本研究分別將陽離子型界面活性劑tetradecyltrimethylammonium bromide （TTMAB）及hexadecyltrimethylammonium bromide（HTMAB）與陰離子型界面活性劑sodium dodecylsulfate（SDS）於水相中以等莫耳比例混合，製備出兩種不同碳鏈長度之離子對雙親分子（ion pair amphiphile, IPA）tetradecyltrimethylammonium-dodecylsulfate（TTMA-DS）及hexadecyltrimethylammonium-dodecylsulfate（HTMA-DS）。然後添加適量的雙十六碳鏈磷酸鹽（dihexadecyl phosphate, DHDP），以強制形成之製程製備出帶負電的陰陽離子液胞（catanionic vesicle），並探討利用此液胞做為維他命E醋酸酯之傳輸載體的可行性。
由不同混合比例之TTMA-DS/DHDP所形成的陰陽離子液胞，皆有物理穩定性不足的問題，添加適量之膽固醇則可提升液胞的物理穩定性。就TTMA-DS及HTMA-DS分別與DHDP所形成之液胞而言，可能由於HTMA-DS中的HTMA與DHDP的碳鏈長度相同，使得HTMA-DS/DHDP液胞雙層膜內的缺陷較少，因而有較佳的物理穩定性。以螢光偏極化及紅外光譜法分析膽固醇對液胞雙層膜流動性的影響，則發現在IPA相轉移溫度之下添加膽固醇，可以使液胞雙層膜中分子碳氫鏈的排列變得較鬆散。
利用以上所提之陰陽離子液胞包覆維他命E醋酸酯時，發現液胞粒徑有變大的趨勢，顯示維他命E醋酸酯成功地被包覆在液胞雙層膜內。此外，維他命E醋酸酯的包覆對於含HTMA-DS之液胞的物理穩定性有明顯的提升，但對於含TTMA-DS之液胞的物理穩定性影響則很有限。就包覆效率而言，含TTMA-DS之液胞的包覆效率略比含HTMA-DS的高。由於膽固醇比維他命E醋酸酯更具疏水性，能競爭插排入液胞雙層膜內，因此膽固醇在液胞雙層膜中所占的比率可能會影響液胞包覆維他命E醋酸酯的能力。
本研究也使用Franz diffusion cell裝置針對不同孔洞大小的醋酸纖維素膜（cellulose acetate membrane），探討液胞及利用高分子膠化後之液胞的穿透行為。結果顯示平均粒徑87 nm的液胞並不能順利通過100及200 nm大小孔洞的膜，但是可以通過400 nm孔洞的膜。經由高分子carbopol940膠化的液胞，其穿透過醋酸纖維素膜的能力則會下降。

In this study, two ion pair amphiphiles（IPAs）, tetradecyltrimethylammonium-dodecylsulfate（TTMA-DS）and hexadecyltrimethylammonium-dodecylsulfate（HTMA-DS）, with different hydrocarbon chain lengths were prepared by mixing cationic surfactants, tetradecyltrimethylammonium bromide（TTMAB）and hexadecyltrimethylammonium bromide （HTMAB）, respectively, with anionic surfactant, sodium dodecylsulfate（SDS）, at equal molar ratio in aqueous phases. Then with the addition of proper amounts of dihexadecyl phosphate（DHDP）, negatively charged catanionic vesicles were fabricated by a forced formation approach and feasibility of using the vesicles as vitamin E acetate carriers was investigated.
The catanionic vesicles formed from different mixing ratios of TTMA-DS to DHDP had a problem of poor physical stability. One can enhance the physical stability of the vesicles by adding optimal amounts of cholesterol. For the vesicles formed from TTMA-DS and HTMA-DS, respectively, with DHDP, probably because the hydrocarbon chain length of HTMA in HTMA-DS was the same as that of DHDP, the bilayers of HTMA-DS/DHDP vesicles had fewer defects and thus had better physical stability. From the fluorescence polarization and Fourier transform infrared analyses of the cholesterol effect on the vesicular bilayer fluidity, it was found that adding cholesterol below the phase transition temperature of IPA could decrease the order of the molecule alkyl chains in the vesicular bilayers.
