非诺贝特自乳化胶囊的研究
|
摘要
非诺贝特自乳化系统是以非诺贝特为主药，以油、乳化剂及助乳化剂等为辅料形成的热力学稳定的自乳化药物传递系统。非诺贝特(fenofibrate，FR)是第三代氯贝丁酯类降血脂药物，在体内经酯酶的作用迅速代谢成非诺贝特酸而起降血脂作用。适用于原发性高胆固醇血症、内源性高甘油三酯血症及混合型高脂血症。是目前临床用于治疗高脂血症的常用药物之一。FR难溶于水，其制剂溶解过程为吸收的限速过程。口服制剂大多存在生物利用度低的问题。本文以自乳化系统为载体，将其制成胶囊，可提高FR的溶出，促进其吸收，提高口服生物利用度。
课题根据不同研究的要求，建立了紫外分光光度法和高效液相色谱法，用于非诺贝特的处方筛选及体内评价的含量测定，为非诺贝特自乳化释药系统的质量研究奠定了坚实的基础。紫外分光光度法可用于不含油相及表面活性剂等干扰物质时非诺贝特含量的测定。上述方法灵敏度高，专属性强，准确度好，满足本研究中的各项分析要求。
通过非诺贝特在各种油、乳化剂和助乳化剂中饱和溶解度的测定及自乳化液处方组成的筛选，选出溶解药物能力和乳化性能较好的辅料，通过正交设计实验，确定了最佳体系是油相油酸乙酯、乳化剂Tween-80、助乳化剂PEG400，从而确定了FR自乳化系统的最优处方。绘制上述体系的假三元相图，考察中发现药物的加入使得两体系的自乳化区面积较大程度减小。研究处方中各组成的含量对自乳化系统乳化性能的影响；同时还考察了温度、乳化溶液的流动形态、PH和体积对自乳化性能的影响。
用总体液平衡反向透析法和样品分离法对FR自乳化胶囊的体外释药过程进行了初步考察。两种溶出方法均表明自制制剂累积释药百分率高于参比制剂，与力平之胶囊的溶出相比无显著性差异。
对影响乳剂粒径的因素进行了考察：①FR—SEDDS加入0.1mol·L~(-1) HCL、水和pH6.8PBS后所得乳剂的粒径无明显差异；②FR-SEDDS乳化后所得乳剂的粒径随载药量的增加无明显变化；③稀释倍数对乳剂粒径无影响。在FR-SEDDS稳定性考察试验中，强光照射试验表明，制剂在强光照射下药物含量无变化；冷热循环(4℃、40℃)加速试验中，制剂的外观、药物含量、乳化速度、乳化后乳剂的稳定性等各项指标基本无变化。非诺贝特自乳化制剂放置6个月，制剂的药物含量、2 h的累计溶出及乳化时间均无变化。加速和留样试验结果表明，FR自乳化系统稳定性良好。
对FR自乳化胶囊和市售微粒化胶囊进行了家犬体内药物动力学研究，结果表明：两者的达峰时间(T_(max))分别为1.52和1.25 h，峰浓度(C_(max))分别为6.86和6.25μg·mL~(-1)，FR自乳化胶囊相对于市售微粒化胶囊的生物利用度为121.29％，两者吸收生物不等效，FR自乳化胶囊有利于吸收。
Fenofibrate Self-Emulsifying Drug Delivery System, choosing fenofibrate as the drug and oils, emulsifier and coemulsifier as vehicles, was thermodynamically stable SEDDS.
As the third Clofibrate hypolipidemic drug, it is effective when metabolized into fenofibrate acid under the action of esterase in vivo, and it is reported to treat essential hypercholesterolemia, endogenous hypertriglyceridemia and combined hyperlipidemia familial as well. It is one of the commonly used hypolipidemic drugs in clinic.Fenofibrate is hardly soluble in water, It's dissolved process is the constraint velocity process of fenofibrate's absorption.So the oral preparation shows a very low bioavailability. In this paper, we prepared Fenofibrate SEDDS capsules, in order to enhance the dissolution, promote its oral absorption and so as to elevate its oral bioavailability.
