Spectrophotometric investigation of the binding of vitamin E to water-containing reversed micelles

The distribution constants of vitamin E partitioned between apolar organic phase and water-containing reversed micelles of sodium bis (2-ethylhexyl) sulfosuccinate (AOT), didodecyldimethylammonium bromide (DDAB), soybean phosphatidylcholine (lecithin) and tetraethylene glycol monododecyl ether (C12E4) have been evaluated by a spectrophotometric method. The results suggest that in the presence of domains from apolar organic solvent to surfactant and to water, vitamin E is partitioned between the micellar palisade layer and the organic solvent and also that its binding strength to reversed micelles depends mainly by specific interactions between the head group of vitamin E and that of the surfactant. Moreover, in addition to the advantageous interactions between vitamin E and water, the dependence of the distribution constants upon the molar ratio R (R=[water]/[surfactant]) indicates a competition between water and vitamin E for the binding sites at the water/surfactant interface. The biological implications of the preferential location and confinement of vitamin E in water-containing reversed micelles are discussed.     

Spectral Studies on the Molecular Interaction of Anticancer Drug Mitoxantrone with CTAB Micelles

The interaction of anticancer drug mitoxantrone with cationic surfactant cetyltrimethylammonium bromide (CTAB) has been investigated by absorption spectroscopy as a function of surfactant concentration ranging from the premicellar to postmicellar region at pH 7.4 and 10. Interaction of mitoxantrone with CTAB micelles induces a bathochromic shift of both absorption maxima and spectral data showed that the micellization reduces the dimerization process and mitoxantrone is bound into micelles in the monomeric form. Binding constant and partition coefficient were estimated using the red shifts of the absorption maxima in the presence of surfactant. From the resulting binding constants for mitoxantrone–surfactant interactions, it was concluded that the hydrophobic interactions have a great effect on the binding of mitoxantrone to CTAB micelles. Also, by comparing the partition coefficients obtained using pseudo-phase model, the hydrophobic interactions have a major role in the distribution of mitoxantrone between micelle–water phases. Gibbs free energy of binding and distribution of mitoxantrone between the bulk aqueous medium and surfactant micelles were calculated.     

Micellar Solubilization of Timobesone Acetate in Aqueous and Aqueous Propylene Glycol Solutions of Nonionic Surfactants

The micellar solubilization of timobesone acetate, a novel topical corticosteroid, was studied in aqueous and aqueous propylene glycol solutions of 1 to 5% nonionic surfactants at 25°C. The surfactants used were polyoxyethylene (POE) sorbitan monofatty acid esters (polysorbates), fatty acid esters (Myrj), and fatty alcohol ethers (Brij), as well as sucrose monolaurate (Crodesta SL40). The increase in the solubility of timobesone acetate in the micellar solutions was dependent on the type and concentration of surfactant. The solubilizing capacity of the surfactant micelles and the distribution coefficient of timobesone acetate in aqueous micellar solutions were found (1) to increase with increasing length of the hydrophobic fatty acid group; (2) to increase according to the structure of the hydrophilic group in the order of POE sorbitan ester, sucrose ester, POE ester, and POE ether; (3) to be unaffected by the increase in POE chain length; and (4) to tend to decrease in surfactant containing unsaturated fatty acid groups. In aqueous propylene glycol solution, the solubilizing capacity increased slightly, i.e., up to 1.5-fold in 50% propylene glycol solution, for the ester-type surfactants (polysorbates and Myrj). But this increase was not observed in the ether-type surfactant (Brij) solution. The distribution coefficient decreased logarithmically with increasing concentrations of propylene glycol in the solution. This was caused by the logarithmic increase in the timobesone acetate solubility in the bulk phase, while the solubility in the micellar phase was practically unchanged. The results support the equilibrium distribution model of micellar solubilization.     