By using the above catanionic vesicles to encapsulate vitamin E acetate, one could find the trend with increased vesicle size, indicating that vitamin E acetate was successfully entrapped into the vesicular bilayers. Besides, the encapsulation of vitamin E acetate could significantly enhance the physical stability of the vesicles containing HTMA-DS, but only had limited effect on the physical stability of the vesicles containing TTMA-DS. As for the encapsulation efficiency, the encapsulation efficiency of TTMA-DS- containing vesicles for vitamin E acetate was slightly higher than that of HTMA-DS-containing vesicles. Because cholesterol was more hydrophobic than vitamin E acetate and could compete in inserting into the vesicular bilayers, the fraction of cholesterol in the vesicular bilayers might affect the ability of vesicles to encapsulate vitamin E acetate.
This study also used the Franz diffusion cell to investigate the penetration behavior of vesicles and gelled vesicles through cellulose acetate membranes with different pore sizes. The results indicated that vesicles with an average size of 87nm could not penetrate through the cellulose acetate membranes with pore sizes of 100 and 200nm, but could penetrate through the membranes with a pore size of 400nm. The ability of the vesicles to penetrate through the membranes was decreased by gelling the vesicles with polymer carbopol940.

參考文獻

Ahmad, I., Longenecker, M., Samuel, J., and Allen, T. M.,“Antibody-
targeted delivery of doxorubicin entrapped in sterically stabilized
liposomes can eradicate lung cancer in mice,” Cancer Research 55,
1484-1487, 1993.
Apel-Paz, M., Doncel, G. F., and Vanderlick, T. K., “Impact of membrane
cholesterol content on the resistance of vesicles to surfactant attack,”
Langmuir 21, 9843-9849, 2005.
Bach, D., and Wachtel, E., “Phospholipid/cholesterol model membranes:
formation of cholesterol crystallites,” Biochimica et Biophysica Acta
1610, 187-197, 2003.
Bhardwaj, U., and Burgess, D. J., “Physicochemical properties of extruded
and non-extruded liposomes containing the hydrophobic drug dexamethasone,” International Journal of Pharmaceutics 388, 181-189,
2010.
Bhattacharya, S., De, S., and Subramanian, M., “Synthesis and vesicle
formation from hybrid bolaphile/amphiphile ion-pairs. Evidence of
membrane property modulation by molecular design,” Journal of
Organic Chemistry 63, 7640-7651, 1998.
Bhattacharya, S., and Haldar, J., “Interactions between cholesterol and lipids
in bilayer membranes. Role of lipid headgroup and hydrocarbon
chain-backbone linkage,” Biochimica et Biophysica Acta 1467, 39-53,
2000.
Bhattacharya, S., and Haldar, S., “Molecular design of surfactants to tailor
its aggregation properties,” Colloids and Surfaces A: Physicochemical
and Engineering Aspects 205, 119-126, 2002.
Blanzat, M., Perez, E., Rico-Latters, R., Prome, D., Prome, J. C. and Lattes,
A., “New catanionic glycolipids. 1. Synthesis, characterization, and
biological activity of double-chain and gemini catanionic analogues of
galactosylceramide(galβ1cer),” Langmuir 15, 6163-6169, 1999.
Borochov, “Phase behavior of mixtures of cholesterol and saturated
phosphatidylglycerols,” Chemistry and Physics of Lipids 76, 85-92,
1995.
Brasher, L. L., Herrington, K. L., and Kaler, E. W., “Electrostatic effects on
the phase behavior of aqueous cetyltrimethylammonium bromide and
sodium octyl sulfate mixtures with added sodium bromide,” Langmuir
11, 4267-4277, 1995.
Campbell, R. B., Balasubramanian, S. V., and Straubinger, R. M.,
“Phospholipid-cationic lipid interactions: influences on membrane and
vesicle properties,” Biochimica et Biophysica Acta 1512, 27-39, 2001.