In order to meet different research requirement, UV spectrophotometry and HPLC-UV method was developed for the determination of the fenofibrate for its quality control as well as in vivo analysis. The methods mentioned above are proved to be of high susceptibility, good specificity and excellent method recovery, which all fit the requirement of analysis.
Solubility of the drug in different excipients was investigated to make the coarse screen of several oils, emulsifier and coemulsifier. Orthogonal design was studied and then ethylis oleas,Tween-80 and PEG400 were selected as s oil, emulsifier and coemulsifier, respectively. The pseudo-ternary phase diagrams of the systems were studied, the results of which indicated that the self-emulsifying region area was significant reduced. We investigated the effects of the vehicle contents, temperature, the flow shape, pH and volume of media on the self-emulsifying efficiency. All results brought us a best FR-SEDDS formulation.
The vitro drug-release profiles of fenofibrate from SEDDS was determined using a bulk-equilibrium reverse dialysis bag method and sample separation method respectively, both of which showed that the cumulative percentage release of fenofibrate from SEDDS was higher than the reference.There was no conspicuous difference between the two preparation in dissolution.
The particle size of FR-SEDDS were studied. The mean size after emulsifying by 0.1 mol·L~(-1) HC1 ,water and PH 6.8 PBS were no evident disparation. The particle size was no change with the increase of drug loading. The particle size did not owe to the the deliquation of the emulsion. The influence tests of FR-SEDDS were evaluated by its characteristics, drug contents, physical stability of the emulsion and cumulative release rate of 2 h. The results showed a good stability of this SEDDS, and the accelerated testing and long term testing for 6 months were showed the stability of SEDDS capsules was satisfactory.
The pharmacokinetics of FR from SEDDS capsules was studied comparing with the reference capsules. The peak time and peak concentration of both were 1.52 h, 1.25 h, and 6.86μg·mL~(-1), 6.25μg·mL~(-1) respectively. The relative bioavailability of FR-SEDDS capsules was 121.29%. The two one-sided t-test results demonstrated that the two dosage forms were of no bioequivalence and the FR-SEDDS capsules can enhance the absorption of FR.
课题根据不同研究的要求，建立了紫外分光光度法和高效液相色谱法，用于非诺贝特的处方筛选及体内评价的含量测定，为非诺贝特自乳化释药系统的质量研究奠定了坚实的基础。紫外分光光度法可用于不含油相及表面活性剂等干扰物质时非诺贝特含量的测定。上述方法灵敏度高，专属性强，准确度好，满足本研究中的各项分析要求。
通过非诺贝特在各种油、乳化剂和助乳化剂中饱和溶解度的测定及自乳化液处方组成的筛选，选出溶解药物能力和乳化性能较好的辅料，通过正交设计实验，确定了最佳体系是油相油酸乙酯、乳化剂Tween-80、助乳化剂PEG400，从而确定了FR自乳化系统的最优处方。绘制上述体系的假三元相图，考察中发现药物的加入使得两体系的自乳化区面积较大程度减小。研究处方中各组成的含量对自乳化系统乳化性能的影响；同时还考察了温度、乳化溶液的流动形态、PH和体积对自乳化性能的影响。
用总体液平衡反向透析法和样品分离法对FR自乳化胶囊的体外释药过程进行了初步考察。两种溶出方法均表明自制制剂累积释药百分率高于参比制剂，与力平之胶囊的溶出相比无显著性差异。
对影响乳剂粒径的因素进行了考察：①FR—SEDDS加入0.1mol·L~(-1) HCL、水和pH6.8PBS后所得乳剂的粒径无明显差异；②FR-SEDDS乳化后所得乳剂的粒径随载药量的增加无明显变化；③稀释倍数对乳剂粒径无影响。在FR-SEDDS稳定性考察试验中，强光照射试验表明，制剂在强光照射下药物含量无变化；冷热循环(4℃、40℃)加速试验中，制剂的外观、药物含量、乳化速度、乳化后乳剂的稳定性等各项指标基本无变化。非诺贝特自乳化制剂放置6个月，制剂的药物含量、2 h的累计溶出及乳化时间均无变化。加速和留样试验结果表明，FR自乳化系统稳定性良好。
对FR自乳化胶囊和市售微粒化胶囊进行了家犬体内药物动力学研究，结果表明：两者的达峰时间(T_(max))分别为1.52和1.25 h，峰浓度(C_(max))分别为6.86和6.25μg·mL~(-1)，FR自乳化胶囊相对于市售微粒化胶囊的生物利用度为121.29％，两者吸收生物不等效，FR自乳化胶囊有利于吸收。
Fenofibrate Self-Emulsifying Drug Delivery System, choosing fenofibrate as the drug and oils, emulsifier and coemulsifier as vehicles, was thermodynamically stable SEDDS.
