磁性介孔炭作为难溶性药物吲哚美辛载体的初步研究
发布时间：2018-12-08 13:00
【摘要】：吲哚美辛(INC)属非甾体抗炎药(NSAID),是最强的COX抑制剂之一,具有显著的解热镇痛及抗炎作用,该药自上世纪60年代上市后,被广泛用于临床,它被认为是比阿司匹林和扑热息痛更有前景的药物。而吲哚美辛属于BCS II类药物,在水中溶解度很低,其普通制剂口服生物利用度低,这很大程度上限制了吲哚美辛在临床上的应用。因此,很有必要开发吲哚美辛的新型制剂以解决上述问题。磁性介孔炭微球孔径在2-50 nm范围内可调,与生物活性药物分子的尺寸相匹配,且生物相容性好,结构稳定、具有较高比表面和孔容,不仅能提高药物的分散性,其纳米孔道还能有效降低药物结晶度或抑制药物再结晶,从而改善难溶性药物的溶解度,故其在药物传递领域具有很大的潜力。本文采用一步法合成磁性介孔炭微球(MMC),以吲哚美辛为模型药物载入磁性介孔炭微球中得到吲哚美辛/磁性介孔炭固体分散体(INC/MMC),提高了吲哚美辛的溶解度和溶出速率。这有利于提高其生物利用度、减少在临床的使用剂量及降低系统毒性,为其临床应用奠定必要的实验基础。本论文主要内容包括以下几个方面:1.建立紫外分光光度法分析吲哚美辛及其制剂,实验结果显示吲哚美辛在常温下24 h内性质稳定,回收率接近100%,证明载体材料对吲哚美辛的含量测定无干扰。考察了吲哚美辛在不同介质中的溶解度,为INC/MMC的制备工艺及释放度测定奠定基础。在蒸馏水、pH 6.8磷酸盐缓冲液和pH 1.2盐酸溶液中的平衡溶解度分别为23.28、849.07和0.26μg·m L-1,其中,在pH 6.8磷酸盐缓冲液中符合漏槽条件,可作为体外溶出介质的参考。2.磁性介孔炭微球的合成工艺研究,以比表面积和孔径为主要指标,通过单因素考察,筛选出最优处方工艺为:聚合温度80℃;焙烧温度850℃;加入的Fe(NO3)3·9H2O浓度为0.05 mg/m L;蔗糖与二氧化硅质量比为2:1。在此条件下制备磁性介孔炭呈球形,平均粒径为17μm;孔径分布均匀,比表面积为1213 m2/g,孔容为3.15 m3/g,孔径集中在6.46 nm处。3.考察了药物/载体的比例及时间对载药量的影响,最终确定药物/载体的比例为1/1,搅拌时间为3h为最佳制备条件,所得的样品载药量为32.87%,INC以无定型态存在于MMC的孔道中。该方法制备的INC/MMC固体分散体6个月内稳定,未出现老化现象。4.对INC/MMC在水中的平衡溶解度进行考察,结果为109.44μg·m L-1,比原药提高将近五倍。体积外溶出度试验选择pH 6.8为溶出介质,结果表明,INC/MMC的溶出度比原药有显著提高,15 min时达到84.2%,其溶出曲线符合First-order经验模型,拟合相关系数为0.99,t=∞时的累积释放率92.2%,释放速率常数k为0.22。不同批次间的INC/MMC的溶出曲线相似因子f2为65.8,表明两条溶出曲线具有重现性。5.采用MTT法对MMC进行体外细胞毒性实验,结果表明MMC在0.1~1000μg/mL浓度范围内对L929细胞没有明显毒性,表明MMC具有良好的生物相容性。
[Abstract]:Indomethacin (INC), a non-steroidal anti-inflammatory drug, is one of the strongest COX inhibitors, and has significant antipyretic, analgesic and anti-inflammatory effects. It has been widely used in clinical practice since it was launched in the 1960s. It is considered a more promising drug than aspirin and paracetamol. Indomethacin is a kind of BCS II drug with low solubility in water and low oral bioavailability of its general preparation which limits the clinical application of indomethacin to a great extent. Therefore, it is necessary to develop new indomethacin preparation to solve these problems. The pore size of magnetic mesoporous carbon microspheres is adjustable in the range of 2-50 nm, which matches the size of bioactive drug molecules, and has good biocompatibility, stable structure, high specific surface and pore volume, which can not only improve the dispersibility of the drug. It can also effectively reduce the crystallinity or inhibit the recrystallization of drugs, thus improving the solubility of insoluble drugs, so it has great potential in the field of drug delivery. In this paper, magnetic mesoporous carbon microspheres (MMC),) were synthesized by one-step method. Indomethacin was loaded into magnetic mesoporous carbon microspheres with indomethacin as a model drug to obtain indomethacin / magnetic mesoporous carbon solid dispersion (INC/MMC). The solubility and dissolution rate of indomethacin were improved. It is beneficial to increase the bioavailability, reduce the dosage in clinical use and reduce the toxicity of the system, and lay the necessary experimental foundation for its clinical application. The main contents of this paper include the following aspects: 1. A UV spectrophotometric method was established for the analysis of indomethacin and its preparation. The results showed that the properties of indomethacin were stable at room temperature for 24 h and the recovery rate was close to 100. It was proved that the carrier material had no interference with the determination of indomethacin. The solubility of indomethacin in different media was investigated, which laid a foundation for the preparation of INC/MMC and the determination of its release. The equilibrium solubility in distilled water, pH 6.8 phosphate buffer solution and pH 1.2 hydrochloric acid solution were 23.28849.07 and 0.26 渭 g mL -1, respectively. It can be used as a reference for dissolution medium in vitro. 