【摘要】：馬錢子是常用有毒中藥,其臨床療效卓越,通絡(luò)止痛、散結(jié)消腫之功尤為顯著。但口服治療劑量與中毒劑量接近,極大地限制了其臨床上安全有效應(yīng)用。近年來(lái),隨著中藥經(jīng)皮給藥系統(tǒng)研究的不斷深入和發(fā)展,越來(lái)越多的中藥和天然藥物采用此種劑型開(kāi)發(fā)成用量明確、持久有效,不良反應(yīng)少的新產(chǎn)品。為此,本文詳細(xì)開(kāi)展了馬錢子凝膠膏的系統(tǒng)研究,以期為含馬錢子制劑臨床安全有效應(yīng)用提供支撐。主要圍繞馬錢子的化學(xué)成分、藥理毒理的現(xiàn)代研究進(jìn)展和中藥經(jīng)皮給藥制劑技術(shù)的沿革以及現(xiàn)代研究進(jìn)行了文獻(xiàn)綜述。為后期開(kāi)展馬錢子凝膠膏的研制奠定了理論基礎(chǔ)。論文首先在單因素考察的基礎(chǔ)上采用Box-Behnken響應(yīng)面法優(yōu)化了馬錢子凝膠膏基質(zhì)處方,以初黏力為評(píng)價(jià)指標(biāo),對(duì)凝膠膏劑處方進(jìn)行優(yōu)選。對(duì)關(guān)鍵因素通過(guò)Box-Behnken響應(yīng)面法進(jìn)行優(yōu)化,采用多元線性回歸與二項(xiàng)式進(jìn)行方程擬合,預(yù)測(cè)出最佳工藝方案。結(jié)果表明聚乙烯吡咯烷酮、聚丙烯酸鈉、甘羥鋁對(duì)凝膠膏劑的性能影響顯著,二項(xiàng)式方程復(fù)相關(guān)系數(shù)R2為0.8883,最佳配比為聚丙烯酸鈉為3.0g,聚乙烯吡咯烷酮為2.0g,甘羥鋁為0.5g。對(duì)透皮促滲劑氮酮、薄荷醇、吐溫-80進(jìn)行篩選,結(jié)果表明3%氮酮優(yōu)于后兩者,可以達(dá)到較好的透皮效果。對(duì)馬錢子凝膠膏中試制備工藝進(jìn)行了初步考察。結(jié)果表明,混漿時(shí)間工藝最佳參數(shù)為30min,涂布初、中、后期涂布均勻。馬錢子堿和士的寧從提取物至成品的轉(zhuǎn)移率分別為83.33%、83.27%,說(shuō)明工藝可行。對(duì)其中試產(chǎn)品質(zhì)量控制方法進(jìn)行了初步研究。經(jīng)測(cè)定馬錢子凝膠膏的含膏量為21 士1.5g/100cm2;黏附力考察了初黏力,結(jié)果為能黏住11號(hào)鋼球;馬錢子凝膠膏放置于傾斜角為60°的鋼板上24小時(shí),膏面無(wú)流淌現(xiàn)象;賦形性符合藥典要求;含量測(cè)定結(jié)果為馬錢子堿含量0.19mg/cm2,士的寧含量為0.11mg/cm2。對(duì)馬錢子凝膠膏進(jìn)行了初步安全性評(píng)價(jià)。分別考察了馬錢子凝膠膏急性毒性、對(duì)家兔皮膚單次、多次刺激的影響以及對(duì)豚鼠皮膚過(guò)敏性的影響。試驗(yàn)表明馬錢子凝膠膏無(wú)急性毒性作用,無(wú)刺激性,無(wú)皮膚過(guò)敏性。對(duì)馬錢子凝膠膏對(duì)骨癌痛療效進(jìn)行了評(píng)價(jià)。復(fù)制了了大鼠骨癌痛模型,基于此,考察了馬錢子凝膠膏60mg/kg、120mg/kg、240mg/kg三個(gè)劑量對(duì)大鼠骨癌痛的療效。最終通過(guò)測(cè)定各組大鼠對(duì)機(jī)械刺激的反應(yīng)潛伏期的變化來(lái)測(cè)定馬錢子凝膠膏其緩解癌痛的情況。外用馬錢子凝膠膏后,第14d及16d給藥高劑量組240mg/kg與模型組骨癌痛模型大鼠縮足反射時(shí)間之間有顯著性差異(P0.01),表明馬錢子凝膠膏在一定程度上緩解了骨癌痛模型大鼠的痛覺(jué)過(guò)敏反應(yīng)。
[Abstract]:Semen strychni is a common toxic Chinese medicine, its clinical efficacy is excellent, Tongluo pain, Sanjie detumescence is particularly significant. However, the dose of oral therapy is close to the dose of poisoning, which greatly limits its safe and effective clinical application. In recent years, with the development of transdermal drug delivery system of Chinese medicine, more and more traditional Chinese medicine and natural drugs are used to develop new products with definite dosage, lasting effectiveness and less adverse reactions. Therefore, the systematic study of brucine gel ointment was carried out in order to provide support for the safe and effective application of brucine preparation. This paper reviews the chemical constituents, pharmacological toxicology, the development of traditional Chinese medicine (TCM) transdermal drug delivery technology and the modern research on the chemical constituents and pharmacological toxicology of semen strychni. It laid a theoretical foundation for the later development of brucine gel paste. Firstly, on the basis of single factor investigation, Box-Behnken response surface method was used to optimize the formulation of brucine gel paste matrix, and the initial viscosity was taken as the evaluation