As the third Clofibrate hypolipidemic drug, it is effective when metabolized into fenofibrate acid under the action of esterase in vivo, and it is reported to treat essential hypercholesterolemia, endogenous hypertriglyceridemia and combined hyperlipidemia familial as well. It is one of the commonly used hypolipidemic drugs in clinic.Fenofibrate is hardly soluble in water, It's dissolved process is the constraint velocity process of fenofibrate's absorption.So the oral preparation shows a very low bioavailability. In this paper, we prepared Fenofibrate SEDDS capsules, in order to enhance the dissolution, promote its oral absorption and so as to elevate its oral bioavailability.
In order to meet different research requirement, UV spectrophotometry and HPLC-UV method was developed for the determination of the fenofibrate for its quality control as well as in vivo analysis. The methods mentioned above are proved to be of high susceptibility, good specificity and excellent method recovery, which all fit the requirement of analysis.
Solubility of the drug in different excipients was investigated to make the coarse screen of several oils, emulsifier and coemulsifier. Orthogonal design was studied and then ethylis oleas,Tween-80 and PEG400 were selected as s oil, emulsifier and coemulsifier, respectively. The pseudo-ternary phase diagrams of the systems were studied, the results of which indicated that the self-emulsifying region area was significant reduced. We investigated the effects of the vehicle contents, temperature, the flow shape, pH and volume of media on the self-emulsifying efficiency. All results brought us a best FR-SEDDS formulation.
The vitro drug-release profiles of fenofibrate from SEDDS was determined using a bulk-equilibrium reverse dialysis bag method and sample separation method respectively, both of which showed that the cumulative percentage release of fenofibrate from SEDDS was higher than the reference.There was no conspicuous difference between the two preparation in dissolution.
The particle size of FR-SEDDS were studied. The mean size after emulsifying by 0.1 mol·L~(-1) HC1 ,water and PH 6.8 PBS were no evident disparation. The particle size was no change with the increase of drug loading. The particle size did not owe to the the deliquation of the emulsion. The influence tests of FR-SEDDS were evaluated by its characteristics, drug contents, physical stability of the emulsion and cumulative release rate of 2 h. The results showed a good stability of this SEDDS, and the accelerated testing and long term testing for 6 months were showed the stability of SEDDS capsules was satisfactory.
The pharmacokinetics of FR from SEDDS capsules was studied comparing with the reference capsules. The peak time and peak concentration of both were 1.52 h, 1.25 h, and 6.86μg·mL~(-1), 6.25μg·mL~(-1) respectively. The relative bioavailability of FR-SEDDS capsules was 121.29%. The two one-sided t-test results demonstrated that the two dosage forms were of no bioequivalence and the FR-SEDDS capsules can enhance the absorption of FR.
引文
[1] Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives fibrates.J.Clin Pharmacokinet, 1998, 34(2): 155-162
[2] Masnatta LD, Cuniberti LA, Rey RH,et al. Determination of bezafrbrate, ciprofibrate and fenofibric acid in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl, 1996, 687(2): 437-442
[3] 李国栋，范伟，居红卫，等。自乳化释药系统的研究进展[J]。国外医药 合成药生化药制剂分册，2001，22(5)：304
[4] 陈曙霞，陈铭生．降脂新药非诺贝特的实验和临床研究．新药与临床，1985，4(2)：22-24
[5] Kerc J, Scric S, Knez Z, et al.Microuization of drugs using supercritical carbon dioxide [J].Farm Vestn (Ljubljana), 1997,48 (Pos.Stev.):282-283
[6] Dudos R, Terracol D.Method for preparing Solid dispersions of pharmaceutical forms [P].WO:9704749,1997-02-13.(CA 1997,126:216668s).
