Structural characterisation of water-Tween 40/Imwitor 308-isopropyl myristate microemulsions using different experimental methods

Pharmaceutically usable microemulsion systems were prepared from water and isopropyl myristate with a constant amount of Tween 40 and Imwitor 308 at a mass ratio of 1. Their type and structure were examined by measuring density and surface tension, and by viscometry, electric conductivity, differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS), and the degree of agreement between the techniques was assessed. A model based on monodisperse hard spheres adequately fits the SAXS data in W/O microemulsions predicting, depending on composition, elongated or spherical droplets. It also suggests the involvement of strong attractive interactions in O/W systems. Results of conductivity, viscosity, density and surface tension measurements confirm the prediction of a percolation transition to a bicontinuous structure. DSC detects the degree of water interaction with surfactants thus identifying the type of microemulsion. The conclusions from all the techniques agree well and indicate that such studies could also be carried out on more complex systems. In future, the ability to determine type and structure of such microemulsion systems could enable partitioning and release rates of drugs from microemulsions to be predicted.     

Characterization of caprylocaproyl macrogolglycerides based microemulsion drug delivery vehicles for an amphiphilic drug

Microemulsion systems composed of water, isopropyl myristate, PEG-8 caprylic/capric glycerides (Labrasol), and polyglyceryl-6 dioleate (Plurol Oleique), were investigated as potential drug delivery vehicles for an amphiphilic model drug (diclofenac diethylamine). Pseudo-ternary phase diagram of the investigated system, at constant surfactant/cosurfactant mass ratio (Km 4:1) was constructed at room temperature by titration, and the oil-to-surfactant/cosurfactant mass ratios (O/SC) that exhibit the maximum in the solubilization of water were found. This allowed the investigation of the continuous structural inversion from water-in-oil to oil-in-water microemulsions on dilution with water phase. Furthermore, electrical conductivity (sigma) of the system at Km 1:4, and O/SC 0.250 was studied, and the percolation phenomenon was observed. Conductivity and apparent viscosity (eta') measurement results well described colloidal microstructure of the selected formulations, including gradual changes during their formation. Moreover, sigma, eta', and pH values of six selected microemulsion vehicles which differ in water phase volume fraction (phi(w)) at the selected Km and O/SC values, were measured. In order to investigate the influence of the amphiphilic drug on the vehicle microstructures, each system was formulated with 1.16% (w/w) diclofenac diethylamine. Electrical conductivity, and eta' of the investigated systems were strongly affected by drug incorporation. The obtained results suggest that diclofenac diethylamine interacts with the specific microstructure of the investigated vehicles, and that the different drug release kinetics from these microemulsions may be expected. The investigated microemulsions should be very interesting as new drug carrier systems for dermal application of diclofenac diethylamine.     

The influence of cosurfactants and oils on the formation of pharmaceutical microemulsions based on PEG-8 caprylic/capric glycerides

