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热熔压敏胶伤湿止痛膏的实验研究
【作者】 黎丽；
【导师】 闫小平；
【作者基本信息】 北京中医药大学 ， 中药制剂， 2012， 硕士
【摘要】 目的：通过伤湿止痛膏的两种不同基质(橡胶基质和热熔压敏胶基质)制备工艺研究比较,研制新型sIs热熔压敏胶贴膏剂,找到传统橡胶膏剂的替代品,解决传统橡胶膏剂的工艺缺陷,以及临床使用刺激性大、易引起过敏等问题；制定热熔压敏胶伤湿止痛膏的质量标准,研制出皮肤黏贴性、稳定性较好的热熔压敏胶贴膏剂；通过体外透皮和释放规律实验,对比两种不同基质伤湿止痛膏的释药性能,为研制热熔压敏胶贴膏剂提供依据。方法：1.工艺研究：了解原橡胶基质工艺；学习新热熔压敏胶基质工艺,以综合粘附性能(初粘力、持黏力、剥离度)和综合物理性能(成型性、弹性、韧性、舒适感、可涂展性)作为评价指标,进行原料选择、用量筛选,以及制备工艺的优选,然后考察热熔压敏胶的载药性能。2.质量标准制定：采用薄层色谱法对热熔压敏胶伤湿止痛膏中的颠茄流浸膏进行定性鉴别；按照2010年版《中国药典》一部附录ⅠⅠ贴膏剂项下贴剂重量差异检测方法进行测定；采用HPLC法测定热熔压敏胶伤湿止痛膏中马钱子碱、士的宁的含量,色谱条件—色谱柱：Agilent SB-C18(250mm×4.6mm,5μm)；流动相：乙腈Acetonitrile-0.01mol／L庚烷磺酸钠与0.02mol／L KH2P04等量混合溶液(用10%磷酸调PH值至2.8)(21：79);流速1ml／min波长：260nm；柱温：30℃3.体外透皮吸收和释放规律研究：采用智能透皮试验仪及释放度测定装置,对两种不同基质的伤湿止痛膏进行离体透皮吸收及释放度试验,用HPLC法测定接受液中马钱子碱、士的宁、硫酸阿托品的含量,分别计算橡胶伤湿止痛膏、热熔压敏胶伤湿止痛膏中硫酸阿托品、马钱子碱、士的宁的释放度和离体透皮率,对两种不同基质贴膏剂的离体透皮率与释放度进行比较。结果：1.经试验筛选,确定了热熔压敏胶制备原料：骨架材料为SIS1105,增粘剂为松香衍生物,增塑剂为液体石蜡；原料处方为：SIS1105/松香衍生物/液体石蜡(100：120：50)；制备工艺条件：反应时温度为120℃,反应时间为30min,涂布温度为90℃；药物加入基质时的最佳温度为105℃。热熔压敏胶基质在贴剂制备中的优势明显大于橡胶基质,新型的SIS热熔压敏胶贴膏剂可以取代传统橡胶膏剂。2.质量标准研究：热熔压敏胶伤湿止痛膏中颠茄流浸膏的薄层鉴别图谱清晰,方法简便。本品的重量差异检查符合规定。HPLC法测定热熔压敏胶伤湿止痛膏中士的宁和马钱子碱的含量：士的宁、马钱子碱在色谱中保留时间分别为16.8min、14.0min,被测色谱峰与其他峰分离良好,生马钱子阴性对照样品溶液无干扰;线性范围分别为0.53-53.0μg·mL-1、0.5~50.0μg·mL1(R2=0.9995)；精密度试验RSD分别为0.50%、0.81%；稳定性试验RSD分别为0.75%、2.69%,样品溶液在16h内稳定；重复性试验：RSD分别为4.90%、2.63%；回收率试验：平均加样回收率分别为90.68%、100.10%,RSD分别为2.94%、1.18%。3批热熔压敏胶伤湿止痛膏中士的宁含量分别为22.12μg·g-1、22.56μg·g-1、22.93μg·g-1；马钱子碱的含量分别为15.52μg·g-1、15.07μg·g-1、15.84μg·g-1.3.体外透皮吸收和释放规律研究：橡胶伤湿止痛膏中马钱子碱、士的宁、硫酸阿托品72h的平均累积透过百分率分别为54.90%,50.24%,46.54%；在30%乙醇生理盐水中24h的释放度分别为92.29%,81.77%,53.28%；热熔压敏胶伤湿止痛膏中马钱子碱、士的宁、硫酸阿托品72h的内平均累积透过百分率分别为53.25%、74.52%、34.32%；在30%乙醇生理盐水中24h的释放度分别为49.62%、82.25%、25.76%。结论：制备的热熔压敏胶伤湿止痛膏具有较好的皮肤黏贴性、释放度与皮肤渗透性。通过制备工艺研究、质量标准制定、体外透皮速和释放规律研究,为热熔压敏胶基质用于制备新型的压敏胶贴膏制剂奠定了良好的基础。
【Abstract】 Objective:In order to develop an new type of SIS Hot-melt pressure sensitive adhesive patch, to find a substitute of the traditional rubber patch, and to solve the problem in life and clinical use that the traditional rubber patch had large excitability and easy to cause allergys; we compered the preparation process of two different stroma of ShangShi ZhiTong Gao Patch;And then drafting quality standards of Hot melt pressure sensitive adhesive ShangShi ZhiTong Gao patch, which is not only have a nice stability and a well adhesion to skin.; Finally conducting a test on the release regularity and the in-vitro transdermal, then contrasted drug release property of two different kinds of ShangShi ZhiTong Gao Patch, the result provide information for the development of hot melt pressure sensitive adhesive patch.Methods::1The study on process:comprehended the original rubber stromal technology:The new technology used comprehensive adhesion (initial tack, holding tack, peel degree) and comprehensive physical properties (formability, flexibility, toughness, comfort, glide) of pressure-sensitive adhesive as indicators, in order to study on raw material selection> dosage screening test and optimization of the preparation technology, and then examining the drug carrier for pressure sensitive adhesive; Contrasting the rubber stromal and the hot melt pressure sensitive adhesive stromal through the relevant literature.2The study on the quality standards for the Preparation:The Atropine Sulfate fluid extract in The New ShangShi ZhiTong Gao Patch were identified by TLC. The weight variation of the preparation were tested according to the method described for adhesive ointment in2010China Pharmacopeia below the relative volumes of appendix I I. The content of atropine sulfate^Strychnine> Brucine in the ShangShi ZhiTong Gao Patch was determined