頭孢泊肟酯牛至油納米乳的研制
發(fā)布時(shí)間：2019-07-05 14:13
【摘要】：目的:為研究頭孢泊肟酯與牛至油在納米水平的聯(lián)合藥效,首次制備頭孢泊肟酯牛至油納米乳(cefpodoxime proxetil and origanum oil nanoemulsion,CFP-OR-NE),并進(jìn)行藥物穩(wěn)定性、有效性、安全性評(píng)價(jià),為治療致病性大腸桿菌病和賽鴿仙臺(tái)沙門(mén)氏菌病提供一種安全有效的新型口服藥物。方法:(1)CFP-OR-NE處方篩選:采用相轉(zhuǎn)變法篩選初步處方。通過(guò)加水滴定至相變點(diǎn)并結(jié)合偽三元相圖的繪制,篩選CFP-OR-NE的初步處方;采用多指標(biāo)正交試驗(yàn)法篩選CFP-OR-NE最優(yōu)處方。以L(fǎng)9(34)正交表設(shè)計(jì)試驗(yàn),以抑菌圈直徑和納米乳穩(wěn)定常數(shù)Ke為考察指標(biāo),選擇頭孢泊肟酯和牛至油質(zhì)量分?jǐn)?shù)比(A)、納米乳水相pH值(B)、乳化溫度(C)作為考察因素,篩選頭孢泊肟酯牛至油納米乳最優(yōu)處方。(2)CFP-OR-NE的質(zhì)量評(píng)價(jià):以多波長(zhǎng)紫外分光光度法建立CFP-OR-NE有效成分含量測(cè)定方法,進(jìn)行回收率試驗(yàn)、進(jìn)樣重復(fù)性試驗(yàn)及日內(nèi)日間精密度試驗(yàn);穩(wěn)定性試驗(yàn)中考察了CFP-OR-NE結(jié)構(gòu)類(lèi)型、形態(tài)觀(guān)察、粒徑分布及Zeta電位等指標(biāo),長(zhǎng)期試驗(yàn)中分別建立兩者含量-時(shí)間回歸方程,計(jì)算藥物有效期。(3)CFP-OR-NE的體外抑菌試驗(yàn):通過(guò)微量肉湯稀釋法測(cè)定CFP-OR-NE對(duì)多種革蘭氏陰性菌(G+)和革蘭氏陽(yáng)性菌(G-)的最低抑菌濃度(minimum inhibitory concentration,MIC)和最低殺菌濃度(minimal bactericidal concentration,MBC)。(4)CFP-OR-NE的安全性評(píng)價(jià):通過(guò)最大耐受計(jì)量法測(cè)定小鼠經(jīng)口急性毒性最大耐受劑量并對(duì)其進(jìn)行組織病理學(xué)檢查,確定CFP-OR-NE是否具有肝毒性、腎毒性、腸毒性。結(jié)果:(1)CFP-OR-NE處方篩選:CFP-OR-NE初步處方各組分質(zhì)量分?jǐn)?shù)為:CFP1.5%、OR1.5%、EL-40 22.51%、1,2-丙二醇1.13%、蒸餾水73.36%;CFP-OR-NE針對(duì)致病性大腸桿菌、沙門(mén)氏菌最優(yōu)處方為CFP 0.33%、OR 2.67%、1,2-丙二醇1.13%、EL-40 22.51%、蒸餾水73.36%,納米乳pH值為6.17。(2)質(zhì)量評(píng)價(jià):建立了CFP-ORNE藥物含量測(cè)定方法,CFP測(cè)定的檢測(cè)波長(zhǎng)和參比波長(zhǎng)分別為263nm和289.8nm,OR測(cè)定的組合波長(zhǎng)為261.6 nm、273.2 nm、284.4 nm。在1~100μg/mL范圍內(nèi),CFP和OR線(xiàn)性關(guān)系均良好(r2=0.999 22;r2=0.999 70);回收率試驗(yàn):9個(gè)試驗(yàn)號(hào)的回收率均符合70%~110%的要求,CFP的RSD范圍在0.4~8.95%之間,OR的RSD范圍在0.26~5.57%之間;進(jìn)樣重復(fù)性試驗(yàn):各試驗(yàn)號(hào)CFP及OR測(cè)定的RSD均小于0.6%,進(jìn)樣重復(fù)性良好;日內(nèi)日間精密度試驗(yàn):CFP-OR-NE中CFP和OR測(cè)定的日內(nèi)、日間精密度RSD均小于5%,日內(nèi)日間精密度良好;CFP-OR-NE為水包油型淡黃色透明液體,形態(tài)觀(guān)察CFPOR-NE乳滴呈圓球形,平均粒徑為18.94 nm,多分散系數(shù)0.258,粒徑大小均一且分布范圍較窄。在環(huán)境溫度25℃條件下,稀釋5倍后的平均pH值為6.39,zeta電位是(-9.96±6.35)mV,加速、離心、光照、溫度梯度實(shí)驗(yàn)、長(zhǎng)期試驗(yàn)結(jié)果均無(wú)分層、絮凝、轉(zhuǎn)型、破乳、酸敗等現(xiàn)象,測(cè)定CFP-OR-NE有效期為21個(gè)月。(3)體外抑菌試驗(yàn):與OR原料藥、頭孢克肟(cefixime,CFM)原料藥相比,CFP-OR-NE的MIC及MBC差異顯著(P0.05)。(4)安全性評(píng)價(jià):最大耐受計(jì)量法測(cè)定小鼠經(jīng)口急性毒性最大耐受劑量大于1 800 mg/kg,組織病理學(xué)檢查CFP-OR-NE無(wú)腎臟毒性和腸毒性,試驗(yàn)組肝臟,輕微出血,少許細(xì)胞變性壞死,分界不清,但未引起小鼠死亡。結(jié)論:研制出CFP-OR-NE并建立了藥物含量測(cè)定方法,質(zhì)量評(píng)價(jià)符合規(guī)定要求;體外抑菌試驗(yàn)表明CFP-OR-NE對(duì)臨床常見(jiàn)G+和G-的抑菌和殺菌效果優(yōu)于同為三代頭孢菌素的CFM;MTD試驗(yàn)表明CFP-OR-NE為低毒藥物,組織病理學(xué)檢查無(wú)腎、腸毒性。
