氟康唑脂质体及脂质体凝胶的研制
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摘要
目的:氟康唑(fluconazole)是1980年由美国辉瑞公司(Pfizer)研制的三唑类抗真菌药,其作用机理主要是通过抑制真菌的细胞色素P-450使真菌细胞麦角固醇合成障碍,从而达到抑制和杀灭真菌的效果,具有抗菌谱广等优点。其血浆半衰期约为30小时,脑脊液浓度相当于血浆浓度的80%～90%。Pfizer公司1991年在美国提出氟康唑用于预防真菌感染的申请,在癌症病人中用做真菌感染预防,已在奥地利、爱尔兰、意大利和瑞士得到批准。目前,氟康唑正在成为公认的安全有效的抗真菌药。
脂质体是将药物包封于类脂双分子层形成的薄膜中间所制成的超微型球状载体制剂。脂质体类似细胞结构,有生物膜的特性和功能。它可以包裹水溶性和脂溶性两种类型的药物,是一种具有多功能的定向药物载体,能够降低药物毒副作用、提高生物利用度、并具有长效缓释作用。皮肤局部应用脂质体时,可使药物最大量地保留在皮肤中,尽量少地进入血液循环,使以脂质体为载体的药物透过角质层,在表皮和真皮内形成药物贮库,成为皮肤靶向并具缓控释作用的给药系统,药物可持久地对局部病变细胞或组织起治疗作用,较少进入体循环,提高治疗指数,减少或避免全身性毒副作用。
本研究采用氟康唑为模型药物,制备氟康唑脂质体凝胶
以增加氟康唑的皮内滞留量,降低药物的毒性,使所包裹的药物长效化等。
方法:在文献和预实验的基础上初步确定氟康唑脂质体的制备方法和处方,通过单因素考察初步确定脂质体制备的影响因素。从几种磷脂当中选择合适的脂质体膜材,并研究不同包封率测定方法对包封率测定结果的影响以及改变葡聚糖凝胶柱的状态对包封率测定结果的影响。
采用薄膜分散法、逆向蒸发法、主动载药法、乙醇注入法四种方法制备脂质体,利用葡聚糖凝胶柱对脂质体与未包封游离药物进行分离。测定脂质体中氟康唑的包封率,确定薄膜分散法为氟康唑脂质体的制备方法。
以包封率为指标,通过单因素实验考察优化脂质体的制备工艺,并考察水化温度,旋转蒸发仪转速等对脂质体制备的影响。在此基础上,采用四因素三水平正交实验设计对各种辅料用量进行筛选,对包封率测定结果进行极差分析最后确定氟康唑脂质体的最佳处方。
分别绘制氟康唑脂质体混悬液和氟康唑溶液的体外释药曲线并比较其体外释药过程,分别用零级、一级、Higuchi和Weibull动力学方程进行拟合,考察相关系数。
考察按照优化处方制备的氟康唑脂质体的形态外观,粒径分布及黏度等,考察脂质体的物理和化学稳定性。在文献报道和预实验基础上,建立高效液相色谱方法测定脂质体及脂质体凝胶中氟康唑含量的方法。
选用卡波普为基质制备氟康唑脂质体凝胶,以小鼠为动物模型,进行氟康唑脂质体凝胶和非脂质体凝胶的离体透皮扩散实验,并比较其释药过程,分别用零级、一级、Higuchi和Weibull动力学方程进行拟合,考察相关系数。
通过影响因素实验,稳定性参数,长期放置沉降比等考察脂质体及脂质体凝胶的稳定性,并考察脂质体对热压灭菌的稳定性。
结果:通过单因素考察和正交实验,筛选出了氟康唑脂质体的优化处方为磷脂640mg,胆固醇106mg,PVP20mg,磷酸盐缓冲液pH值为7.0。采用薄膜分散法制备脂质体,葡聚糖凝胶柱层析法测定脂质体的包封率。葡聚糖凝胶柱的径高比,流速,葡聚糖上方磷酸盐缓冲液的体积等都可影响葡聚糖凝胶柱对脂质体与未包封游离药物的分离效果。根据优化处方制备的氟康唑脂质体外观为均匀的乳白色混悬液,包封率为55.03%,平均粒径约为249.8nm,多分散系数为0.281。
氟康唑溶液及氟康唑脂质体的体外释药均符合Weibull方程。其方程分别为lnln[1/(1-Q)]=0.703lnt-0.4304和lnln[1/(1-Q)]=0.5043lnt-0.801,相关系数分别为R2=0.9813和R2=0.9847。T50及Td分别为1.10h、1.84h和2.37h、4.89h。以2h时相点为分界线,研究2h前后脂质体及药物溶液的释药,脂质体的释药在前两小时最符合Higuchi方程,以扩散过程为主,这可能是游离的氟康唑及附着于脂质体表面的氟康唑释放。两小时以后的释药最符合Weibull方程。
用最常用的卡波普941为基质制得的脂质体凝胶黏度适宜,以鼠皮进行的透皮扩散实验结果表明氟康唑脂质体及非脂质体凝胶中药物的释放对零级动力学、一级动力学和Weibull方程拟合的R2都大于0.99。脂质体凝胶的皮肤内滞留量大于非脂质体凝胶的皮肤内滞留量(P<0.05)。
稳定性实验表明,脂质体及脂质体凝胶均对热不稳定。但脂质体的稳定性参数较小,为0.066。长期放置性质较稳定,三个月后才出现少量沉淀。
结论:以磷脂、胆固醇为主要膜材,采用薄膜分散法制备氟康唑脂质体,制备工艺简单,质量可控。以卡波普为基质制备脂质体凝胶,制得的凝胶性质稳定,经透皮扩散实验证实其皮肤内药物滞留量远大于非脂质体凝胶。脂质体凝胶作为氟康唑的经皮给药剂型有望开发成为有良好应用前景的新剂型。
Objective: Fluconazole is a triazole antifungal drug which was developed by Pfizer Company in 1980. Its mechanism action is contribution to dyssynthesis of ergosterin in fungal cell by inhibition of fungus cytochrome P-450, so it achieves the effect of inhibition and killing of fungus, and has the advantage of wide antimicrobial spectrum. Its half-life in blood plasma is about 30 hours, and concentration in cerebrospinal fluid is correspondent to 80~90% of concentration in blood plasma. In 1991 Pfizer Company raised the application of fluconazole in precaution of fungous infection in USA, and it already got authorization in Austria、Ireland、Italy and Switzerland to be used to prevent fungous infection in cancer patients. At present, fluconazole is gradually taken to be a safe and valid antifungal drug.
