Membrane, interactions with nonionic

Interactions of Nonionic Polyoxyethylene Alkyl and Aryl Ethers with Membranes and Other Biological Systems... 

In this section several recently published studies on the interaction of nonionic surfactants with a variety of biological systems, including enzymes, bacteria, erythrocytes, leukocytes, membrane proteins, low density lipoproteins and membranes controlling absorption from the gastrointestinal tract, nasal and rectal cavities, will be assessed. This is a selective account, work having been reviewed that throws light on structure-activity relationships and on mechanisms of surfactant action. 

The difficulty with HLB as an index of physicochemical properties is that it is not a unique value, as the data of Zaslavsky et al. (1) on the haemolytic activity of three alkyl mercaptan polyoxyethylene derivatives clearly show in Table 1. Nevertheless data on promotion of the absorption of drugs by series of nonionic surfactants, when plotted as a function of HLB do show patterns of behaviour which can assist in pin-pointing the necessary lipophilicity required for optimal biological activity. It is evident however, that structural specificity plays a part in interactions of nonionic surfactants with biomembranes as shown in Table 1. It is reasonable to assume that membranes with different lipophilicities will"require" surfactants of different HLB to achieve penetration and fluidization one of the difficulties in discerning this optimal value of HLB resides in the problems of analysis of data in the literature. For example, Hirai et al. (8 ) examined the effect of a large series of alkyl polyoxyethylene ethers (C4,C0, Cj2 and C 2 series) on the absorption of insulin through the nasal mucosa of rats. Some results are shown in Table II. 

Photon correlation spectroscopy was used to study the effects of a series of nonionic surfactants on the Stokes radius (R) of low density lipoprotein (LDL2) particles (Jl, 32). LDL2 interacted with surfactants in a manner similar to membranes. 

Recently, a new class of inhibitors (nonionic polymer surfactants) was identified as promising agents for drug formulations. These compounds are two- or three-block copolymers arranged in a linear ABA or AB structure. The A block is a hydrophilic polyethylene oxide) chain. The B block can be a hydrophobic lipid (in copolymers BRIJs, MYRJs, Tritons, Tweens, and Chremophor) or a poly(propylene oxide) chain (in copolymers Pluronics [BASF Corp., N.J., USA] and CRL-1606). Pluronic block copolymers with various numbers of hydrophilic EO (,n) and hydrophobic PO (in) units are characterized by distinct hydrophilic-lipophilic balance (HLB). Due to their amphiphilic character these copolymers display surfactant properties including ability to interact with hydrophobic surfaces and biological membranes. In aqueous solutions with concentrations above the CMC, these copolymers self-assemble into micelles. 

The effect of a number of other surfactants on human skin has also been investigated calorimetrically [97-99]. However, interpretation of the results, as well as correlation to the enhancing capacity, is often obscured by the simple fact that the penetration-enhancing ability of surfactants is strongly dependent on their concentration and on their physicochemical nature (cationic, anionic, or nonionic). That is, the total enhancing effect is dependent not only on the membrane interaction of the surfactant, but also on thermodynamic considerations dictated by the interplay of the permeant with the micellar surfactant [68,100]. 

The majority of anesthetics have pKas such that when aqueous solutions of their salts (e.g., hydrochlorides) are injected into the pH 7.4 buffer of the extracellular fluid, they will equilibrate so that the neutral form will readily penetrate through the neuronal membrane (e.g., lidocaine would be 24% nonionized). Once inside, this form would again equilibrate to afford a 75% majority of ionic species, which presumably can then interact with the putative receptor. These concepts are represented in Figure 13-10. It is interesting that since early experiments (1927) appeared to show that these drugs were more active when administered in a basic solution, it was assumed the neutralized form (nonionic) was the active anesthetic species. Later work demonstrated this to be wrong, since nerve preparations that were blocked by an anesthetic that was shown to be bound to the nerve could be easily reactivated by bathing it in an alkaline buffer of about pH 9.5. 

Many drug carriers are made of hydrophobic materials such as lipids and poly(butyl cyanoacrylate). It will be thermodynamically unstable for submicron particles made of these materials to remain dispersed in an aqueous environment such as blood circulation. Surfactants or block co-polymers are therefore routinely included in these formulations to prevent particle aggregation. Studies showed that a number of these agents, most noticeably the nonionic surfactants such as polysorbates (also known as Tweens) and Tritons and block co-polymers such as poloxamers (also known as Pluronics), may inhibit the ABC transporters [97-99]. As previously discussed, ABC transporters interact with their substrates in the lipid bilayers of the plasma membrane. Surfactants can disrupt the arrangement of the lipid bilayer expressing the transporters and subsequently inhibit their drug efflux activities [97, 100]. It... 

Outside the field of membrane biochemistry, few researchers investigate the interactions of nonionic surfactants with proteins [75]. In general, the nonionic surfactants exhibit little substantivity for skin and hair [76]. However, their effects on the barrier properties of skin are well known and will be discussed later in this chapter. Because of their passivity, nonionic surfactants are key ingredients in many skin care products, especially facial and sensitive -skin products (Table 5). 

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