發(fā)布時(shí)間：2018-05-27 21:13

  本文選題：伊維菌素 + 緩釋��； 參考：《中國農(nóng)業(yè)大學(xué)》2017年博士論文

【摘要】：利用固體分散體技術(shù)研制緩釋型伊維菌素固體分散體(IVM-SD),延長IVM在動物體內(nèi)的持效期,減少給藥次數(shù),將有助于提高藥物的抗寄生蟲效果。本研究以伊維菌素(Ivermectin,IVM)為目標(biāo)藥物,固體分散體(Solid dispersion,SD)為載藥系統(tǒng),氫化蓖麻油(hydrogenated castor oil,HCO)作為緩釋載體,采用溶劑-熔融法制備緩釋型伊維菌素固體分散體(IVM-SD)。對IVM-SD的理化性質(zhì)、體外釋藥動力學(xué)和穩(wěn)定性進(jìn)行了系統(tǒng)評價(jià),通過給自然感染兔耳螨蟲的兔子皮下注射IVM-SD混懸注射劑評價(jià)其臨床治療效果。首先,本研究以IVM為目標(biāo)藥物,HCO為載體,采用溶劑-熔融法制備出了 IVM-SDs。并采用偏光顯微鏡、掃描電鏡觀察IVM-SD的形態(tài)特征,用高效液相色譜測定IVM-SD中IVM的含量和制備過程中的IVM回收率;通過傅里葉紅外光譜和核磁共振技術(shù)檢測IVM-SD中藥物和載體的相容性和相互作用;采用X射線粉末衍射法、差示掃描量熱法、熱臺顯微鏡分析IVM-SD中IVM的相容性和存在狀態(tài);通過熱重分析等測定IVM-SD降解溫度和樣品干燥程度等;通過溶出度試驗(yàn)對IVM-SD進(jìn)行了釋藥動力學(xué)研究,檢測IVM-SD體外緩釋效果并分析釋放機(jī)制;用MDCK細(xì)胞對IVM-SD的細(xì)胞毒性進(jìn)行了評價(jià)。含量和回收率的測定表明溶劑-熔融法是制備IVM-SD的有效方法。偏光顯微鏡和掃描電鏡下IVM-SDs中IVM與HCO形成一個(gè)整體,呈現(xiàn)為均一的不規(guī)則顆粒,而IVM-PMs中藥物和載體獨(dú)立存在。X射線粉末衍射分析表明SD1:3,SD1:5,SD1:7中,IVM以無定型存在于固體分散體中,而且傅里葉紅外光譜顯示產(chǎn)生了分子間氫鍵,這有助于提高固體分散體的穩(wěn)定性。核磁共振結(jié)果說明IVM-SDs制備過程中沒有產(chǎn)生新的化學(xué)物質(zhì)。差示掃描量熱結(jié)果表明藥物與載體之間有很好的相容性,熱重分析法結(jié)果顯示制備成IVM-SDs提高了 IVM的熱穩(wěn)定性,而且制備時(shí)使用的溶劑已徹底除去。熱臺顯微鏡分析再次表明SD1:3,SD1:5中IVM以無定型存在。體外溶出實(shí)驗(yàn)結(jié)果表明,IVM-SDs在體外具有明顯的緩釋作用,其溶出符合Higuchi模型,屬于擴(kuò)散釋放,載體比例是影響藥物溶出的關(guān)鍵因素。細(xì)胞毒性試驗(yàn)結(jié)果顯示IVM-SD提高了 IVM對MDCK細(xì)胞的安全性。為了給IVM-SD的貯存條件提供選擇依據(jù),并了解其長期貯存過程中的變化,開展了 IVM-SD穩(wěn)定性試驗(yàn):影響因素試驗(yàn)(光照4500 lx,高溫60℃,高濕度90%),加速試驗(yàn)(40℃,相對濕度75%)、長期穩(wěn)定性試驗(yàn)(常規(guī)條件25℃,冷凍條件-20℃,冷藏條件5℃,相對濕度60%)和UVA光穩(wěn)定性試驗(yàn)。影響因素試驗(yàn)結(jié)果顯示:IVM-SD在強(qiáng)光照射下顏色變微黃;在高溫條件下顏色變黃并結(jié)塊;在高濕條件下外觀沒有明顯變化。加速試驗(yàn)和長期穩(wěn)定性試驗(yàn)的結(jié)果表明:IVM-SDs在40-C(相對濕度75%)儲存6個(gè)月,在25℃、5℃和-20℃(相對濕度60%)儲存12個(gè)月,樣品沒有發(fā)生重結(jié)晶,IVM仍以無定型穩(wěn)定存在。但是在40℃條件下,樣品出現(xiàn)輕微結(jié)塊現(xiàn)象,DSC圖譜顯示IVM-SD的吸熱峰面積變寬,可能是載體發(fā)生了老化。在各個(gè)儲存條件下,不同藥物-載體比例的IVM-SD,溶出初始速率都有減慢。UVA光穩(wěn)定性試驗(yàn)結(jié)果顯示HCO對IVM有很好的光保護(hù)作用,這可能與氫鍵的產(chǎn)生有關(guān)。根據(jù)穩(wěn)定性試驗(yàn)結(jié)果,IVM-SD在避光、干燥、低溫下貯存可以利于樣品的性質(zhì)穩(wěn)定。給自然感染兔耳螨蟲的兔子皮下注射IVM-SD(SD1:3)混懸注射劑評價(jià)其臨床治療效果。結(jié)果表明IVM-SD(2mg/kg)單次頸部皮下注射給藥可以有效殺滅兔耳螨蟲,14d時(shí)殺滅效率達(dá)100%,持效期長達(dá)42 d,明顯長于伊維菌素普通注射劑(害獲滅)。本研究利用固體分散體技術(shù),成功制備緩釋型伊維菌素固體分散體。通過對理化性質(zhì)、釋藥動力學(xué)、穩(wěn)定性和藥效學(xué)等方面的研究表明:所研制的IVM-SD具有安全、質(zhì)量穩(wěn)定和緩釋的特點(diǎn),用其制備而成的IVM-SD混懸注射劑,能徹底殺滅兔耳螨、持效期長達(dá)42 d。本研究解決了臨床上治療寄生蟲感染時(shí)頻繁給藥的問題,促進(jìn)畜牧業(yè)持續(xù)健康發(fā)展,保障畜產(chǎn)品消費(fèi)安全。并為獸藥新制劑的研制提供借鑒和理論基礎(chǔ)。
[Abstract]:The development of sustained release ivermectin solid dispersion (IVM-SD) by solid dispersion technique, prolonging the duration of IVM in the animal and reducing the number of drug delivery will help to improve the anti parasitic effect of the drug. This study uses the Ivermectin (IVM) as the target drug, the solid dispersion (Solid dispersion, SD) as the drug loading system, the hydrogenated castor Hydrogenated castor oil (HCO) was