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Miscibility of Egg Yolk Lecithin with Palmitic Acid and Hexadecanol At Journal of Oleo Science Copyright ©2013 by Japan Oil Chemists’ Society J. Oleo Sci. 62, (7) 471-480 (2013) Miscibility of Egg Yolk Lecithin with Palmitic Acid and Hexadecanol at the Air-Water Interface Hiromichi Nakahara and Osamu Shibata＊ Department of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Nagasaki International University; 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan Abstract: The miscibility of Langmuir monolayers of egg yolk lecithin (eggPC) with n-hexadecanoic acid (PA), 1-hexadecanol (HD), and their equimolar mixture (PA/HD) was investigated thermodynamically and morphologically. Surface pressure (π)-molecular area (A) and surface potential (ΔV)-A isotherms for the binary and ternary systems were measured, employing the Wilhelmy method and the ionizing 241Am electrode method, respectively. From the thermodynamic perspective, eggPC was partially miscible with PA, HD, and PA/HD within the monolayer state, in terms of an excess Gibbs free energy of mixing calculated from the π-A isotherms and a two-dimensional phase diagram based on a monolayer collapse pressure. This was also directly supported by phase behavior observations using fluorescence microscopy (FM). EggPC formed a typical liquid-expanded (LE) monolayer, and the others formed liquid-condensed (LC) monolayers. The FM images exhibited miscible modes at middle molar fractions of PA, HD, and PA/ HD, and immiscible patterns at large molar fractions for all the systems examined. A new finding in the present study was that the eggPC/PA, eggPC/HD, and eggPC/(PA/HD) systems exhibited partial miscibility, although the systems were made of both LE (eggPC) and LC monolayers (the others). This miscibility is considered to be attributable to the molecular species comprising eggPC. Key words: Langmuir monolayer, EggPC, Palmitic acid, Hexadecanol, Surface pressure, Surface potential 1 INTRODUCTION classified into two types: protein（or peptide）-free prepara- Pulmonary surfactants, lipid-protein complexes secreted tion（s e.g., Exosurf®）2－4） and protein（peptide）-containing from alveolar type II cells, are essential for the mainte- preparation（s e.g., Surfaxin®）5－7）. Indeed, the protein nance of respiration in human beings and animals. Their （peptide）-containing preparation is currently under inves- main function is to reduce the surface tension of the tigation with the aim of developing effective treatments for alveoli1）. An infant with a native lack of pulmonary surfac- NRDS and other conditions. As replacements of the lipid tants suffers neonatal respiratory distress syndrome components in pulmonary surfactants, DPPC, phosphati- （NRDS）. The artificial pulmonary surfactant preparation, dylglycero（l PG）, PA, and hexadecano（l HD）are often uti- ® 4, 6, 8, 9） 10, 11） 12, 13） Surfacten , a bovine-derived pulmonary surfactant extract lized . Further examples, such as KL4 , rSP-C , supplemented with dipalmitoylphosphatidylcholine and Hel 13-5 peptides14－16）, are also under consideration as （DPPC）, palmitic acid（PA）, and tripalmitin, is used in protein（or peptide）mimics of natural SP-B and SP-C pro- Japan as a first-line treatment for NRDS. In addition, many teins, which are the hydrophobic proteins in pulmonary medical doctors have recognized the possibility of applying surfactants. pulmonary surfactants to a wide range of pulmonary dis- As a biophysical function, pulmonary surfactant prepara- eases. However, the current preparation is expensive, such tions must form a stable monolayer that can reduce the that the application of Surfacten® only in NRDS is covered surface tension nearly to zero at the air-alveolar fluid inter- by health insurance in Japan. A further complication stems face during expiration17）. The stability is also deeply related from the risk of anthropozoonosis. As the development of a to the prevention of alveolar collapse during periods of lower cost preparation with fewer side effects is necessary, lung compression17）. It is widely accepted that these func- synthetic preparations which are not derived from animal tions are primarily induced by phospholipid（s particularly sources have been extensively investigated. These can be DPPC）in pulmonary surfactants. However, the convention- ＊Correspondence to: Osamu Shibata, Department of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Nagasaki International University; 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan E-mail: [email protected] Accepted February 13, 2013 (received for review January 5, 2013) Journal of Oleo Science ISSN 1345-8957 print / ISSN 1347-3352 online http://www.jstage.jst.go.jp/browse/jos/ http://mc.manusriptcentral.com/jjocs 471 H. Nakahara and O. Shibata al artificial pulmonary surfactant preparation, which is con- mitic acid（PA）; 99％）was purchased from Sigma-Aldrich tains DPPC as its main component, is considered to be pro- Co（. St. Louis, MO）. 