固体自微乳化给药系统的研究
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摘要
自微乳化给药系统(SMEDDS)能够显著提高水难溶性药物的口服生物利用度,是很有发展前途的载药系统,近年来得到越来越多的关注。但它一般是液体剂型,封装在软胶囊或硬胶囊中,因而带来生产过程复杂、成本较高、制剂成分与胶囊壳的相容性、长期储存中可能发生胶囊泄露以及剂型单一等缺点。为克服这些缺点,并整合SMEDDS和固体制剂的双重优点,固体自微乳化给药系统(S-SMEDDS)的研究开始萌芽。
S-SMEDDS的固体载体、制备方法、微观结构、释药机理和体内行为是需要研究的重要问题,其中S-SMEDDS是否能保持液体SMEDDS(L-SMEDDS)原有的体内外优点是最关键的问题。围绕以上问题,本文以水溶性辅料为固体载体,采用喷雾干燥法和离子凝胶化法制备了具有不同释药特征的S-SMEDDS,完成的主要研究工作有:
(1)首先研究水溶性辅料对L-SMEDDS的微观结构和载药能力的影响。以尼莫地平为模型药,制备和表征L-SMEDDS;采用电导率法和体外分散试验来研究右旋糖酐40、麦芽糖糊精、阿拉伯胶、聚乙烯吡咯烷酮K30和羟丙甲基纤维素(HPMC)等各种水溶性辅料的影响。结果表明这些水溶性辅料对L-SMEDDS的微观结构没有明显影响,却能显著增强L-SMEDDS的载药能力,抑制体外分散时药物的沉淀,可以作为制备S-SMEDDS的固体载体。
(2)速释S-SMEDDS的体内外研究。选择多种水溶性辅料作为固体载体,采用喷雾干燥法制备尼莫地平速释S-SMEDDS。通过透射电镜(TEM)、扫描电镜(SEM)、差热扫描量热分析(DSC)、粉末X-射线衍射分析(PXRD)和体外溶出试验研究固体载体对S-SMEDDS外观、重分散性、药物的物理状态等性质的影响。其中以右旋糖酐40为载体的S-SMEDDS,由分离良好的球形颗粒组成,药物以无定形或分子分散状态存在,水重分散后形成粒径小于50nm的微乳,体外溶出快速,显著高于市售片剂。兔口服生物利用度研究结果显示,在禁食和进食两种条件下,以右旋糖酐40为载体的S-SMEDDS的AUC0→12h分别是片剂的2.5倍和2.6倍,Cmax分别是片剂的6.6倍和5.8倍;但和L-SMEDDS比较,没有统计学上的显著性差异。以上结果说明S-SMEDDS能够保持L-SMEDDS的体内外优点。
(3)在速释S-SMEDDS体内外研究的基础上,进一步研究缓释S-SMEDDS。以高粘度级别的HPMC为固体载体,采用喷雾干燥法制备尼莫地平的自微乳化缓释颗粒,并同法制备相应的非自微乳化缓释颗粒作为参比制剂。TEM结果显示缓释S-SMEDDS遇水重分散后能形成粒径小于100nm的微乳;在SEM、DSC和PXRD分析结果基础上,提出缓释自微乳化HPMC颗粒和非自微乳化HPMC颗粒的微观结构假设,推测两者的结构差异可能会导致体外释药行为的改变。应用零级动力学模型、Hixson-Crowell模型、Higuchi模型和经验公式power law对两类制剂的体外释药数据进行模型拟合。结果表明两者释药机制不同,扩散机制在缓释S-SMEDDS的体外释药行为中起到相对更加重要的作用。这也验证了HPMC颗粒结构假设的合理性。
(4)为扩大SMEDSS的药物适用范围,对肠溶S-SMEDDS进行了初步研究。以吲哚美辛为模型药,采用离子凝胶化法制备肠溶自微乳化胶珠。重分散性试验结果表明肠溶自微乳化胶珠能在人工肠液中形成粒径小于150nm的微乳;SEM结果显示胶珠为表面致密、内部疏松的球形;DSC和PXRD分析结果表明药物在胶珠中为无定形状态。采用相似因子法和模型拟合对体外释药行为的处方影响因素和释药机理进行初步探讨,结果显示肠溶自微乳化胶珠的体外释药行为主要受液体自微乳与海藻酸钠的质量比、海藻酸钠浓度的影响,载体的溶蚀可能是主要的释药机制。
本文研究建立了具有不同释药特征的S-SMEDDS,能够保持L-SMEDDS的体内外优点,既丰富了SMEDDS的固体剂型,又扩大了药物适用范围,为S-SMEDDS的研究发展提供了新思路、新方法。在本文对S-SMEDSS的固体载体、微观结构、释药机理和体内行为的初步研究基础上,有必要通过进一步研究固体载体的分子量、粘度等性质的影响和S-SMEDDSS的体内吸收行为,建立新的释药动力学模型和体内外相关性,为指导S-SMEDDS的处方筛选和体内外评价提供基础。
In recent years, increasing attention has been focused on self-microemulsifying drug delivery system (SMEDDS), which has shown a great success in improving oral bioavailability of poorly soluble drugs and becomes a potential drug delivery system. Conventionally, SMEDDS is prepared as liquid dosage forms that can be encapsulated in hard or soft gelatin capsules, which has some shortcomings especially in the manufacturing process, leading to high production costs. Moreover, these dosage forms may be prone to leakage during shelf-life, and incompatibility problems with the shells of the soft gelatin are usual. In order to overcome the shortcomings of liquid formulations and to combine the advantages of SMEDDS with those of solid dosage forms, studies on solid self-microemulsifying drug delivery system (S-SMEDDS) have begun.
Solid carriers, preparation method, microstructure, drug release mechanism and in vivo absorption are important aspects of S-SMEDDS. It is the key issue that whether S-SMEDDS could maintain the in vitro and in vivo characteristics of L-SMEDDS. In this dissertation, S-SMEDDS with various drug release patterns were prepared by spray-drying or ion gelation, using water soluble excipients as solid carriers.
(1) L-SMEDDS was prepared and characterized using nimodipine as a model drug. The effects of various water soluble carriers on internal microstructure and solubilization of L-SMEDDS were investigated by conductivity and in vitro dispersion. The results showed that water soluble carriers did not seem to have a remarkable effect on microstructure of L-SMEDDS. However, the water soluble carriers had increased solubilization of nimodipine in the self-microemulsifying system and decreased drug precipitation when dispersed in aqueous media.
