格列本脲固体自微乳化胶囊的研究
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摘要
格列本脲固体自微乳化系统是以格列本脲为主药,以油及非离子表面活性剂等为辅料形成的热力学稳定的自微乳化药物传递系统。格列本脲为第二代口服磺酰脲类降糖药,主要用于单靠饮食和锻炼不能满意控制高血糖的Ⅱ型糖尿病患者。由于格列本脲为水难溶性药物,水中溶解度较低,因此,本文以格列本脲(GLB)为模型药物,制备热力学稳定的自微乳化药物传递系统,以达到提高药物的溶解度和溶出度、促进格列本脲在体内吸收的目的。
在测定了药物在各种介质中的饱和溶解度的基础上,通过油与表面活性剂的配伍试验以及助溶剂增溶表面活性剂的能力等,初步确定了两个最佳混合表面活性剂,分别是聚氧乙烯氢化蓖麻油(RH40)／单甘酯(GM)和Tween80/GM。在固体自微乳化体系筛选的过程中,通过绘制伪三元相图,考察了混合表面活性剂的不同质量比(Km)、不同油相、不同助表面活性剂和药物等因素对自乳化形成的影响,确定了两个较好的自微乳化体系。根据相图中自微乳化区域的面积大小、体系的最低共熔点、自微乳粒径和自乳化效率为评价指标,最终确定了Miglyol 812/RH40/GM (Km=6)/1,2-Propanediol作为研究体系进行体外分析方法的研究。
我们进一步选择了表面活性剂质量分数在50%-60%的六个处方,考察其自微乳化后乳剂的粘度、电导、表面张力、Zeta电位、粒径和载药量等理化性质,对处方进行筛选,最终确定了格列本脲固体自微乳化体系的最终处方(w):Miglyol 81230%, RH40/GM (Km=6) 55%,1,2-Propanediol 15%。
将含药固体自微乳制备成胶囊,对其进行制剂学评价。分别考察了温度、溶液流动形态、分散介质和溶液体积对自乳化性能的影响。用总体液平衡反向透析法对格列本脲自微乳化胶囊的溶出过程进行了初步考察,其释药曲线符合Hixson-Crowell方程。与市售格列本脲胶囊相比,GLB SSMEDDS胶囊溶出速度快。考察了GLB SSMEDDS的稳定性,通过低温试验和留样实验,GLB SSMEDDS的外观性状、自微乳化时间和GLB含量均未见明显变化。经测定GLB SSMEDDS胶囊以不同体积0.1 mol·L-1HCl稀释后所得乳剂的粒径略有增加。
评价GLB SSMEDDS胶囊与市售GLB片剂对正常大鼠的降糖效果。结果显示,GLBSSMEDDS胶囊对正常大鼠有一定的降糖作用。
Glibenclamide Solid Self-Microemulsifying Drug Delivery System (GLB SSMEDDS), choosing GLB as the drug and oils and surfactants as vehicles, was thermodynamically stable SSMEDDS. GLB is a potent, second generation oral sulfonnyurea hypoglycemic agent, mainly for the treatment of typeⅡdiabetic patients who had been proved insufficient only by diet. GLB is a kind of drug with low water solubility and low dissolution. Therefore, choosing poorly water-soluble GLB as a model drug, thermodynamically stable SSMEDDS had been prepared to increase dissolution and enhance absorption of GLB.
Firstly, the drug solubility was determined. Mixed surfactants were made sure through the investigation of compatible combination between various surfactants and oils and the cosolvent ability of increasing solubility, which were RH40/GM and Tween80/GM. To identify the SSMEDDS, pesudo-ternary phase diagrams were constructed to investigate weight ratios (Km) of mixed surfactant, the effect of oils, cosurfactants and GLB on SSMEDDS. Two systems were established. Area of self-microemulsion region, the lowest eutectic point, droplet size and self-microemulsification efficiency of two kinds of systems were studied, the results of which indicated that the system of Miglyol 812/RH40/GM (Km=6)/1,2-Propanediol was regarded as the definite one just to investigate the method of in vitro analysis.
For further studies, six potential SSMEDDS vehicles were prepared at Km=6 with different ratios of surfactant (50%、60%and 70%, w), and the physicochemical properties of SSMEDDS were studied by measuring solubilization of GLB, surface tension, viscosity, Zeta potential, electric conductivity and droplet size after self-microemusdifying. All results brought a best SSMEDDS formulation (w):Miglyol 81230%, RH40/GM (Km=6) 55%, 1,2-Propanediol 15%.