[7] Aigner Z,Bencz Ⅰ.Increasing the solubility characteristics of fenofibrate with cydodextrin [J].J Inclusion Phenom Mol Recognit Chen,1994-1995(Pub.1995),20(3):241-252
[8] (Speiser P. Lipid nanopellent oral drag formulation [P].DE:3421468,1985-12-19).CA 1986,104:116113j.
[9] (Boyer J.Pharmaceutical fenofibrate granules with improved solubility [P].EP:256933,1988-02-24).CA 1988,109:197197t.
[10] 李国栋，范伟，居红卫，等。自乳化释药系统的研究进展[J]。国外医药 合成药生化药制剂分册，2001，22(5)：304
[11] Gao ZC, Choi HG,Shin Ⅲ,et al.Phsicocliemical system for oral delivery of cyclosprin A[J].Int J Pharm,1998,161:75
[12] Sami Nazzal,Mausoor A Khan.Respouse surface metbodology for the optimization of Ubiquinone self-nanoemulsifed drug delivery system[J].AAPS Pharm Sci Tech,2002,3(1):1
[13] Cottens S, Haeberlin B, Sedraui R, et al. Pharmaceutical microemulsion preconcentrates containing cyclosporings and macrocides.Switzerland wo9613273,1996-OS-O1
[14] Pather IS, Cmpte SV, Khankari RK, et al. Microemulsious as solid dosage forms for oral administration. US 6280770,2001-08-28
[15] Dollo G, Corre PL, Guerin A, et al. Spray-dried redispersible oil-in-water emulsion to improve oral bioavailabilty of poorly soluble drugs. Eur J Pharm Sci, 2003,19(4):273-280.
[16] Corveleyn S, Remon JP. Formulation of a lyophilized dry emulsion tablet for delivery of poorly soluble drugs, lnt J Pharm, 1998,166(1):65-74
[17] Attama AA, Nzekwe IT, Nnamani PO, et al. The use of solid sell-emulsifying systems in the delivery of diclofenac, lnt J Pharm, 2003,262(1):23-28
[18] Kommuru TR, Gurley B, Khan MA, et al, Reduced inter- and intra-dividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci, 1994, 83(3):444
[19] Gershanik T, Benita S. Sell-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Bio. 2000, 50(2):179-188.
[20] Craig DQM, Lievens HSP,, Pitt KG et al. An investigation into the physico-chemical properties of sell-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis. Int. J Pharm. 1993, 96(1-3): 147-155.
[21] Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption; physical and biopharmaceutical aspects. Pharm Res, 1995, 12(11):1561-1572.
[22] Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, sell-emulsifying and self-microemulsifying drug delivery systems. Pharm Sci. 2000, 2, s 93-98.
[23] Pouton CW. Formulations of Sell-emulsifying drug delivery systems. Adv Drug Delivery Rev. 1997(25):47-58.
[24] Rene Holm, Christopher JH, Glenn A, et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in sell-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. Eur J.Pharm.Sci 2003(20):91-97.
[25] 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.
[26] 李国栋，许付，沈爱军等．莪术油自乳化制剂处方研究．第二军医大学学报，23(8)：896-898
[27] Solomon J, Harry Seager, Pouton CW. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv Drug Delivery Rev. 1997(25):33-46.