2. The synthesis process of magnetic mesoporous carbon microspheres was studied. With the specific surface area and pore size as the main indexes, the optimum preparation conditions were obtained by single factor investigation: polymerization temperature 80 鈩，
本文编号：2368387
[Abstract]:Indomethacin (INC), a non-steroidal anti-inflammatory drug, is one of the strongest COX inhibitors, and has significant antipyretic, analgesic and anti-inflammatory effects. It has been widely used in clinical practice since it was launched in the 1960s. It is considered a more promising drug than aspirin and paracetamol. Indomethacin is a kind of BCS II drug with low solubility in water and low oral bioavailability of its general preparation which limits the clinical application of indomethacin to a great extent. Therefore, it is necessary to develop new indomethacin preparation to solve these problems. The pore size of magnetic mesoporous carbon microspheres is adjustable in the range of 2-50 nm, which matches the size of bioactive drug molecules, and has good biocompatibility, stable structure, high specific surface and pore volume, which can not only improve the dispersibility of the drug. It can also effectively reduce the crystallinity or inhibit the recrystallization of drugs, thus improving the solubility of insoluble drugs, so it has great potential in the field of drug delivery. In this paper, magnetic mesoporous carbon microspheres (MMC),) were synthesized by one-step method. Indomethacin was loaded into magnetic mesoporous carbon microspheres with indomethacin as a model drug to obtain indomethacin / magnetic mesoporous carbon solid dispersion (INC/MMC). The solubility and dissolution rate of indomethacin were improved. It is beneficial to increase the bioavailability, reduce the dosage in clinical use and reduce the toxicity of the system, and lay the necessary experimental foundation for its clinical application. The main contents of this paper include the following aspects: 1. A UV spectrophotometric method was established for the analysis of indomethacin and its preparation. The results showed that the properties of indomethacin were stable at room temperature for 24 h and the recovery rate was close to 100. It was proved that the carrier material had no interference with the determination of indomethacin. The solubility of indomethacin in different media was investigated, which laid a foundation for the preparation of INC/MMC and the determination of its release. The equilibrium solubility in distilled water, pH 6.8 phosphate buffer solution and pH 1.2 hydrochloric acid solution were 23.28849.07 and 0.26 渭 g mL -1, respectively. It can be used as a reference for dissolution medium in vitro. 2. The synthesis process of magnetic mesoporous carbon microspheres was studied. With the specific surface area and pore size as the main indexes, the optimum preparation conditions were obtained by single factor investigation: polymerization temperature 80 鈩，
本文编号：2368387
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