The GLB SSMEDDS weres prapared for capsules. The effects of the temperature and other factors were investigated. The results from drug dissolution mechanism were consistent with Hixson-Crowell equation by bulk-equilibrium reverse dialysis bag technique. Compared with commercial GLB capsule, the dissolution of GLB SSMEDDS capsule was rapid. The stability of GLB SSMEDDS was good after storing 2 months at 4℃and room temperature, the content of GLB, appearance and the time of self-microemulsifying were studied and the results proved that GLB SSMEDDS was very stable thermodynamically. The droplet sizes after emulsifying by 0.1 mol·L-1 HCl with different volumes were bigger.
The GLB SSMEDDS capsule produced a certain reduction in blood glucose levels.
在测定了药物在各种介质中的饱和溶解度的基础上,通过油与表面活性剂的配伍试验以及助溶剂增溶表面活性剂的能力等,初步确定了两个最佳混合表面活性剂,分别是聚氧乙烯氢化蓖麻油(RH40)／单甘酯(GM)和Tween80/GM。在固体自微乳化体系筛选的过程中,通过绘制伪三元相图,考察了混合表面活性剂的不同质量比(Km)、不同油相、不同助表面活性剂和药物等因素对自乳化形成的影响,确定了两个较好的自微乳化体系。根据相图中自微乳化区域的面积大小、体系的最低共熔点、自微乳粒径和自乳化效率为评价指标,最终确定了Miglyol 812/RH40/GM (Km=6)/1,2-Propanediol作为研究体系进行体外分析方法的研究。
我们进一步选择了表面活性剂质量分数在50%-60%的六个处方,考察其自微乳化后乳剂的粘度、电导、表面张力、Zeta电位、粒径和载药量等理化性质,对处方进行筛选,最终确定了格列本脲固体自微乳化体系的最终处方(w):Miglyol 81230%, RH40/GM (Km=6) 55%,1,2-Propanediol 15%。
将含药固体自微乳制备成胶囊,对其进行制剂学评价。分别考察了温度、溶液流动形态、分散介质和溶液体积对自乳化性能的影响。用总体液平衡反向透析法对格列本脲自微乳化胶囊的溶出过程进行了初步考察,其释药曲线符合Hixson-Crowell方程。与市售格列本脲胶囊相比,GLB SSMEDDS胶囊溶出速度快。考察了GLB SSMEDDS的稳定性,通过低温试验和留样实验,GLB SSMEDDS的外观性状、自微乳化时间和GLB含量均未见明显变化。经测定GLB SSMEDDS胶囊以不同体积0.1 mol·L-1HCl稀释后所得乳剂的粒径略有增加。
评价GLB SSMEDDS胶囊与市售GLB片剂对正常大鼠的降糖效果。结果显示,GLBSSMEDDS胶囊对正常大鼠有一定的降糖作用。
Glibenclamide Solid Self-Microemulsifying Drug Delivery System (GLB SSMEDDS), choosing GLB as the drug and oils and surfactants as vehicles, was thermodynamically stable SSMEDDS. GLB is a potent, second generation oral sulfonnyurea hypoglycemic agent, mainly for the treatment of typeⅡdiabetic patients who had been proved insufficient only by diet. GLB is a kind of drug with low water solubility and low dissolution. Therefore, choosing poorly water-soluble GLB as a model drug, thermodynamically stable SSMEDDS had been prepared to increase dissolution and enhance absorption of GLB.
Firstly, the drug solubility was determined. Mixed surfactants were made sure through the investigation of compatible combination between various surfactants and oils and the cosolvent ability of increasing solubility, which were RH40/GM and Tween80/GM. To identify the SSMEDDS, pesudo-ternary phase diagrams were constructed to investigate weight ratios (Km) of mixed surfactant, the effect of oils, cosurfactants and GLB on SSMEDDS. Two systems were established. Area of self-microemulsion region, the lowest eutectic point, droplet size and self-microemulsification efficiency of two kinds of systems were studied, the results of which indicated that the system of Miglyol 812/RH40/GM (Km=6)/1,2-Propanediol was regarded as the definite one just to investigate the method of in vitro analysis.
For further studies, six potential SSMEDDS vehicles were prepared at Km=6 with different ratios of surfactant (50%、60%and 70%, w), and the physicochemical properties of SSMEDDS were studied by measuring solubilization of GLB, surface tension, viscosity, Zeta potential, electric conductivity and droplet size after self-microemusdifying. All results brought a best SSMEDDS formulation (w):Miglyol 81230%, RH40/GM (Km=6) 55%, 1,2-Propanediol 15%.