[Abstract]:Objective: To study the effect of cefpodoxime proxetil (Cefpodoxime proxetil) and bovine-to-oil at nanometer level, and to prepare cefpodoxime and oil nanoemulsion (CFP-OR-NE) for the first time, and to evaluate the stability, effectiveness and safety of cefpodoxime proxetil (CFP-OR-NE). In ord to provide a safe and effective novel oral medicine for treating that pathogenic E. coli and the salmonellosis. Methods: (1) CFP-OR-NE prescription screening: a phase transition method was used to screen the initial prescription. The initial formulation of CFP-OR-NE was selected by titration of water to the phase change point and the pseudo-ternary phase diagram, and the optimal formulation of the CFP-OR-NE was selected by the multi-index orthogonal test method. The experiment was designed with L9 (34) orthogonal table, and the diameter of the bacteriostatic ring and the stability constant of the nano-emulsion Ke were selected as the study index, and the ratio (A), the pH value (B) of the nano-emulsion water phase and the emulsification temperature (C) were selected as the factors of the investigation. The optimal formulation of the cefpodoxime proxetil to the oil nanoemulsion is screened. (2) The quality evaluation of CFP-OR-NE: The determination method of the effective component of CFP-OR-NE was established by multi-wavelength ultraviolet spectrophotometry, the recovery test, the injection repeatability test and the day-day precision test were carried out, and the structure type and morphology of the CFP-OR-NE were investigated in the stability test. In the long-term test, the content-time regression equation was established, and the validity of the drug was calculated. (3) In vitro antibacterial test of CFP-OR-NE: the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CFP-OR-NE on a variety of Gram-negative bacteria (G +) and gram-positive bacteria (G-) were determined by a microbroth dilution method. (4) Safety evaluation of CFP-OR-NE: The maximum tolerated dose of the oral acute toxicity of the mouse was determined by the maximum tolerance measurement method and the histopathological examination was performed to determine whether the CFP-OR-NE had hepatotoxicity, renal toxicity, and intestinal toxicity. Results: (1) CFP-OR-NE prescription was selected: CFP1.5%, OR1.5%, EL-40 22.51%, 1,2-propanediol 1.13%, distilled water 73.36%, CFP-OR-NE for pathogenic E. coli, the optimal prescription of Salmonella was CFP 0.33%, OR 2.67%, 1,2-propanediol 