Drug-surfactant interactions: effect on transport properties

The physico-chemical interactions between three model drugs and a variety of surfactants were characterized by measuring the apparent permeability coefficients of the drugs in the presence and absence of surfactants in vitro. The extent of interaction between the model drugs and the surfactants can best be described by the hydrophobic effect (primarily determined by the hydrophobic surface area of the drug molecule) and the electrostatic effect (primarily determined by the charge associated with the drug molecule as well as the surfactant molecules). For drugs that do not possess a significant hydrophobic surface area (timolol and cefoxitin), their interactions can best be described based on electrostatic effects (charge effects). This interaction being strong with oppositely charged surfactants. The interactions of L-692 585 (a model drug with appreciable hydrophobic surface area) in the presence of surfactants is dominated by the hydrophobic effect, with the electrostatic effect playing a minor secondary role. The apparent permeability coefficient of timolol as a function of the amount of surfactant in solution is modelled in light of micellar formation and entrapment and/or interaction of free drug with this micellar structure. Briefly, the extent of interaction as a function of amount of added surfactant for timolol indicates that initially as surfactant is added the activity of drug for transport declines significantly until a breaking point is reached, after which the drug activity available for transport remains relatively constant upon addition of more surfactant. A model is derived which is capable of describing this behavior and provides reasonable estimates for the critical micellar concentration of the surfactant, the affinity or binding constant for the interaction of drug with an equivalent micellar structure, and the loading capacity of the equivalent micellar structure. These observations are potentially significant for drug formulation of poorly bioavailable drugs.     

Selectivity manipulation in micellar electrokinetic chromatography.

Micellar electrokinetic chromatography (MEKC) permits the separation of electrically neutral analytes by chromatographic principles in a capillary electrophoresis system. The most effective way to obtain high resolution in MEKC is to increase the separation factor, as in conventional chromatography. The separation factor in MEKC depends on the molecular structure of the micelle and hence on the surfactant used, the pH of solution, and the nature of any additives to the micellar solution. The hydrophilic moieties of surfactant molecules generally affect selectivity more than do the hydrophobic moieties. Chiral surfactants enable the enantiomeric separation of mixtures of chiral solutes to be achieved. Mixed micelles consisting of ionic and nonionic surfactants display different selectivity from that of single ionic micelles. Additives such as cyclodextrins, ion-pair reagents, urea, organic solvents and metals can also serve as useful modifiers of the micellar solution for improving separation. In particular, cyclodextrins are useful for the separation of aromatic isomers and enantiomers. A general introductory guide to the design of successful separations by MEKC is proposed, based primarily on the author's work.     

Micelles based on HPMA copolymers

Polymeric micelles have been under extensive investigation during the past years as drug delivery systems, particularly for anticancer drugs. They are formed by the self-assembly of amphiphilic block copolymers in aqueous solutions and have a spherical shape and a size in the nano-range (< 200 nm). Tumor accumulation of polymeric micelles upon intravenous administration can occur as a result of the leaky vasculature of tumor tissue (called the enhanced permeation and retention (EPR) effect).To benefit from the EPR effect, polymeric micelles need to have prolonged circulation times as well as high and stable drug loadings. Poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA) is a hydrophilic polymer currently under investigation for its use in polymer-drug conjugates. Its biocompatibility, non-immunogenicity and the possibility for functionalization are properties that resulted in broad pharmaceutical and biomedical applications, also in the micelle technology research. Being hydrophilic, it can serve as a micellar stealth corona, while it can also be modified with hydrophobic moieties to serve as a micellar core in which hydrophobic drugs can be solubilized and retained. HPMA-based polymeric micelles have been showing very promising in vitro and in vivo results. This review summarizes the applications of pHPMA in the field of polymeric micelles, either serving as a micellar stealth corona, or, if hydrophobically rendered by derivatization, as a micellar core.     

Combined antioxidant effects of rutin and vitamin C in Triton X-100 micelles

UV-vis spectra, fluorescence emission spectra and cyclic voltammetric measurements were used to study the influence of Vitamin C on the antioxidant of rutin in Triton X-100 micelles. Rutin can be located in Triton X-100 micelles spontaneously through hydrophobic force, and the binding constant K between rutin and Triton X-100 increases with the rutin concentration. The embedment of two hydroxyl groups on rutin into the more hydrophobic micellar microenvironment makes the oxidation of rutin harder and the radical scavenging activity decrease. With low concentration of Vitamin C, the antioxidant capacity of rutin against hydroxyl radical is enhanced, while that capacity is partly inhibited when the concentration of Vitamin C become higher.     