Liposome is a kind of ultra-fine form globular carrier preparation which encapsulates the drug in the thin film formed by lipid bilayer. Liposome is analog to cellular structure, and has the characteristics and function of biological membrane. It has the ability of enveloping both water-solubility and lipo-solubility drug, and it is a kind of multi-functional targeted durg carrier which could cut down toxic and side effect, elevate bioavailability, prolong action and delay release. Liposomes for transdermal use can increase the drugs retained in the skin to the maximum, and reduce the drugs in the blood circulation to the minimum. Drugs in the liposomes carrier could penetrate stratum corneum, and formed medicine library between dermis and epidermis. It is a skin-targeted administration system of delayed and control release effect. Drugs could lastingly cure the topical damaged cells or tissues, boost therapeutic index and reduce or avoid general side and toxic effect because less amount of drugs enter greater circulation.
Fluconazole being used as model drug, liposomal fluconazole gel was prepared to increase the intradermal hold-up and cut down toxicity to achieve the effect of prolonged action.
Methods: Preparation technique and prescription of liposomal fluconazole gel was initially determined on the basis of literature and preliminary test, and influential factors were determined by single factor investigation. Suitable membrane stuff for liposomes was selected from several kinds of phospholipids. The impact of encapsulated ratio determination result by different assay methods and different sephadex column conditions was studied.
Four methods such as film dispersion method, reverse-phase method, active loading method, injection method were used to produce liposomes, and sephadex column was used to separate liposomes with free drugs. The encapsulated ratio of the liposomes was determined, which showed that the film dispersion method was the best preparation method.
Encapsulated ratio as index, the preparation technology of liposomes was optimized by single factor investigation, and the hydration temperature and rotary speed of rotary evaporation were studied as influential factors. Consequently, L9(34) orthogonal design was made to screen the dosage of adjuvant. The optimized prescription was decided by range analysis to the encapsulated ratio determination result.
The accumulative release curve of fluconazole liposomes and fluconazole solution were mapped respectively and compared. Zero order、first order、Higuchi、and Weibull equation were used to fit the release process, and coefficient correlation were calculated and studied.
The shape、appearance、particle size distribution、viscosity、and physical and chemical stability were studied. The HPLC method to determine the quality of fluconazole in liposomes and liposomal gel was constructed on the basis of literature and preliminary test.
Carbopol was used as matrix to make liposomal fluconazole gel. Mice being used as animal model, the transdermal delivery test ex vivo were done to compare their release process which were fitted by zero order、first order、Higuchi and Weibull equation respectively,and the correlation coefficient was calculated and studied.
Stress test, stability paramer and sedimentation ratio were done to investigate the stability of lipsomes and lipsomal gel. And the stability of fluconazole liposomes to hot pressing sterilization was also studied.