[28] 徐贵霞，王玉丽，全东琴等．自乳化释药系统的体外评价．解放军药学学报，19(3)：195
[29] 张正全，陆彬．微乳给药系统研究概况。中国医药工业杂志．2001；32(3)：139
[30] Kommuru TR, Gurley B, Khan MA, et al. Self-emulsifying drug delivery systems (SEDDS) of coenzymeQ 10 formulation, development and bioavailability assessment. Int J Pharm, 2001;212(1):233
[31] 王晓黎，蒋雪涛．微乳在药剂学上的应用．解放军药学学报．2000；18(2)：88
[32] 平其能等．现代药剂学．北京：中国医药科技出版社，1998，1～9．
[33] 郑俊民主编．经皮给药新剂型[M]．北京：人民卫生出版社，1997：276-279．
[34] R.Neslihan Gursoy, Simon Benita. Self-emulsifying drug delivery systems for improved oral delivery of lipophilic drugs[J].Biomedicine & Pharmacotherapy, 2004(58): 173-182.
[35] 彭盛德，周密妹，李性天，酮洛芬肠溶胶囊的溶出速率测定，中国药房，1992，4(2)：12-13
[36] Owen I.C, Yvonne Devlin, Jackie Buffer. Influence of dissolution medium buffer composition on ketoprofen release from ER products and in vitro-in vivo correlation. Int J Pharm.2003, 254:147-154.
[37] Attwood, D. And Florence, A.T. Surfactant systems: their chemistry, pharmacy and biology. Chapman and Hall, London.
[38] Swenson, E.S., Milisen, W.B. and Curatolo, W. Intestinal permeability enhancement: efficacy, acute local toxicity and reversibility. Pharm Res, 1997, 11:1132-1142.
[39] Xiao Yanyu, Song Yunmei, Chen Zhipeng, Ping Qineng. The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats. lnt J Pharm,2006 (307): 77-82.
[40] Shinoda K, Friberg S. Adv Colloid Interface Sci. 1975, 4:281
[41] Malcolmson C, Lawrence M.J. A comparison of the incorporation of steroids into nonionic micellar and microemulsion systems [J]. J Phann Pharmacol. 1993, 45(2): 141—143
[42] Warisnoicharoen W, Lansley AB, Lawrence MJ. Nonionic oil-in-water micro- emulsions: the effect of oil type on phase behaviour[J]. Int J Pharm, 2000, 198:7-27
[43] 赵振国编著，界面化学基础，化学工业出版社，2003
[44] Pouton. Formulation of self-emulsifying drug delivery systems. Adv. Drug Deltv. Rev. 1997(25): 27-58.
[45] Bachynsky MO, Shah NH, Patel CI, et al. Factors affecting the efficiency of a self- emulsifying oral delivery system. Drug Development and Industrial Pharmacy, 1997; 23(8):809
[46] Khoo S M, Humberstone, A J, Porter C J H, et al. Formulations design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm, 1998,167: 155-164.
[47] Halbant L, Barbe c, Pozo A D. An investigation into physical and chemical properties of semi-solid self-emulsifying systems for hard gelatin capsules. Int J Pharm. 1996, 130:203-212.
[48] Pouton CW, Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. Int J Pharm,1985,27:335-348.
[49] Gershanik T ,Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharma Biopharmac,2000,50(1):179
[50] Trotta M. Affluence of phase transformation on indomethacin release from microemulsious [J] .J Control Release, 1999,(60):399-405.
[51] 陆彬．药物新剂型与新技术[M]．北京：人民卫生出版社，1998
[52] 何军，奉建芳，张乐乐，等．水飞蓟素固体脂质纳米粒体内药代动力学研究[J]．中成药，2005，27(1)：19～21．
[53] 江波，印春华．水飞蓟素磷脂复合物家兔体内生物利用度的研究[J]．中国医药工业杂志，2002，33(12)：598～600．
[54] 魏数礼主编，生物药剂学与药物动力学[M]．人民卫生出版社，1997．
[55] 黄圣凯，韩可勤．生物等效性评价的统计方法[J]．中国药学杂志，1993，9(1)：43-46
[56] 梁文权．生物药剂学与药物动力学[M]．北京：人民卫生出版社，2000：174—194
[2] Masnatta LD, Cuniberti LA, Rey RH,et al. Determination of bezafrbrate, ciprofibrate and fenofibric acid in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl, 1996, 687(2): 437-442
[3] 李国栋，范伟，居红卫，等。自乳化释药系统的研究进展[J]。国外医药 合成药生化药制剂分册，2001，22(5)：304
[4] 陈曙霞，陈铭生．降脂新药非诺贝特的实验和临床研究．新药与临床，1985，4(2)：22-24
[5] Kerc J, Scric S, Knez Z, et al.Microuization of drugs using supercritical carbon dioxide [J].Farm Vestn (Ljubljana), 1997,48 (Pos.Stev.):282-283
[6] Dudos R, Terracol D.Method for preparing Solid dispersions of pharmaceutical forms [P].WO:9704749,1997-02-13.(CA 1997,126:216668s).