(2) S-SMEDDS of nimodipine were prepared by spray drying with water-soluble solid carriers. The effects of various water soluble carriers on the properties of S-SMEDDS were investigated by TEM, SEM, DSC, PXRD and in vitro dissolution. The results shown that solid carriers, especially the molecular weight of carrier, had an obvious influence on the surface morphologies of S-SMEDDS, reconstitution of microemulsion and the physical state of nimodipine in S-SMEDDS. The S-SMEDDS with dextran 40 as solid carrier, consisted of well-separated spherical particles and could form microemulsion with droplet size less than 50nm followed by dilution in water. Nimodipine in the S-SMEDDS was in the amorphous or molecular dispersion state. The S-SMEDDS had a faster in vitro release rate than the conventional tablet.
(3) A comparative bioavailability study was performed in rabbits with the solid SMEDDS, the liquid SMEDDS and a conventional tablet of nimodipine. In fasted and fed conditions, the areas under the curves (AUC0→12h) for the S-SMEDDS were 2.5 and 2.6 times greater, respectively, and the mean values of Cmax for the S-SMEDDS were 6.6 and 5.5 times greater, respectively, compared to the conventional tablet. However, both AUC0→12h and Cmax for the S-SMEDDS and L-SMEDDS were not statistically different (p > 0.05). It suggested that the S-SMEDDS maintained the absorption characteristics of the L-SMEDDS.
(4) HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system. TEM micrograph revealed that the reconstituted microemulsions with droplet size less than 100nm were released from the S-SMEDDS when exposed to aqueous media. Based on investigation by TEM, SEM, DSC and X-ray powder diffraction, differences were found in the particle structure between both types of formulations and potential structures were supposed. Dissolution data of both formulations were fitted to various mathematical models in order to describe the release kinetics. It was found that diffusion was the comparatively important drug release mechanism of the controlled release S-SMEDDS, differed from the controlled release formulation without self-microemulsifying ingredients. The differences in the particle structure could be an explanation for the difference in drug release mechanism.
(5) Self-microemulsifying enteric gel beads (SMEGB) were prepared by ion gelation, using indomethacin as a model drug. Reconstitution test results showed that the reconstituted microemulsion with droplet size less than 150nm was released from SMEGB when exposed to aqueous media. SEM micrographs illustrated that the gel bead showed a regular spherical shape, with more compact surface and looser internal structure. Indomethacin in the SMEGB was in the amorphous or molecular dispersion state. The influence factors and drug release mechanisms were preliminarily investigated by the similarity factor and model fitting. It was found that the main influence factors were the mass ratio of L-SMEDDS/sodium alginate and the concentration of sodium alginate. It was possible that erosion of carrier was the main drug release mechanisms of SMEGB.
In present work, S-SMEDDS with various drug release patterns were successfully prepared, maintaining the in vitro and in vivo characteristics of L-SMEDDS. Effects of water soluble carriers, changes of microstructure, drug release mechanisms and in vivo absorptions of S-SMEDDS were also preliminarily investigated. In the future, further investigations are necessary to establish new model of drug release and in vitro and in vivo correlation, providing an important base on S-SMEDDS formulation strategy and in vitro and in vivo assessment.
S-SMEDDS的固体载体、制备方法、微观结构、释药机理和体内行为是需要研究的重要问题,其中S-SMEDDS是否能保持液体SMEDDS(L-SMEDDS)原有的体内外优点是最关键的问题。围绕以上问题,本文以水溶性辅料为固体载体,采用喷雾干燥法和离子凝胶化法制备了具有不同释药特征的S-SMEDDS,完成的主要研究工作有:
(1)首先研究水溶性辅料对L-SMEDDS的微观结构和载药能力的影响。以尼莫地平为模型药,制备和表征L-SMEDDS;采用电导率法和体外分散试验来研究右旋糖酐40、麦芽糖糊精、阿拉伯胶、聚乙烯吡咯烷酮K30和羟丙甲基纤维素(HPMC)等各种水溶性辅料的影响。结果表明这些水溶性辅料对L-SMEDDS的微观结构没有明显影响,却能显著增强L-SMEDDS的载药能力,抑制体外分散时药物的沉淀,可以作为制备S-SMEDDS的固体载体。
(2)速释S-SMEDDS的体内外研究。选择多种水溶性辅料作为固体载体,采用喷雾干燥法制备尼莫地平速释S-SMEDDS。通过透射电镜(TEM)、扫描电镜(SEM)、差热扫描量热分析(DSC)、粉末X-射线衍射分析(PXRD)和体外溶出试验研究固体载体对S-SMEDDS外观、重分散性、药物的物理状态等性质的影响。其中以右旋糖酐40为载体的S-SMEDDS,由分离良好的球形颗粒组成,药物以无定形或分子分散状态存在,水重分散后形成粒径小于50nm的微乳,体外溶出快速,显著高于市售片剂。兔口服生物利用度研究结果显示,在禁食和进食两种条件下,以右旋糖酐40为载体的S-SMEDDS的AUC0→12h分别是片剂的2.5倍和2.6倍,Cmax分别是片剂的6.6倍和5.8倍;但和L-SMEDDS比较,没有统计学上的显著性差异。以上结果说明S-SMEDDS能够保持L-SMEDDS的体内外优点。
(3)在速释S-SMEDDS体内外研究的基础上,进一步研究缓释S-SMEDDS。以高粘度级别的HPMC为固体载体,采用喷雾干燥法制备尼莫地平的自微乳化缓释颗粒,并同法制备相应的非自微乳化缓释颗粒作为参比制剂。TEM结果显示缓释S-SMEDDS遇水重分散后能形成粒径小于100nm的微乳;在SEM、DSC和PXRD分析结果基础上,提出缓释自微乳化HPMC颗粒和非自微乳化HPMC颗粒的微观结构假设,推测两者的结构差异可能会导致体外释药行为的改变。应用零级动力学模型、Hixson-Crowell模型、Higuchi模型和经验公式power law对两类制剂的体外释药数据进行模型拟合。结果表明两者释药机制不同,扩散机制在缓释S-SMEDDS的体外释药行为中起到相对更加重要的作用。这也验证了HPMC颗粒结构假设的合理性。
(4)为扩大SMEDSS的药物适用范围,对肠溶S-SMEDDS进行了初步研究。以吲哚美辛为模型药,采用离子凝胶化法制备肠溶自微乳化胶珠。重分散性试验结果表明肠溶自微乳化胶珠能在人工肠液中形成粒径小于150nm的微乳;SEM结果显示胶珠为表面致密、内部疏松的球形;DSC和PXRD分析结果表明药物在胶珠中为无定形状态。采用相似因子法和模型拟合对体外释药行为的处方影响因素和释药机理进行初步探讨,结果显示肠溶自微乳化胶珠的体外释药行为主要受液体自微乳与海藻酸钠的质量比、海藻酸钠浓度的影响,载体的溶蚀可能是主要的释药机制。
本文研究建立了具有不同释药特征的S-SMEDDS,能够保持L-SMEDDS的体内外优点,既丰富了SMEDDS的固体剂型,又扩大了药物适用范围,为S-SMEDDS的研究发展提供了新思路、新方法。在本文对S-SMEDSS的固体载体、微观结构、释药机理和体内行为的初步研究基础上,有必要通过进一步研究固体载体的分子量、粘度等性质的影响和S-SMEDDSS的体内吸收行为,建立新的释药动力学模型和体内外相关性,为指导S-SMEDDS的处方筛选和体内外评价提供基础。
In recent years, increasing attention has been focused on self-microemulsifying drug delivery system (SMEDDS), which has shown a great success in improving oral bioavailability of poorly soluble drugs and becomes a potential drug delivery system. Conventionally, SMEDDS is prepared as liquid dosage forms that can be encapsulated in hard or soft gelatin capsules, which has some shortcomings especially in the manufacturing process, leading to high production costs. Moreover, these dosage forms may be prone to leakage during shelf-life, and incompatibility problems with the shells of the soft gelatin are usual. In order to overcome the shortcomings of liquid formulations and to combine the advantages of SMEDDS with those of solid dosage forms, studies on solid self-microemulsifying drug delivery system (S-SMEDDS) have begun.