by HPLC. The chromatography conditions were that the Agilent SB-C18(250mmx4.6mm,5μm) column was used; that mobile phase was composed of Acetonitrile-O.Olmol/L sodium1-heptanesulfonate and0.02mol/L KH2PO4equivalent mixture(used10%phosphoric acid regulating PH value to2.8)(21:79); the flow rate was1mL/min with UV detection at260nm, and that the column temperature was30℃3The study on the release rate and the in vitro percutaneous absorption rate:The equipment of release and aptitude percutaneous absorption were used to carry out the experiments of two different stroma of ShangShi ZhiTong Gao Patch. The content of Strychnine、Brucine、 Atropine Sulfate released and in vitro permeated from ShangShi ZhiTong Gao Patch were determined by HPLC. Calculated the release rate and the in vitro percutaneous absorption rate of rubber ShangShi ZhiTong Gao Patch and hot melt pressure sensitive adhesive ShangShi ZhiTong Gao Patch, contrasting the drug release property between two different stroma of ShangShi ZhiTong Gao Results:1Through the experiment selection that determined raw material of Hot melt pressure sensitive adhesive choose SIS1105as skeleton material, rosin derivatives as tackifier, liquid paraffin as plasticizer. And the prescription ratio of raw material was SIS1105:Rosin derivatives:liquid paraffin (100:120:50); The preparation conditions:reaction temperature wasl20℃, reaction time was30min, coating temperature was90℃; and the optimum temperature of medicine mixed in stromal was105℃. Compared to rubber stromal, hot melt pressure sensitive adhesive stromal had obviously superiority. New hot melt pressure sensitive adhesive patch will replace tradition rubber patch.2The study on the quality standards:TLC was used to identify Belladonna in Hot melt pressure sensitive adhesive ShangSh ZhiTong Gao Patch preparation. The examination of the weight variation of the patch preparation were right to the regulation. Determined the content by HPLC:the determination of Strychnine and Brucine had shown that retention time of the chromate graphy were16.8min and14.0min, the measured peaks and other peaks well separated; Raw Strychnos negative reference substance sample solution without interference; the liner rang were0.53-53.0μg-g-’and0.5-50.0μg.g-1(R2=0.9995), and the precision RSD were0.50%and0.81%; The Stability RSD were0.75%and2.69%, sample solution was stable within16h; The redupplicate RSD were4.90%and2.63%; And the average recovery were90.68%and100.10%, with RSD were2.94%and1.18%; Three batches of Hot melt pressure sensitive adhesive ShangShi ZhiTong Gao Patch in which the content of Strychnine were22.12μg.g-1,22.56μg.g-1、22.93μg.g-1、 and content of Brucine were15.52μg.g-1、15.07μg.g-1、15.84μg.g-1、3The study on the release rate and the in vitro percutaneous rate:The cumulative permeation rate of strychnine. Strychnine, Atropine sulfate from Rubber ShangShi ZhiTong Gao Patch within72hours were54.90%.50.24%,46.54%;and the release rate in the30%ethanol saline were92.29%,81.77%.53.28%in24hours;And the cumulative permeation rate of strychnine, Strychnine, Atropine sulfate from Hot-melt pressure sensitive adhesive ShangShi ZhiTong Gao Patch within72hours were53.25%,74.52%.34.32%;and the release rate in the30%ethanol saline were49.62%,82.25%,25.76%in24hours,Conclusion:prepared of Hot-melt pressure sensitive adhesive ShangShi ZhiTong Gao have well skin-adhesive, release rate and skin permeability. Through the preparation of technology, studying on in-vitro permeated and release rate of the regularity, drawing up the quality standards, laid a good foundation for development of pressure-sensitive adhesive matrix for Plaster preparations.