Influence of ceramides in the solubilization of stratum corneum lipid liposomes by C(12)-betaine/sodium dodecyl sulfate mixtures.

The solubilization of liposomes modeling the stratum corneum (SC) lipid composition and those obtained varying the proportion of ceramides by means of dodecyl betaine (C(12)-Bet)/sodium dodecyl sulfate (SDS) mixtures was studied. The surfactant/lipid molar ratios (Re) and the bilayer/aqueous phase partition coefficients (K) were determined by monitoring the changes in the static light scattering of the system during solubilization. The fact that the free surfactant concentration was always similar to its critical micelle concentration (CMC) indicates that the liposome solubilization was mainly ruled by the formation of mixed micelles. The mole fraction of the zwitterionic component (X(zwitter)) of 0.4 showed the lowest ability to saturate or solubilize liposomes, although exhibiting the highest degree of partitioning into liposomes. This X(zwitter) corresponded to the highest derivation of the CMCs of these mixtures (negative synergism) and to the highest reduction in the skin irritation with respect to the anionic component. Higher and lower proportion of ceramides in the mixture led to a fall and to a rise in both the activity and the partitioning of a specific surfactant mixture (X(zwitter)=0.4). This finding could be related to the recently reported dependences of the level of ceramides in skin and function barrier abnormalities. Comparison of the present Re and K values with those reported for phosphatidylcholine (PC) liposomes shows that, although SC liposomes were more resistant to the action of surfactant mixtures, the surfactant partitioning into SC bilayers was similar to that reported for PC ones in all cases.     

Characterization of micellar solubilization of antibiotics using micellar electrokinetic chromatography

Micellar electrokinetic chromatography (nMEKC) method was applied to the determination of the partition behaviour between water and micelle for a group of antibiotics using sodium dodecyl sulphate (SDS) as an anionic model surfactant. In the method, the running buffer contains both the micelles and the drug, and the injected solution contains the same concentration of the micelles as the running buffer but no drug. The mobility of the drug can be measured from a negative peak recorded in the chromatogram. The required parameters for the determination of the capacity factor were measured by the MEKC technique. Thermodynamic properties such as enthalpy and entropy changes of micellar solubilization were calculated from the temperature dependence of the partition coefficients. The critical micellar concentrations (CMC) of the SDS salt were determined in phosphate solutions at pH 7 at different temperatures using the MEKC. The method described in this article based on MEKC is efficient and very fast in order to determine parameters for characterizing micellar solubilization of drugs.     

Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymer micelles: theoretical and experimental data and correlations

The solubilization of five model hydrophobic drugs by a series of micelle-forming, water-soluble methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymers (MePEG-b-PCL) with varying methoxy poly(ethylene glycol) (MePEG) and polycaprolactone (PCL) block lengths was investigated. Variation of the feed weight ratio of MePEG to caprolactone resulted in the synthesis of copolymers with predictable block lengths. The micelle diameter and pyrene partition coefficient (Kv) were directly related to the PCL block length whereas the critical micelle concentrations (CMC) were inversely related to the PCL block length. The aqueous solubilities of the model hydrophobic drugs, indomethacin, curcumin, plumbagin, paclitaxel, and etoposide were increased by encapsulation within the micelles. Drug solubilization was directly related to the compatibility between the solubilizate and PCL as determined by the Flory-Huggins interaction parameter (chisp). Furthermore, the concentration of solubilized drug was also directly related to the PCL block length.     

The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs

The effects of types of surfactants on the solubilization and dissolution of poorly soluble acidic drugs were compared to identify the most suitable surfactant for conducting an acidic drug dissolution test. Cetyltrimethylammonium bromide (CTAB) as a cationic surfactant, sodium lauryl sulfate (SLS) as an anionic surfactant, and polysorbate 80 as a non-ionic surfactant were used in the study. And, mefenamic acid, nimesulide, and ibuprofen were selected as model drugs. The dissolution rates of these acidic drugs were substantially enhanced in medium containing CTAB. Electrostatic interactions between acidic drugs and cationic surfactants were confirmed by measuring UV spectra of each drug. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics. For acidic drugs, the ability of media containing a cationic surfactant to discriminate rates of dissolution of acidic drugs seemed to be greater than that of media containing other surfactant types.     