Solid carriers, preparation method, microstructure, drug release mechanism and in vivo absorption are important aspects of S-SMEDDS. It is the key issue that whether S-SMEDDS could maintain the in vitro and in vivo characteristics of L-SMEDDS. In this dissertation, S-SMEDDS with various drug release patterns were prepared by spray-drying or ion gelation, using water soluble excipients as solid carriers.
(1) L-SMEDDS was prepared and characterized using nimodipine as a model drug. The effects of various water soluble carriers on internal microstructure and solubilization of L-SMEDDS were investigated by conductivity and in vitro dispersion. The results showed that water soluble carriers did not seem to have a remarkable effect on microstructure of L-SMEDDS. However, the water soluble carriers had increased solubilization of nimodipine in the self-microemulsifying system and decreased drug precipitation when dispersed in aqueous media.
(2) S-SMEDDS of nimodipine were prepared by spray drying with water-soluble solid carriers. The effects of various water soluble carriers on the properties of S-SMEDDS were investigated by TEM, SEM, DSC, PXRD and in vitro dissolution. The results shown that solid carriers, especially the molecular weight of carrier, had an obvious influence on the surface morphologies of S-SMEDDS, reconstitution of microemulsion and the physical state of nimodipine in S-SMEDDS. The S-SMEDDS with dextran 40 as solid carrier, consisted of well-separated spherical particles and could form microemulsion with droplet size less than 50nm followed by dilution in water. Nimodipine in the S-SMEDDS was in the amorphous or molecular dispersion state. The S-SMEDDS had a faster in vitro release rate than the conventional tablet.
(3) A comparative bioavailability study was performed in rabbits with the solid SMEDDS, the liquid SMEDDS and a conventional tablet of nimodipine. In fasted and fed conditions, the areas under the curves (AUC0→12h) for the S-SMEDDS were 2.5 and 2.6 times greater, respectively, and the mean values of Cmax for the S-SMEDDS were 6.6 and 5.5 times greater, respectively, compared to the conventional tablet. However, both AUC0→12h and Cmax for the S-SMEDDS and L-SMEDDS were not statistically different (p > 0.05). It suggested that the S-SMEDDS maintained the absorption characteristics of the L-SMEDDS.
(4) HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system. TEM micrograph revealed that the reconstituted microemulsions with droplet size less than 100nm were released from the S-SMEDDS when exposed to aqueous media. Based on investigation by TEM, SEM, DSC and X-ray powder diffraction, differences were found in the particle structure between both types of formulations and potential structures were supposed. Dissolution data of both formulations were fitted to various mathematical models in order to describe the release kinetics. It was found that diffusion was the comparatively important drug release mechanism of the controlled release S-SMEDDS, differed from the controlled release formulation without self-microemulsifying ingredients. The differences in the particle structure could be an explanation for the difference in drug release mechanism.
(5) Self-microemulsifying enteric gel beads (SMEGB) were prepared by ion gelation, using indomethacin as a model drug. Reconstitution test results showed that the reconstituted microemulsion with droplet size less than 150nm was released from SMEGB when exposed to aqueous media. SEM micrographs illustrated that the gel bead showed a regular spherical shape, with more compact surface and looser internal structure. Indomethacin in the SMEGB was in the amorphous or molecular dispersion state. The influence factors and drug release mechanisms were preliminarily investigated by the similarity factor and model fitting. It was found that the main influence factors were the mass ratio of L-SMEDDS/sodium alginate and the concentration of sodium alginate. It was possible that erosion of carrier was the main drug release mechanisms of SMEGB.
In present work, S-SMEDDS with various drug release patterns were successfully prepared, maintaining the in vitro and in vivo characteristics of L-SMEDDS. Effects of water soluble carriers, changes of microstructure, drug release mechanisms and in vivo absorptions of S-SMEDDS were also preliminarily investigated. In the future, further investigations are necessary to establish new model of drug release and in vitro and in vivo correlation, providing an important base on S-SMEDDS formulation strategy and in vitro and in vivo assessment.
引文
[1] Amidon GL, Shah VP, Crison JR. A theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research, 1995, 12: 413-420.
[2] Pouton, CW. Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. European Journal of Pharmaceutical Sciences, 2006, 29(3-4): 278-287.
[3] Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutical classification system. European Journal of Pharmaceutics and Biopharmaceutics, 2004, 58: 265-278.
[4] Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomedicine & Pharmacotherapy, 2004, 58(3): 173-182.
[5] Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. Journal of Pharmaceutical Sciences, 1999, 88(10): 1058-1066.
[6] Rasenack N, Muller BW. Micron-size drug particles: common and novel micronization techniques. Pharmaceutical development and technology, 2004, 9(1): 1-13.