1.13%, EL-40 22.51%, The distilled water was 73.36%, and the pH value of the nano-emulsion was 6.17. (2) Quality evaluation: The method for determination of the content of CFP-ORNE was established. The detection wavelength and reference wavelength of CFP were 263 nm and 289.8 nm, respectively, and the combined wavelength was 261.6 nm, 273.2 nm and 284.4 nm respectively. In the range of 1 to 100 & mu; g/ mL, the linear relationship between the CFP and the OR was good (r2 = 0.999 22; r2 = 0.999 70); the recovery test: the recovery rate of the 9 test numbers met the requirements of 70% to 110%, the RSD of the CFP was between 0.4 and 8.95%, the RSD of the OR was between 0.26 and 5.57%, and the injection repeatability test: The RSD of each test number CFP and OR was less than 0.6% and the injection repeatability was good; intra-day precision test: the day-day precision RSD was less than 5% within the day of the CFP and OR measurement in the CFP-OR-NE, and the intra-day precision was good; and the CFP-OR-NE is an oil-in-water type light yellow transparent liquid, The form of CFPOR-NE emulsion is spherical, the average particle size is 18.94 nm, the polydispersity coefficient is 0.258, the particle size is uniform and the distribution range is narrow. The mean pH value after 5-fold dilution at ambient temperature was 6.39, the zeta potential was (-9.96-6.35) mV, acceleration, centrifugation, illumination, temperature gradient experiment, and the results of long-term test were no delamination, flocculation, transformation, demulsification, rancidity, etc., and the validity period of CFP-OR-NE was 21 months. (3) In vitro antibacterial test: Compared with the drug substance of OR drug substance and cefixime (CFM), the MICs and MBC of CFP-OR-NE were significant (P0.05). (4) Safety evaluation: The maximum tolerated dose of the oral acute toxicity in mice was more than 1 800 mg/ kg, and the histopathological examination of CFP-OR-NE had no renal toxicity and intestinal toxicity. Conclusion: CFP-OR-NE has been developed and the drug content determination method is established, and the quality evaluation is in accordance with the specified requirements; in vitro antibacterial test shows that the antibacterial and bactericidal effect of CFP-OR-NE on the clinical common G + and G-is better than that of the three-generation cephalosporin; and the MTD test shows that the CFP-OR-NE is a low-toxic medicine, Histopathological examination showed no renal or intestinal toxicity.
