Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants based on erucyl and behenyl (C22) alcohols

Studies on erucyl alcohol ethoxylated with 24 units and on behenyl alcohol ethoxylated with 21 ethylene oxide units gave values of 10·2 times 10³ and 25·4 times 10³ for the micellar weights, 74 and 203 for the aggregation number, and 134 and 106 moles water mole^?1 surfactant for the micellar hydration, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants, and in cetomacrogol. Excluding sulphadiazine, a linear relationship was found between moles solubilized/mole surfactant, and (log P)/molar volume of solubilizate.     

Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: variation of oxyethylene content on properties of C22 monoethers

Studies on erucyl alcohol ethoxylated with 40 and 47 units, and on behenyl alcohol ethoxylated with 33 and 43 units, gave values of 106, 101, 271, and 304 (all × 10³) for the micellar weight, 51, 42, 152, and 137 for the aggregation numbers, and 257, 362, 209, and 311 moles water mol^?1 surfactant for the micellar hydration, respectively. Measurements of the solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone showed that the erucyl derivatives were better solubilizers than the behenyl compounds, and that solubilization increased as the polyoxyethylene chain was shortened; this change was more pronounced with the erucyl compounds.     

Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants containing very long hydrocarbon chains

Polyoxyethylene mono-ethers of dotriacontanol (C₃₂E₄₁) and 4, 9-dimethyltritriacontanol (C₃₅E₄₀) have been synthesized. The micellar weights in water at 298K were 4·82 × 10⁵ and 5·90 × 10⁵, the aggregation numbers 212 and 260, and the levels of hydration 290 and 283 mol water mol^?1 surfactant, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants. The presence of large micelles did not result in increased solubilization; C₃₂E₄₁ and C₃₅E₄₀ had a lower solubilizing capacity than that of cetomacrogol.     

Effect of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants with semi-polar hydrophobes

Novel non-ionic surfactants have been synthesized in which a polar group (either an ether or a keto group) has been introduced into the hydrocarbon chain of an octadecylpolyoxyethylene glycol monoether (C18En) with an oxyethylene chain length, n, of 17-18 units. Light scattering studies have indicated aggregation numbers for these semi-polar surfactants in aqueous solution of between 55-65% of that of an unsubstituted octadecylpolyoxyethylene glycol monoether, C18E22. The solubilizing capacities of the semi-polar surfactant micelles for test compounds which were mainly solubilized at the polyoxyethylene/core interface were lower than those of C18E22 whilst solubilizates which exhibited a reasonable degree of solubility in both the interface and the micellar core showed an increased solubilization.     

Effect of structural variations of non-ionic surfactants on surface properties: surfactants with semi-polar hydrophobes

The surface properties of a series of non-ionic surfactants in which a polar group (either an ether or a keto group) has been introduced into a hydrocarbon chain of octadecylpolyoxyethylene glycol monoether (C18E17-19) have been investigated. Surface tension measurements indicated that the critical micelle concentrations for these semi-polar surfactants in aqueous solution were all significantly higher than those of C18E22, the corresponding unsubstituted octadecylpolyoxyethylene glycol monoether. The minimum areas per molecule of the semi-polar surfactants in the surface monolayer were all larger than the area obtained for C18E22, from which it was concluded that the hydrophobe, and not the polyoxyethylene chain was the main determinant of surface area.     

Effects of some non-ionic surfactants on transepithelial permeability in Caco-2 cells

The effects of the non-ionic surfactants polysorbate 20, polysorbate 60, polysorbate 85, cholesteryl poly (24) oxyethylene ether (Solulan C24) and the lanolin-based poly (16) oxyethylene ether (Solulan 16) on the epithelial integrity of monolayers of human intestinal epithelial (Caco-2) cells has been studied using metformin as a model drug. The aim was to identify the surfactants and their optimal concentrations capable of enhancing drug transport while causing no, or only minor, cellular damage. Effects on cell permeability were assessed by measurements of the transport of metformin, a hydrophilic drug, by monitoring transepithelial electrical resistance. Cell viability was determined by the diphenyltetrazolium bromide test (the MTT test). All the surfactants studied demonstrated concentration-dependent effects on cell permeability and cell viability. The effects on transepithelial electrical resistance correlated with cell viability, i.e. increased transepithelial electrical resistance and increased cell-monolayer permeability for metformin corresponded to decreased cell viability. The results indicate that the Solulan and polysorbate surfactants were active as absorption enhancers, Solulan C24 and 16 being more effective than polysorbates 20, 60 or 85, causing an increase in metformin transport at lower concentrations than the polysorbates. Polysorbate 20 exerted its greatest effect at a concentration of 5%-increasing the flux of metformin after 3 h by a factor of around 20 over the control. Large increases in the transport of metformin, especially at surfactant levels of 0.05%, 0.1% and 0.5%, were related to the effect of Solulan C24 and Solulan 16 on the cell permeability. The Caco-2 cell monolayer experiments confirmed the ability, especially of polysorbate 20, Solulan C24 and Solulan 16, to increase the absorption of metformin. The polysorbates increased permeability as a result of solubilisation of membrane components, while Solulans did so by penetrating and solubilising the membrane. Correlation between increase in membrane permeability and the toxicity of the surfactants towards the cell membrane has been established.     