In the present study the effect of type and concentration of a cosurfactant and oil on the ability of nonionic surfactant PEG-8 caprylic/capric glycerides (Labrasol) to solubilize both oil and water phases was evaluated. Seven different cosurfactants (polyglyceryl-6 dioleate (Plurol Oleique) (PO), polyglyceryl-6 isostearate (Plurol Isostearique (PI), polyglyceryl-4 isostearate (Isolan GI 34) (IGI34), octoxynol-12 (and) polysorbate 20 (Solubilisant gamma) 2421) (SG2421), octoxynol-12 (and) polysorbate 20 (and) PEG-40 hydrogenated castor oil (Solubilisant gamma 2429) (SG2429), PEG-40 hydrogenated castor oil (Cremophor) RH 40) (CRH40) and diethyleneglycol monoethyl ether (Transcutol) and six oils (isopropyl myristate, ethyl oleate, decyl oleate, medium chain triglycerides, mineral oil and olive oil) were used in phase behaviour studies of a quaternary system Labrasol/cosurfactant/oil/water. The amount of surfactant required to completely homogenize equal masses of oil and water to form a single phase microemulsion (termed as balanced microemulsion) (S min, %w/w), the minimal concentration of the surfactant/cosurfactant blend required to produce a balanced microemulsion (SCoS min, %w/w) as well as the maximum concentration of water solubilized in investigated surfactant/oil and surfactant/cosurfactant/oil mixtures (W(max), %w/w) were determined. The obtained results indicated that Labrasol showed a good efficiency in the presence of lower molecular volume fatty acid esters with a preferred chemical structure such as isopropyl myristate (S min 56.14% (w/w); W(max) 12.28% (w/w)). Oils with high molecular volume (olive oil and mineral oil) do not result in microemulsion formation. Transcutol decreased the capacity of Labrasol for solubilization of oil and water phases. The tendency of Labrasol to solubilize both, water and oil phases, was favoured by polyglycerol-6 ester type of cosurfactants (PO and PI) while the influence of the polyglycerol-4 ester (IGI34) as well as of polyoxyethylene type of cosurfactants (CRH40, SG2421 and SG2429) on the surfactant efficiency, was not significant. Furthermore, the results revealed the significant influence of the surfactant/cosurfactant mass ratio (K(m)) on synergistic effect between polyglyceryl-6 esters and Labrasol in the formation of microemulsions using isopropyl myristate as oil phase. Optimized microemulsion systems were stabilized with Labrasol/polyglyceryl-6 esters blend at K(m) 5:5 (SCoS min, 27.5% (w/w) and W(max), 71.43% (w/w) for PI; SCoS min, 29.18% (w/w) and W(max), 65.00% (w/w) for PO) and the electrical conductivity measurement results for optimized balanced microemulsions showed that their structures were highly conductive indicating a bicontinuous microstructure.     

Investigation of microemulsion microstructures and their relationship to transdermal permeation of model drugs: ketoprofen, lidocaine, and caffeine

In this study, microemulsion microstructures, key formulation variables, and their relationship to drug transdermal permeation enhancement were investigated. A microemulsion system with high water soluble capacity was developed, using isopropyl myristate, Labrasol, and Cremophor EL as oil, surfactant, and co-surfactant, respectively. The microstructures of the microemulsions were characterized by a combination of techniques including electrical conductivity measurement (EC), differential scanning calorimetry (DSC), electro-analytical cyclic voltammetry (CV), dynamic light scattering (DLS). Three microemulsion formulations with the model drugs at water contents of 20%, 40%, and 70% representing the microstructures of W/O, Bi-continuous, and O/W were prepared along the water dilution line of oil to surfactant ratio of 1/9. Skin permeation of hydrophobic and hydrophilic model drugs, ketoprofen, lidocaine, and caffeine in the microemulsion formulations was studied using Franz-cells and dermatomed porcine skin. Permeation of all drugs from microemulsions was enhanced significantly compared with the control propylene glycol formulation. The drug permeation flux and the cumulative permeation amount after 24 h increased with water content in the microemulsions, thus correlated to the formulation microstructures of W/O, Bi-continuous, and O/W. The permeation of lipophilic drugs ketoprofen and lidocaine increased with water content in a more pronounced manner, which seemed to follow an exponential growth trend, while the permeation of hydrophilic drug caffeine appeared to increase linearly. Additionally, at the same water content, increasing oil content led to higher ketoprofen permeation.     

Bicontinuous cyclosporin a loaded water-AOT/Tween 85-isopropylmyristate microemulsion: structural characterization and dermal pharmacokinetics in vivo

Topical delivery of Cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders. Microemulsion systems prepared by AOT/Tween85/isopropyl myristate (IPM)/water possessing a potentially improved skin bioavailability of CysA were designed. The structure of microemulsions was investigated by diffusion-ordered NMR spectroscopy (DOSY) and differential scanning calorimetry (DSC) measurements. The DOSY measurements indicated the presence of bicontinuous and water-in-oil microemulsions depending on microemulsion composition. The DSC measurement confirmed that the microemulsion containing 30.0 wt% water was bicontinuous type, in agreement with the DOSY findings. We also evaluated the therapeutic advantage of dermal administration of CysA in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the bicontinuous microemulsion containing CysA, the deposition of the drug into skin and subcutaneous fat was respectively almost 30 and 15-fold higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical administration than that of following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical microemulsion vehicle loaded with CysA might deliver maximal therapeutic effect to local tissue while avoiding side effects seen with systemic therapy. The histopathological findings revealed that the new bicontinuous microemulsion was a safe vehicle for topical drug delivery of CysA.     