The spectrophotometric study of the binding of vitamin E to water + dimethyl sulfoxide and water + diethyl sulfoxide containing reversed micelles

The effect of dimethyl sulfoxide (DMSO) and its nearest homologue diethyl sulfoxide (DESO) as a polar cosolvents on the binding of vitamin E to water + DMSO (DESO) containing reversed micelles of sodium bis(2-ethylhexyl) sulfosuccinate (AOT) has been investigated by a spectrophotometric method. The results suggest that compare with water without organic cosolvent-containing reversed micelles in this case an increase of binding constant of vitamin E in reversed micelles takes place. The results obtained shown that with the addition of DMSO and DESO it will be possible to monitoring a penetration of vitamin E into micellar core.     

A diffusion-ordered NMR spectroscopy study of the solubilization of artemisinin by octanoyl-6-O-ascorbic acid micelles

Artemisinin (QHS) is a natural drug with a very low solubility in water. To improve its availability in hydrophilic media, it was solubilized in micellar dispersions of octanoyl-6-O-ascorbic acid (ASC8), a relatively novel surfactant that combines surface activity with powerful performance as radical scavenger. In this article we report a study based on diffusion-ordered NMR spectroscopy (DOSY) measurements carried out on QHS/ASC8 micellar dispersions. QHS is efficiently solubilized by ASC8 micelles, with no significant perturbation of the micellisation.     

胺类药物的胶束色谱研究

以十二烷基硫酸钠(SDS)和溴化十六烷基三甲胺(CTAB)两者的胶束水溶液为流动相,利用高效液相色谱法,研究了七种具有典型分配率的胺类药物和有机弱酸的胶束色谱保留机理,以及胶束溶液在不同pH值时对溶质保留值的影响,提出了胶束色谱保留机理的指数模型公式。该公式可用于估计溶质的胶束色谱类型,对溶质与三相(胶束相、表面活性剂修饰的固定相及总水相)的静电作用、疏水作用对溶质保留值的影响做了合理的解释。     

Quantitative assessment of the negative catalytic effects of a cationic surfactant myristyl-γ-picolinium chloride on the specific-acid catalyzed epimerization of 15(S)-15-methyl prostaglandin F2α

The specific-acid catalyzed epimerization of 15(S)-15-methyl PGF_2α was found to be significantly inhibited in the presence of a cationic surfactant, myristyl-γ-picolinium chloride, at pH 2.5 and 25°C. The micellar inhibition observed is attributed to electrostatic repulsion between hydronium ion and the cationic polar heads of the micellar phase. As expected, at a given concentration of prostaglandin, the observed rate decreased as the surfactant concentration increased. When the concentration of prostaglandin was in the order of 7 × 10⁻² mg/ml (2 × 10⁻⁷M), the observed epimerization rate in a 1.0% surfactant solution was found to be approximately 120 times slower than that observed in the absence of surfactant. A quantitative analysis showed that the epimerization rate constant in the micellar phase is in the order of 6 × 10⁻⁷ s⁻¹ (cf. 2 × 10⁻⁴ s⁻¹ in the absence of the surfactant).However, the extent of micellar inhibition decreased as the initial concentration of prostaglandin increased in a series of solutions containing a constant amount of the surfactant. In order to quantitatively interpret this result, the apparent partition coefficient (ψm) of the prostaglandin between the micellar phase and the aqueous bulk phase was determined using a partitioning technique. Heterogeneity of the binding sites was detected in the analysis of ψm using the Scatchard equation.The primary binding sites are postulated to occur by a short penetration of prostaglandin molecules in the palisade layer. The secondary binding sites can be provided by either a simple adsorption process of prostaglandin onto the surface of micelles or the formation of mixed micelles. Although the primary binding sites show approximately 75-fold greater affinity towards the prostaglandin than the secondary binding sites, the number of available sites of the latter is approximately 25 times greater than that of the former. It is proposed that the Scatchard equation be used in the quantitative analysis of the effects of the substrate concentration at a constant surfactant concentration upon the observed micellar catalysis, a subject which has been unjustifiably neglected in the past.     