Inhibiting efflux with novel non-ionic surfactants: Rational design based on vitamin E TPGS

Tocopheryl Polyethylene Glycol Succinate 1000 (TPGS 1000) can inhibit P-glycoprotein (P-gp); TPGS 1000 was not originally designed to inhibit an efflux pump. Recent work from our laboratories demonstrated that TPGS activity has a rational PEG chain length dependency. In other recent work, inhibition mechanism was investigated and appears to be specific to the ATPase providing P-gp energy. Based on these observations, we commenced rational surface-active design. The current work summarizes new materials tested in a validated Caco-2 cell monolayer model; rhodamine 123 (10 μM) was used as the P-gp substrate. These results demonstrate that one may logically construct non-ionic surfactants with enhanced propensity to inhibit in vitro efflux. One new surfactant based inhibitor, Tocopheryl Polypropylene Glycol Succinate 1000 (TPPG 1000), approached cyclosporine (CsA) in its in vitro efflux inhibitory potency. Subsequently, TPPG 1000 was tested for its ability to enhance the bioavailability of raloxifene – an established P-gp substrate – in fasted male rats. Animals dosed with raloxifene and TPPG 1000 experienced an increase in raloxifene oral bioavailability versus a control group which received no inhibitor. These preliminary results demonstrate that one may prepare TPGS analogs that possess enhanced inhibitory potency in vitro and in vivo.     

Effects of non-ionic surfactants that modify experimental tuberculosis on lipase activity of macrophages

1. Six series of non-ionic surface active polyethylene glycol ethers, whose effects on experimental tuberculosis have previously been correlated with their polyoxyethylene chain lengths, were examined for their influence on the activity of a lipase present in homogenates of normal mouse peritoneal macrophages. The surfactants are concentrated in the lysosomes of macrophages-a cell type in which the host-parasite confrontation takes place. A preparation of soy bean oil was used as triglyceride substrate; and hydrolysis at pH 4.5 was compared in the presence and absence of surfactant, the products of hydrolysis being assayed by photodensitometry of thin-layer chromatograms.2. The compounds with short polyoxyethylene chains inhibited the release of fatty acid, compared with surfactant-free standard, more than did those with long chains; and some of the latter showed actual enhancement of release. Accumulation of monoglyceride was observed in the presence of six of the seven long-chained compounds, but with none of the seven short-chained compounds.3. The similarity between this correlation of chain length of the surfactants with their effect on macrophage lipase activity, and the known correlation of their chain length with their effect on experimental tuberculosis, suggests a possible connection. How this connection might relate to the mechanism of the varying effects on tuberculosis is briefly discussed.     

Solubilizing and lithogenolitic properties of water solutions of non-ionic surfactants of cholesterol oxyethylenation products

Research was conducted into the properties and identity of the products oxyethylenation of cholesterol, which were obtained with the use of a selective catalyst (K-4) and standard alkaline catalyst (Na/NaOH). The 1HNMR method was employed to assess the content of oxyethylated segments and the analytic level of hydrophilic--lipophilic balance (HLB). Basic viscosity and hydrodynamic values were determined for the solubilizers and their micellar adduct with ibuprofen, ketoprofen, naproxen and cholesterol. In addition, the amount of solubilized therapeutic agents and cholesterol as well as the micellar partition coefficient--K(m)w. was estimated. The results obtained in the course of research served as a basis for determining the solubilization mechanism and the stability of the micellar adduct for the purpose of application.     

A nuclear magnetic resonance (nmr) investigation of the micellar structure of a long-chain non-ionic surfactant

Peak integrals, peak widths at half-height (delta nu 1/2), spin-lattice relaxation times (T1), and chemical shifts (delta) of the alkyl and oxyethylene protons of CH3(CH2)21[OCH2CH2]27OH (C22E27) were measured in D2O at various temperatures. The peak integrals, delta nu 1/2, and delta values of the alkyl protons showed a large dependence on temperature below 313K, while the values for the oxyethylene protons were unaffected by temperature. These observations were explained by considering an intrusion of some oxyethylene groups into the hydrocarbon core of the micelle.     