Transdermal delivery of diclofenac using microemulsions

A transdermal preparation containing diclofenac diethylammonium (DDA) was developed using an O/W microemulsion system. Of the oils tested, lauryl alcohol was chosen as the oil phase of the microemulsion, as it showed a good solubilizing capacity and excellent skin permeation rate of the drug. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant and cosurfactant for microemulsion formation, and the effect of these additives on skin permeation of DDA was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 1.16% of DDA, 5% of lauryl alcohol, 60% of water in combination with the 34.54% of Labrasol (surfactant)/ethanol (cosurfactant) (1:2). The efficiency of formulation in the percutaneous absorption of DDA was dependent upon the contents of water and lauryl alcohol as well as Labrasol:ethanol mixing ratio. It was concluded that the percutaneous absorption of DDA from microemulsions was enhanced with increasing the lauryl alcohol and water contents, and with decreasing the Labrasol:ethanol mixing ratio in the formulation.     

Water-Tween 40/Imwitor 308-isopropyl myristate microemulsions as delivery systems for ketoprofen: small-angle X-ray scattering study

Small-angle X-ray scattering technique has been used to study the structural properties of the quaternary microemulsion Tween 40/Imwitor 308/isopropyl myristate/water and of five-component system obtained by the addition of the drug ketoprofen to the original quaternary system. The results enlighten the structuration of the studied systems and represent new complementary findings to the previous study [Podlogar, F., Bester-Rogac, M., Gasperlin, M., 2005. The effect of internal structure of selected water-Tween 40 (R)-Imwitor 308 (R)-IPM microemulsions on ketoprofene release. Int. J. Pharm. 302, 68-77] on the correlation between the structuration of these systems and the release rates of the ketoprofen. The present results indicate that in the samples with the moderate to high concentration of water where the latter is a continuous phase the addition of smaller amounts of the ketoprofen does not change their inner structuration significantly. The quaternary sample containing 46.2wt.% of water seems to be very near the composition where the transition from the bicontinuous to the lamellar structure of the microemulsion occurs. In the samples containing from 46.2 to 62.7wt.% of water the swelling of lamellar phases with constant thickness of double-layer can be characterized. At approximately the latter composition another noticeable transition in the inner structuration of the microemulsion has been observed. Interestingly, all these changes in the inner structuration of the studied systems did not affect the trend of the drug release rates in this regime of water concentrations.     

三七总皂苷油包水微乳的处方筛选及体内外评价

筛选口服油包水(W/O)微乳处方以提高三七总皂苷(panax notoginsenoside，PNS)中人参皂苷Rb₁的体内肠吸收，分别采用大鼠体内肠吸收、脂质体和平行人工膜(parallel artificial membrane permeability assay，PAMPA)等模型分别研究微乳的体内药代动力学及体外对膜流动性和药物膜转运性质的影响。主要以磷脂/乙醇(SP/EtOH)为表面活性剂，与PNS水溶液(400 mg·mL^-1)和不同油相分别制备11个W/O微乳处方。多数微乳处方可提高药物的大鼠体内肠吸收，其吸收促进作用除与所含表面活性剂有关外，不同油相的选用也会产生一定影响，其吸收促进作用大小为月桂酸甘油酯≈肉蔻豆酸异丙脂>棕榈酸异丙脂>棕榈酸异辛酯。长链(>C₁₄)脂肪酸酯的吸收促进作用低于中链脂肪酸酯(C₈~C₁₄)。多数微乳处方可不同程度的提高脂质体的膜流动性。PAMPA研究中，稀释后微乳(D-ME)中药物的有效透过系数(P_e)多数高于PNS对照溶液，表明微乳中的组分可以提高药物的膜透过能力，稀释前微乳(ME)的P_e与大鼠体内肠吸收具有相对较好的直线相关性(r=0.774 0)。W/O微乳可以促进人参皂苷Rb₁的肠吸收，吸收促进作用与其提高生物膜流动性有一定关系。PAMPA可以尝试引入制剂处方研究(如吸收促进剂等)的某些领域中。     