The GLB SSMEDDS weres prapared for capsules. The effects of the temperature and other factors were investigated. The results from drug dissolution mechanism were consistent with Hixson-Crowell equation by bulk-equilibrium reverse dialysis bag technique. Compared with commercial GLB capsule, the dissolution of GLB SSMEDDS capsule was rapid. The stability of GLB SSMEDDS was good after storing 2 months at 4℃and room temperature, the content of GLB, appearance and the time of self-microemulsifying were studied and the results proved that GLB SSMEDDS was very stable thermodynamically. The droplet sizes after emulsifying by 0.1 mol·L-1 HCl with different volumes were bigger.
The GLB SSMEDDS capsule produced a certain reduction in blood glucose levels.
引文
[1]Shah N H, Carvajal M T, Patal CI et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm,1994,10(6):15-23.
[2]Pouton CW. Formulations of Self-emulsifying drug delivery systems. Adv Drug Delivery Rev.1997, (25):47-58.
[3]Newton M, Petersson J, Podczeck F, et al. The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture [J]. JPharm Sci,2001,90(8):98729951.
[4]Patil P, Paradkar A. Porous polystyrene beads as carriers for self-emulsifying system containing loratadine [J]. AAPS Pharm Sci Tech,2006,7(1):E12-E71.
[5]Nazzal S, Nutan M, Palamakula A, et al. Optimization of a self-nanoemulsified tablet dosage form of ubiquinone using response surface methodology:effect of formulation ingredients[J]. Int J Pharm,2002, 240(122):10321141.
[6]Craig DQM, Lievens HSR, Pitt KG, et al. An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis. Int JPharm.1993,96(1-3):147-155.
[7]程玉钏,周建平,吕慧侠,张振海.固体自乳化药物传递系统的研究概况.中国药科大学药剂学教研室,2008,32(2)：68-75.
[8]陆彬.药物新剂型与新技术北京：人民卫生出版社,1998,53.
[9]Nazzal S, Khan MA. Controlled release of a self-emulsifying formulation from a tablet dosage form: Stability assessment and optimization of some processing parameters [J]. Int J Pharm,2006,315(1-2): 110-121.
[10]Serratoni M, Newton M, Booth S, et al. Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system[J]. Eur JPharm Biopharm,2007,65(1):94-98.
[11]Kommuru TR, Gurley B, Khan MA, et al. Reduced inter-and intra-dividual variability in cyclosporine pharmacokinetics form a microemulsion formulation. JPharm Sci,1994,83(3):444.
[12]Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur JPharm Bio,2000,50(2):179-188.
[13]Craig DQM, Lievens HSR, Pitt KG, et al. An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surfxe tension measurements and particle size analysis. Int. JPharm,1993,96(1-3):147-155.
[14]Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption; physical and biopharmaceutical aspects. Pharm Res,1995,12(11):1561-1572.
[15]Pouton CW. Formulations of self-emulsifying drug delivery systems. Adv Drug Delivery Rev,1997, (25):47-5893-98.
[16]Ping Li, Anasuya Ghosh, Robert F, et al. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions. In J Pharm,2004,173:155-164.
[17]Bachynsky MO, Shah NH, Patel CI, et al. Factors affecting the effecting the efficiency of a self-emulsifying oral delivery system[J]. Drug Devol and Indust Pharma,1997,23(8):809.
[18]Chanana G D, Sheth B B, Particle size reduction of emulsions by formulation design-Ⅱ:Effect of oil and surfactant concentration. J. Pharm. Sci Technol,1995,49(2):71-76.
[19]李国栋,许付,沈爱军等.获术油自乳化制剂处方研究.第二军医大学学报,23(8)：896-898.
[20]Franceschinis E, Voinovich D, Grassi M, et al. Self-emulsifying pellets prepared by wet granulation in high-shear mixer:influence of formulation variables and preliminary study on the in vitro absorption[J]. Int JPharm,2005,291(122):87-97.
[21]宁光.糖尿病-施虐全球的流行病[J].世界科学,1999,20(11)：25.
[22]陈灏珠主编.实用内科学[M].人民卫生出版社,1999,828-860.
[23]陈灏珠主编.内科学[M].人民卫生出版社,1998,716-729.
[24]曲静伟.口服降血糖药物进展[J].现代实用医学,2002,14(8)：444-445.
[25]张木勋.对口服磺脲类降糖药的临床应用再认识[J].医药导报,1999,18(4)：219-220.
[26]Warisnoicharoen. W, Lansley. A.B, Lawrence. M.J.Nonionic oil-in-water microemulsions:the effect of oil type on phase behaciour[J]. Int J Pharm,2000,198:7-27.
