Mixed micelles amphiphile

Van Bloois, L., Dekker, D. D., and Crommelin, D. J. A. (1987). Solubilization of lipophilic drugs by amphiphiles Improvement of the apparent solubility of almitrine bismesylate by liposomes, mixed micelles and O/W emulsions, Acta Pharmaceut. TechnoL,... 

Similar experiments with PEG-phosphatidyl ethanolamine mixed micelles with a core-incorporated amphiphilic " In- or Gd-loaded chelating agent PAP demonstrated fast and efficient gamma and MR visualization of different compartments of the lymphatic system. Upon subcutaneous administration, the micelles penetrate the lymphatics and effect visualization (Figure 6). Micelles mostly stay within the lymph fluid rather than accumulate in the nodal macrophages (because of protective effect of surface PEG fragments) and rapidly move via the lymphatic pathway. 

In methanol as solvent, the results are comparable with respect to activity and enantioselectivity (Tab. 6.2, entry (1)) whereas in water the complex of the amphiphilic ligand shows a significant increase in activity and enantioselectivity compared with the BPPM complex (entry (2)). The values obtained for mixed micelles... 

These statements lead to the conclusion that the limiting proportion of 1 gram of Na cholate associated to 1 gram of lecithin is simply imposed by the size of a certain form of mixed micelle which can remain in equilibrium with an excess of Na cholate in micellar solution. Thus, it clearly appears that association is governed by the necessity of securing the proper hydrophilic-lipophilic balance of the mixture of two components. Here, as in the case of other amphiphilic substances, by the progressive increase in proportion of the more hydrophilic amphiphile. the association can reach complete micellar dispersion in water. 

For ionic amphiphiles the first formed aggregates are closely spherical. At higher amphiphile concentrations there is a tendency for the formation of rod-shaped micelles168. Also the addition of salt favours the rod-shape aggregates33. It has been suggested that disc-shaped micelles also occur160 but experimental evidence in favor of this view has only been obtained for mixed micelles of lecithin and sodium cho-late179. ... 

Cholesterol does not form micelles because (1) it is not amphiphilic and (2) its flat, rigid, fused-ring structure gives a solid rather than a liquid, mobile hydrocarbon phase necessary for micellar formation. Cholesterol forms mixed micelles with amphiphilic lipids and will enter monolayers. 

This study is a continuation of our previous investigations, in which the aggregation phenomena of surfactant molecules (amphiphiles) in aqueous media to form micelles above the critical micelle concentration (c.m.c.) has been described based on different physical methods (11-15). In the current literature, the number of studies where mixed micelles have been investigated is scarcer than for pure micelles (i.e., mono-component). Further, in this study we report various themodynamlc data on the mixed micelle system, e.g., ci H25soi4Na (NaDDS) and sodium deoxycholate (NaDOC), enthalpy of micelle formation (by calorimetry), and aggregation number and second virial coefficient (by membrane osmometry) (1 6). 

As the data from Fig. 10.5 suggests, the PHis-PEG micelles are unstable and can release their contents at neutral pH. In order to deal with this problem, an amphiphilic block copolymer, PLLA-PEG, was added to make mixed micelles, in which the core was expected to contain poly(L-lactic acid) (PLLA) and PHis chains. The PLLA block in the core stabilized the micelles and hence suppressed the drug release at the near neutral pH. The optimum content of PLLA-PEG was found to be about 25 0% (Fig. 10.7). The DOX delivered from such mixed micelles showed low cytotoxicity at pH above 7.0 but high cytotoxicity at pH 6.8 [143]. 

The lamellar phases on the surface of the emulsion particles are mainly composed of monoacylglycerides, lyso-phospholipids and ionized fatty acids. When the phases have reached a certain size, they will desorb from the emulsion surface and form multi-lamellar vesicles, which are transformed into uni-lamellar vesicles upon increased incorporation of bile salts (Rigler et al., 1986). Upon further incorporation of bile salts, the ratio of lipid amphiphiles to bile salts will decrease to 1 or lower, whereby the uni-lamellar vesicles are transformed to mixed micelles (Staggers et al., 1990). These events are presented in Figure 4. 

The formed mixed micelles can diffuse to the unstirred water layer that lines the epithelium, where the micelles disintegrate and lipid amphiphiles are ahsorhed. Bile salts are recycled hack into the lumen and continue to interact with lipid digestion. Thus at any given time during lipid digestion, a complex mixture of different colloid phases is present in the intestinal lumen (Rigler et al., 1986). 

The relevance of discussing these two classes of lipids becomes obvious when it is appreciated that bile acids alone can solubilize lipids with only low efficiency. However, when mixed with a swelling amphiphile, such as phosphatidylcholine, the capacity of bile acids for solubilizing a nonswelling amphiphile is greatly increased. For example, cholesterol in bile is solubilized by bile acid-phosphatidylcholine mixed micelles much more efficiently than by bile acid micelles alone. As is discussed later, mixed micelles are also important in fat solubilization and absorption in the intestine. 

