Lecithin Lipophilicity

Lipid microspheres were used instead of liposomes as a carrier of lipophilic drugs in this study. Because the outside layer of liposomes and lipid microspheres is lecithin the distribution into the body was expected to be similar. 

Figure 7.17 shows the asymmetry ratios of a series of compounds (acids, bases, and neutrals) determined at iso-pH 7.4, under the influence of sink conditions created not by pH, but by anionic surfactant added to the acceptor wells (discuss later in the chapter). The membrane barrier was constructed from 20% soy lecithin in dodecane. All molecules show an upward dependence on lipophilicity, as estimated by octanol-water apparent partition coefficients, log KdaA). The bases are extensively cationic at pH 7.4, as well as being lipophilic, and so display the highest responses to the sink condition. They are driven to interact with the surfactant by both hydrophobic and electrostatic forces. The anionic acids are largely indifferent... 

Kansy et al. [550] reported the permeability-lipophilicity relationship for about 120 molecules based on the 10% wt/vol egg lecithin plus 0.5% wt/vol cholesterol in dodecane membrane lipid (model 15.0 in Table 7.3), shown in Fig. 7.23. The vertical axis is proportional to apparent permeability [see Eq. (7.9)]. For log Kd > 1.5, Pa decreases with increasing log Kd. In terms of characteristic permeability-lipophilicity plots of Fig. 7.19, the Kansy result in Fig. 7.23 resembles the bilinear case in Fig. (7.19d). Some of the Pa values may be underestimated for the most lipophilic molecules because membrane retention was not considered in the analysis. 

The peculiar depression of metoprolol and quinine permeabilities in 2% DOPC (model 1.0) was not seen in the egg lecithin models. Metoprolol and quinine were significantly more permeable in the lecithins, in line with expectations based on relative octanol-water lipophilicities and relative in vivo absorptions of (3-blockers [593],... 

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

The negative-charge lipid content in the egg lecithins is not as high as that found in BBM and especially BBB lipids (Table 7.1). Furthermore, the negative-charge content in the egg lecithin is about one-fourth that in the soy lecithin. This is clearly evident in the membrane retention parameters for the bases at the 10% lecithin levels (models 12.0 or 14.0 in Table 7.8 vs. model 16.0 in Table 7.12), as they are 20-30% lower for the lipophilic bases in egg, compared to soy. 

The 20% soy lecithin (Table 7.17) and the 2% DOPC (Table 7.15) intrinsic permeabilities may be compared in a Collander equation, as shown in Fig. 7.44. The slope of the regression line, soy versus DOPC, is greater than unity. This indicates that the soy membrane is more lipophilic than the DOPC membrane. Intrinsic permeabilities are generally higher in the soy system. Three molecules were significant outliers in the regression metoprolol, quinine, and piroxicam. Metoprolol and quinine are less permeable in the DOPC system than expected, based on their apparent relative lipophilicities and in vivo absorptions [593]. In contrast, piroxicam is more permeable in DOPC than expected based on its relative lipophilicity. With these outliers removed from the regression calculation, the statistics were impressive at r2 0.97. 

Membrane-interactive compounds are lipophilic molecules which have high affinity for lipid membranes and consequently possess long membrane residence times. Examples include the lipophilic neutral molecules (cholesterol, lecithin, pesticides, oleyl alcohol, tocopherols, etc.) and large organic cations (chlorproma-... 

Different factors govern the formation of these molecular compounds. Where lipids and related substances are concerned the governing factor is the realization of the best hydrophilic-lipophilic balance producing hydration or dispersion. The case of lecithin and sodium cholate associated in the presence of water may be used to illustrate the conditions of association and formation of different types of structure and of micelles. 

This solution of the cholate molecules between the chains of the lecithin is conceivable only if the cholate molecules are associated by their OH groups, showing their lipophilic sides outward. Thus, where the cholate molecules are associated in pairs, the maximum quantity incorporated in the lamellar phase corresponds at the most to one pair of cholate mole-... 

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. 

The hydrophilicity of nonionic surfactants can be characterized numerically as their hydrophile-lipophile balance (HLB). An HLB value of 3-6 indicates that the compound is a likely W/O emulsifier 7-9, a wetting agent 8-13, an O/W emulsifier 13-15, a detergent and 15-18, a solubilizer (of oil or other nonpolar compounds) in water. The HLB values of some common compounds are presented in Table 34.12.170 An HLB value of 8.0 is shown in Table 34.12 for lecithin, but manufacturers are able to supply modified lecithins with values of2-12. 

With the exception of lecithin, all emulsifiers used in foods are synthetic. They are characterized as ionic or nonionic and by their hydrophile/lipophile balance (HLB). All of the synthetic emulsifiers are derivatives of fatty acids. 

Both hydrophilic and lipophilic surfactants can be used to stabilize the polymeric nanoparticles. Generally the lipophilic surfactant is a natural lecithin of relatively low phosphotidylcholine content, whereas the hydrophilic one is synthetic anionic (lauryl sulfate), cationic (quaternary ammonium), or more commonly nonionic [poly(oxyethylene)-poly(propylene)glycol]. Nanoparticles can be prepared in the absence of surfactants, but there are lots more chances to get aggregated during storage. 

These functional characteristics are primarily derived from the chemical structures of lecithin s major phospholipids (Figure 1) (7). Phospholipid molecules contain two long-chain fatty acids esterified to glycerol, as well as a phosphodiester bonding a choline, inositol, or ethanolamine group. A phospholipid s fatty acid end is nonpolar and thereby lipophilic (or fat loving). Conversely, the phosphodiester, with the above-mentioned constiments, is zwitterionic (or dipolar), which... 

Emulsifying properties. One of the major functions of commercial lecithins is to emulsify fats. In an oihwater system, the phosphohpid components concentrate at the oUrwater interface. The polar, hydrophilic parts of the molecules are directed toward the aqueous phase, and the nonpolar, hydrophobic (or lipophilic) parts are directed toward the oil phase. The concentration of phospholipids at the oihwater interface lowers the surface tension and makes it possible for emulsions to form. Once the emulsion is formed, the phosphohpid molecules at the surface of the oil or water droplets act as barriers that prevent the droplets from coalescing, thus stabilizing the emulsion (159). 

Commercial lecithins are used in both water-in-oil (w/o) and oil-in-water (o/w) emulsions. For w/o emulsions, like margarine or ready-to-use frostings, oil-loving, lipophilic lecithins are typically used. For o/w emulsions, like sauces or infant formulas, water-dispersible, hydrophilic lecithins are typically used (7, 31). The use of... 

The manner in which lecithin is modified to achieve increased hydrophilicity will greatly affect its emulsification properties. Different modifications will create lecithin products with different apparent HLB (hydrophile-lipophile balance) values, a term used to convey the approximate degree of water dispersibility (hydrophilicity) of lecithin products (31). The higher its HLB value, the more water dispersible the lecithin product. In o/w emulsions, the type of fat to be emulsified may require a specific type of hydrophilic lecithin for optimum emulsion stability. Dashiell (31) provides a short listing of fat types, and the corresponding class of lecithin found to give the most stable emulsion in model systems of water/fat/ emulsifier. 

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