[27]吴顺芹.氟比洛芬微乳制剂的研究,2004.
[28]赵振国编著.界面化学基础.化学工业出版社,2003.
[29]Hsiu-o Ho, Chih-chuan Hsiao, Ming-thau Sheu. Preparation of microemulsions using polyglycerol fatty acid esters as surfactant for the delivery of protein drugs[J]. J Pharm Sci,1996,85:138-143.
[30]R. Aboofazeli, C.B. Lawrence, S.R. Wicks, et al. Investigations into formation and characterization of phospholipid microemulsions. Pseuo-ternary phase diagrams of systems containing water-lecithin-isopropyl myristate and either an alkanoic acid, amine, alkanediol, polyethylene glycol alkyl ether or alcohol as cosurfactant[J]. Int J Pharm,1994,111:63-72.
[31]王晓黎,蒋雪涛,李干佐等.非离子型表面活性剂微乳的基础研究[J].解放军药学学报,2001, 17(6):297-300.
[32]Pouton CW. Self-emulsifying drug delivery systems:assessment of the efficiency of emulsification.Int. J. Pharm,1985,27:335.
[33]Kommuru TR, Gurley B, Khan MA, et al. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10 formulation, development and bioavailability assessment. Int J Pharmac,2001,212(1):233.
[34]徐贵霞,王玉丽,全东琴等.自乳化溶出系统的体外评价.解放军药学学报,19(3)：195.
[35]OwenI.C, Yvonne Devlin, Jackie Butler, Influence of dissolution medium buffer composition on ketoprofen felease form ER products and in vitro-incorrelation.Int J Pharm,2003,254:147-154.
[36]刘华.酮洛芬自乳化胶囊的研究[M].沈阳药科大学硕士论文,2005.
[37]CONSTANTINIDES P P. Lipid microemulsions for improving drug dissolution and oral absorption: Physical and biopharmaceutical aspects[J]. Pharm Res,1995,12(11):1561-1572.
[38]Craig DQM, Barker SA, Banning D, et al. An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm,1995,114(1):103.
[39]Blonde L, Wogen J, Kreilick C, et al. Greater reductions in A1C in type 2 diabetic patients new to therapy with glyburide/metformin tablets as compared to glyburide co-administered with metformin. Diabetes-Obes-Metab,2003,5(6):424-431.
[40]Washinton C. Drug release form microdisperse systems:a critical review [J]. Int J Pharm,1990, 58:1-12.
[41]Levy MY, Benita S. Drug release form submicronized O/W emulsion:a new in vitro kinetic evaluation model [J]. Int J Pharm,1990,66:29-37.
[42]生化检验学,安乙敏主编.成都,四川省科学技术出版社,1994,63.
[43]金方.胰岛素口服自微乳化给药系统的研究[M].上海医学工业研究院博士论文,2004.
[44]马蕊.格列本脲乳胶剂的研究.沈阳药科大学硕士论文,2008.
[2]Pouton CW. Formulations of Self-emulsifying drug delivery systems. Adv Drug Delivery Rev.1997, (25):47-58.
[3]Newton M, Petersson J, Podczeck F, et al. The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture [J]. JPharm Sci,2001,90(8):98729951.
[4]Patil P, Paradkar A. Porous polystyrene beads as carriers for self-emulsifying system containing loratadine [J]. AAPS Pharm Sci Tech,2006,7(1):E12-E71.
[5]Nazzal S, Nutan M, Palamakula A, et al. Optimization of a self-nanoemulsified tablet dosage form of ubiquinone using response surface methodology:effect of formulation ingredients[J]. Int J Pharm,2002, 240(122):10321141.
[6]Craig DQM, Lievens HSR, Pitt KG, et al. An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis. Int JPharm.1993,96(1-3):147-155.
[7]程玉钏,周建平,吕慧侠,张振海.固体自乳化药物传递系统的研究概况.中国药科大学药剂学教研室,2008,32(2)：68-75.
[8]陆彬.药物新剂型与新技术北京：人民卫生出版社,1998,53.
[9]Nazzal S, Khan MA. Controlled release of a self-emulsifying formulation from a tablet dosage form: Stability assessment and optimization of some processing parameters [J]. Int J Pharm,2006,315(1-2): 110-121.
[10]Serratoni M, Newton M, Booth S, et al. Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system[J]. Eur JPharm Biopharm,2007,65(1):94-98.
[11]Kommuru TR, Gurley B, Khan MA, et al. Reduced inter-and intra-dividual variability in cyclosporine pharmacokinetics form a microemulsion formulation. JPharm Sci,1994,83(3):444.
[12]Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur JPharm Bio,2000,50(2):179-188.