[7] Veiga F, Teixeira F. Oral bioavailability and hypoglycemic activity of tolbutamide/ cyclodextrin inclusion complexes. International Journal of Pharmaceutics, 2000, 202: 165-171.
[8] Patravale VB, Kulkarni RM. Nanosuspensions: a promising drug delivery strategy. J. Pharm. Pharmacol, 2004, 56: 827-840.
[9] Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems. European Journal of Pharmaceutical Sciences, 2000, 11(Supplement 2): S93-S98.
[10] Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies. Advanced Drug Delivery Reviews, 2008, 60(6): 625-637.
[11] Khoo SM, Humberstone AJ, Porter CJH. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. International Journal of Pharmaceutics, 1998, 167(1-2): 155-164.
[12] Holm R, Porter CJH, Edwards GA. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. European Journal of Pharmaceutical Sciences, 2003, 20: 91-97.
[13] Kang BK, Lee JS, Chon SK. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. International Journal of Pharmaceutics, 2004, 274(1-2): 65-73.
[14] Wu W, Wang Y, Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 63(3): 288-294.
[15] Shah NH, Carvajal MT, Patel CI. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. International Journal of Pharmaceutics, 1994, 106(1): 15-23.
[16] Zhang P, Liu Y, Feng N. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin. International Journal of Pharmaceutics, 2008, 355(1-2): 269-276.
[17] Borhade V, Nair H, Hegde D. Design and Evaluation of Self-MicroemulsifyingDrug Delivery System (SMEDDS) of Tacrolimus. AAPS PharmSciTech, 2008, 9(1): 13-21.
[18] Pouton CW. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. International Journal of Pharmaceutics, 1985, 27(2-3): 335-348.
[19] Constantinides PP. Lipid Microemulsions for Improving Drug Dissolution and Oral Absorption: Physical and Biopharmaceutical Aspects. Pharmaceutical Research, 1995, 12(11): 1561-1572.
[20] Yang S, Gursoy RN, Lambert G. Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors. Pharmaceutical Research, 2004, 21(2): 261-270.
[21] Kommuru TR, Gurley B, Khan MA. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. International Journal of Pharmaceutics, 2001, 212(2): 233-246.
[22] Pouton CW. Formulation of self-emulsifying drug delivery systems. Advanced Drug Delivery Reviews, 1997, 25(1): 47-58.
[23] Gershanik T, Benita S. Positively charged self-emulsifying oil formulation for improving oral bioavailability of progesterone. Pharmaceutical development and technology, 1996, 1(2): 147-157.
[24] Gershanik T, Benzeno S, Benita S. Interaction of a Self-Emulsifying Lipid Drug Delivery System with the Everted Rat Intestinal Mucosa as a Function of Droplet Size and Surface Charge. Pharmaceutical Research, 1998, 15(6): 863-869.
[25] Sha X, Yan G, Wu Y. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. European Journal of Pharmaceutical Sciences, 2005, 24(5): 477-486.
[26] Magee GA, French J, Gibbon B. Bile salt/lecithin mixed micelles optimized for the solubilization of a poorly soluble steroid molecule using statistical experimental design. Drug development and industrial pharmacy, 2003, 29(4): 441-450.
[27] Wiedmann TS, Kamel L. Examination of the solubilization of drugs by bile salt micelles. Journal of pharmaceutical sciences, 2002, 91(8): 1743-1764.
[28] Cai X, Grant DJ, Wiedmann TS. Analysis of the solubilization of steroids by bile salt micelles. Journal of pharmaceutical sciences, 1997, 86(3): 372-377.
[29] Mithani SD, Bakatselou V, TenHoor CN. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharmaceutical research, 1996, 13(1): 163-167.
[30] Zangenberg NH, Mullertz A, Kristensen HG. A dynamic in vitro lipolysis model II: Evaluation of the model. Eur J Pharm Sci, 2001, 14(3): 237-244.
[31] Zangenberg NH, Mullertz A, Kristensen HG. A dynamic in vitro lipolysis model I: Controlling the rate of lipolysis by continuous addition of calcium. Eur J Pharm Sci, 2001, 14(2): 115-122.
[32] Kaukonen AM, Boyd BJ, Charman WN. Drug solubilization behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in triglyceride lipids. Pharm Res, 2004, 21(2): 254-260.
[33] Kaukonen AM, Boyd BJ, Porter CJ. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res, 2004, 21(2): 245-253.
[34] Kossena GA, Charman WN, Boyd BJ. Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: a phase diagram approach. Journal of pharmaceutical sciences, 2004, 93(2): 332-348.
[35] Brogard M, Troedsson E, Thuresson K. A new standardized lipolysis approach for characterization of emulsions and dispersions. Journal of Colloid and Interface Science, 2007, 308(2): 500-507.
[36] Yu LX, Lipka E, Crison JR. Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Advanced drug delivery reviews, 1996, 19(3): 359-376.
[37] MacGregor KJ, Embletona JK, Lacy JE. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Advanced drug delivery reviews, 1997, 25(1): 33-46.
[38] Nicolaides E, Galia E, Efthymiopoulos C. Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res, 1999, 16(12): 1876-1882.
[39] Kobayashi M, Sada N, Sugawara M. Development of a new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract. International journal of pharmaceutics, 2001, 221(1-2): 87-94.
[40] Porter CJ, Kaukonen AM, Taillardat-Bertschinger A. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. Journal of pharmaceutical sciences, 2004, 93(5): 1110-1121.
[41] Dahan A, Hoffman A. Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm Res, 2006, 23(9): 2165-2174.
[42] Fatouros DG, Nielsen FS, Douroumis D. In vitro-in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks. European Journal of Pharmaceutics and Biopharmaceutics, 2008, In Press, Corrected Proof.
[43] Patel D, Sawant KK. Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS). Drug development and industrial pharmacy, 2007, 33(12): 1318-1326.
[44] Grove M, Mulertz A, Nielsen JL. Bioavailability of seocalcitol II: Development and characterization of self-microemulsifying drug delivery systems (SMEDDS) fororal administration containing medium and long chain triglycerides. European Journal of Pharmaceutical Sciences, 2006, 28(3): 233-242.
[45] Wei L, Sun P, Nie S. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug development and industrial pharmacy, 2005, 31(8): 785-794.
[46] Holm R, Porter CJH, Edwards GA. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. European Journal of Pharmaceutical Sciences, 2003, 20(1): 91-97.
[47] Swenson ES, Curatolo WJ. Means to enhance penetration. Advanced Drug Delivery Reviews, 1992, 8: 39-92.