Carrion, F. J., Maza, A. D., and Parra, J. L., “The influence of ionic strength
and lipid bilayer charge on the stability of liposomes,” Journal of Colloid and Interface Science 164, 78-87, 1994.
Chien, C.-L., Yeh, S.-J., Yang, Y.-M., Chang, C.-H., and Maa, J.-R.,
“Formation and encapsulation of catanionic vesicles,” Journal of the
Chinese Colloid and Interface Society 24, 31-45, 2002.
Chiruvolu, S., Israelachvili, J. N., Naranjo, E., Xu, Z., and Zasadzinski, J. A.,
“Measurement of forces between spontaneous vesicle-forming
bilayers,” Langmuir 11, 4256-4266, 1995.
Chung, M. H., and Chung, Y. C., “Polymerized ion pair amphiphile that
shows remarkable enhancement in encapsulation efficiency and very
slow release of fluorescent markers,” Colloids and Surfaces B:
Biointerfaces 24, 111-121, 2002.
Chung, M. H., Park, M. J., Chun, B. C., and Chung, Y. C., “Encapsulation
and permeation properties of the polymerized ion pair amphiphile vesicle that has an additional carboxyl group on anionic chain,”
Colloids and Surfaces B: Biointerfaces 28, 83-93, 2003.
Chung, M. H., Park, C., Chun, B. C., and Chung, Y. C., “Polymerized ion
pair amphiphile vesicles with pH-sensitive transformation and controlled release property,”Colloids and Surfaces B: Biointerfaces 34,
179-184, 2004.
Eastman, S. J., Siegel, C., Tousignant, J., Smith, A. E., Cheng, S. H., and
Scheule R. K., “Biophysical characterization of cationic lipid:DNA complexes,” Biochimica et Biophysica Acta 1325, 41-62, 1997.
El Maghraby, G. M., Barry B.W., and Williams A.C., “Liposomes and skin:
From drug delivery to model membranes,” European Journal of
Pharmaceutical Sciences 34, 203-222, 2008.
Fischer, A., Hebrant, M., and Tondre, C., “Glucose encapsulation in
catanionic vesicles and kinetic study of the entrapment/release processes in the sodium dodecyl benzene sulfonate/cetyltrimethylam- monium tosylate/water system,” Journal of Colloid and Interface
Science 248, 163-168, 2002.
Fukuda, H., Kawata, K., and Okuda, H., “Bilayer-forming ion-pair
amphiphiles from single-chain surfactants,” Journal of the American
Chemical Society 112, 1635-1637, 1990.
Gallarate, M., Chirio D., Trotta M., and Carlotti M. E., “Deformable
liposomes as topical formulations containing α-tocopherol,” Journal
of Dispersion Science and Technology 27, 703-713, 2006.
Ganesan, M. G., Weiner, N. D., Flynn, G. L. and Ho, N. F. H., “Influence of
liposomal drug entrapment on percutaneous absorption,” International Journal of Pharmaceutics 20, 139-154, 1984.
Gunarsa, C. A., “含雙十六碳鏈磷酸鹽之陰陽離子液胞的物理穩定性及維
他命E包覆效率，” 國立成功大學化學工程學系碩士論文，2010。
Hincha, D. K., “Effects of a-tocopherol (vitamin E) on the stability and
lipid dynamics of model membranes mimicking the lipid composition
of plant chloroplast membranes,” FEBS Letters 582, 3687-3692,
2008.
Hirano, K., and Fukuda, H., “Polymerizable ion-paired amphiphiles,”
Langmuir 7, 1045-1047, 1991.
Ho, C., Slater S. J., and Subbs C.D. “Hydration and order in lipid bilayers,”
Biochemistry 34, 6188-6195, 1995.
Holmberg, K., Handbook of applied surface and colloid chemistry, John
Wiley and Sons, England, 2, 45-54, 2002.
Israelachvili, J. N., Mitchell, D. J., and Ninham, B. W., “Theory of
self-assembly of hydrocarbon amphiphiles into micelles and bilayers,”Journal of the Chemical Society-Faraday Transactions 72, 1525, 1976.