[13]Craig DQM, Lievens HSR, Pitt KG, et al. An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surfxe tension measurements and particle size analysis. Int. JPharm,1993,96(1-3):147-155.
[14]Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption; physical and biopharmaceutical aspects. Pharm Res,1995,12(11):1561-1572.
[15]Pouton CW. Formulations of self-emulsifying drug delivery systems. Adv Drug Delivery Rev,1997, (25):47-5893-98.
[16]Ping Li, Anasuya Ghosh, Robert F, et al. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions. In J Pharm,2004,173:155-164.
[17]Bachynsky MO, Shah NH, Patel CI, et al. Factors affecting the effecting the efficiency of a self-emulsifying oral delivery system[J]. Drug Devol and Indust Pharma,1997,23(8):809.
[18]Chanana G D, Sheth B B, Particle size reduction of emulsions by formulation design-Ⅱ:Effect of oil and surfactant concentration. J. Pharm. Sci Technol,1995,49(2):71-76.
[19]李国栋,许付,沈爱军等.获术油自乳化制剂处方研究.第二军医大学学报,23(8)：896-898.
[20]Franceschinis E, Voinovich D, Grassi M, et al. Self-emulsifying pellets prepared by wet granulation in high-shear mixer:influence of formulation variables and preliminary study on the in vitro absorption[J]. Int JPharm,2005,291(122):87-97.
[21]宁光.糖尿病-施虐全球的流行病[J].世界科学,1999,20(11)：25.
[22]陈灏珠主编.实用内科学[M].人民卫生出版社,1999,828-860.
[23]陈灏珠主编.内科学[M].人民卫生出版社,1998,716-729.
[24]曲静伟.口服降血糖药物进展[J].现代实用医学,2002,14(8)：444-445.
[25]张木勋.对口服磺脲类降糖药的临床应用再认识[J].医药导报,1999,18(4)：219-220.
[26]Warisnoicharoen. W, Lansley. A.B, Lawrence. M.J.Nonionic oil-in-water microemulsions:the effect of oil type on phase behaciour[J]. Int J Pharm,2000,198:7-27.
[27]吴顺芹.氟比洛芬微乳制剂的研究,2004.
[28]赵振国编著.界面化学基础.化学工业出版社,2003.
[29]Hsiu-o Ho, Chih-chuan Hsiao, Ming-thau Sheu. Preparation of microemulsions using polyglycerol fatty acid esters as surfactant for the delivery of protein drugs[J]. J Pharm Sci,1996,85:138-143.
[30]R. Aboofazeli, C.B. Lawrence, S.R. Wicks, et al. Investigations into formation and characterization of phospholipid microemulsions. Pseuo-ternary phase diagrams of systems containing water-lecithin-isopropyl myristate and either an alkanoic acid, amine, alkanediol, polyethylene glycol alkyl ether or alcohol as cosurfactant[J]. Int J Pharm,1994,111:63-72.
[31]王晓黎,蒋雪涛,李干佐等.非离子型表面活性剂微乳的基础研究[J].解放军药学学报,2001, 17(6):297-300.
[32]Pouton CW. Self-emulsifying drug delivery systems:assessment of the efficiency of emulsification.Int. J. Pharm,1985,27:335.
[33]Kommuru TR, Gurley B, Khan MA, et al. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10 formulation, development and bioavailability assessment. Int J Pharmac,2001,212(1):233.
[34]徐贵霞,王玉丽,全东琴等.自乳化溶出系统的体外评价.解放军药学学报,19(3)：195.
[35]OwenI.C, Yvonne Devlin, Jackie Butler, Influence of dissolution medium buffer composition on ketoprofen felease form ER products and in vitro-incorrelation.Int J Pharm,2003,254:147-154.
[36]刘华.酮洛芬自乳化胶囊的研究[M].沈阳药科大学硕士论文,2005.
[37]CONSTANTINIDES P P. Lipid microemulsions for improving drug dissolution and oral absorption: Physical and biopharmaceutical aspects[J]. Pharm Res,1995,12(11):1561-1572.
[38]Craig DQM, Barker SA, Banning D, et al. An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm,1995,114(1):103.
[39]Blonde L, Wogen J, Kreilick C, et al. Greater reductions in A1C in type 2 diabetic patients new to therapy with glyburide/metformin tablets as compared to glyburide co-administered with metformin. Diabetes-Obes-Metab,2003,5(6):424-431.
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[41]Levy MY, Benita S. Drug release form submicronized O/W emulsion:a new in vitro kinetic evaluation model [J]. Int J Pharm,1990,66:29-37.
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