[7] Aigner Z,Bencz Ⅰ.Increasing the solubility characteristics of fenofibrate with cydodextrin [J].J Inclusion Phenom Mol Recognit Chen,1994-1995(Pub.1995),20(3):241-252
[8] (Speiser P. Lipid nanopellent oral drag formulation [P].DE:3421468,1985-12-19).CA 1986,104:116113j.
[9] (Boyer J.Pharmaceutical fenofibrate granules with improved solubility [P].EP:256933,1988-02-24).CA 1988,109:197197t.
[10] 李国栋，范伟，居红卫，等。自乳化释药系统的研究进展[J]。国外医药 合成药生化药制剂分册，2001，22(5)：304
[11] Gao ZC, Choi HG,Shin Ⅲ,et al.Phsicocliemical system for oral delivery of cyclosprin A[J].Int J Pharm,1998,161:75
[12] Sami Nazzal,Mausoor A Khan.Respouse surface metbodology for the optimization of Ubiquinone self-nanoemulsifed drug delivery system[J].AAPS Pharm Sci Tech,2002,3(1):1
[13] Cottens S, Haeberlin B, Sedraui R, et al. Pharmaceutical microemulsion preconcentrates containing cyclosporings and macrocides.Switzerland wo9613273,1996-OS-O1
[14] Pather IS, Cmpte SV, Khankari RK, et al. Microemulsious as solid dosage forms for oral administration. US 6280770,2001-08-28
[15] Dollo G, Corre PL, Guerin A, et al. Spray-dried redispersible oil-in-water emulsion to improve oral bioavailabilty of poorly soluble drugs. Eur J Pharm Sci, 2003,19(4):273-280.
[16] Corveleyn S, Remon JP. Formulation of a lyophilized dry emulsion tablet for delivery of poorly soluble drugs, lnt J Pharm, 1998,166(1):65-74
[17] Attama AA, Nzekwe IT, Nnamani PO, et al. The use of solid sell-emulsifying systems in the delivery of diclofenac, lnt J Pharm, 2003,262(1):23-28
[18] Kommuru TR, Gurley B, Khan MA, et al, Reduced inter- and intra-dividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci, 1994, 83(3):444
[19] Gershanik T, Benita S. Sell-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Bio. 2000, 50(2):179-188.
[20] Craig DQM, Lievens HSP,, Pitt KG et al. An investigation into the physico-chemical properties of sell-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis. Int. J Pharm. 1993, 96(1-3): 147-155.
[21] Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption; physical and biopharmaceutical aspects. Pharm Res, 1995, 12(11):1561-1572.
[22] Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, sell-emulsifying and self-microemulsifying drug delivery systems. Pharm Sci. 2000, 2, s 93-98.
[23] Pouton CW. Formulations of Sell-emulsifying drug delivery systems. Adv Drug Delivery Rev. 1997(25):47-58.
[24] Rene Holm, Christopher JH, Glenn A, et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in sell-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. Eur J.Pharm.Sci 2003(20):91-97.
[25] 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.
[26] 李国栋，许付，沈爱军等．莪术油自乳化制剂处方研究．第二军医大学学报，23(8)：896-898
[27] Solomon J, Harry Seager, Pouton CW. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv Drug Delivery Rev. 1997(25):33-46.