【學(xué)位授予單位】：西北農(nóng)林科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：S859.79
本文編號(hào)：2510581
[Abstract]:Objective: To study the effect of cefpodoxime proxetil (Cefpodoxime proxetil) and bovine-to-oil at nanometer level, and to prepare cefpodoxime and oil nanoemulsion (CFP-OR-NE) for the first time, and to evaluate the stability, effectiveness and safety of cefpodoxime proxetil (CFP-OR-NE). In ord to provide a safe and effective novel oral medicine for treating that pathogenic E. coli and the salmonellosis. Methods: (1) CFP-OR-NE prescription screening: a phase transition method was used to screen the initial prescription. The initial formulation of CFP-OR-NE was selected by titration of water to the phase change point and the pseudo-ternary phase diagram, and the optimal formulation of the CFP-OR-NE was selected by the multi-index orthogonal test method. The experiment was designed with L9 (34) orthogonal table, and the diameter of the bacteriostatic ring and the stability constant of the nano-emulsion Ke were selected as the study index, and the ratio (A), the pH value (B) of the nano-emulsion water phase and the emulsification temperature (C) were selected as the factors of the investigation. The optimal formulation of the cefpodoxime proxetil to the oil nanoemulsion is screened. (2) The quality evaluation of CFP-OR-NE: The determination method of the effective component of CFP-OR-NE was established by multi-wavelength ultraviolet spectrophotometry, the recovery test, the injection repeatability test and the day-day precision test were carried out, and the structure type and morphology of the CFP-OR-NE were investigated in the stability test. In the long-term test, the content-time regression equation was established, and the validity of the drug was calculated. (3) In vitro antibacterial test of CFP-OR-NE: the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CFP-OR-NE on a variety of Gram-negative bacteria (G +) and gram-positive bacteria (G-) were determined by a microbroth dilution method. (4) Safety evaluation of CFP-OR-NE: The maximum tolerated dose of the oral acute toxicity of the mouse was determined by the maximum tolerance measurement method and the histopathological examination was performed to determine whether the CFP-OR-NE had hepatotoxicity, renal toxicity, and intestinal toxicity. Results: (1) CFP-OR-NE prescription was selected: CFP1.5%, OR1.5%, EL-40 22.51%, 1,2-propanediol 1.13%, distilled water 73.36%, CFP-OR-NE for pathogenic E. coli, the optimal prescription of Salmonella was CFP 0.33%, OR 2.67%, 1,2-propanediol 1.13%, EL-40 22.51%, The distilled water was 73.36%, and the pH value of the nano-emulsion was 6.17. (2) Quality evaluation: The method for determination of the content of CFP-ORNE was established. The detection wavelength and reference wavelength of CFP were 263 nm and 289.8 nm, respectively, and the combined wavelength was 261.6 nm, 273.2 nm and 284.4 nm respectively. In the range of 1 to 100 & mu; g/ mL, the linear relationship between the CFP and the OR was good (r2 = 0.999 22; r2 = 0.999 70); the recovery test: the recovery rate of the 9 test numbers met the requirements of 70% to 110%, the RSD of the CFP was between 0.4 and 8.95%, the RSD of the OR was between 0.26 and 5.57%, and the injection repeatability test: The RSD of each test number CFP and OR was less than 0.6% and the injection repeatability was good; intra-day precision test: the day-day precision RSD was less than 5% within the day of the CFP and OR measurement in the CFP-OR-NE, and the intra-day precision was good; and the CFP-OR-NE is an oil-in-water type light yellow transparent liquid, The form of CFPOR-NE emulsion is spherical, the average particle size is 18.94 nm, the polydispersity coefficient is 0.258, the particle size is uniform and the distribution range is narrow. The mean pH value after 5-fold dilution at ambient temperature was 6.39, the zeta potential was (-9.96-6.35) mV, acceleration, centrifugation, illumination, temperature gradient experiment, and the results of long-term test were no delamination, flocculation, transformation, demulsification, rancidity, etc., and the validity period of CFP-OR-NE was 21 months. (3) In vitro antibacterial test: Compared with the drug substance of OR drug substance and cefixime (CFM), the MICs and MBC of CFP-OR-NE were significant (P0.05). (4) Safety evaluation: The maximum tolerated dose of the oral acute toxicity in mice was more than 1 800 mg/ kg, and the histopathological examination of CFP-OR-NE had no renal toxicity and intestinal toxicity. Conclusion: CFP-OR-NE has been developed and the drug content determination method is established, and the quality evaluation is in accordance with the specified requirements; in vitro antibacterial test shows that the antibacterial and bactericidal effect of CFP-OR-NE on the clinical common G + and G-is better than that of the three-generation cephalosporin; and the MTD test shows that the CFP-OR-NE is a low-toxic medicine, Histopathological examination showed no renal or intestinal toxicity.
【學(xué)位授予單位】：西北農(nóng)林科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：S859.79
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 張濤;顧起有;楊后貴;郭楊慶;;頭孢泊肟酯與頭孢克肟治療急性細(xì)菌性感染隨機(jī)對(duì)照研究[J];海峽藥學(xué);2006年02期
，本文編號(hào)：2510581
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