摘要
目的：痛风是一种由于体内嘌呤代谢紊乱所导致的慢性代谢性疾病,其中急性痛风性关节炎是骨科中常见的疑难病症之一,是由尿酸盐沉积于关节囊、滑囊、软骨、骨质和其他组织中而引起的病理损害性炎性反应。进入21世纪,伴随人民生活水平的不断提高以及饮食结构的变化,急性痛风性关节炎的发病率呈现逐渐上升的一种趋势,从而对人民的身体健康和生活质量构成了严重的威胁。针对该病的治疗,在国内外临床上主要是采取药物进行抗炎、镇痛、抑制血液尿酸盐沉积等方面的治疗。此类药物中,秋水仙碱对急性痛风的治疗具有很好的疗效。但秋水仙碱主要口服给药,且不良作用较多,在一定程度上影响了该药在临床的广泛应用。本研究旨在制备两种磷脂材料(大豆磷脂和氢化磷脂)的秋水仙碱醇质体及其经皮贴剂,不仅改变了给药途径,还有效提高了秋水仙碱药物的透皮吸收。方法：本研究采用注入法分别制备两种磷脂材料的秋水仙碱醇质体,并验证各项指标；通过均匀设计软件分析,用均匀设计法以初粘力与持粘力的综合评分为考察指标优化贴剂压敏胶中药物秋水仙碱与Ⅳ#丙烯酸树脂、柠檬酸三乙酯、琥珀酸以及氮酮的组成,制备上述比例的两种醇质体的贴剂；用智能溶出度测试仪和改良的Franz扩散池分别比较二者释放度和透皮性能,并考察贴剂光照、湿度和高温条件下稳定性,并进行了兔皮肤的刺激性试验和小鼠体内药物动力学研究。结果：注入法制得两种磷脂材料的秋水仙碱醇质体各项指标符合文献要求。经均匀设计制备的两种秋水仙碱醇质体贴剂,符合2010年版《中国药典》规定的贴剂粘性要求。秋水仙碱普通、大豆磷脂和氢化磷脂醇质体贴剂体外释放度符合Higuchi方程；三者体外透皮拟合拟合零级方程,透皮速率J依次提高；氢化磷脂醇质体贴剂的稳定性指标尤其是色泽变化明显低于大豆磷脂脂醇质体贴剂。兔皮肤刺激性试验在48h内三种贴剂均无红斑、水肿等刺激反应。考察贴剂在小鼠体内药物动态变化,与口服药物相比,两种秋水仙碱醇质体经皮给药达峰时间Tmax和药物体内平均滞留时间MRTX明显延长(p<0.05),峰浓度Cmax降低(p<0.05),AUC明显增高(p<0.05),且氢化磷脂醇质体贴剂AUC高于大豆磷脂醇质体贴剂。
结论：与普通贴剂相比,两种磷脂醇质体贴剂均具有较高的体外累积释放度Q和透皮速率J,表明醇质体具有提高药物透皮吸收的作用。对大豆磷脂和氢化磷脂两种材料的醇质体贴剂稳定性(色泽变化)和小鼠体内药物参数(AUC、Cmax等)进行比较,可见,氢化磷酯醇质体贴剂性能优于大豆磷脂醇质体贴剂,氢化磷脂是一种新型优良的磷脂材料,可替代大豆磷脂,提高醇质体的稳定性以及药物体内的吸收程度。
Objective:Gout is a chronic metabolic disease caused by the disorder of purine metabolism in the body.Acute gouty arthritis is one of the common orthopedic illness which is the inflammatory reaction of pathological damage caused by the urate deposition in the joint capsule, bursa, cartilage, boneand and other tissues. In the21st century, accompanied by of the continuous improvement of people's living standards and the structure changes of diet, the incidence of acute gouty arthritis showes a gradual increase in a trend, and thus pose a serious threat to people's health and quality of life. In the domestic and international clinical treatment for the disease, the main treatment is to take advantage of various drugs for anti-inflammatory, relieving pain, decreasing urate deposition in the blood and so on. Between these drugs, colchicine has a good effect on the treatment of acute gout. However, colchicine mainly through the oral administration, and has more adverse effects, and thus to some extent, they impact the clinical comprehensive applications of the drug. The purpose of this study is to prepare colchicine ethosomes, to design the preparation of its pressure-sensitive adhesive patches, and investigate the feasibility and quality of preparation of the patch in transdermal drug delivery systems.
Method:By the uniform design sotfware, the uniform design was used to optimize the patch components of polyacrylic resin Ⅳ#,succinic acid and triethyl citrate,with its initial adhesion and hold tack as the composite indice.Then the colchicine ethosomes patches of soybean lecithin(SL) and hydrogenated soybean phosphatidylcholine(HSPC) were prepared.The automated dissolution test analyzer and improved Franz diffusion cell were adopted to compare the release and transdermal properties of the two types of colchicine ethosomes patches respectively.Moreover, they were studied by their stability of the preparation of light, humidity and high temperature conditions, and a rabbit skin irritation test and in vivo drug kinetics study. The colchicine dynamic changes were investigated for the patches in mice.
Result:The viscosity requirements of colchicine ethosomes patches were in line with the provisions of the2010edition of Chinese Pharmacopoeia. The vitro release of the colchicine ordinary patches, the ethosomes patches of SL and HSPC fitted to the Higuchi equation.Their transdermal absorption fitted to the zero level quation, and their transdermal rates of J were improved in turn. The stability of the ethosome patches of HSPC was higher than SL, especially for colours. The ethosome patches of SL and HSPC had no stimulation for48h by the rabbit skin irritation test.Compared with the oral administration, two colchicine ethosome transdermal patches had various differences that their Tmax and mean retention time MRTX were extended (p<0.05), peak plasma concentration Cmax was decreased (p<0.05), and AUC was significantly higher (p<0.05).And the HSPC Colchicine ethosome patches had the higher AUC than the SL Colchicine ethosome patches.
Conclusion:Compared with ordinary patches, the two ethosomes patches have high in vitro cumulative release rate of Q and transdermal rate J.It indicates that ethosomes can have the role of improving transdermal drug absorption. And the stability test of the HSPC.patches,especially for color change, and in vivo drug parameters such as AUC, Cmax, and so on in mice are superior to the SL ones. So HSPC is a novel kind of excellent phospholipid material that can replace SL, and that can improve the stability and the drug absorption rate of ethosomes in the body.
引文
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