Physicochemical characterization and toxicity evaluation of steroid-based surfactants designed for solubilization of poorly soluble drugs

To overcome poor water-solubility of new drug candidates, four innovative surfactants based on naturally-occuring hydrophilic and hydrophobic moities were designed and synthesized: cholesteryl-glutamic acid, cholesteryl-poly[N-2-hydroxyethyl-l-glutamine] (PHEG), ursodeoxycholanyl-PHEG (UDCA-PHEG) and ursodeoxycholanyl-poly-l-glutamic acid (UDCA-PGA). Their self-assembling capacity was evaluated using pyrene fluorescence measurements which allow to determine their critical aggregation concentration (CAC). Size measurements were carried out using dynamic light scattering (DLS). Surfactant cytotoxicity was investigated on human umbilical vein endothelial cells (HUVEC) by determining tetrazolium salt (MTT) activity and lactate dehydrogenase (LDH) release. In addition, surfactant haemolytic activity was assessed using rat red blood cells (RBCs). Finally, the ability of these surfactants to solubilize a model poorly soluble drug was quantified. Surfactant self-assembly, cytotoxicity and solubilization properties were compared to those obtained with polysorbate 80, a model solubilizer. Except for cholesteryl-glutamic acid, surfactants were water-soluble. UDCA-PGA was not able to self-assemble or to increase significantly drug solubility. Results showed that cholesteryl-PHEG and UDCA-PHEG were self-assembling with low CAC values (17 and 120μg/ml) into nano-structures with mean diameters of 13 and 250nm, respectively. Cholesteryl-PHEG was the most efficient surfactant in increasing drug solubility (2mg/ml) but exhibited a similar or higher toxicity than polysorbate 80. UDCA-PHEG did not present any cytotoxicity but was far less efficient to solubilize the drug (0.2mg/ml). These results evidence interesting properties of cholesteryl-PHEG and UDCA-PHEG as novel solubilizers.     

Solubilization of flurbiprofen in pH-surfactant solutions

Based on an investigation on furbiprofen solubilization in polysorbate 80 solutions at different pH, this study proposed an equilibrium-based model to characterize the drug-surfactant interactions in pH controlled system. The model reflected both interactions and interdependence among all drug-containing species: unionized drug in water D(u), ionized drug in water D(i), unionized drug in micelles D(u)M, and ionized drug in micelles D(i)M. The micelles were defined and quantitated as the micellized surfactants, so both D(u)M and D(i)M were also seen as unionized and ionized drug associated with micellized surfactants. This mathematical treatment enables the modeling of the drug solubilization in pH-surfactant solutions without making unsound approximations. Using a separate set of solubility data at a different pH, a comparison was conducted between experimental data and the solubility estimated by this model, and by the partition model proposed by Rippie et al. It was found that both models yielded reasonably good estimation compared with experimental data. It was also found that the solubility data estimated by the proposed model were more reliable especially when the surfactant concentration was high in the system. This suggests that the consideration of interrelations and interdependence of all drug species in pH-surfactant solutions by this model is justified and appropriate.     

壳寡糖嫁接硬脂酸阳离子聚合物胶团的制备及其理化性质

目的考察阳离子型壳寡糖硬脂酸嫁接物胶团的理化性质及载药胶团的体外药物释放。方法以碳二亚胺为交联偶合剂制备壳寡糖硬脂酸嫁接物；芘荧光法测定该聚合物的临界聚集浓度，微粒粒度及电泳分析仪测定聚合物胶团的粒径和表面电位；以甲氨蝶呤为模型药物，考察胶团作为药物载体的可行性。结果嫁接物的临界聚集浓度为0.05 g·L^-1；去离子水中的胶团粒径为26.7 nm，表面电位为(55.9±0.1) mV；三聚磷酸钠修饰可使胶团粒径增加、表面电位降低、药物包封率增加；降低胶团溶液的pH值，可使胶团的粒径和表面电位上升，药物包封率下降，体外释药速度加快。 结论壳寡糖硬脂酸嫁接物胶团是一种良好的药物载体，其体外释药具有一定的pH依赖性。     

Study of the solubilization of gliclazide by aqueous micellar solutions

It was of interest to increase the solubility of gliclazide in aqueous media. Therefore, solubilization of gliclazide in a variety of surfactants was investigated. Anionic and cationic surfactants exhibited dramatic solubilizing ability for gliclazide, whereas nonionic surfactants showed significantly lower solubilizing ability. It was found that gliclazide solubility increases with increasing the carbon chain length of cationic surfactants and decreases with increasing the carbon chain length of anionic surfactants. The solubilization data were analyzed on the basis of a pseudo-phase model with gliclazide exhibiting moderate partition coefficients into the micellar phase. The possible sites of solubilization of gliclazide in the micelle were examined by studying the effect of NaCl on solubilization and by comparing the absorption spectra of gliclazide in different solvents. The results obtained from these two experiments indicated that gliclazide is solubilized mainly in the inner core of the cationic surfactant micelles and in the outer regions of the anionic surfactant micelles.     

