磁性介孔炭作為難溶性藥物吲哚美辛載體的初步研究
發(fā)布時(shí)間：2018-12-08 13:00
【摘要】：吲哚美辛(INC)屬非甾體抗炎藥(NSAID),是最強(qiáng)的COX抑制劑之一,具有顯著的解熱鎮(zhèn)痛及抗炎作用,該藥自上世紀(jì)60年代上市后,被廣泛用于臨床,它被認(rèn)為是比阿司匹林和撲熱息痛更有前景的藥物。而吲哚美辛屬于BCS II類藥物,在水中溶解度很低,其普通制劑口服生物利用度低,這很大程度上限制了吲哚美辛在臨床上的應(yīng)用。因此,很有必要開(kāi)發(fā)吲哚美辛的新型制劑以解決上述問(wèn)題。磁性介孔炭微球孔徑在2-50 nm范圍內(nèi)可調(diào),與生物活性藥物分子的尺寸相匹配,且生物相容性好,結(jié)構(gòu)穩(wěn)定、具有較高比表面和孔容,不僅能提高藥物的分散性,其納米孔道還能有效降低藥物結(jié)晶度或抑制藥物再結(jié)晶,從而改善難溶性藥物的溶解度,故其在藥物傳遞領(lǐng)域具有很大的潛力。本文采用一步法合成磁性介孔炭微球(MMC),以吲哚美辛為模型藥物載入磁性介孔炭微球中得到吲哚美辛/磁性介孔炭固體分散體(INC/MMC),提高了吲哚美辛的溶解度和溶出速率。這有利于提高其生物利用度、減少在臨床的使用劑量及降低系統(tǒng)毒性,為其臨床應(yīng)用奠定必要的實(shí)驗(yàn)基礎(chǔ)。本論文主要內(nèi)容包括以下幾個(gè)方面:1.建立紫外分光光度法分析吲哚美辛及其制劑,實(shí)驗(yàn)結(jié)果顯示吲哚美辛在常溫下24 h內(nèi)性質(zhì)穩(wěn)定,回收率接近100%,證明載體材料對(duì)吲哚美辛的含量測(cè)定無(wú)干擾�？疾炝诉胚崦佬猎诓煌橘|(zhì)中的溶解度,為INC/MMC的制備工藝及釋放度測(cè)定奠定基礎(chǔ)。在蒸餾水、pH 6.8磷酸鹽緩沖液和pH 1.2鹽酸溶液中的平衡溶解度分別為23.28、849.07和0.26μg·m L-1,其中,在pH 6.8磷酸鹽緩沖液中符合漏槽條件,可作為體外溶出介質(zhì)的參考。2.磁性介孔炭微球的合成工藝研究,以比表面積和孔徑為主要指標(biāo),通過(guò)單因素考察,篩選出最優(yōu)處方工藝為:聚合溫度80℃;焙燒溫度850℃;加入的Fe(NO3)3·9H2O濃度為0.05 mg/m L;蔗糖與二氧化硅質(zhì)量比為2:1。在此條件下制備磁性介孔炭呈球形,平均粒徑為17μm;孔徑分布均勻,比表面積為1213 m2/g,孔容為3.15 m3/g,孔徑集中在6.46 nm處。3.考察了藥物/載體的比例及時(shí)間對(duì)載藥量的影響,最終確定藥物/載體的比例為1/1,攪拌時(shí)間為3h為最佳制備條件,所得的樣品載藥量為32.87%,INC以無(wú)定型態(tài)存在于MMC的孔道中。該方法制備的INC/MMC固體分散體6個(gè)月內(nèi)穩(wěn)定,未出現(xiàn)老化現(xiàn)象。4.對(duì)INC/MMC在水中的平衡溶解度進(jìn)行考察,結(jié)果為109.44μg·m L-1,比原藥提高將近五倍。體積外溶出度試驗(yàn)選擇pH 6.8為溶出介質(zhì),結(jié)果表明,INC/MMC的溶出度比原藥有顯著提高,15 min時(shí)達(dá)到84.2%,其溶出曲線符合First-order經(jīng)驗(yàn)?zāi)Ｐ?擬合相關(guān)系數(shù)為0.99,t=∞時(shí)的累積釋放率92.2%,釋放速率常數(shù)k為0.22。不同批次間的INC/MMC的溶出曲線相似因子f2為65.8,表明兩條溶出曲線具有重現(xiàn)性。5.采用MTT法對(duì)MMC進(jìn)行體外細(xì)胞毒性實(shí)驗(yàn),結(jié)果表明MMC在0.1~1000μg/mL濃度范圍內(nèi)對(duì)L929細(xì)胞沒(méi)有明顯毒性,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，
本文編號(hào)：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，
本文編號(hào)：2368387
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