Intestinal permeation and metabolism of a model peptide (leuprolide) and mechanisms of permeation enhancement by non-ionic surfactants

The intestinal permeability of leuprolide, a model nonapeptidel was determined using an in vitro model involving everted intestinal sacs of rat. Degradation of leuprolide by intestinal proteolytic enzymes was suppressed with a mixture of protease inhibitors which was shown to completely inhibit degradation in separate experiments using intestinal homogenates. This allowed the true permeability coefficient of leuprolide to be determined. The enhancement of this intestinal permeability by the Igepal CO’ homologue series of surfactants was investigated using members of this series with hydrophilic-lipophilic balance values (HLB) ranging between 12 and 19. Enhancement showed a non-monotonic dependence on HLB with a maximum at HLB = 15, while at both lower and higher HLB values an enhancement decrease was observed. Surfactant uptake into the tissue showed a similar non-monotonic dependence on HLB. On the other hand, red blood cell lysis and lecithin solubilization potencies of the Igepal CO showed a monotonic decrease with increasing HLB within the HLB range studied. Hence, it is suggested that the process of permeation enhancement should be dissociated from that of membrane solubilization in terms of the mechanism of surfactant-membrane interaction. While membrane disruption, for example, in the case of hemolysis, seems to be correlated with phospholipid solubilization it does not appear to be a prerequisite for permeation enhancement. Permeability increase of the plasma membrane may conceivably be accomplished by surfactant incorporation into the bilayer causing highly permeable disorder points and/or an increased membrane fluidity.     

Lecithin based nanoemulsions: A comparative study of the influence of non-ionic surfactants and the cationic phytosphingosine on physicochemical behaviour and skin permeation

Charged drug delivery systems are interesting candidates for the delivery of drugs through skin. In the present study, it was possible to create negatively and positively charged oil/water nanoemulsions by using sucrose laureate and polysorbate 80 as non-ionic surfactants. The positively charged nanoemulsions were generated by adding cationic phytosphingosine (PS). The relationship between the physicochemical properties of the nanoemulsions was shown by particle size and zeta potential measurements. These properties were dependent on the type of non-ionic surfactant and the concentration of PS. Furthermore the cationic PS had a positive impact on the skin permeation rates (flux) of the incorporated model drugs fludrocortisone acetate and flumethasone pivalate. An enhancement factor between 1.1 and 1.5 was obtained in relation to the control. The interaction of pre-impregnated porcine skin with positively and negatively charged nanoemulsions was confirmed by DSC analysis. The generated DSC-curves showed a slight difference in the phase transition temperature assigned to the characteristic lipid transition. However, it was not possible to assign the effect to one of the ingredients in the multicomponent system.     

Assay of terpene alcohols in pharmacopoeial essential oils by micellar electrokinetic capillary chromatography (MEKC)

Micellar electrokinetic capillary chromatography (MEKC) was used to separate and determine terpene alcohols of wide occurrence in herbal extracts and essential oils, namely eugenol, linalool, geraniol, citronellol and thymol. In the present paper sodium dodecyl sulfate (SDS) has been used as a micelle-forming additive to the CZE background electrolytes. Effects of SDS concentration, buffer type, its pH and concentration, addition of organic solvents on the migration times and separation efficiency were investigated. The optimal electrolyte system consisted of 20 mM TAPSO and 30 mM SDS in aqueous 10% (v/v) acetonitrile of pH 7.5 (adjusted by the addition of TRIS). The separation capillary was a fused silica tube (50 microm I. D., total length 75 cm, 42 cm effective length) maintained at 25 degrees C. The separations were performed at the applied voltage of 20 kV. Samples were injected hydrodynamically at a pressure of 50 mbar for 6 s. Detection was carried out at 200 nm. The calibration curves were rectilinear for 50-200 mg l(-1) (for eugenol, thymol and geraniol) and 100-400 mg l(-1) (for linalool and citronellol). The limits of detection varied between 5 mg l(-1) (for thymol) and 16 mg l(-1) (for linalool). The devised MEKC method was employed for the determination of the cited terpene alcohols as major quality-affecting constituents in commercial pharmacopoeial essential oils such as Geranii etheroleum, Caryophylli floris etheroleum, Lavandulae etheroleum and Thymi etheroleum. The results agreed well with those of a reference gas chromatographic method.     

The solubility-permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.     

Effect of some selected salts and non-ionic surfactants on the antimicrobial activity of nalidixic acid

The effect of different concentrations of some selected salts, namely, sodium chloride, potassium chloride, ammonium chloride, monosodium dihydrogen phosphate, calcium chloride, dibasic sodium phosphate, sodium sulphate, aluminium chloride and sodium citrate on the antimicrobial activity of nalidixic acid was investigated. It was found that all the salts tested, except aluminium chloride and sodium citrate, exert no antimicrobial activity. The effect of 10% non-ionic surface active agents, namely, Myrj 51, 52, 59, Brij 35, 58, 98, Tween 20, 40, 60, and 80 on the antimicrobial activity of nalidixic acid was studied. The results indicated that the activity of nalidixic acid was decreased in the presence of these surfactants. Furthermore, the effect of different concentrations of sodium chloride on the antimicrobial activity of nalidixic acid-surfactants systems was reported.