Results: The optimized prescription of fluconazole liposomes was: 640mg phospholipids, 106mg cholesterol, 20mg PVP, and pH 7.0 PBS. Liposomes were made by film dispersion method and the encapsulation was determined by sephadex G-75 column. The diameter/height ratio, flow rate of the PBS solution and volume of PBS above the column all had effect to the separation result. The appearance of fluconazole liposomes was uniform ivory yellow suspension, with the encapsulated ratio 55.03% and mean diameter 249.8nm.The polydispersity was 0.281.
The release process in vitro of both fluconazole solution and fluconazole liposomes fitted the Weibull equation. The equation were lnln[1/(1-Q)]=0.703lnt-0.4304 and lnln[1/(1-Q)]= 0.5043lnt-0.801, with the correlation coefficient R2=0.9813 and R2=0.9847 respectively. T50 and Td were 1.10h、1.84hand 2.37h、4.89h, respectively. The release process of fluconazole liposomes and solution before and after 2h were studied: the release process of liposomes before 2h was mainly diffusion process and fitted Higuchi equation, which was probably the free and topical drug release process. The release process after 2h fitted Weibull equation best.
The liposomal gel made by carbopol 941 had suitable viscosity. Transdermal delivery test showed that the release process of liposomal and non-liposomal gel all fitted zero order、first order、and Weibull equation with R2>0.99. The drugs of liposomal gel retained in the skin was much more than that of non-liposomal gel (P<0.05).
Stability test showed that liposomes and liposomal gel were not stable to high temperature. But the stability parameter of fluconazole liposomes was 0.066, and the fluconazole liposomes suspension was stable when laid up for a long period, only small amount of precipitation was formed after 3 months.
Conclusion: Phospholipids and cholesterol were used as membrane stuff, fluconazole liposomes were made by film dispersion method. This preparation technology was simple and convenient. Liposomal gel made by carbopol matrix was stable, and the transdermal delivery test result showed that the liposomal gel had more drugs retained in skin than that of non-liposomal gel. Liposomal gel as fluconazole percutaneous absorption dosage form was expected to be a new applicable preparation.
脂质体是将药物包封于类脂双分子层形成的薄膜中间所制成的超微型球状载体制剂。脂质体类似细胞结构,有生物膜的特性和功能。它可以包裹水溶性和脂溶性两种类型的药物,是一种具有多功能的定向药物载体,能够降低药物毒副作用、提高生物利用度、并具有长效缓释作用。皮肤局部应用脂质体时,可使药物最大量地保留在皮肤中,尽量少地进入血液循环,使以脂质体为载体的药物透过角质层,在表皮和真皮内形成药物贮库,成为皮肤靶向并具缓控释作用的给药系统,药物可持久地对局部病变细胞或组织起治疗作用,较少进入体循环,提高治疗指数,减少或避免全身性毒副作用。
本研究采用氟康唑为模型药物,制备氟康唑脂质体凝胶
以增加氟康唑的皮内滞留量,降低药物的毒性,使所包裹的药物长效化等。
方法:在文献和预实验的基础上初步确定氟康唑脂质体的制备方法和处方,通过单因素考察初步确定脂质体制备的影响因素。从几种磷脂当中选择合适的脂质体膜材,并研究不同包封率测定方法对包封率测定结果的影响以及改变葡聚糖凝胶柱的状态对包封率测定结果的影响。
采用薄膜分散法、逆向蒸发法、主动载药法、乙醇注入法四种方法制备脂质体,利用葡聚糖凝胶柱对脂质体与未包封游离药物进行分离。测定脂质体中氟康唑的包封率,确定薄膜分散法为氟康唑脂质体的制备方法。
以包封率为指标,通过单因素实验考察优化脂质体的制备工艺,并考察水化温度,旋转蒸发仪转速等对脂质体制备的影响。在此基础上,采用四因素三水平正交实验设计对各种辅料用量进行筛选,对包封率测定结果进行极差分析最后确定氟康唑脂质体的最佳处方。
分别绘制氟康唑脂质体混悬液和氟康唑溶液的体外释药曲线并比较其体外释药过程,分别用零级、一级、Higuchi和Weibull动力学方程进行拟合,考察相关系数。
考察按照优化处方制备的氟康唑脂质体的形态外观,粒径分布及黏度等,考察脂质体的物理和化学稳定性。在文献报道和预实验基础上,建立高效液相色谱方法测定脂质体及脂质体凝胶中氟康唑含量的方法。
选用卡波普为基质制备氟康唑脂质体凝胶,以小鼠为动物模型,进行氟康唑脂质体凝胶和非脂质体凝胶的离体透皮扩散实验,并比较其释药过程,分别用零级、一级、Higuchi和Weibull动力学方程进行拟合,考察相关系数。
通过影响因素实验,稳定性参数,长期放置沉降比等考察脂质体及脂质体凝胶的稳定性,并考察脂质体对热压灭菌的稳定性。
结果:通过单因素考察和正交实验,筛选出了氟康唑脂质体的优化处方为磷脂640mg,胆固醇106mg,PVP20mg,磷酸盐缓冲液pH值为7.0。采用薄膜分散法制备脂质体,葡聚糖凝胶柱层析法测定脂质体的包封率。葡聚糖凝胶柱的径高比,流速,葡聚糖上方磷酸盐缓冲液的体积等都可影响葡聚糖凝胶柱对脂质体与未包封游离药物的分离效果。根据优化处方制备的氟康唑脂质体外观为均匀的乳白色混悬液,包封率为55.03%,平均粒径约为249.8nm,多分散系数为0.281。