[48] Ueda K, Yoshida A, Amachi T. Recent progress in P-glycoprotein research. Anticancer Drug Design, 1999, 14: 115-121.
[49] Hunter J, Hirst BH. Intestinal secretion of drugs: The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Advanced Drug Delivery Reviews, 1997, 25: 129-157.
[50] Woo JS, Lee CH, Shim CK, Hwang SC. Enhanced oral bioavailability of paclitaxel by co-administration of the P-glycoprotein inhibitor KR30031. Pharmaceutical Research, 2003, 20: 24-30.
[51] Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharmaceutical Research, 1999, 16: 1550-1556.
[52] Chervinsky DS, Brecher BL, Hoelcle MJ. Cremophor EL enhances taxol efficacy in a multidrug resistant C1300 neuroblastoma cell line. Anticancer Research, 1993, 13: 93-96.
[53] Constantinides PP, Wasan KM. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: In vitro/In vivocase studies. Journal of pharmaceutical sciences, 2007, 96(2): 235-248.
[54] Hauss DJ, Fogal SE, Ficorilli JV, Price CA, Roy T, Jayaraj AA, Keirns JJ. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. Journal of Pharmaceutical Science, 1998, 87(2): 164-169.
[55] O'Driscoll CM. Lipid-based formulations for intestinal lymphatic delivery. European Journal of Pharmaceutical Sciences, 2002, 15(5): 405-415.
[56] Porter CJH, Pouton CW, Cuine JF. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Advanced Drug Delivery Reviews, 2008, 60(6): 673-691.
[57] Newton M, Petersson J, Podczeck F, Clarke A, Booth S. The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture. Journal of pharmaceutical sciences, 2001, 90(8): 987-995.
[58] Franceschinis E, Voinovich D, Grassi M. Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption. International Journal of Pharmaceutics, 2005, 291(1-2): 87-97.
[59] Abdalla A, Mader K. Preparation and characterization of a self-emulsifying pellet formulation. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 66(2): 220-226.
[60] Cannon JB. Oral solid dosage forms of lipid-based drug delivery systems. Am Pharmaceut Rev, 2005, 8: 108-115.
[61] Tuleu C, Newton M, Rose J. Comparative bioavailability study in dogs of a self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesterone. Journal of pharmaceutical sciences, 2004, 93(6): 1495-1502.
[62] Nazzal S, Khan MA. Controlled release of a self-emulsifying formulation from atablet dosage form: Stability assessment and optimization of some processing parameters. International Journal of Pharmaceutics, 2006, 315(1-2): 110-121.
[63] Newton JM, Pinto MR, Podczeck F. The preparation of pellets containing a surfactant or a mixture of mono- and di-gylcerides by extrusion/spheronization. European Journal of Pharmaceutical Sciences, 2007, 30(3-4): 333-342.
[64] Iosio T, Voinovich D, Grassi M. Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: Influence of formulation variables and preliminary study on the in vivo absorption. Eur J Pharm Biopharm, 2008, In Press, Corrected Proof.
[65] Nazzal S, Nutan M, Palamakula A. Optimization of a self-nanoemulsified tablet dosage form of Ubiquinone using response surface methodology: effect of formulation ingredients. International Journal of Pharmaceutics, 2002, 240(1-2): 103-114.
[66] Attama AA, Nzekwe IT, Nnamani PO. The use of solid self-emulsifying systems in the delivery of diclofenac. International Journal of Pharmaceutics, 2003, 262(1-2): 23-28.
[67] Patil P, Paradkar A. Porous polystyrene beads as carriers for self-emulsifying system containing loratadine. AAPS PharmSciTech, 2006, 7(1): E199-E205.
[68] Kim CK, Shin HJ, Yang SG, Kim JH, Oh YK. Once-a-Day Oral Dosing Regimen of Cyclosporin A: Combined Therapy of Cyclosporin A Premicroemulsion Concentrates and Enteric Coated Solid-State Premicroemulsion Concentrates. Pharmaceutical Research, 2001, 18(4): 454-459.
[69] Serratoni M, Newton M, Booth S. Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 65(1): 94-98.
[70] Podlogar F, Bester RM, Gasperlin M. The effect of internal structure of selected water-Tween 40(R)-Imwitor 308(R)-IPM microemulsions on ketoprofene release.International Journal of Pharmaceutics, 2005, 302(1-2): 68-77.
[71] Garti N, Avrahami M, Aserin A. Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structural transitions with progressive aqueous dilution. Journal of Colloid and Interface Science, 2006, 299(1): 352-365.
[72] Podlogar F, Gasperlin M, Tomsic M. Structural characterization of water-Tween 40(R)/Imwitor 308(R)-isopropyl myristate microemulsions using different experimental methods. International Journal of Pharmaceutics, 2004, 276(1-2): 115-128.
[73] Fanun M. Structure probing of water/mixed nonionic surfactants/caprylic-capric triglyceride system using conductivity and NMR. Journal of Molecular Liquids, 2007, 133(1-3): 22-27.
[74] Fanun M. Conductivity, viscosity, NMR and diclofenac solubilization capacity studies of mixed nonionic surfactants microemulsions. Journal of Molecular Liquids, 2007, 135(1-3): 5-13.
[75] Clarkson MT. Electrical conductivity and permittivity measurements near the percolation transition in a microemulsion II: Interpretation. Physical review, 1988, 37(6): 2079-2090.
[76] Clarkson MT, Smedley SI. Electrical conductivity and permittivity measurements near the percolation transition in a microemulsion I: Experiment. Physical review, 1988, 37(6): 2070-2078.
[77] Dijk MA. Dielectric study of percolation phenomena in a microemulsion. Physical review letters, 1985, 55(9): 1003-1005.
[78] Porter CJ, Charman WN. In vitro assessment of oral lipid based formulations. Advanced drug delivery reviews, 2001, 50(Suppl 1): S127-S147.
[79] Langley MS, Sorkin EM. Nimodipine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic. Drugs, 1989, 37: 669-699.
[80] Grunenberg A, Keil B, Henck JO. Polymorphism in binary mixture, as exemplifiedby nimodipine. International Journal of Pharmaceutics, 1995, 118: 11-21.
[81] Tu QR, Zhu JB. Study on formulation of nimodipine self-microemulsifying drug delivery system. Chin. Pharm. J. 2005, 40: 43-46.
[82] Urbanetz NA, Lippold BC. Solid dispersions of nimodipine and polyethylene glycol 2000: dissolution properties and physico-chemical characterisation. European Journal of Pharmaceutics and Biopharmaceutics, 2005, 59: 107-118.