Effect of Nonionic Surfactant on Transport of Model Drugs in Emulsions

Purpose. To investigate the influence of excess surfactant on transport kinetics in emulsions, using phenylazoaniline (PAA), benzocaine, benzoic acid and phenol as model drugs. Mineral oil was chosen as the oil phase and the nonionic surfactant, polyoxyethylene oleyl ether (Brij 97) as the emulsifier. Methods. Model drug transport in emulsions was investigated using side by side diffusion cells mounted with hydrophilic dialysis or hydrophobic membranes. A novel method, involving a combination of a membrane equilibrium technique and surface tension measurement (Wilhelmy plate method), was developed to determine surfactant critical micelle concentration (CMC) in the presence of O/W emulsions. Emulsion stability was determined by droplet size analysis as a function of time, temperature and dilution using photon correlation spectroscopy and a light blockage technique. Model drug mineral oil/water partition coefficients and aqueous solubilities were determined in the presence of surfactant. Results. The emulsion CMC value was used to calculate micellar phase concentration. The transport rates of PAA and benzocaine in emulsions increased with increase in Brij 97 micellar concentration up to 1.0 % w/v and then decreased at higher surfactant concentrations. The transport rates of the more hydrophilic compounds, benzoic acid (ionized form, pH 7.0) and phenol, were not affected by the presence of micellar phase. Conclusions. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug lipophilicity. Transport rates measured using side by side diffusion cells appeared to be governed by model drug partitioning rates from the oil to the continuous phases and by membrane type.     

Behavior of itraconazole and benzyl alcohol in aqueous solution containing nonionic surfactants

In order to investigate the behavior of itraconazole and benzyl alcohol in aqueous solution containing surfactants, the distribution of itraconazole and benzyl alcohol between the micellar and aqueous phases was determined and the partition of itraconazole between the hydrophilic and lipophilic moieties in micelles was measured. From these experiments, we can conclude that: (1) in aqueous surfactant solution, itraconazole mainly exists in the micellar phase; (2) the cosolvency effect of benzyl alcohol has a negligible effect on the solubility of itraconazole in aqueous solution; (3) itraconazole tends to align itself in an intermediate position (palisade layer) within the surfactant molecules forming the micelle, which may result in the destruction of the micellar structure; and (4) the precipitation of itraconazole may occur in the process of the exchange of benzyl alcohol between the aqueous and micellar phases. This is the mechanism of destabilization of colloidal drug carriers based on benzyl alcohol.     

Mathematical Modelling of Drug Transport in Emulsion Systems

Two mathematical models for the prediction of drug transport in triphasic (oil, water and micellar) emulsion systems as a function of micellar concentration have been developed and these models were evaluated by comparing experimental and simulated data. Fick's first law was used to derive a transport model for hydrophilic drugs, assuming that the oil/water (o/w) partitioning process was fast compared with membrane transport and therefore drug transport was limited by the membrane. Consequetive rate equations were used to model transport of hydrophobic drugs in emulsion systems assuming that the o/w interface acts as a barrier to drug transport. Benzoic acid and phenol were selected as hydrophilic model drugs. Phenylazoaniline and benzocaine were selected as hydrophobic model drugs. Transport studies at pH 3.0 and 7.0 were conducted using side-by-side diffusion cells. According to the hydrophilic model, an increase in micellar concentration is expected to decrease drug transport rates. The effective permeability coefficients (P_eff) of drugs were calculated using an equation relating P_eff and the total apparent volume of drug distribution (determined experimentally using drug/membrane permeability and partition coefficient values). The hydrophobic model was fitted to the experimental data for the cumulative amount of model drug in the receiver cells using a weighted least-squares estimation program (PCNONLIN). The oil/continuous phase partitioning rates (k₁) and the membrane transport rates (k₂) were estimated. The goodness of fit was assessed from the correlation coefficients of plots of predicted versus experimental data. The predicted data were consistent with the experimental data for both the hydrophilic and hydrophobic models.     

