發(fā)布時間：2018-01-18 10:22

  本文關(guān)鍵詞：鹽酸地芬尼多滲透泵制劑的研究　出處：《南方醫(yī)科大學》2017年碩士論文　論文類型：學位論文

  更多相關(guān)文章： 鹽酸地芬尼多 雙層滲透泵片 單層滲透泵片 單因素考察 Box-Behnken設(shè)計-效應(yīng)面法 穩(wěn)定性考察

【摘要】：鹽酸地芬尼多是目前治療眩暈癥常用的藥物之一,具有減弱前庭刺激、抑制迷路功能、抑制惡心和嘔吐在延髓化學感受性觸發(fā)區(qū)及改善椎動脈血流量等藥理特點,還有較弱抗膽堿作用。被廣泛用于抗眩暈和止吐,臨床主要用于運動病或中耳及內(nèi)耳眩暈病所致眩暈。也適用于抗腫瘤藥物、麻醉、射線照射等導致的惡心嘔吐。目前,已有鹽酸地芬尼多普通片劑上市,臨床療效確切。但由于其生物半衰期較短,約為3-4h,為維持藥物治療濃度,需日服3次,頻繁的給藥方式不僅造成患者的順服性下降,而且導致血藥濃度出現(xiàn)谷峰現(xiàn)象。本課題以鹽酸地芬尼多為模型藥物,分別制備了單層和雙層滲透泵制劑,對二者的制劑處方、制備工藝和體外釋放行為進行考察。并進行了鹽酸地芬尼多雙層滲透泵片的處方優(yōu)化和制劑穩(wěn)定性進行研究。本課題選取氯化鈉和不同分子量的聚氧乙烯(PEO)用作片芯主輔料,聚乙二醇(PEG)和醋酸纖維素(CA)選作包衣材料,丙酮為有機包衣溶媒,制備鹽酸地芬尼多雙層滲透泵片。采用FDA推薦的f2相似因子法作為釋放度評價指標,研究其片芯處方、包衣工藝、體外釋放條件等對釋藥行為的影響。通過單因素考察,找出對12小時內(nèi)體外累積釋放度(Y1)和曲線擬合度(Y2)影響較為顯著的因素:助推層PEO含量(A)、含藥層氯化鈉含量(B)及包衣增重(C)。將以上三個因素作為自變量,以12h累積釋放度和釋放曲線的擬合度為考察因變量,采用Box-Behnken設(shè)計-效應(yīng)面法,進行三因素三水平的優(yōu)化實驗。得到優(yōu)化處方,并按照最佳處方進行驗證。試驗結(jié)果顯示,實際測得值與軟件優(yōu)化值基本一致,差異較小,優(yōu)化處方制得的鹽酸地芬尼多雙層滲透泵片的體外釋藥曲線符合零級模型(r=0.9901),重現(xiàn)性好。本課題還對鹽酸地芬尼多單層滲透泵片進行了初步單因素研究,對載藥量、滲透壓促進劑、包衣增重等影響釋藥行為的因素進行研究。最后,本文考察了自制鹽酸地芬尼多雙層滲透泵片的穩(wěn)定性,影響因素實驗表明:該制劑在置于60℃和4500Lx光照條件下10天后穩(wěn)定,而在RH92.5%放置10天后,釋藥孔中有內(nèi)容物流出,表明本制劑對濕度較敏感,因此應(yīng)選擇密封性能較好的包裝材料。加速試驗結(jié)果表明:在40℃、相對濕度75%的條件下,對模擬上市包裝的三批樣品進行加速試驗,各項考察指標3個月內(nèi)均在正常范圍內(nèi),未見異常變化,后續(xù)試驗正在進行中。長期試驗結(jié)果表明:在25℃、相對濕度60%條件下,對模擬上市包裝的三批樣品進行長期試驗,各項考察指標3個月內(nèi)未見明顯變化,后續(xù)試驗正在進行中。
[Abstract]:Finney hydrochloride in the treatment of vertigo is one of the drugs commonly used at present, has weakened the vestibular stimulation, inhibition of the lost function, inhibition of nausea and vomiting in the medullary chemoreceptor trigger zone and improve the blood flow of vertebral artery and other pharmacological characteristics, and weaker anticholinergic effects. Widely used in anti vertigo and vomiting, clinical mainly for motion sickness or the middle ear and inner ear vertigo caused by vertigo. Also suitable for anticancer drugs, anesthesia, nausea and vomiting caused by irradiation. At present, the existing Finney hydrochloride ordinary tablets listed, clinical curative effect. But because of its biological half-life is short, about 3-4h, in order to maintain the concentration of drug therapy, need to take 3 days second, frequent administration not only cause compliance in patients with decreased, and cause the blood concentration of Gu Feng phenomenon. This subject to Finney hydrochloride as a model drug, were prepared by the single-layer and double-layer osmotic pump Preparation of the two formulation, preparation and in vitro release behavior were investigated. And the study optimized the prescription and preparation stability of multi bi layer osmotic pump tablets hydrochloride Finney. The study chooses sodium chloride and different molecular weight polyethylene (PEO) as core materials, polyethylene glycol (PEG) and cellulose acetate (CA) is selected as the coating materials and acetone as the organic solvent coating, preparation of Finney multi bi layer osmotic pump tablets. Recommended by FDA F2 similarity factor method as the evaluation index of the release, tablet formulation, coating process, effect of in vitro release conditions on drug release behavior. Through single factor within 12 hours of investigation, find out the in vitro cumulative release (Y1) and curve fitting (Y2) factors are significant: push layer PEO content (A), containing layer of sodium chloride content (B) and the coating weight (C). The above three factors as independent variable The amount, accumulative release rate and release curve fitting as the dependent variable in 12h, using Box-Behnken design and response surface method were optimized, three factors and three levels. The optimized formulation, and verified in accordance with the best prescription. The test results show that the actual measured values are basically the same, and software optimization difference optimized formulation of hydrochloric acid to Finney bi layer osmotic pump tablets in vitro release curve with zero order model (r=0.9901), with good reproducibility. This article also investigates the hydrochloride osmotic pump tablets Finney monolayer conducted a preliminary study of single factor, on drug loading, osmotic pressure accelerant, factors of coating weight etc. effect of drug release behavior. Finally, this paper examines the stability of self-made hydrochloride Finney bi layer osmotic pump tablets, showed that the experimental factors: the preparation in 60 C and 4500L light stable after 10 days under the conditions in the RH92.5% After 10 days, the drug release hole in content, indicating that the preparation is sensitive to humidity, so we should choose the good sealing performance of packaging materials. The results show that the acceleration test at 40 degrees C and 75% relative humidity conditions, the simulation of listed packaging in three batches of accelerated test, each index of 3 months were within the normal range, no abnormal changes, subsequent trials are underway. The long-term test results show that: in the 25 degrees, 60% relative humidity conditions, long-term simulation test on listed packaging three batch samples, significant changes in each index within 3 months no subsequent trials are ongoing.

【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R943

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