[83] Christensen KL, Pedersen GP, Kristensen HG. Preparation of redispersible dry emulsions by spray drying. International Journal of Pharmaceutics, 2001, 212: 187-194.
[84] Dollo G, Corre PL, Guérin A, Chevanne F, Burgot JL, Leverge R. Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs. European Journal of Pharmaceutical Sciences, 2003, 19: 273-280.
[85] He ZG, Zhong DF, Chen XY, Liu XH, Tang X, Zhao LM. Development of a dissolution medium for nimodipine tablets based on bioavailability evaluation. European Journal of Pharmaceutical Sciences, 2004, 21: 487-491.
[86] Christensen KL, Pedersen GP, Kristensen HG. Physical stability of redispersible dry emulsions containing amorphous sucrose. European Journal of Pharmaceutics and Biopharmaceutics, 2002, 53: 147-153.
[87] Swanepoel E, Liebenberg W, Devarakonda B, Villiers MM. Developing a discriminating dissolution test for three mebendazole poly-morphs based on solubility defference. Pharmazie, 2003, 58: 117-121.
[88] Colombo P. Swelling-controlled release in hydrogel matrices for oral route. Advanced Drug Delivery Reviews, 1993, 11: 37-57.
[89] Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in oral drug delivery. J. Pharm. Pharmacol, 2005, 57: 533-546.
[90] Costa P, Sousa LJM. Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences, 2001, 13: 123-133.
[91] Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Advanced Drug Delivery Reviews, 2001, 48: 139-157.
[92] Panomsuk SP, Hatanaka T, Aiba T. A study of the hydrophilic cellulose matrix: effect of indomethacin and a water soluble additive on swelling properties. International Journal of Pharmaceutics, 1995, 126: 147-153.
[93] Campos-Aldrete ME, Villafuerte-Robles L. Influence of the viscosity grade and the particle size of HPMC on metronidazole release from matrix tablets. European Journal of Pharmaceutics and Biopharmaceutics, 1997, 43: 173-178.
[94] Langer R, Peppas NA. Chemical and physical structure of polymers as carriers for controlled release of bioactive agents: a review. Rev. Macromol. Chem. Phys, 1983, 23: 61-126.
[95] Ford JL, Rubinstein MH, McCaul F. Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets. International Journal of Pharmaceutics, 1987, 40: 223-234.
[96] Tahara K, Yamamoto K, Nishihata T. Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained release tablets. International Journal of Pharmaceutics, 1996, 133: 17-27.
[97] Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Advanced Drug Delivery Reviews, 2001, 48: 139-157.
[98] Kim JY, Ku YS. Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats. International Journal of Pharmaceutics, 2000, 194(1): 81-89.
[99]沙先谊,陈小飞,李婵. 9-硝基喜树碱自微乳化给药系统研究.中国医药工业杂志, 2004, 35(8): 469-472.
[2] Pouton, CW. Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. European Journal of Pharmaceutical Sciences, 2006, 29(3-4): 278-287.
[3] Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutical classification system. European Journal of Pharmaceutics and Biopharmaceutics, 2004, 58: 265-278.
[4] Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomedicine & Pharmacotherapy, 2004, 58(3): 173-182.
[5] Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. Journal of Pharmaceutical Sciences, 1999, 88(10): 1058-1066.
[6] Rasenack N, Muller BW. Micron-size drug particles: common and novel micronization techniques. Pharmaceutical development and technology, 2004, 9(1): 1-13.
[7] Veiga F, Teixeira F. Oral bioavailability and hypoglycemic activity of tolbutamide/ cyclodextrin inclusion complexes. International Journal of Pharmaceutics, 2000, 202: 165-171.
[8] Patravale VB, Kulkarni RM. Nanosuspensions: a promising drug delivery strategy. J. Pharm. Pharmacol, 2004, 56: 827-840.
[9] Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems. European Journal of Pharmaceutical Sciences, 2000, 11(Supplement 2): S93-S98.
[10] Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies. Advanced Drug Delivery Reviews, 2008, 60(6): 625-637.
[11] Khoo SM, Humberstone AJ, Porter CJH. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. International Journal of Pharmaceutics, 1998, 167(1-2): 155-164.
[12] Holm R, Porter CJH, Edwards GA. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. European Journal of Pharmaceutical Sciences, 2003, 20: 91-97.
[13] Kang BK, Lee JS, Chon SK. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. International Journal of Pharmaceutics, 2004, 274(1-2): 65-73.
[14] Wu W, Wang Y, Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 63(3): 288-294.
[15] Shah NH, Carvajal MT, Patel CI. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. International Journal of Pharmaceutics, 1994, 106(1): 15-23.
[16] Zhang P, Liu Y, Feng N. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin. International Journal of Pharmaceutics, 2008, 355(1-2): 269-276.
[17] Borhade V, Nair H, Hegde D. Design and Evaluation of Self-MicroemulsifyingDrug Delivery System (SMEDDS) of Tacrolimus. AAPS PharmSciTech, 2008, 9(1): 13-21.
[18] Pouton CW. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. International Journal of Pharmaceutics, 1985, 27(2-3): 335-348.
[19] Constantinides PP. Lipid Microemulsions for Improving Drug Dissolution and Oral Absorption: Physical and Biopharmaceutical Aspects. Pharmaceutical Research, 1995, 12(11): 1561-1572.
[20] Yang S, Gursoy RN, Lambert G. Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors. Pharmaceutical Research, 2004, 21(2): 261-270.
[21] Kommuru TR, Gurley B, Khan MA. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. International Journal of Pharmaceutics, 2001, 212(2): 233-246.
[22] Pouton CW. Formulation of self-emulsifying drug delivery systems. Advanced Drug Delivery Reviews, 1997, 25(1): 47-58.
[23] Gershanik T, Benita S. Positively charged self-emulsifying oil formulation for improving oral bioavailability of progesterone. Pharmaceutical development and technology, 1996, 1(2): 147-157.
[24] Gershanik T, Benzeno S, Benita S. Interaction of a Self-Emulsifying Lipid Drug Delivery System with the Everted Rat Intestinal Mucosa as a Function of Droplet Size and Surface Charge. Pharmaceutical Research, 1998, 15(6): 863-869.
[25] Sha X, Yan G, Wu Y. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. European Journal of Pharmaceutical Sciences, 2005, 24(5): 477-486.