卵磷脂微乳的制备与理化性质考察

目的：对25℃各卵磷脂系统中微乳的形成区域以及微乳理化性质随系统中各组分的变化情况进行研究。方法：卵磷脂作表面活性剂,短链醇类作助表面活性剂,采用不同油相考察相图中油包水型微乳形成区域的变化;选择不同处方组分的微乳测定微乳理化性质。结果：各个系统均可形成油包水型微乳,室温下放置数月未见分层。卵磷脂/醇质量比(K_m)与水相量对微乳的粘度有显著影响;电导率随着水相含量增加而增大;微乳的粒径随着体系中水相的增加而增大。结论：K_m较大,水相含量适中的微乳体系较为适合制备药物载体。     

Protein delivery using nanoparticles based on microemulsions with different structure-types

Poly(alkylcyanoacrylate) nanoparticles based on microemulsions with different structure-types and containing insulin as a model protein were prepared and characterised in this study. A phase diagram of the pseudoternary system isopropyl myristate, caprylocaproyl macrogolglycerides, polyglycerol oleate and water was established. All compounds used in this study were pharmaceutically acceptable and biocompatible. The area in the phase diagram containing optically isotropic, monophasic systems was designated as the microemulsion region. Systems within this region were identified as water-in-oil (w/o), bicontinuous and oil-in-water (o/w) microemulsions with viscosity, conductivity, differential scanning calorimetry and self-diffusion NMR. The size distributions of the resulting nanoparticles prepared by interfacial polymerisation from selected microemulsions using ethyl (2) cyanoacrylate and butyl (2) cyanoacrylate were unimodal but template- and monomer-dependent and ranged from 160 to 400 nm. Entrapment and release of insulin were also studied. Entrapment ranged from 11.5 to 20.9% and a near zero-order release was observed after an initial burst. Release of insulin was monitored for 6 h. Insulin-loaded nanoparticles were 320–350 nm in size. The microemulsion-structure was retained during the polymerisation process as determined by NMR. This study showed that these microemulsions with flexible formulation possibilities for the solubilisation of peptides and proteins depending on their microstructure could serve well as a platform for designing encapsulation processes for oral delivery of insulin.     

Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen

The aim of this study was to prepare novel microemulsion for transdermal drug delivery of ketoprofen (KP). The microemulsion composed of ketoprofen as model drug, isopropyl myristate (IPM) as oil phase, surfactant mixture consisting of polyoxyl 40 hydrogenated castor oil (Cremophor RH40) as surfactant and polyethylene glycol 400 (PEG400) as co-surfactant at the ratio 1:1, and water were prepared. The viscosity, droplet size, pH, conductivity of microemulsions, and skin permeation of KP through shed snake skin were evaluated. The particle size, pH, viscosity and conductivity of microemulsions were in the range of 114-210 nm, 6.3-6.8, 124-799 cPs and 1-45 μS/cm, respectively. The ratio of IPM, and surfactant mixture played the important role in the skin permeation of KP microemulsions. As the amount of surfactant mixture and IPM increased, the skin permeation of KP decreased. The formulation composed of 30% IPM, 45% surfactant mixture and 25% water showed the highest skin permeation flux. The incorporation of terpenes in the 2.5% KP microemulsions resulted in significant enhancement in skin permeation of KP. The rank order of enhancement ratio for skin permeation enhancement of terpenes was α-pinene > limonene > menthone. The results suggested that the novel microemulsion system containing IPM, water, Cremophor RH40:PEG400 and terpenes can be applied for using as a transdermal drug delivery carrier.     