氟康唑溶液及氟康唑脂质体的体外释药均符合Weibull方程。其方程分别为lnln[1/(1-Q)]=0.703lnt-0.4304和lnln[1/(1-Q)]=0.5043lnt-0.801,相关系数分别为R2=0.9813和R2=0.9847。T50及Td分别为1.10h、1.84h和2.37h、4.89h。以2h时相点为分界线,研究2h前后脂质体及药物溶液的释药,脂质体的释药在前两小时最符合Higuchi方程,以扩散过程为主,这可能是游离的氟康唑及附着于脂质体表面的氟康唑释放。两小时以后的释药最符合Weibull方程。
用最常用的卡波普941为基质制得的脂质体凝胶黏度适宜,以鼠皮进行的透皮扩散实验结果表明氟康唑脂质体及非脂质体凝胶中药物的释放对零级动力学、一级动力学和Weibull方程拟合的R2都大于0.99。脂质体凝胶的皮肤内滞留量大于非脂质体凝胶的皮肤内滞留量(P<0.05)。
稳定性实验表明,脂质体及脂质体凝胶均对热不稳定。但脂质体的稳定性参数较小,为0.066。长期放置性质较稳定,三个月后才出现少量沉淀。
结论:以磷脂、胆固醇为主要膜材,采用薄膜分散法制备氟康唑脂质体,制备工艺简单,质量可控。以卡波普为基质制备脂质体凝胶,制得的凝胶性质稳定,经透皮扩散实验证实其皮肤内药物滞留量远大于非脂质体凝胶。脂质体凝胶作为氟康唑的经皮给药剂型有望开发成为有良好应用前景的新剂型。
Objective: Fluconazole is a triazole antifungal drug which was developed by Pfizer Company in 1980. Its mechanism action is contribution to dyssynthesis of ergosterin in fungal cell by inhibition of fungus cytochrome P-450, so it achieves the effect of inhibition and killing of fungus, and has the advantage of wide antimicrobial spectrum. Its half-life in blood plasma is about 30 hours, and concentration in cerebrospinal fluid is correspondent to 80~90% of concentration in blood plasma. In 1991 Pfizer Company raised the application of fluconazole in precaution of fungous infection in USA, and it already got authorization in Austria、Ireland、Italy and Switzerland to be used to prevent fungous infection in cancer patients. At present, fluconazole is gradually taken to be a safe and valid antifungal drug.
Liposome is a kind of ultra-fine form globular carrier preparation which encapsulates the drug in the thin film formed by lipid bilayer. Liposome is analog to cellular structure, and has the characteristics and function of biological membrane. It has the ability of enveloping both water-solubility and lipo-solubility drug, and it is a kind of multi-functional targeted durg carrier which could cut down toxic and side effect, elevate bioavailability, prolong action and delay release. Liposomes for transdermal use can increase the drugs retained in the skin to the maximum, and reduce the drugs in the blood circulation to the minimum. Drugs in the liposomes carrier could penetrate stratum corneum, and formed medicine library between dermis and epidermis. It is a skin-targeted administration system of delayed and control release effect. Drugs could lastingly cure the topical damaged cells or tissues, boost therapeutic index and reduce or avoid general side and toxic effect because less amount of drugs enter greater circulation.
Fluconazole being used as model drug, liposomal fluconazole gel was prepared to increase the intradermal hold-up and cut down toxicity to achieve the effect of prolonged action.
Methods: Preparation technique and prescription of liposomal fluconazole gel was initially determined on the basis of literature and preliminary test, and influential factors were determined by single factor investigation. Suitable membrane stuff for liposomes was selected from several kinds of phospholipids. The impact of encapsulated ratio determination result by different assay methods and different sephadex column conditions was studied.
Four methods such as film dispersion method, reverse-phase method, active loading method, injection method were used to produce liposomes, and sephadex column was used to separate liposomes with free drugs. The encapsulated ratio of the liposomes was determined, which showed that the film dispersion method was the best preparation method.