Pharmacological effects of formulation vehicles : implications for cancer chemotherapy

The non-ionic surfactants Cremophor EL (CrEL; polyoxyethyleneglycerol triricinoleate 35) and polysorbate 80 (Tween) 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy.CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound alteration of drug accumulation in erythrocytes, thereby reducing the free drug fraction available for cellular partitioning and influencing drug distribution as well as elimination routes. The existence of CrEL and Tween 80 in blood as large polar micelles has also raised additional complexities in the case of combination chemotherapy regimens with taxanes, such that the disposition of several coadministered drugs, including anthracyclines and epipodophyllotoxins, is significantly altered. In contrast to the enhancing effects of Tween 80, addition of CrEL to the formulation of oral drug preparations seems to result in significantly diminished drug uptake and reduced circulating concentrations.The drawbacks presented by the presence of CrEL or Tween 80 in drug formulations have instigated extensive research to develop alternative delivery forms. Currently, several strategies are in progress to develop Tween 80- and CrEL-free formulations of docetaxel and paclitaxel, which are based on pharmaceutical (e.g. albumin nanoparticles, emulsions and liposomes), chemical (e.g. polyglutamates, analogues and prodrugs), or biological (e.g. oral drug administration) strategies. These continued investigations should eventually lead to more rational and selective chemotherapeutic treatment.     

Preparation and evaluation of folate-modified cationic Pluronic micelles for poorly soluble anticancer drug

The aim of this study was to construct novel targeting polymeric micelles. Folate-Poly (ethylenimine)-Pluronic copolymers were synthesized. A paclitaxel (PTX)-loaded mixed micelles consisting of Folate-Poly (ethylenimine)-Pluronic and Pluronic L121 copolymers have been developed. The mixed micelles showed nano-sized spherical morphology. The solubilization capacity of the mixed micelles was higher than Folate-Poly (ethylenimine)-Pluronic micelles because L121 has high solubilization capacity. MTT colorimetric test revealed that PTX in Folate-Poly (ethylenimine)-Pluronic micelles demonstrated the maximum anticancer activity. Pluronic-poly (ethylenimine) micelles and folate-modified Pluronic-poly(ethylenimine) micelles showed a marked increase of cellular accumulation compared with Pluronic P123 micelles. The biodistribution and retention of intravenously (i.v.) administered micelles to rats were determined. Folate-Poly (ethylenimine)-Pluronic micelles demonstrated enhanced pulmonary retention in rats after injection when compared to Pluronic P123 micelles.     

Solubilization of hydrocortisone, dexamethasone, testosterone and progesterone by long-chain polyoxyethylene surfactants.

Solubility and dialysis methods were used to study the solubilization of hydrocortisone, dexamethasone, testosterone and progesterone in aqueous long-chain polyoxyethylene non-ionic surfactant solutions. Partition coefficients, Km, between micellar and aqueous phases were calculated between 10-50 degrees. Km decreased with temperature and polyoxyethylene chain length but increased with decrease in steroid polarity. The standard free energy change, deltaGOS, for the solubilization of the steroids decreased with decrease in steroid polarity and surfactant hydrophilic chain length but was essentially independent of temperature. The enthalpies and entropies for the process were determined from the variation of Km with temperature. deltaHOS and deltaSOS increased with decreasing steroid polarity but were essentially independent of temperature and polyoxyethylene chain length.     

Bilayer to micelle transition of DMPC and alcohol ethoxylate surfactants as studied by isoperibol calorimetry

The interaction of dimyristoylphosphatidylcholine (DMPC) with non-ionic surfactants has been studied using isoperibol calorimetry. Phospholipid-surfactant systems were formed in the isoperibol calorimeter with varying amounts of surfactant and the change in enthalpy on formation was measured. Solubilization of the phospholipid lamellae was assessed as a decrease in the enthalpy of reaction of co-films containing DMPC and increasing amounts of three linear alcohol ethoxylate surfactants: C(10)H(21)(OCH(2)CH(2))(3)OH, C(10)H(21)(OCH(2)CH(2))(5)OH, or C(12)H(25)(OCH(2)CH(2))(7)OH. The isoperibol calorimetry data for DMPC/surfactant/water systems were consistent with a theoretical three-stage model for the solubilization of phospholipids by surfactants, whereby phospholipid bilayers are transformed into mixed micelles with increasing amounts of surfactant. The results indicate that: (i) the interaction between phospholipid and surfactants results in a non-linear correlation between the enthalpy of reaction and the surfactant concentration; (ii) the structural stage of the lamellar to micelle transition (mixed bilayers, mixed micelles, or both) can be determined from calorimetric data; (iii) phase boundaries in the solubilization process (bilayer saturation, micelle saturation) can be identified as break points in the enthalpy-concentration curve; and (iv) increasing the hydrophilicity of the surfactant results in a decrease of the surfactant concentration producing the onset of solubilization.     