Solubilisation in aqueous micellar solutions of block copoly(oxyalkylene)s

The solubilisation capacities of micellar solutions of diblock and triblock copolymers composed of hydrophilic poly(ethylene oxide) and hydrophobic poly(styrene oxide) have been compared using the poorly water-soluble drug griseofulvin as a model solubilisate. Our results showed an increase of solubilisation capacity (expressed as mg griseofulvin per gram of hydrophobic block) with temperature and, for spherical micelles, with core volume before reaching limiting values. A change of micelle shape from spherical to cylindrical (or worm-like) resulting from an increase in micelle aggregation number was accompanied by a further enhancement of solubilisation capacity. Comparison with the solubilisation of the same drug in micellar solutions of block copolymers of poly(ethylene oxide) and poly(1,2-butylene oxide) showed that the solubilisation capacity of a poly(styrene oxide) block was approximately four times that of a poly(1,2-butylene oxide) block for spherical micelles. Solubilisation capacity at 25 degrees C was approximately doubled when griseofulvin was incorporated into a copolymer melt and micelles initially formed from the drug-loaded melt at 65 degrees C rather than by loading the drug into pre-micellised solution at 25 degrees C in the usual manner.     

Dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery

Abstract

In this article, we prepared a dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery by using a degradable pH-responsive ketal derivative, mPEG2000-Isopropylideneglycerol (mPEG-IS, PI) polymer. The purpose of this study is to develop an injectable dual-responsive micellar nanogel system which has a sol-gel phase transition by the stimulation of body temperature with improved stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. The pH-responsive PI was designed with pH-responsive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties. The PI micelles encapsulated paclitaxel (PTX) was fabricated. Then, the PI micelles were formed in a thermo-nanogel. The micellar nanogel could improve the solubility and stability of PTX. The physiochemical properties of PI micelles and micellar nanogel were characterized. The results showed that dual-responsive micellar nanogel could carry out sol-gel transition at 37?°C. The PI polymer can spontaneously self-assemble into micellar structure with size of 100–200?nm. The dual-responsive micellar nanogel could be degraded under lower pH condition. The test in vitro PTX release showed that dual-responsive micellar nanogel could release about 70% for 70?h under pH 5.0 while about 10% release at pH 7.4 and pH 9.0. The dual-responsive micellar nanogel was of lower cytotoxicity and suppressed tumor growth most efficiently. The micellar nanogel will be a new potential dual-responsive drug delivery system for cancer therapy.     

Polysorbate 80 and Cremophor EL micelles deaggregate and solubilize nystatin at the core-corona interface

The extent and the location of nystatin solubilization by nonionic surfactant micelles were determined. The critical aggregation concentrations (CAC) of nystatin in 4 x 10(-3) M surfactant were determined by dynamic light scattering. The resulting CAC values for nystatin in Cremophor EL (CrEL), Tween 80 (T80), and Nofable ESO-9920 (NOF) were 150, 150, and 300 microM compared to 10 microM for the phosphate-buffered saline (PBS) control. The surfactants were able to solubilize and deaggregate nystatin from 50 to 75 times more than the PBS control. The core polarity of CrEL micelles, determined by pyrene fluorescence, was significantly lower than T80 and NOF micelles. The micelle-water partition coefficients (P) of nystatin and pyrene were determined by fluorescence spectroscopy. The partition coefficient values of 7.5 microM nystatin in CrEL and NOF micelles were 1100 +/- 60 and 1000 +/- 110, an insignificant difference (p > 0.1). However, there was a significant increase in pyrene partitioning in micelles with lower core polarity. Additionally, the P of nystatin decreased when the nystatin concentration was increased, whereas the pyrene P did not. The unusual partitioning behavior of nystatin revealed a good fit with the Langmuir adsorption isotherm, indicating solubilization at the micellar core-corona interface.     

The study of the influence of surfactant charge on alkaline hydrolysis reactions of acetylsalicylic acid (ASA) and triflusal (TFL) using spectrophotometric methods.

In this research, the effects of micellar systems on alkaline hydrolysis reactions of acetylsalicylic acid (ASA) and triflusal (TFL) were found to be dependant upon the surfactant charge within the micelle. In cationic micelles, there is a catalytic effect at low concentrations of surfactant. However, this reaction is inhibited at higher surfactant concentrations. In anionic micelles, a catalytic effect occurs, while in zwitterionic and non-ionic micelles there is an inhibitory effect. Such reactions are attributable to changes in reactants on the micellar surface, or to the fact that both reactants are found in different microenvironments. The pseudophase (PS) and ion-exchange (PPIE) models were found to be consistent with the experimental result. Furthermore, the association constants for both drugs could be determined together with micellar rate constants in heterogeneous media.