index to optimize the formulation of gel paste. The key factors are optimized by Box-Behnken response surface method, and the best process scheme is predicted by fitting the equation with multivariate linear regression and binomial equation. The results showed that polyvinylpyrrolidone, sodium polyacrylate and aluminum glycolate had significant effects on the properties of the gel paste. The binomial equation complex correlation coefficient R2 was 0.8883, the optimum ratio was 3.0 g for sodium polyacrylate, 2.0 g for polyvinylpyrrolidone and 0.5 g for aluminum glycolate. The results showed that 3% azone was superior to the latter, and the transdermal effect was better than that of Tween-80. The results showed that the transdermal permeation agents of azone, menthol and Tween-80 were better than those of the latter. The pilot-scale preparation of brucine gel paste was preliminarily investigated. The results show that the optimum parameters of mixing time are 30 min, and the initial, middle and late coating is uniform. The transfer rates of brucine and strychnine from extract to finished product were 83.33 and 83.27, respectively, indicating that the process was feasible. The quality control method of pilot products was studied. The paste content of brucine gel paste was determined to be 21 + 1.5 g / 100 cm ~ (2). The initial adhesion force was investigated, and the result was that it could stick to No. 11 steel ball, and the brucine gel paste was placed on the steel plate with an angle of 60 擄for 24 hours, and there was no flowing phenomenon on the surface of the paste. The content of brucine was 0.19 mg / cm ~ (2) and strychnine was 0.11 mg / cm ~ (2). The safety of brucine gel ointment was evaluated. The acute toxicity of brucine gel ointment, the effects of single and multiple irritation on rabbit skin and the effect on skin hypersensitivity of guinea pigs were investigated. The results showed that strychnine gel ointment had no acute toxicity, no irritation and no skin allergy. The curative effect of brucine gel ointment on bone cancer pain was evaluated. The pain model of bone cancer in rats was established. Based on this, the therapeutic effects of brucine gel ointment 60 mg / kg ~ (120 mg / kg) ~ (120 mg / kg) ~ (240 mg / kg) on bone cancer pain in rats were investigated. Finally, the effect of strychnine gel ointment on relieving cancer pain was determined by measuring the latency of response to mechanical stimulation in each group. After topical application of brucine gel cream, There was a significant difference in reflex time between the high dose group (14 d and 16 d) and the model group (P0.01), which indicated that strychnine gel ointment alleviated the hyperalgesia in the model rats with bone cancer pain to some extent.
【學(xué)位授予單位】：南京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R283.6;R285.5

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