Encapsulated ratio as index, the preparation technology of liposomes was optimized by single factor investigation, and the hydration temperature and rotary speed of rotary evaporation were studied as influential factors. Consequently, L9(34) orthogonal design was made to screen the dosage of adjuvant. The optimized prescription was decided by range analysis to the encapsulated ratio determination result.
The accumulative release curve of fluconazole liposomes and fluconazole solution were mapped respectively and compared. Zero order、first order、Higuchi、and Weibull equation were used to fit the release process, and coefficient correlation were calculated and studied.
The shape、appearance、particle size distribution、viscosity、and physical and chemical stability were studied. The HPLC method to determine the quality of fluconazole in liposomes and liposomal gel was constructed on the basis of literature and preliminary test.
Carbopol was used as matrix to make liposomal fluconazole gel. Mice being used as animal model, the transdermal delivery test ex vivo were done to compare their release process which were fitted by zero order、first order、Higuchi and Weibull equation respectively,and the correlation coefficient was calculated and studied.
Stress test, stability paramer and sedimentation ratio were done to investigate the stability of lipsomes and lipsomal gel. And the stability of fluconazole liposomes to hot pressing sterilization was also studied.
Results: The optimized prescription of fluconazole liposomes was: 640mg phospholipids, 106mg cholesterol, 20mg PVP, and pH 7.0 PBS. Liposomes were made by film dispersion method and the encapsulation was determined by sephadex G-75 column. The diameter/height ratio, flow rate of the PBS solution and volume of PBS above the column all had effect to the separation result. The appearance of fluconazole liposomes was uniform ivory yellow suspension, with the encapsulated ratio 55.03% and mean diameter 249.8nm.The polydispersity was 0.281.
The release process in vitro of both fluconazole solution and fluconazole liposomes fitted the Weibull equation. The equation were lnln[1/(1-Q)]=0.703lnt-0.4304 and lnln[1/(1-Q)]= 0.5043lnt-0.801, with the correlation coefficient R2=0.9813 and R2=0.9847 respectively. T50 and Td were 1.10h、1.84hand 2.37h、4.89h, respectively. The release process of fluconazole liposomes and solution before and after 2h were studied: the release process of liposomes before 2h was mainly diffusion process and fitted Higuchi equation, which was probably the free and topical drug release process. The release process after 2h fitted Weibull equation best.
The liposomal gel made by carbopol 941 had suitable viscosity. Transdermal delivery test showed that the release process of liposomal and non-liposomal gel all fitted zero order、first order、and Weibull equation with R2>0.99. The drugs of liposomal gel retained in the skin was much more than that of non-liposomal gel (P<0.05).
Stability test showed that liposomes and liposomal gel were not stable to high temperature. But the stability parameter of fluconazole liposomes was 0.066, and the fluconazole liposomes suspension was stable when laid up for a long period, only small amount of precipitation was formed after 3 months.
Conclusion: Phospholipids and cholesterol were used as membrane stuff, fluconazole liposomes were made by film dispersion method. This preparation technology was simple and convenient. Liposomal gel made by carbopol matrix was stable, and the transdermal delivery test result showed that the liposomal gel had more drugs retained in skin than that of non-liposomal gel. Liposomal gel as fluconazole percutaneous absorption dosage form was expected to be a new applicable preparation.