Jubeh, T. T., Barenholz, Y., and Rubinstein, A., “Differential adhesion of
normal and inflamed rat colonic mucosa by charged liposomes,”
Pharmaceutical Research 21, 447-453, 2004
Kaler, E. W., Murthy-, A. K., Rodriguez, B. E., and Zasadzinski, A. N.,
“Spontaneous vesicle formation in aqueous mixtures of single-tailed
surfactants,” Science 245, 1371-1374, 1989.
Lasic, D. D., “Liposomes: from physics to applications,” Elsevier, New
York, 265-318, 1993.
Lasic, D. D., and Papahadjopoulos, D., “Liposomes and biopolymers in drug
and gene delivery,” Solid State and Materials Science 1, 392-400, 1996.
Lasic, D. D., “Liposomes in gene delivery,” CRC Press, New York, 67-112,
1997.
Liu, D. Z., Chen, W. Y., Tasi, L. M., and Yang, S. P., “Microcalorimetric
and shear studies on the effects of cholesterol on the physical stability of lipid vesicles,” Colloids and Surfaces A: Physicochemical and
Engineering Aspects 172, 57-67, 2000.
Manosroi, A., Wongtrakul P., Manosroi J., Sakai H., Sugawara F., Yuasa
M., and Abe M. “Characterization of vesicles prepared with various
non-ionic surfactants mixed with cholesterol,” Colloids and Surfaces
B:Biointerfaces 30, 129-138, 2003.
Marques, E. F., Regev O., Khan A., and Lindman B., “Self-organization
of double-chained and pseudodouble-chained surfactants: counterion and geometry effects,” Advances in Colloid and Interface Science 100,
83-104, 2003.
McMullen, T. P. W., Lewis, N. A. H., and McElhaney, R. N., “Differential
scanning calorimetric study of the effect of cholesterol on the
thermotropic phase behavior of a homologous series of linear saturated
phosphatidylcholines,” Biochemistry 32, 516-522, 1993.
McMullen, T. P. W., Lewis, R. N. A. H., and McElhaney, R. N.,
“Differential scanning calorimetric and fourier transform infrared spectroscopic studies of the effects of cholesterol on the thermotropic phase behavior and organization of a homologous series of linear saturated phosphatidylserine bilayer membranes,” Biophysical Journal
79, 2056-2065, 2000.
Menger, F. M., Binder, W. H., and Keiper, J. S., “Cationic surfactants with
counterions of glucuronate glycosides,” Langmuir 13, 3247-3250,
1997.
Miyajima, K., Komatsu, H., Sun, C. Q., Aoki, H., Handa, T., Xu, H. J., Fuji,
K. R., and Okada, S., “Effects of cholesterol on the miscibility of
synthetic glucosamine diesters in lipid bilayers and the entrapment of
superoxide-dismutase into the positively charged liposomes,”
Chemical and Pharmaceutical Bulletin 41, 1889-1894, 1993.
Montenegro, L., Panico, A. M., Ventimiglia, A., and Bonina, F. P. “In
vitro retinoic acid release and skin permeation from different liposome formulations,” International Journal of Pharmaceutics 133, 89-96,
1996.
New, R. R. C., “Liposomes: a practical approach,” Oxford University Press,
New York, 1-32, 1990.
Padamwar, M. N., and Pokharkar, V. B., “Development of vitamin loaded
topical liposomal formulation using factorial design approach: drug
deposition and stability,” International Journal of Pharmaceutics
320, 37-44, 2006.
Panda, A. K., Possmayer, F., Petersen, N. O., Nag, K., and Moulik, S. P.,
“Physico-chemical studies on mixed oppositely charged surfactants:
their uses in the preparation of surfactant ion selective membrane and
monolayer behavior at the air water interface,” Colloids and Surfaces A: Physicochemistry and Engineering Aspects 264, 106-113, 2005.