[26] Magee GA, French J, Gibbon B. Bile salt/lecithin mixed micelles optimized for the solubilization of a poorly soluble steroid molecule using statistical experimental design. Drug development and industrial pharmacy, 2003, 29(4): 441-450.
[27] Wiedmann TS, Kamel L. Examination of the solubilization of drugs by bile salt micelles. Journal of pharmaceutical sciences, 2002, 91(8): 1743-1764.
[28] Cai X, Grant DJ, Wiedmann TS. Analysis of the solubilization of steroids by bile salt micelles. Journal of pharmaceutical sciences, 1997, 86(3): 372-377.
[29] Mithani SD, Bakatselou V, TenHoor CN. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharmaceutical research, 1996, 13(1): 163-167.
[30] Zangenberg NH, Mullertz A, Kristensen HG. A dynamic in vitro lipolysis model II: Evaluation of the model. Eur J Pharm Sci, 2001, 14(3): 237-244.
[31] Zangenberg NH, Mullertz A, Kristensen HG. A dynamic in vitro lipolysis model I: Controlling the rate of lipolysis by continuous addition of calcium. Eur J Pharm Sci, 2001, 14(2): 115-122.
[32] Kaukonen AM, Boyd BJ, Charman WN. Drug solubilization behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in triglyceride lipids. Pharm Res, 2004, 21(2): 254-260.
[33] Kaukonen AM, Boyd BJ, Porter CJ. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res, 2004, 21(2): 245-253.
[34] Kossena GA, Charman WN, Boyd BJ. Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: a phase diagram approach. Journal of pharmaceutical sciences, 2004, 93(2): 332-348.
[35] Brogard M, Troedsson E, Thuresson K. A new standardized lipolysis approach for characterization of emulsions and dispersions. Journal of Colloid and Interface Science, 2007, 308(2): 500-507.
[36] Yu LX, Lipka E, Crison JR. Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Advanced drug delivery reviews, 1996, 19(3): 359-376.
[37] MacGregor KJ, Embletona JK, Lacy JE. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Advanced drug delivery reviews, 1997, 25(1): 33-46.
[38] Nicolaides E, Galia E, Efthymiopoulos C. Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res, 1999, 16(12): 1876-1882.
[39] Kobayashi M, Sada N, Sugawara M. Development of a new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract. International journal of pharmaceutics, 2001, 221(1-2): 87-94.
[40] Porter CJ, Kaukonen AM, Taillardat-Bertschinger A. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. Journal of pharmaceutical sciences, 2004, 93(5): 1110-1121.
[41] Dahan A, Hoffman A. Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm Res, 2006, 23(9): 2165-2174.
[42] Fatouros DG, Nielsen FS, Douroumis D. In vitro-in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks. European Journal of Pharmaceutics and Biopharmaceutics, 2008, In Press, Corrected Proof.
[43] Patel D, Sawant KK. Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS). Drug development and industrial pharmacy, 2007, 33(12): 1318-1326.
[44] Grove M, Mulertz A, Nielsen JL. Bioavailability of seocalcitol II: Development and characterization of self-microemulsifying drug delivery systems (SMEDDS) fororal administration containing medium and long chain triglycerides. European Journal of Pharmaceutical Sciences, 2006, 28(3): 233-242.
[45] Wei L, Sun P, Nie S. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug development and industrial pharmacy, 2005, 31(8): 785-794.
[46] Holm R, Porter CJH, Edwards GA. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. European Journal of Pharmaceutical Sciences, 2003, 20(1): 91-97.
[47] Swenson ES, Curatolo WJ. Means to enhance penetration. Advanced Drug Delivery Reviews, 1992, 8: 39-92.
[48] Ueda K, Yoshida A, Amachi T. Recent progress in P-glycoprotein research. Anticancer Drug Design, 1999, 14: 115-121.
[49] Hunter J, Hirst BH. Intestinal secretion of drugs: The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Advanced Drug Delivery Reviews, 1997, 25: 129-157.
[50] Woo JS, Lee CH, Shim CK, Hwang SC. Enhanced oral bioavailability of paclitaxel by co-administration of the P-glycoprotein inhibitor KR30031. Pharmaceutical Research, 2003, 20: 24-30.
[51] Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharmaceutical Research, 1999, 16: 1550-1556.
[52] Chervinsky DS, Brecher BL, Hoelcle MJ. Cremophor EL enhances taxol efficacy in a multidrug resistant C1300 neuroblastoma cell line. Anticancer Research, 1993, 13: 93-96.
[53] Constantinides PP, Wasan KM. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: In vitro/In vivocase studies. Journal of pharmaceutical sciences, 2007, 96(2): 235-248.
[54] Hauss DJ, Fogal SE, Ficorilli JV, Price CA, Roy T, Jayaraj AA, Keirns JJ. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. Journal of Pharmaceutical Science, 1998, 87(2): 164-169.
[55] O'Driscoll CM. Lipid-based formulations for intestinal lymphatic delivery. European Journal of Pharmaceutical Sciences, 2002, 15(5): 405-415.
[56] Porter CJH, Pouton CW, Cuine JF. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Advanced Drug Delivery Reviews, 2008, 60(6): 673-691.
[57] Newton M, Petersson J, Podczeck F, Clarke A, Booth S. The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture. Journal of pharmaceutical sciences, 2001, 90(8): 987-995.
[58] Franceschinis E, Voinovich D, Grassi M. Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption. International Journal of Pharmaceutics, 2005, 291(1-2): 87-97.
[59] Abdalla A, Mader K. Preparation and characterization of a self-emulsifying pellet formulation. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 66(2): 220-226.
[60] Cannon JB. Oral solid dosage forms of lipid-based drug delivery systems. Am Pharmaceut Rev, 2005, 8: 108-115.
[61] Tuleu C, Newton M, Rose J. Comparative bioavailability study in dogs of a self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesterone. Journal of pharmaceutical sciences, 2004, 93(6): 1495-1502.
[62] Nazzal S, Khan MA. Controlled release of a self-emulsifying formulation from atablet dosage form: Stability assessment and optimization of some processing parameters. International Journal of Pharmaceutics, 2006, 315(1-2): 110-121.
[63] Newton JM, Pinto MR, Podczeck F. The preparation of pellets containing a surfactant or a mixture of mono- and di-gylcerides by extrusion/spheronization. European Journal of Pharmaceutical Sciences, 2007, 30(3-4): 333-342.
[64] Iosio T, Voinovich D, Grassi M. Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: Influence of formulation variables and preliminary study on the in vivo absorption. Eur J Pharm Biopharm, 2008, In Press, Corrected Proof.