引文
1 焦章群.氟康唑临床应用进展.中原医刊,1999,26(10):53
2 国家药典委员会编.中国药典.化学工业出版社,2005(Vol.Ⅱ):401
3 郑雅铭,张怀亮.新一代抗真菌药—氟康唑.天津药学,1998,10(3):25~26
4 张建丽,郎丽峰,邬玲花.抗真菌药物氟康唑.包头医学,1999,23(1):24
5 杨莉,齐宪荣,石靖等.8-氯腺苷脂质体的制备及性质考察.中国新药杂志,2004,13(10):898~902
6 国家药典委员会编.中国药典.化学工业出版社,2005(Vol.Ⅱ):附录158
7 朱晓亮,曾抗,李国锋等.脂质体鬼臼毒素混悬液的制备,及包封率测定.中国医院药学杂志,2005,25(6):569~570
8 陈亮,江远明.天麻素脂质体的研制.中国生化药物杂志,2002,23(6):295~296
9 刘湘新,肖洪波,孙志良.吡喹酮脂质体的制备及包封率测定.湖南农业大学学报,1998,24(3):251~253
10 中国药学(英文版)编辑部.中国药学(英文版)投稿须知.中国药学(英文版),2005,14(2):135~136
11 周莉玲,王岩,刘清飞等.青藤碱脂质体包封率的测定.中国中药杂志,2006,31(9):731~734
12 洪慧,龙晓英,李历任等.葡聚糖微型凝胶柱测定辣椒碱柔性脂质体包封率的条件探讨.广东药学院学报,2005,21(2):120~123
13 吴翠栓,邓意辉,郝劲松等.微型柱离心法测定硝酸益康唑脂质体的包封率.中国药科大学学报,2002,33(Suppl):297~300
14 高晓黎,季兴梅.葡聚糖凝胶柱色谱法测定脂质体包封率的条件筛选.中国药学杂志,2003,23(7):515~517
15 张俊红,朱家壁,王虹.阿米卡星脂质体的包封率测定.中国药学杂志,1999,34(12):818~820
16 仵文英,席枝侠,薛红安等.紫外分光光度法测定黄芩苷脂质体的包封率与渗漏率.医药导报,2005,24(7):624~626
17 莫穗林,陈玉玲,郭海燕等.丹参酮脂质体的稳定性及包封率研究.中药材,2004,27(4):293~294
18 刘辉,汤韧,何晓霞等.脂质体处方和制备方法对阿昔洛韦棕榈酸酯脂质体稳定性的影响.药学学报,2002,37(7):563~566
19 赵荣生,侯新朴,严宝霞. 两性霉素B脂质体的制备及稳定性研究.中国医药工业杂志,2001,32(4):160~162
20 席枝侠,仵文英,薛红安等. 黄芩苷脂质体的制备和稳定性考察.中国医院药学杂志,2005,25(1):75~76
21 张华,齐宪荣,张强.柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学研究.药学学报, 2002,37(4):299~303
22 朱盛山主编.药物新剂型.化学工业出版社,2003:434
23 赵鲁松. 酮康唑脂质体滴眼剂和克霉唑脂质体凝胶剂的研究.万方硕博论文全文数据库.
24 刘辉,陈鹰,吴菡子等.阿昔洛韦棕榈酸酯脂质体凝胶剂的研制.中国药学杂志,2000,35(7):457~460
25 郭毅,闻京伟.高效液相色谱法测定氟康唑滴眼液的含量.药物分析杂志,1999,19(5):347~348
26 平其能等编著.现代药剂学.中国医药科技出版社,1998:612
27 于波涛,张志荣,曾仁杰等.PEG表面修饰黄芩苷脂质体制备工艺研究.西南国防医药,2005,15(1):33~37
28 张小滨,侯新朴.不同表面活性剂对伊文思蓝脂质体体内外性质的影响.中国药物与临床,2003,3(1):5~8
29 ZHANG Xiao-bin,HOU Xin-pu. Comparative Efficacy and Distribution of Evans Blue Liposome Modified with DSPE-PEG,Tween80,and Brij35. Journal of Chinese Pharmaceutical Sciences,2003,12(2):71-75
30 赵鲁松.酮康唑脂质体滴眼剂和克霉唑脂质体凝胶剂的研究.万方硕博论文全文数据库.
31 毕殿洲主编.药剂学.人民卫生出版社:453
1 朱盛山主编.药物新剂型.化学工业出版社,2003:434
2 国家药典委员会编.中国药典.化学工业出版社,2005(Vol.Ⅱ):附录39
3 胡静,封钦锋.硫唑嘌呤脂质体制备方法的研究.西北药 学杂志,2002,17(4):167~169
4 毕殿洲主编.药剂学.人民卫生出版社:218
5 韩季红等.抗癌药物脂肪乳物理化学性质的研究.沈阳药 学院院报,1991,8(1):14
6 王伶,张明臣,王晶等.高效液相色谱法测定氟康唑凝胶剂的含量.药物分析杂志,1998,18(增刊):89~90
7 王娟,阚全程,叶凡.高效液相色谱法测定氟康唑软膏的含量.中国民康医学杂志,2003,15(11)
8 李晓光,翟所迪.甘草酸单铵脂质体体内外药剂学行为研究.中国新药杂志,2003,12(11):915~918
9 齐宪荣,刘明辉,张克斌. 硝酸益康唑脂质体凝胶的释放和经皮渗透性研究.中国新药杂志,2001,10(7):507~510
10 王学清,齐宪荣,刘明辉.盐酸丁卡因脂质体凝胶剂的制备与释放度的测定.中国现代应用药学杂志,2003,20(1):37~40
11 何文,王辉,王宗春.甲氧沙林脂质体凝胶体外释药动力学.中国医院药学杂志,2000,25(9):805~806
12 张青,朱家壁,邱丽梅.盐酸左氧氟沙星脂质体的包封率和体外释放研究.中国药科大学学报,2004,35(6): 508~512
13 罗云,何文,李荣凌.补骨脂素脂质体凝胶体外释药模式的考察.广东药学院学报,2005,21(1):24~29