1-Hexadecano（l palmityl alcoho（l HD）; hibitively expensive for extending its application to other ＞99％）was obtained from nacalai tesque（Kyoto, Japan）. pulmonary diseases. In fact, the drug cost of Surfaxin®, the 3,6-Bi（s diethylamino）-9（- 2-octadecyloxycarbonyl）phenyl first FDA-approved peptide-containing synthetic surfac- chloride（R18）from Molecular Probes Inc（. Eugene, OR） tant, amounts to about $700 per infant treated. Surfaxin® is was employed as a fluorescent probe. These lipids were formulated as an 8.5 mL intratracheal suspension in a glass used without further purification. n-Hexane（98.5％）and vial. According to Discovery Laboratories, Inc（. PA, USA）, ethano（l 99.5％）were purchased from Merck（Uvasol ®, each milliliter contains 30 mg phospholipid［s 22.50 mg Darmstadt, Germany）and nacalai tesque, respectively. A DPPC and 7.50 mg palmitoyloleoylphosphatidylglycerol 9:1 v/v n-hexane/ethanol mixture was used as a spreading sodium sal（t POPG, Na）］, 4.05 mg PA, and 0.862 mg KL4. solvent. Sodium chloride（nacalai tesque）was roasted at Thus, Surfaxin® consists mainly of DPPC. Considering also 1023 K for 24 h to remove all surface-active organic impuri- the drug cost of Surfacten（® ～￥100,000）, the synthetic- ties. The substrate solution was prepared using thrice-dis- surfactant types of RDS drugs obviously have not achieved tilled wate（r surface tension＝72.0 mN m－1 at 298.2 K; extensive cost reductions for RDS treatments. This short- electrical resistivity＝18 MΩ cm）. coming, related to the high production costs of DPPC, prompted our exploration for a DPPC alternative. In the 2.2 Methods present study, we targeted virus-free egg yolk phosphati- 2.2.1 Surface pressure-area isotherms dylcholine（eggPC）, extracted and purified from relatively The surface pressure（s π）of the monolayers were mea- less expensive egg yolk lecithin. DPPC possesses double sured using an automated homemade Wilhelmy balance. saturated hydrocarbon chain（s 2C16:0）. Similarly, the fatty The surface pressure balanc（e Mettler Toledo, AG-64）had a acid moieties in eggPC are double hydrocarbon chains, resolution of 0.01 mN m－1. The pressure-measuring system comprising combinations of both saturated and unsaturat- was equipped with filter pape（r Whatman 541, periphery＝ ed acyl chains. Thus, we considered PA（C16:0）and HD 4 cm）. The trough was made from Teflon®-coated brass （C16:0）as materials complementary to the degree of satu- （area＝750 cm2）, and Teflon® barrier（s both hydrophobic ration in eggPC. and lipophobic）were used in this study. Surface pressure In a first approach, we considered two-dimensiona（l 2D） （π）-molecular are（a A）isotherms were recorded at 298.2± monolayers at the air-water interface to investigate the 0.1 K. Stock solutions of eggPC（1.3 mM）, PA（1.3 mM）, and physicochemical interactions of eggPC with PA, HD, and an HD（1.3 mM）were prepared in n-hexane/ethano（l 9:1 v/v）. equimolar PA/HD mixture. The only structural difference The spreading solvents were allowed to evaporate for 15 between PA and HD is their head group; their monolayer min prior to compression. The monolayer was compressed properties are very similar. Thus, in this study, the compo- at a speed of ～0.10 nm2 molecule－1 min－1. The standard sition of the PA/HD mixture was kept constant at a 1:1 deviation（s SD）for molecular surface area and surface molar ratio. Our objective was to elucidate the miscibility, pressure were ～0.01 nm2 and ～0.1 mN m－1, respective- interactions, and phase behaviors of the binary and ternary ly14, 18, 19）. mixtures. The interfacial behaviors of eggPC with PA, HD, 2.2.2 Surface potential-area isotherms and their equimolar mixture in the monolayer state were The surface potentia（l ΔV）was recorded simultaneously evaluated by surface pressure（π）-molecular are（a A）and with surface pressure, when the monolayer was com- surface potentia（l ΔV）-A isotherms on 0.15 M NaCl at 298.2 pressed and expanded at the air-water interface. It was K. The excess Gibbs free energy of mixing was calculated monitored with an ionizing 241Am electrode at 1－2 mm from the isotherm data, and a 2D phase diagram was con- above the interface, while a reference electrode was dipped structed from the monolayer collapse pressures. In addi- in the subphase. An electromete（r Keithley 614）was used tion, the phase behaviors for the monolayers upon com- to measure the surface potential. The SD for the surface pression were examined using in situ fluorescence potential was 5 mV20, 21）. microscop（y FM）. 2.2.3 Fluorescence microscop（y FM） Fluorescence microscopi（c U.S.I. System BM-1000）ob- servations and compression isotherm measurements were carried out simultaneously. A spreading solution of the sur- 2 EXPERIMENTAL factants was prepared as a mixed solution doped with 1 2.1 Materials mol％ fluorescence probe（R18）. A 300 W xenon lamp（XL Egg yolk lecithin PC-98N（＞98％ phosphatidylcholine; 300, Pneum）was used for the excitation of the FM probe. virus-free; lot# AT2002）, abbreviated as eggPC, was a gift Excitation and emission wavelengths were selected by an from the Kewpie Corporation Fine Chemical Division appropriate beam splitter/filter combination（Mitutoyo band （Tokyo, Japan）.
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