Micellar distribution equilibria: ultracentrifugal study of apparent partition coefficients.

Ultracentrifugation was used for the partial isolation of polysorbate 80 micelles in aqueous media to determine the apparent partition coefficients of various drug species between water and the micellar pseudophase. The ratio of solute concentration in the micelles to that in water was measured for procaine, salicylic acid, sulfapyridine, sulfisoxazole, and sodium 2-naphthalensulfonate over ranges of pH, surfactant concentration, drug concentration, and micelle sedimentation. Apparent partition coefficients for the systems investigated were independent of both drug concentration and surfactant concentration, indicating that the mode(s) of surfactant-drug interaction are essentially invariant over the ranges of systematic variables studied. The method provides a relatively simple and rapid means of quantitatively evaluating drug-surfactant interactions above the CMC, when surfactant and solute can be assayed in mixtures without interference.     

In vitro characterization of PEGylated phospholipid micelles for improved drug solubilization: effects of PEG chain length and PC incorporation

Sterically stabilized micelles (SSM) composed of poly(ethylene glycol-2000)-grafted distearoylphosphatidylethanolamine (DSPE-PEG) and sterically stabilized mixed micelles (SSMM) composed of DSPE-PEG and egg-phosphatidyl choline (PC) have recently been introduced as novel lipid based carriers for water-insoluble drugs. However, factors that affect the solubilization behavior of these phospholipid micelles are not well understood. This study investigates the effect of PEG chain length and PC content on physical properties and solubilization potential of PEGylated phospholipid micelles. Critical micelle concentrations (CMC) determined for DSPE-PEG with different PEG chain lengths (2000, 3000, and 5000) using a fluorescent probe were in the micromolar range (0.5-1.5 microM) with higher CMC for longer PEG chain length. The size of micelles determined by quasi-elastic light scattering (QELS) showed that micellar systems became heterogeneous when PC was added at > or =25% for DSPE-PEG 2000 and > or = 40% for DSPE-PEG 5000, respectively. Above these critical PC ratios a significant increase in aggregation number and formation of rodlike particles were observed by small angle neutron scattering (SANS). Solubilization of diazepam was greater with DSPE-PEG 2000 than DSPE-PEG 5000 simple micelles as determined by RP-HPLC. However, DSPE-PEG 5000 micelles showed greater improvement in solubilization of the water-insoluble drug with an increase in PC content. In conclusion, phospholipid micelle size and solubilization potential varied with PEG chain length and PC content in the mixed micelle. Aggregation number and shape of the micelles did not significantly change until the critical PC concentrations.     

Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents.

The solubilization behavior of a poorly soluble model drug, phenytoin (PHT), under combined use of surfactants (sodium dodecyl sulfate (SDS), Tween 80) and cosolvents (dimethylacetoamide (DMA), ethanol, poly(ethylene glycol) 400 (PEG), glycerol) was examined. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. The solubility of PHT in water-cosolvent mixtures roughly followed the log-linear model, which is widely accepted to explain the solubilization behavior of poorly soluble compounds in water-cosolvent mixtures, except for the case of glycerol, in which the solubility was minimal at 10% (w/v) of glycerol. When the cosolvents were added to the aqueous surfactant solutions, their effect on the solubility depended on the combination of the surfactant and the cosolvent. The most striking increase in solubility was observed with DMA, regardless of the type of surfactant. When ethanol was added, an increase in the solubility was observed with the Tween 80 solution, while a dramatic decrease was found with the SDS solution. The addition of glycerol or PEG to the surfactant solutions had only a minor impact on the solubility. These solubilization behaviors of PHT in the surfactant-cosolvent mixtures were partially explained by the solubility model introduced in our previous paper [Kawakami, K., Miyoshi, K., Ida, Y., 2004. Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent. J. Pharm. Sci. 93, 1471-1479]. Addition of the cosolvents to the surfactant solutions generally offered only a small advantage from the viewpoint of improving solubility because of the decrease in the solubilization capacity of the micelles.     