[65] Nazzal S, Nutan M, Palamakula A. Optimization of a self-nanoemulsified tablet dosage form of Ubiquinone using response surface methodology: effect of formulation ingredients. International Journal of Pharmaceutics, 2002, 240(1-2): 103-114.
[66] Attama AA, Nzekwe IT, Nnamani PO. The use of solid self-emulsifying systems in the delivery of diclofenac. International Journal of Pharmaceutics, 2003, 262(1-2): 23-28.
[67] Patil P, Paradkar A. Porous polystyrene beads as carriers for self-emulsifying system containing loratadine. AAPS PharmSciTech, 2006, 7(1): E199-E205.
[68] Kim CK, Shin HJ, Yang SG, Kim JH, Oh YK. Once-a-Day Oral Dosing Regimen of Cyclosporin A: Combined Therapy of Cyclosporin A Premicroemulsion Concentrates and Enteric Coated Solid-State Premicroemulsion Concentrates. Pharmaceutical Research, 2001, 18(4): 454-459.
[69] Serratoni M, Newton M, Booth S. Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 65(1): 94-98.
[70] Podlogar F, Bester RM, Gasperlin M. The effect of internal structure of selected water-Tween 40(R)-Imwitor 308(R)-IPM microemulsions on ketoprofene release.International Journal of Pharmaceutics, 2005, 302(1-2): 68-77.
[71] Garti N, Avrahami M, Aserin A. Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structural transitions with progressive aqueous dilution. Journal of Colloid and Interface Science, 2006, 299(1): 352-365.
[72] Podlogar F, Gasperlin M, Tomsic M. Structural characterization of water-Tween 40(R)/Imwitor 308(R)-isopropyl myristate microemulsions using different experimental methods. International Journal of Pharmaceutics, 2004, 276(1-2): 115-128.
[73] Fanun M. Structure probing of water/mixed nonionic surfactants/caprylic-capric triglyceride system using conductivity and NMR. Journal of Molecular Liquids, 2007, 133(1-3): 22-27.
[74] Fanun M. Conductivity, viscosity, NMR and diclofenac solubilization capacity studies of mixed nonionic surfactants microemulsions. Journal of Molecular Liquids, 2007, 135(1-3): 5-13.
[75] Clarkson MT. Electrical conductivity and permittivity measurements near the percolation transition in a microemulsion II: Interpretation. Physical review, 1988, 37(6): 2079-2090.
[76] Clarkson MT, Smedley SI. Electrical conductivity and permittivity measurements near the percolation transition in a microemulsion I: Experiment. Physical review, 1988, 37(6): 2070-2078.
[77] Dijk MA. Dielectric study of percolation phenomena in a microemulsion. Physical review letters, 1985, 55(9): 1003-1005.
[78] Porter CJ, Charman WN. In vitro assessment of oral lipid based formulations. Advanced drug delivery reviews, 2001, 50(Suppl 1): S127-S147.
[79] Langley MS, Sorkin EM. Nimodipine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic. Drugs, 1989, 37: 669-699.
[80] Grunenberg A, Keil B, Henck JO. Polymorphism in binary mixture, as exemplifiedby nimodipine. International Journal of Pharmaceutics, 1995, 118: 11-21.
[81] Tu QR, Zhu JB. Study on formulation of nimodipine self-microemulsifying drug delivery system. Chin. Pharm. J. 2005, 40: 43-46.
[82] Urbanetz NA, Lippold BC. Solid dispersions of nimodipine and polyethylene glycol 2000: dissolution properties and physico-chemical characterisation. European Journal of Pharmaceutics and Biopharmaceutics, 2005, 59: 107-118.
[83] Christensen KL, Pedersen GP, Kristensen HG. Preparation of redispersible dry emulsions by spray drying. International Journal of Pharmaceutics, 2001, 212: 187-194.
[84] Dollo G, Corre PL, Guérin A, Chevanne F, Burgot JL, Leverge R. Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs. European Journal of Pharmaceutical Sciences, 2003, 19: 273-280.
[85] He ZG, Zhong DF, Chen XY, Liu XH, Tang X, Zhao LM. Development of a dissolution medium for nimodipine tablets based on bioavailability evaluation. European Journal of Pharmaceutical Sciences, 2004, 21: 487-491.
[86] Christensen KL, Pedersen GP, Kristensen HG. Physical stability of redispersible dry emulsions containing amorphous sucrose. European Journal of Pharmaceutics and Biopharmaceutics, 2002, 53: 147-153.
[87] Swanepoel E, Liebenberg W, Devarakonda B, Villiers MM. Developing a discriminating dissolution test for three mebendazole poly-morphs based on solubility defference. Pharmazie, 2003, 58: 117-121.
[88] Colombo P. Swelling-controlled release in hydrogel matrices for oral route. Advanced Drug Delivery Reviews, 1993, 11: 37-57.
[89] Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in oral drug delivery. J. Pharm. Pharmacol, 2005, 57: 533-546.
[90] Costa P, Sousa LJM. Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences, 2001, 13: 123-133.
[91] Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Advanced Drug Delivery Reviews, 2001, 48: 139-157.
[92] Panomsuk SP, Hatanaka T, Aiba T. A study of the hydrophilic cellulose matrix: effect of indomethacin and a water soluble additive on swelling properties. International Journal of Pharmaceutics, 1995, 126: 147-153.
[93] Campos-Aldrete ME, Villafuerte-Robles L. Influence of the viscosity grade and the particle size of HPMC on metronidazole release from matrix tablets. European Journal of Pharmaceutics and Biopharmaceutics, 1997, 43: 173-178.
[94] Langer R, Peppas NA. Chemical and physical structure of polymers as carriers for controlled release of bioactive agents: a review. Rev. Macromol. Chem. Phys, 1983, 23: 61-126.
[95] Ford JL, Rubinstein MH, McCaul F. Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets. International Journal of Pharmaceutics, 1987, 40: 223-234.
[96] Tahara K, Yamamoto K, Nishihata T. Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained release tablets. International Journal of Pharmaceutics, 1996, 133: 17-27.
[97] Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Advanced Drug Delivery Reviews, 2001, 48: 139-157.
[98] Kim JY, Ku YS. Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats. International Journal of Pharmaceutics, 2000, 194(1): 81-89.
[99]沙先谊,陈小飞,李婵. 9-硝基喜树碱自微乳化给药系统研究.中国医药工业杂志, 2004, 35(8): 469-472.