1 毛世瑞,王蕾,蔡翠芳等.甲磺酸培氟沙星凝胶基质的研究.沈阳药科大学学报,2002,19(1):9~13
2 朱盛山主编. 药物新剂型.化学工业出版社:325
3 毕殿洲主编.药剂学(第四版).人民卫生出版社:381
4 齐宪荣,刘明辉,张克斌等.硝酸益康唑脂质体凝胶的释放和经皮渗透性研究.中国新药杂志,2001,10(7):507~509
5 郑俊民主编.经皮给药新剂型.人民卫生出版社:100
6 罗云,何文,李容凌.补骨脂素脂质体凝胶的研制及体外释药研究.中国药房,2005,16(10):746~747
7 陈鹰,汤韧,刘辉.阿昔洛韦棕榈酸酯脂质体凝胶剂的局部透皮实验.中国医院药学杂志,2000,20,(6):324~327
8 王学清,齐宪荣,刘明辉等.盐酸丁卡因脂质体凝胶剂的制备与释放度的测定.中国现代应用药学杂志,2003,20(1):37~40
9 旷英姿,马全红,郝小祯等.茶多酚脂质体体外透皮实验研究.株洲工学院学报,2006,20(2):25~28
10 Weng Weiyu, Xu Huinan, Li Hong. Skin permeability and anti-inflammatory analgesic activities of bulleyaconitine A liposomes. CHINESE JOURNAL OF CLINICAL PHARMACY, 2003, 12(3): 131-135
11 赵凯,王昆,张敬如等.双氯芬酸钾脂质体制剂的制备及大鼠体外透皮研究.第三军医大学学报,2004,26(6):509~512
12 解素花,闫阅.高效液相色谱法测定脂质体中醋酸氯已定的含量药物分析杂志,2006,26(2):263~264
13 杨雯姝,邱利焱,金一.RP-HPLC法测定脂质体中重酒石酸长春瑞滨的含量.药物分析杂志,2006,26(5):646~648
14 李冬梅,路绪文,苏芳.阿西美辛脂质体凝胶剂的研制.中国现代应用药学杂志,2004,21(4):290~292
15 Vaibhav Dubey, Dinesh Mishra, Abhay Asthana et al. Transdermal delivery of a pineal hormone: Melatonin viaelastic liposomes. Biomaterials, 2006(7): 3491–3496
16 李冬梅,路绪文,苏芳.阿西美辛脂质体凝胶剂的体外透皮扩散研究.中国医院药学杂志,2003,23(6):330~333
17 曾抗,周再高.脂质体制剂对荧光素钠透皮、皮肤贮留量和皮肤分布影响的初步实验研究.万方数据资源系统:45
18 殿洲主编.药剂学(第四版),人民卫生出版社:382
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2 国家药典委员会编.中国药典.化学工业出版社,2005(Vol.Ⅱ):401
3 郑雅铭,张怀亮.新一代抗真菌药—氟康唑.天津药学,1998,10(3):25~26
4 张建丽,郎丽峰,邬玲花.抗真菌药物氟康唑.包头医学,1999,23(1):24
5 杨莉,齐宪荣,石靖等.8-氯腺苷脂质体的制备及性质考察.中国新药杂志,2004,13(10):898~902
6 国家药典委员会编.中国药典.化学工业出版社,2005(Vol.Ⅱ):附录158
7 朱晓亮,曾抗,李国锋等.脂质体鬼臼毒素混悬液的制备,及包封率测定.中国医院药学杂志,2005,25(6):569~570
8 陈亮,江远明.天麻素脂质体的研制.中国生化药物杂志,2002,23(6):295~296
9 刘湘新,肖洪波,孙志良.吡喹酮脂质体的制备及包封率测定.湖南农业大学学报,1998,24(3):251~253
10 中国药学(英文版)编辑部.中国药学(英文版)投稿须知.中国药学(英文版),2005,14(2):135~136
11 周莉玲,王岩,刘清飞等.青藤碱脂质体包封率的测定.中国中药杂志,2006,31(9):731~734
12 洪慧,龙晓英,李历任等.葡聚糖微型凝胶柱测定辣椒碱柔性脂质体包封率的条件探讨.广东药学院学报,2005,21(2):120~123
13 吴翠栓,邓意辉,郝劲松等.微型柱离心法测定硝酸益康唑脂质体的包封率.中国药科大学学报,2002,33(Suppl):297~300
14 高晓黎,季兴梅.葡聚糖凝胶柱色谱法测定脂质体包封率的条件筛选.中国药学杂志,2003,23(7):515~517
15 张俊红,朱家壁,王虹.阿米卡星脂质体的包封率测定.中国药学杂志,1999,34(12):818~820
16 仵文英,席枝侠,薛红安等.紫外分光光度法测定黄芩苷脂质体的包封率与渗漏率.医药导报,2005,24(7):624~626
17 莫穗林,陈玉玲,郭海燕等.丹参酮脂质体的稳定性及包封率研究.中药材,2004,27(4):293~294
18 刘辉,汤韧,何晓霞等.脂质体处方和制备方法对阿昔洛韦棕榈酸酯脂质体稳定性的影响.药学学报,2002,37(7):563~566
19 赵荣生,侯新朴,严宝霞. 两性霉素B脂质体的制备及稳定性研究.中国医药工业杂志,2001,32(4):160~162
20 席枝侠,仵文英,薛红安等. 黄芩苷脂质体的制备和稳定性考察.中国医院药学杂志,2005,25(1):75~76
21 张华,齐宪荣,张强.柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学研究.药学学报, 2002,37(4):299~303
22 朱盛山主编.药物新剂型.化学工业出版社,2003:434
23 赵鲁松. 酮康唑脂质体滴眼剂和克霉唑脂质体凝胶剂的研究.万方硕博论文全文数据库.