used as a sustained-release carrier to prepare sustained-release ivermectin solid dispersion (IVM-SD) by solvent melting method. The physical and chemical properties of IVM-SD, the release kinetics and stability of IVM-SD in vitro were systematically evaluated. By subcutaneous injection of IVM-SD suspension injection to rabbits with natural infection of the rabbit ear mites, the clinical evaluation was made. First, in this study, IVM was used as the target drug, HCO was used as the carrier, IVM-SDs. was prepared by solvent melting method, and polarizing microscope was used to observe the morphological characteristics of IVM-SD. The content of IVM in IVM-SD and the recovery rate of IVM in the preparation process were measured by high performance liquid chromatography; Fourier infrared spectroscopy and nuclear magnetic resonance technique were used. The compatibility and interaction of drugs and carriers in IVM-SD were detected. The compatibility and existence of IVM in IVM-SD were analyzed by X ray powder diffraction, differential scanning calorimetry, thermal table microscope, and the degradation temperature of IVM-SD and the drying degree of samples were measured by thermogravimetric analysis. The release kinetics of IVM-SD was carried out by dissolution test. The effect of the release of IVM-SD in vitro was detected and the release mechanism was analyzed. The cytotoxicity of IVM-SD was evaluated with MDCK cells. The determination of the content and recovery showed that the solvent melting method was an effective method for the preparation of IVM-SD. The IVM and HCO formed a whole in IVM-SDs under polarizing microscope and scanning electron microscope, showing the uniform irregular particles, The independent existence of.X ray powder diffraction analysis in IVM-PMs shows that in SD1:3, SD1:5, SD1:7, IVM exists in the solid dispersion in amorphous form, and the Fourier infrared spectrum shows the hydrogen bond between molecules, which helps to improve the stability of solid dispersion. The results of nuclear magnetic resonance show that the process of IVM-SDs preparation is not produced. The results of differential scanning calorimetry showed that there was a good compatibility between the drug and the carrier. The thermo gravimetric analysis showed that the preparation of IVM-SDs increased the thermal stability of IVM, and the solvent used in the preparation had been completely removed. The thermal stage microscope analysis again showed that the IVM in the SD1:5 was amorphous. In vitro dissolution test. The results showed that IVM-SDs had a significant release effect in vitro, and its dissolution accords with the Higuchi model, which belongs to the diffusion release, and the carrier ratio is the key factor affecting the dissolution of the drug. The cytotoxicity test results show that IVM-SD improves the safety of MDCK