尼美舒利—羟丙基-β-环糊精包合物滴眼剂的研究
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摘要
尼美舒利(Nimesulide, Nim) ,是一新型的具有选择性抑制COX-2作用的非甾体抗炎药(NSAIDs),其抗炎作用强,临床上可用于退热、类风湿性关节炎、软组织损伤及骨关节炎、术后疼痛和其它原因引起的疼痛、耳鼻喉科炎症、呼吸道等疾病。但Nim在水中几乎不溶(0.01mg·mL-1),限制了其在临床上更广泛的应用。
羟丙基-β-环糊精(Hydroxypropyl-beta-Cyclodextrin, HP-β-CD)极易溶于水,具有溶血性低、安全等特点,是美国FDA批准的第一个可供静脉注射的β-环糊精类衍生物。本实验选择HP-β-CD为包合材料,采用超声法制备尼美舒利-羟丙基-β-环糊精(Nim-HP-β-CD)包合物,可大幅度提高药物的溶解度和溶出速度,并避免使用有机溶剂,减少刺激性,进而制备滴眼剂,将能和其他非甾体抗炎药滴眼剂一样治疗眼部炎症。
本文建立了UV和HPLC含量测定方法,方法学研究结果表明,本方法简便快速,结果准确,重现性好,满足样品的含量测定要求。通过相溶解度研究、紫外吸收峰位确定、红外分光光度法、X-射线粉末衍射分析、差示扫描量热法和扫描电子显微镜法验证包合物的形成。并比较包合物与Nim原料药及药物与HP-β-CD物理混合物之间的溶出性能。以包合率为指标,采用正交设计考察了制备工艺条件,经方差分析,结果显示延长超声时间和增加HP-β-CD的量能提高包合物的包合率,确定优化工艺条件为:HPMC浓度为0.1%,5×10-3 M氢氧化钠,15%的HP-β-CD,超声破碎的时间为30 min。采用优化工艺条件制备Nim-HP-β-CD,结果Nim与HP-β-CD形成稳定的包合物,Nim溶解度为原料本身的100倍,体外溶出速率显著加快,包合率高达96.89%。
本文考察了滴眼剂的理化性质,如性状、pH值、澄明度、渗透压、密度、黏度和表面张力。稳定性实验和3个月的加速实验表明:制剂稳定,温度变化不会影响制剂的外观和pH值,并对Nim含量的影响不大,仅光照时含量略有下降。该制剂符合中华人民共和国药典(2005版)的规定。
对滴眼剂的药效学和对兔眼的刺激性进行考察,结果表明本制剂优于醋酸可的松滴眼剂,对兔眼无刺激性和毒性。
Nim-HP-β-CD包合物滴眼剂制备工艺稳定,性质符合药典规定,能有效治疗眼部炎症疾病,开创了Nim新给药途径,具有非常好的市场前景。
Nimesulide (Nim) is COX-2-selective non-steroidal anti-inflammatory drug (NSAID) with strong antiinflammatory, analgesic and antipyretic activity. It is widely used for the treatment of rheumatoid arthritis, osteoarthritis, postoperative trauma and other diseases. Nimesulide is practically insoluble in water (0.01mg·mL-1). The very poor aqueous solubility and wettability of these drugs gives rise to difficulties in pharmaceutical formulations for oral or parenteral delivery, which may lead to variable bioavailability.
2-hydroxylpropyl-β-cyclodextrin (HP-β-CD), a hydroxyalkyl derivative, with improved water solubility properties and may be slightly more toxicologically benign and its safety over other cyclodextrins for ocular administration has been well documented. To overcome these drawbacks of Nim, increasing the aqueous solubility of Nim is an important goal. Hence, in the present investigation inclusion complexation of Nim with HP-β-CD was tried with the aim to improve their pharmaceutical properties i.e. solubility in water and dissolution properties. HP-β-CD is relatively non-toxic compared with organic solvents and surfactant formulations. It has also been used to reduce ophthalmic drug irritation and to increase chemical stability of drugs in aqueous ophthalmic formulations.
The UV and HPLC methods were selected to determinate the content of inclusion complex. The result of methodology studies showed that these methods are simple, accurate and good repeatability. Nim-HP-β-CD was preparation by ultrasonic method and identified by phase solubility study, UV spectroscopy, infrared spectrophotometry, X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscope (SEM). The dissolution rates of Nim, physical mixture and inclusion complex were also studied. Inclusion complex lead to a higher solubility and dissolution rate. The inclusion rate of inclusion complex was used as an indicator. The conditions of preparation were investigated with the orthogonal test and analyzed by ANOVA. It was found that the increasing reaction time and the amount of HP-β-CD could enhance the inclusion rate of inclusion complex. And then the optimized conditions were 0.1% HPMC, 5×10-3M NaOH, 15% HP-β-CD and the reaction time 30 min. In this condition, it was helpful to increase solubility and stability by preparing Nim into the Nim-HP-β-CD inclusion complex. The solubility of Nim in inclusion complex was 100 times higher than that of pure Nim. The dissolution of Nim was greatly improved by HP-β-CD. The inclusion rate of inclusion complex reached up to 96.89%.
The physicochemical properties of eye drops were studied. Such as appearance, pH, clarity, osmotic pressure, density, viscosity and surface tension. The preliminary stability of the prepared eye drops was investigated and the results showed that the drug content of the eye drops had little change during the accelerated experiment in 3 months. It fit the requirement on eye drops regulated by Chinese Pharmacopoeia.
The results of rabbit-eye test indicated that the nimesulide eye drops had no irritation. In addition,the pharmacodynamics of the eye drops were studied.