pH敏感释药两亲性壳聚糖共聚物胶束的制备及其性质考察

目的在合成了两亲性接枝共聚物丁酰基-羧甲基-壳聚糖(butyryl-carboxymethyl-chitosan,BR-CM-CS)的基础上,采用化学键合载药方式结合透析法制备了阿霉素pH敏感两亲性共聚物胶束并对其相关性质进行考察。方法利用芘荧光探针技术测定胶束的临界胶束浓度(CMC);通过透析法结合紫外分光光度法测定胶束的载药量及包封率;分别利用透射电镜(TEM)、扫描电镜(SEM)、动态光散射法(DLS)和zeta电位分析仪对胶束及其冷冻干燥产品的形态、粒径和表面电位进行了表征;采用透析法考察了载药聚合物胶束的体外释放行为。结果胶束的CMC值为1.0 mg.L-1,载药量可达12.5%,包封率为89.1%;胶束的粒度分布很窄,平均粒径为205.2 nm;胶束粒子为类球形且分散良好,其表面zeta电位值为25.94 mV;胶束释药行为体现pH敏感性。结论以壳聚糖为载体的化学腙键释药胶束作为抗肿瘤药物的传递系统具有可行性及良好的应用前景。     

Interaction of substituted benzoic acids with polysorbate 20 micelles.

Equilibrium solubilities of a series of substituted benzoic acids in different concentrations of polysorbate 20 at controlled pH were measured. The maintenance of pH was achieved using a pH-stat assembly. A linear relationship was found between the amount of benzoic acid solubilized and surfactant concentration. As solubilizate polarity increased, the amount solubilized also increased. Solubility data were analyzed, and the interaction between solubilizate molecules and micelles was calculated in terms of partition coefficients of ionized and unionized molecules between aqueous and micellar phases. A linear relationship between pi values (log partition coefficients) of functional groups and aqueous-micellar partition coefficient was found.     

Investigations of the solubilization kinetics of binary mixtures of non-polar oils by non-ionic surfactants

An investigation of the solubilization kinetics of binary mixtures of non-polar oils by a non-ionic surfactant has been made using the drop-on-fibre technique. Variables studied were the oil composition, surfactant concentration and the temperature. Rates vary linearly with the surfactant concentration for all oil compositions. The observed rate during nearly total solubilization of each oil drop was constant, implying that in these systems solubilization is non-selective. The rates increase as the lower consolute (cloud) temperature of the surfactant is approached. Activation energies of the solubilization process are shown to be independent of the oil composition for the system studied. This suggests that the important stage of the process involves dissociation of the surfactant micelles.     

The usefulness of sugar surfactants as solubilizing agents in parenteral formulations

The usefulness of sugar surfactants as solubilizing agents was assessed and compared to commercial polyoxyethylene-based surfactants. The sugar surfactants examined comprised of monosaccharides or disaccharides with alkyl chains ranging from C(8) to C(12). Each surfactant was investigated with respect to solubilization capacity for felodipine and haemolytic activity. The haemolytic activity was determined using a static method in which surfactant solutions were added to fresh dog blood. The polyoxyethylene-based surfactants were found to be more suitable as solubilizing agents than the sugar surfactants due to better solubilization capacities combined with lower haemolytic activities. The sugar surfactants caused severe haemolysis below or at the critical micelle concentration, in contrast to the polyoxyethylene-based surfactants that are nonhaemolytic in this concentration range. The structure-related variations in haemolytic activity are probably due to variations in the surfactants partition coefficients for the distribution equilibrium between the aqueous phase and the cell membrane. Longer alkyl chains cause higher haemolytic activity, while larger saccharide groups lower the activity. The clear difference between sugar and polyoxyethylene surfactants, which are considerably less haemolytic, is due to a combination of low critical micelle concentrations and presumably low degrees of partitioning of the latter surfactants into the cell membranes.     

Role of Formulation Vehicles in Taxane Pharmacology

The non-ionic surfactants Cremophor EL (CrEL) and Tween 80,both used as formulation vehicles of many (anticancer) agentsincluding paclitaxel and docetaxel, are not physiologicalinert compounds. We describe their biological properties,especially the toxic side effects, and their pharmacologicalproperties, such as modulation of P-glycoprotein activity. Indetail, we discuss their influence on the disposition of thesolubilized drugs, with focus on CrEL and paclitaxel, and ofconcomitantly administered drugs. The ability of thesurfactants to form micelles in aqueous solution as well asbiological fluids (e.g. plasma) appears to be of greatimportance with respect to the pharmacokinetic behavior of theformulated drugs. Due to drug entrapment in the micelles,plasma concentrations and clearance of free drug changesignificant leading to alteration in pharmacodynamiccharacteristics. We conclude with some perspectives related tofurther investigation and development of alternative methodsof administration.