cells by IVM. In order to provide the selection basis for the storage conditions of IVM-SD, and to understand its long-term storage. In the process of storage, IVM-SD stability test was carried out: influence factors test (light 4500 LX, high temperature 60, high humidity 90%), accelerated test (40 C, relative humidity 75%), long-term stability test (conventional condition 25, freezing condition -20, 5 C, relative humidity 60%) and UVA photostability test. The influence factor test results showed IV The color becomes yellowed under strong light, and the color becomes yellow and caked under high temperature conditions. The appearance of M-SD has no obvious change in the high humidity condition. The results of accelerated and long-term stability tests show that IVM-SDs is stored for 6 months at 40-C (relative humidity 75%) and stored at 25, 5 and -20 (relative humidity 60%) for 12 months, and the recrystallization does not occur in the sample. IVM still exists with amorphous stability. But at 40 C, the sample appears slight caking. DSC atlas shows that the acreage of the endothermic peak of IVM-SD is broadened. It may be that the carrier is aging. Under various storage conditions, the IVM-SD of different drug carrier ratio and the initial rate of dissolution have slowed down.UVA light stability test results showing HCO to IVM There is a good light protection effect, which may be related to the production of hydrogen bonds. According to the results of stability test, IVM-SD can be used to avoid light, dry and low temperature storage for the stability of the sample. A IVM-SD (SD1:3) suspension injection for rabbits with natural infection of the rabbit ear mites is subcutaneously evaluated for its clinical treatment effect. The results show that IVM-SD (2mg/kg) single time The subcutaneous injection of the cervix could effectively kill the rabbit ear mites. The killing efficiency of 14d was 100% and the duration was 42 d, which was obviously longer than the common injections of ivermectin. The solid dispersion of the sustained-release ivermectin was successfully prepared by the solid dispersion technique. The research and other studies show that the developed IVM-SD has the characteristics of safety, quality stability and sustained release. The IVM-SD suspension injection made by it can kill the ear mites of rabbit completely, and the duration of its holding effect is 42 d.. The study solves the problem of frequent drug delivery in the clinical treatment of parasite infection, promote the healthy development of animal husbandry and guarantee the animal products. Consumption safety. It also provides reference and theoretical basis for the development of new veterinary drug preparations.
【學(xué)位授予單位】：中國農(nóng)業(yè)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：S859.5

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