3~107.3 C; to study through the crystalline powder X ray diffraction and differential scanning calorimetry technique of ML4000, the result shows that the ML4000 is amorphous compounds; ML4000 in acetonitrile, two methyl formamide, acetone, chloroform and two chlorine Methane dissolved in organic solvents such as ether, slightly soluble in methanol and ethanol, low dissolved, insoluble in water; in different pH buffer solution were solubility; ML4000 is not hygroscopic.ML4000 can not dissolve in water, has significant advantages of solid dispersion technique to improve the solubility of insoluble drug. This paper will become the preparation of ML4000 solid dispersion (Solid Dispersions, SD), and pressed into tablets, which aims to improve the dissolution of drugs in vitro, increase the bioavailability. A HPLC method was established for the ML4000 API, SD content and its tablets, dissolution of determination, and validation, verification results show that the method has a good reproducibility and high accuracy. This study also carried out preliminary investigation and quality evaluation on the stability of SD and its tablets. With Bo Losham 188, polyethylene glycol 4000 (PEG4000), polyethylene glycol 6000 (PEG6 000), polyvinylpyrrolidone (PVP K30, PVP K90), copovidone Co-PVP and SOLUPLUS? As the carrier, using their own suitable preparation method (melting method, solvent melting method and solvent evaporation method) the preparation of SD, and through the investigation on the dissolution in vitro screening prescription and preparation technology the results showed that these carriers prepared SD can improve the dissolution rate and solubility in a certain extent, poloxamer 188, PEG4000 and PEG6000 compared with other materials for preparation of SD solubilization effect is not obvious. Compared to the above three methods, preparation process and solvent evaporation method the preparation of SD dissolution effect was better than that of the other two kinds of.PVP K90 and SOLUPLUS? In the preparation process, the product viscosity is too large, the preparation of SD is difficult to scrape or.Co-PVP solid dispersions prepared for medicine auxiliary ratio is 1:5 and the required carrier amount is far greater than the PVP K30 (1:2). The final solution Agent evaporation method, with PVP K30 as the carrier, the auxiliary drug is 1:2, dichloromethane as solvent, solvent dosage to 1g ML4000 and 40ml dichloromethane as the optimum formulation. By differential scanning calorimetry (DSC) and Fu Liye transform infrared spectroscopy scanning technology (FT-IR) to the characterization of ML4000-PVP K30 solid dispersions to determine drug in the solid dispersion in the presence of interaction between the state and the results of.DSC drug and excipients showed that ML4000 has an obvious endothermic peak, PVP K30 itself is amorphous excipients, physical mixture drug crystallization peak weakened, but still exists, SD (1:2,1:3) crystal peak in basic drugs that ML4000:PVP K30=1:2 can disappear, the formation of SD, and the drug in SD in the amorphous state; FT-IR results shows that there are hydrogen bond interaction between drug and carrier materials; the mass fraction of SD in drug dissolution and reproducibility of Fu The requirements. The solid dispersion of the preliminary stability test results show that the dispersion is stable in high temperature and light conditions ML4000 solid, dissolution and drug concentration had no obvious change, but SD has a certain amount of moisture, therefore closed dry; long-term observation experiments show that the SD sample was stable in 3 months. Can be further prepared into tablets. Based on solid dispersions on straight by powder press technology solid dispersion powder pressed into tablets. The tablets fluidity powder, compressibility and tablet appearance, dissolution as criterion, formulation and technology factors on solid dispersion tablets were the single factor investigation, screening for PVPP type disintegrating agent, lubricant type for magnesium stearate. On this basis, choose the disintegrating agent, lubricant dosage and filler type three factors, three levels of each factor, the application of L9 (34) orthogonal experimental design Optimization prescription. According to the optimization of the prescription of preparation of 3 batches of samples, the prescription of uniformity and good reproducibility, evaluate the quality and stability of the research. The results showed that the content uniformity of ML4000 solid dispersion tablets, content and dissolution conditions are in line with the requirements of preliminary stability test, the samples in the light (4500lx + 500lx), high temperature (60 DEG C) and high humidity (RH75% + 5%) under the condition of placing 10d or accelerated test conditions were stable for 1 months.

【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943;R927

【相似文献】