24 刘辉,陈鹰,吴菡子等.阿昔洛韦棕榈酸酯脂质体凝胶剂的研制.中国药学杂志,2000,35(7):457~460
25 郭毅,闻京伟.高效液相色谱法测定氟康唑滴眼液的含量.药物分析杂志,1999,19(5):347~348
26 平其能等编著.现代药剂学.中国医药科技出版社,1998:612
27 于波涛,张志荣,曾仁杰等.PEG表面修饰黄芩苷脂质体制备工艺研究.西南国防医药,2005,15(1):33~37
28 张小滨,侯新朴.不同表面活性剂对伊文思蓝脂质体体内外性质的影响.中国药物与临床,2003,3(1):5~8
29 ZHANG Xiao-bin,HOU Xin-pu. Comparative Efficacy and Distribution of Evans Blue Liposome Modified with DSPE-PEG,Tween80,and Brij35. Journal of Chinese Pharmaceutical Sciences,2003,12(2):71-75
30 赵鲁松.酮康唑脂质体滴眼剂和克霉唑脂质体凝胶剂的研究.万方硕博论文全文数据库.
31 毕殿洲主编.药剂学.人民卫生出版社:453
1 朱盛山主编.药物新剂型.化学工业出版社,2003:434
2 国家药典委员会编.中国药典.化学工业出版社,2005(Vol.Ⅱ):附录39
3 胡静,封钦锋.硫唑嘌呤脂质体制备方法的研究.西北药 学杂志,2002,17(4):167~169
4 毕殿洲主编.药剂学.人民卫生出版社:218
5 韩季红等.抗癌药物脂肪乳物理化学性质的研究.沈阳药 学院院报,1991,8(1):14
6 王伶,张明臣,王晶等.高效液相色谱法测定氟康唑凝胶剂的含量.药物分析杂志,1998,18(增刊):89~90
7 王娟,阚全程,叶凡.高效液相色谱法测定氟康唑软膏的含量.中国民康医学杂志,2003,15(11)
8 李晓光,翟所迪.甘草酸单铵脂质体体内外药剂学行为研究.中国新药杂志,2003,12(11):915~918
9 齐宪荣,刘明辉,张克斌. 硝酸益康唑脂质体凝胶的释放和经皮渗透性研究.中国新药杂志,2001,10(7):507~510
10 王学清,齐宪荣,刘明辉.盐酸丁卡因脂质体凝胶剂的制备与释放度的测定.中国现代应用药学杂志,2003,20(1):37~40
11 何文,王辉,王宗春.甲氧沙林脂质体凝胶体外释药动力学.中国医院药学杂志,2000,25(9):805~806
12 张青,朱家壁,邱丽梅.盐酸左氧氟沙星脂质体的包封率和体外释放研究.中国药科大学学报,2004,35(6): 508~512
13 罗云,何文,李荣凌.补骨脂素脂质体凝胶体外释药模式的考察.广东药学院学报,2005,21(1):24~29
1 毛世瑞,王蕾,蔡翠芳等.甲磺酸培氟沙星凝胶基质的研究.沈阳药科大学学报,2002,19(1):9~13
2 朱盛山主编. 药物新剂型.化学工业出版社:325
3 毕殿洲主编.药剂学(第四版).人民卫生出版社:381
4 齐宪荣,刘明辉,张克斌等.硝酸益康唑脂质体凝胶的释放和经皮渗透性研究.中国新药杂志,2001,10(7):507~509
5 郑俊民主编.经皮给药新剂型.人民卫生出版社:100
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