At least three components are present in systems where solubihzation takes place, i.e., the solvent, the miceUe-forming amphiphile, and the component that is solubilized. In this chapter we only deal with aqueous systems. The micelle-forming amphiphile is termed surfactant here, and the third component is termed the solute. Of course, the micelles can be composed of a mixture of surfactants and several solutes can be added. However, we concentrate on micelles of one surfactant with one solute added, although a short review of mixed micelles is given. 

Eqnation 9.3 is satisfactory only when micelles are small and spherical and solubilization is relatively low. While the above derivation can apply either to nonpolar species solubilized in the micelle interior or to amphiphilic species such as alcohols that basically form mixed micelles with the surfactant, caution should be used in the latter case. The reason is that alcohols less hydrophilic than the surfactant can cause the micelles to become rodUke, thus violating the assumption of spherical micelles employed in the analysis. 

In an earlier review [3], mixed micelles formed by bile salts were classified into those with (i) non-polar lipids (e.g., linear or cyclic hydrocarbons) (ii) insoluble amphiphiles (e.g., cholesterol, protonated fatty acids, etc.) (iii) insoluble swelling amphiphiles (e.g., phospholipids, monoglycerides, acid soaps ) and (iv) soluble amphiphiles (e.g., mixtures of bile salts with themselves, with soaps and with detergents) and the literature up to that date (1970) was critically summarized. Much recent work has appeared in all of these areas, but the most significant is the dramatic advances that have taken place in our understanding of the structure, size, shape, equilibria, and thermodynamics of bile salt-lecithin [16,18,28,29,99-102,127, 144,218,223,231-238] and bile salt-lecithin-cholesterol [238,239] micelles which are of crucial importance to the solubihty of cholesterol in bile [1]. This section briefly surveys recent results on the above subclasses. Information on solubilization, solubilization capacities or phase equilibria of binary, ternary or quaternary systems or structures of liquid crystalline phases can be found in several excellent reviews [5,85,207,208,210,211,213,216,217] and, where relevant, have been referred to earlier. 

Fig. 17. Longitudinal and cross-sectional views of the proposed molecular models for the structure of bile salt-lecithin (BS-L) mixed micelles. All recent experimental data for BS-swelling amphiphile micelles are consistent with model B. In this model, reverse BS aggregates are present in high concentrations within the hydrophobic domains of L or other swelling amphiphile bilayers. BS also coat the perimeter of the disks as a bilayered ribbon . (From ref. 102 with permission.)...

In the lumen of the small intestine, dietary fat does not only meet bile salt but the much more complex bile in which bile salts are about half saturated with lecithin in a mixed micellar system of bile salt-lecithin-cholesterol. On dilution in the intestinal content, the micelles grow in size as the phase limit is approached and large disk-like micelles form which fold into vesicles [49]. These changes are due to the phase transition that occurs when the bile salt concentration is decreased and the solubility limit for lecithin in the mixed micelles is exceeded. The information is mostly derived from in vitro studies with model systems but most probably is applicable to the in vivo situation. What in fact takes place when the bile-derived lamellar bile salt-lecithin-cholesterol system meets the partly digested dietary fat can only be pictured. Most probably it involves an exchange of surface components, a continuous lipolysis at the interphase by pancreatic enzymes and the formation of amphiphilic products which go into different lamellar systems for further uptake by the enterocyte. Due to the relatively low bile salt concentration and the potentially high concentration of product phases in intestinal content early in fat digestion, the micellar and monomeric concentration of bile salt can be expected to be low but to increase towards the end of absorption. 

The impact of different surfactants (SDS, DOSS, CTAB and hexadimethrine bromide, bile salts °), nonionic and mixed micelles, and additives (neutral and anionic CDs," " tetraalkylammonium salts, organic solvents in EKC separations has been demonstrated with phenol test mixtures. In addition, phenols have been chosen to introduce the applicability of more exotic EKC secondary phases such as SDS modified by bovine serum albumin, water-soluble calixarene, " starburstdendrimers, " " cationic replaceable polymeric phases, ionenes, amphiphilic block copolymers,polyelectrolye complexes,and liposome-coated capillaries. The separation of phenols of environmental interest as well as the sources and transformations of chlorophenols in the natural environment have been revised. Examples of the investigation of phenols by EKC methodologies in aquatic systems, soil," " and gas phase are compiled in Table 31.3. Figure 31.3 illustrates the electromigration separation of phenols by both CZE and EKC modes. 

Alternatively, the level of stmctural complexity may be affected in a totally different manner employing co-assembly of chemically unlike molecules instead of self-assembly of chemically identical molecules [12-20]. We refer to the resultant micelles as mixed micelles or co-micelles to indicate that this type of micelle consists of more than one type of molecule, whereas classical micelles consist of identical molecules (polydispersity effects not taken into account). Consider two chemically distinguishable amphiphilic molecules A-B and C-D. Self-assembly into A/C or B/D micelles consisting of a core-shell structure, with a core solely consisting of A or C units and a shell solely consisting of B or D units, will only occur if the A or C units are solvophobic and the B or D units are solvophilic. However, if all units (A and B, or C and D) are solvophobic, phase separation will occur on a macroscopic level and result in a macroscopically inhomogeneous two-phase system. Conversely, if all units (A and B, or C and D) are solvophilic, phase separation... 

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