Linker-based lecithin microemulsions for transdermal delivery of lidocaine

In this work, we introduce alcohol-free lecithin microemulsions formulated with linkers to produce transdermal delivery vehicles. The food-grade linker system consists of a combination of sodium caprylate and caprylic acid (hydrophilic linkers), and sorbitan monooleate (lipophilic linker). A "carrier" oil (isopropyl myristate) was used to predissolve a model lipophilic drug, lidocaine. The first part of the article describes the phase behavior and physical properties of these linker-based lecithin microemulsions. In the second part of the article, we evaluate the transdermal permeation and cytotoxicity of lidocaine formulated in oil-in-water (Type I), water-in-oil (Type II), and bicontinuous (Type IV) linker microemulsions. The transdermal permeation studies show that compared to a conventional Type II alcohol-based lecithin microemulsion, Type II linker-based microemulsions provide twice the absorption and penetration of lidocaine through skin. The larger flux obtained with linker systems is due to the presence of sodium caprylate and caprylic acid. These hydrophilic linkers accelerate the microemulsion-skin mass transfer by reducing the interfacial rigidity of the systems. Furthermore, the cytotoxicity studies show that these linker microemulsions are significantly less toxic than the alcohol-based system. The Type II linker microemulsion (containing approximately 4% lidocaine) has a comparable cytotoxicity to water saturated with lidocaine (0.4% lidocaine).     

Gelation of microemulsions and release behavior of sodium salicylate from gelled microemulsions

A novel gelled microemulsion was prepared in the presence of the low molecular weight gelator N-stearine-N′-stearyl-l-phenylalanine at a very low concentration. It is completely different from the conventional microemulsion-based gels (MBGs) usually formed by polymeric gelling agents, such as gelatin, agar and κ-carrageenan. The microemulsion consists of i-propyl myristate, Tween 80, propylene glycol and water. The gelled microemulsions showed good thermo-reversibility. The gel-to-sol transition temperature (T_GS) of gelled microemulsion depends upon the concentration of gelator and the composition of the microemulsions. The gelation mechanism was investigated by polarized optical microscopy (POM) and FT-IR. POM images show elongated and strand-like crystallites formed by the aggregation of the gelator, ultimately resulting in the gelation of the microemulsion. FT-IR analysis indicates that intermolecular hydrogen bonds are responsible for the formation of gelator aggregates. Water-soluble sodium salicylate was used as a model drug for the investigation of the release from the gelled microemulsions. The release profiles exhibited a controlled release and followed the first-order release kinetics. The release rates decreased with an increase of the gelator and isopropyl myristate contents. These results reveal potential applications of gelled microemulsion in drug delivery systems.     

应用电导率-含水量曲线法研究广东王不留行提取物为模型药物的O/W型微乳

目的:建立广东王不留行提取物为模型药物的O/W型微乳处方筛选及制备成型的一种方法。方法:选取文献及本实验室15个处方空白微乳建立电导率-含水量曲线,同时与目测法进行对比研究,选取其中4个稳定的微乳处方,分别建立以广东王不留行提取物为模型药物的O/W型微乳的电导率-含水量曲线,进行其方法学考察及微乳质量评价。结果:O/W型空白及含药微乳成型的临界点均是电导率-含水量曲线的顶点,进一步验证其值显著高于目测法测定的临界值,目测法所测定的O/W型微乳临界值在双连续区域内,通过电导率-含水量曲线确定的空白及含药O/W型微乳方法学实验RSD<1%,空白及含药微乳平均粒径均在10~100 nm之间。结论:电导率-含水量曲线法制备的O/W型微乳分布均匀、具备量化、准确、重复性好,应用于微乳处方筛选及制备工艺研究具有理论及实际可行性,能准确反应微乳的相行为及结构变化。     

Investigation of surfactant/cosurfactant synergism impact on ibuprofen solubilization capacity and drug release characteristics of nonionic microemulsions