[28] 徐贵霞，王玉丽，全东琴等．自乳化释药系统的体外评价．解放军药学学报，19(3)：195
[29] 张正全，陆彬．微乳给药系统研究概况。中国医药工业杂志．2001；32(3)：139
[30] Kommuru TR, Gurley B, Khan MA, et al. Self-emulsifying drug delivery systems (SEDDS) of coenzymeQ 10 formulation, development and bioavailability assessment. Int J Pharm, 2001;212(1):233
[31] 王晓黎，蒋雪涛．微乳在药剂学上的应用．解放军药学学报．2000；18(2)：88
[32] 平其能等．现代药剂学．北京：中国医药科技出版社，1998，1～9．
[33] 郑俊民主编．经皮给药新剂型[M]．北京：人民卫生出版社，1997：276-279．
[34] R.Neslihan Gursoy, Simon Benita. Self-emulsifying drug delivery systems for improved oral delivery of lipophilic drugs[J].Biomedicine & Pharmacotherapy, 2004(58): 173-182.
[35] 彭盛德，周密妹，李性天，酮洛芬肠溶胶囊的溶出速率测定，中国药房，1992，4(2)：12-13
[36] Owen I.C, Yvonne Devlin, Jackie Buffer. Influence of dissolution medium buffer composition on ketoprofen release from ER products and in vitro-in vivo correlation. Int J Pharm.2003, 254:147-154.
[37] Attwood, D. And Florence, A.T. Surfactant systems: their chemistry, pharmacy and biology. Chapman and Hall, London.
[38] Swenson, E.S., Milisen, W.B. and Curatolo, W. Intestinal permeability enhancement: efficacy, acute local toxicity and reversibility. Pharm Res, 1997, 11:1132-1142.
[39] Xiao Yanyu, Song Yunmei, Chen Zhipeng, Ping Qineng. The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats. lnt J Pharm,2006 (307): 77-82.
[40] Shinoda K, Friberg S. Adv Colloid Interface Sci. 1975, 4:281
[41] Malcolmson C, Lawrence M.J. A comparison of the incorporation of steroids into nonionic micellar and microemulsion systems [J]. J Phann Pharmacol. 1993, 45(2): 141—143
[42] Warisnoicharoen W, Lansley AB, Lawrence MJ. Nonionic oil-in-water micro- emulsions: the effect of oil type on phase behaviour[J]. Int J Pharm, 2000, 198:7-27
[43] 赵振国编著，界面化学基础，化学工业出版社，2003
[44] Pouton. Formulation of self-emulsifying drug delivery systems. Adv. Drug Deltv. Rev. 1997(25): 27-58.
[45] Bachynsky MO, Shah NH, Patel CI, et al. Factors affecting the efficiency of a self- emulsifying oral delivery system. Drug Development and Industrial Pharmacy, 1997; 23(8):809
[46] Khoo S M, Humberstone, A J, Porter C J H, et al. Formulations design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm, 1998,167: 155-164.
[47] Halbant L, Barbe c, Pozo A D. An investigation into physical and chemical properties of semi-solid self-emulsifying systems for hard gelatin capsules. Int J Pharm. 1996, 130:203-212.
[48] Pouton CW, Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. Int J Pharm,1985,27:335-348.
[49] Gershanik T ,Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharma Biopharmac,2000,50(1):179
[50] Trotta M. Affluence of phase transformation on indomethacin release from microemulsious [J] .J Control Release, 1999,(60):399-405.
[51] 陆彬．药物新剂型与新技术[M]．北京：人民卫生出版社，1998
[52] 何军，奉建芳，张乐乐，等．水飞蓟素固体脂质纳米粒体内药代动力学研究[J]．中成药，2005，27(1)：19～21．
[53] 江波，印春华．水飞蓟素磷脂复合物家兔体内生物利用度的研究[J]．中国医药工业杂志，2002，33(12)：598～600．
[54] 魏数礼主编，生物药剂学与药物动力学[M]．人民卫生出版社，1997．
[55] 黄圣凯，韩可勤．生物等效性评价的统计方法[J]．中国药学杂志，1993，9(1)：43-46
[56] 梁文权．生物药剂学与药物动力学[M]．北京：人民卫生出版社，2000：174—194