Saarinen-Savolainen, P., Jarvinen, T., Taipale, H., and Urtti, A., “Method for
evaluating drug release from liposomes in sink conditions,” International Journal of Pharmaceutics 159, 27-33, 1997.
Segota, S. and Tezak, D. “Spontaneous formation of vesicles,” Advances in
Colloid and Interface Science 121, 51-75, 2006.
Srivastava, S., Phadke R. S., Govil G., and Rao C. N. R., “Fluidity
permeability and antioxidant behaviour of model membranes incorporated with [alpha] – tocopherol and vitamin E acetate,” Biochimica et Biophysica Acta - Biomembranes 734, 353-362, 1983.
Tomasic, V., Stefanic, I., and Filipovic-Vincekovic, N., “Adsorption,
association and precipitation in hexadecyltrimethylammonium
bromide/sodium dodecyl sulfate mixtures,” Colloid and Polymer
Science 277, 153-163, 1999.
Touitou, E., Dayan, N., Bergelson, L., Godin, B., and Eliaz, M., “Ethosomes-
novel vesicular carriers for enhanced delivery:characterization and skin penetration properties,” Journal of Controlled Release 65, 403- 418, 2000.
Virden, J. W., and Berg, J. C., “NaCl-induced aggregation of
dipalmitoylphosphatidylglycerol small unilamellar vesicles with varying amounts of incorporated cholesterol,” Langmuir 8, 1532- 1537, 1992.
Walker, S. A., and Zasadzinski, A. J., “Electrostatic control of spontaneous
vesicle aggregation,” Langmuir 13, 5076-5081, 1997.
Yokouchi, Y., Tsunoda, T., Imura, T., Yamauchi, H., Yokoyama, S., Sakai,
H., and Abe, M., “Effect of adsorption of bovine serum albumin on
liposomal membrane characteristics,” Colloids and Surfaces B:
Biointerfaces 20, 95-103, 2001.
Yokoyama, S., Inagaki, A., Imura, T., Ohkubo, T., Tsubaki, N., Sakai, H.,
and Abe, M., “Membrane properties of cationic liposomes composed of dipalmitoylphosphatidylcholine and dipalmityldimethylammonium
bromide,” Colloids and Surfaces B: Biointerfaces 44, 204-210, 2005.
Zhang, J. A., Anyarambhatla G., Ma L., Ugwu S., Xuan T., Sardone T., and
Ahmad I., “ Development and characterization of a novel Cremophor® EL free liposome-based paclitaxel (LEP-ETU) formulation,” European Journal of Pharmaceutics and Biopharmaceutics 59,
177–187, 2005.
李威漢，“陰陽離子界面活性劑的製備及其相轉移行為的熱卡分析，” 國
立成功大學化學工程學系碩士論文，2010。
李雅鈺，“含膽固醇之陰陽離子液胞穩定性及包覆行為的研究，” 國立成
功大學化學工程學系碩士論文，2004。
吳芷容，“利用帶正電的陰楊離子液胞做為DNA載體之可行性的研究，”
國立成功大學化學工程學系碩士論文，2008。
吳國彰，“陰陽離子液胞穩定性及包覆/釋放行為的研究，” 國立成功大
學化學工程學系碩士論文，2006。
林冠豪，“帶電的陰陽離子液胞之製備及物理穩定性研究，”國立成功
大學化學工程學系碩士論文，2004。
徐立銘，“陰陽離子液胞包覆行為之探討，” 國立成功大學化學工程學系
碩士論文，2002。
黃鉦琳，“帶電陰陽離子液胞的形成及其膠化之研究，” 國立成功大學
化學工程學系碩士論文，2007。
葉紹任，“共溶劑對陰陽離子液胞穩定性的影響，” 國立成功大學化學工
程學系碩士論文，2003。
廖怡芬，“長碳鏈醇類添加劑對帶電陰陽離子液胞物理穩定性的影響，”
國立成功大學化學工程學系碩士論文，2006。
簡振龍，“陰/陽離子界面活性劑的混合增效作用之研究，” 國立成功大
學化學工程學系碩士論文，2000。