In a word, the preparing technology of Nim-HP-β-CD eye drop was stable. Its characteristics could meet the standard of Chinese Pharmacopoeia. The anti-inflammatory effect of eye drops on rabbit ocular inflammation caused by 10% capsicum tincture is significant. It starts the new route of administration of Nim, and will have amazing market prospect.
羟丙基-β-环糊精(Hydroxypropyl-beta-Cyclodextrin, HP-β-CD)极易溶于水,具有溶血性低、安全等特点,是美国FDA批准的第一个可供静脉注射的β-环糊精类衍生物。本实验选择HP-β-CD为包合材料,采用超声法制备尼美舒利-羟丙基-β-环糊精(Nim-HP-β-CD)包合物,可大幅度提高药物的溶解度和溶出速度,并避免使用有机溶剂,减少刺激性,进而制备滴眼剂,将能和其他非甾体抗炎药滴眼剂一样治疗眼部炎症。
本文建立了UV和HPLC含量测定方法,方法学研究结果表明,本方法简便快速,结果准确,重现性好,满足样品的含量测定要求。通过相溶解度研究、紫外吸收峰位确定、红外分光光度法、X-射线粉末衍射分析、差示扫描量热法和扫描电子显微镜法验证包合物的形成。并比较包合物与Nim原料药及药物与HP-β-CD物理混合物之间的溶出性能。以包合率为指标,采用正交设计考察了制备工艺条件,经方差分析,结果显示延长超声时间和增加HP-β-CD的量能提高包合物的包合率,确定优化工艺条件为:HPMC浓度为0.1%,5×10-3 M氢氧化钠,15%的HP-β-CD,超声破碎的时间为30 min。采用优化工艺条件制备Nim-HP-β-CD,结果Nim与HP-β-CD形成稳定的包合物,Nim溶解度为原料本身的100倍,体外溶出速率显著加快,包合率高达96.89%。
本文考察了滴眼剂的理化性质,如性状、pH值、澄明度、渗透压、密度、黏度和表面张力。稳定性实验和3个月的加速实验表明:制剂稳定,温度变化不会影响制剂的外观和pH值,并对Nim含量的影响不大,仅光照时含量略有下降。该制剂符合中华人民共和国药典(2005版)的规定。
对滴眼剂的药效学和对兔眼的刺激性进行考察,结果表明本制剂优于醋酸可的松滴眼剂,对兔眼无刺激性和毒性。
Nim-HP-β-CD包合物滴眼剂制备工艺稳定,性质符合药典规定,能有效治疗眼部炎症疾病,开创了Nim新给药途径,具有非常好的市场前景。
Nimesulide (Nim) is COX-2-selective non-steroidal anti-inflammatory drug (NSAID) with strong antiinflammatory, analgesic and antipyretic activity. It is widely used for the treatment of rheumatoid arthritis, osteoarthritis, postoperative trauma and other diseases. Nimesulide is practically insoluble in water (0.01mg·mL-1). The very poor aqueous solubility and wettability of these drugs gives rise to difficulties in pharmaceutical formulations for oral or parenteral delivery, which may lead to variable bioavailability.
2-hydroxylpropyl-β-cyclodextrin (HP-β-CD), a hydroxyalkyl derivative, with improved water solubility properties and may be slightly more toxicologically benign and its safety over other cyclodextrins for ocular administration has been well documented. To overcome these drawbacks of Nim, increasing the aqueous solubility of Nim is an important goal. Hence, in the present investigation inclusion complexation of Nim with HP-β-CD was tried with the aim to improve their pharmaceutical properties i.e. solubility in water and dissolution properties. HP-β-CD is relatively non-toxic compared with organic solvents and surfactant formulations. It has also been used to reduce ophthalmic drug irritation and to increase chemical stability of drugs in aqueous ophthalmic formulations.
The UV and HPLC methods were selected to determinate the content of inclusion complex. The result of methodology studies showed that these methods are simple, accurate and good repeatability. Nim-HP-β-CD was preparation by ultrasonic method and identified by phase solubility study, UV spectroscopy, infrared spectrophotometry, X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscope (SEM). The dissolution rates of Nim, physical mixture and inclusion complex were also studied. Inclusion complex lead to a higher solubility and dissolution rate. The inclusion rate of inclusion complex was used as an indicator. The conditions of preparation were investigated with the orthogonal test and analyzed by ANOVA. It was found that the increasing reaction time and the amount of HP-β-CD could enhance the inclusion rate of inclusion complex. And then the optimized conditions were 0.1% HPMC, 5×10-3M NaOH, 15% HP-β-CD and the reaction time 30 min. In this condition, it was helpful to increase solubility and stability by preparing Nim into the Nim-HP-β-CD inclusion complex. The solubility of Nim in inclusion complex was 100 times higher than that of pure Nim. The dissolution of Nim was greatly improved by HP-β-CD. The inclusion rate of inclusion complex reached up to 96.89%.
The physicochemical properties of eye drops were studied. Such as appearance, pH, clarity, osmotic pressure, density, viscosity and surface tension. The preliminary stability of the prepared eye drops was investigated and the results showed that the drug content of the eye drops had little change during the accelerated experiment in 3 months. It fit the requirement on eye drops regulated by Chinese Pharmacopoeia.
The results of rabbit-eye test indicated that the nimesulide eye drops had no irritation. In addition,the pharmacodynamics of the eye drops were studied.
In a word, the preparing technology of Nim-HP-β-CD eye drop was stable. Its characteristics could meet the standard of Chinese Pharmacopoeia. The anti-inflammatory effect of eye drops on rabbit ocular inflammation caused by 10% capsicum tincture is significant. It starts the new route of administration of Nim, and will have amazing market prospect.
引文
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