The current study investigates the performances of the multicomponent mixtures of nonionic surfactants regarding the microemulsion stabilisation, drug solubilization and in vitro drug release kinetic. The primary surfactant was PEG-8 caprylic/capric glycerides (Labrasol). The cosurfactants were commercially available mixtures of octoxynol-12 and polysorbate 20 without or with the addition of PEG-40 hydrogenated castor oil (Solubilisant gamma 2421 and Solubilisant gamma 2429, respectively). The oil phase of microemulsions was isopropyl myristate. Phase behaviour study of the pseudo-ternary systems Labrasol/cosurfactant/oil/water at surfactant-to-cosurfactant weight ratios (K(m)) 40:60, 50:50 and 60:40, revealed a strong synergism in the investigated tensides mixtures for stabilisation of microemulsions containing up to 80% (w/w) of water phase at surfactant +cosurfactant-to-oil weight ratio (SCoS/O) 90:10. Solubilization of a model drug ibuprofen in concentration common for topical application (5%, w/w) was achieved at the water contents below 50% (w/w). Drug free and ibuprofen-loaded microemulsions M1-M6, containing 45% (w/w) of water phase, were prepared and characterized by polarized light microscopy, conductivity, pH, rheological and droplet size measurements. In vitro ibuprofen release kinetics from the microemulsions was investigated using paddle-over-enhancer cell method and compared with the commercial 5% (w/w) ibuprofen hydrogel product (Deep Relief, Mentholatum Company Ltd., USA). The investigated microemulsions were isotropic, low viscous Bingham-type liquids with the pH value (4.70-6.61) suitable for topical application. The different efficiency of the tensides mixtures for microemulsion stabilisation was observed, depending on the cosurfactant type and K(m) value. Solubilisant gamma 2429 as well as higher K(m) (i.e., lower relative content of the cosurfactant) provided higher surfactant/cosurfactant synergism. The drug molecules were predominantly solubilized within the interface film. The amount of drug released from the formulations M3 (10.75%, w/w) and M6 (13.45%, w/w) (K(m) 60:40) was limited in comparison with the reference (22.22%, w/w) and follows the Higuchi model. Microemulsions M2 and M5 (K(m) 50:50) gave zero order drug release pattern and ～15% (w/w) ibuprofen released. The release profiles from microemulsions M1 and M4 (K(m) 40:60) did not fit well with the models used for analysis, although the amounts of ibuprofen released (24.47%, w/w) and 17.99% (w/w), respectively) were comparable to that of the reference hydrogel. The drug release mechanism was related with the surfactant/cosurfactant synergism, thus the lower efficiency of the tensides corresponded to the faster drug release.     

Phase behavior of the microemulsions and the stability of the chloramphenicol in the microemulsion-based ocular drug delivery system

Microemulsion systems composed of Span20/80+Tween20/80+n-butanol+H2O+isopropyl palmitate (IPP)/isopropyl myristate (IPM) were investigated as model systems of drug carriers for eye drops. Effects of chloramphenicol, normal saline, sodium hyaluronate and various oils on the phase behavior were studied. The phase transition was investigated by the electrical conductivity measurements. The electrical conductivity of the microemulsion was affected by the encapsulation of the drug into the system, and the addition of normal saline and sodium hyaluronate. The chloramphenicol is used to treat the diseases such as trachoma and keratitis. However, this drug in the common eye drops hydrolyzes easily. The main product of the hydrolysis is glycols. Here, the chloramphenicol was trapped into the oil-in-water (o/w) microemulsions and its stability was investigated by the high performance liquid chromatography (HPLC) assays in the accelerated experiments of 3 months. Its location in the microemulsion formulations was determined by means of 1H NMR spectroscopy. The results of HPLC revealed that the contents of the glycols in the microemulsion formulations were much lower than that in the commercial eye drops at the end of the accelerated experiments. It implied that the stability of the chloramphenicol in the microemulsion formulations was increased remarkably. The NMR experiments confirmed that the chloramphenicol molecules should be trapped into the hydrophilic shells of the microemulsion drops, which was composed of many oxyethylene groups. The nitro-groups of the chloramphenicol molecules were near the alpha2-CH2 of the surfactant molecules and the benzene rings of the chloramphenicol molecules were near the oxyethylene groups of the surfactant molecules. It was this reason that enabled the chloramphenicol molecules in the microemulsions to be screened from the bulk water and its stability to be increased remarkably.     

Transdermal delivery of capsaicin derivative-sodium nonivamide acetate using microemulsions as vehicles

The objective of this study was to prepare sodium nonivamide acetate (SNA) microemulsion for topical administration. Microemulsions consisted of a mixed surfactant of Tween 80 and Span 20 as surfactant, ethanol as cosurfactant, isopropyl myristate (IPM) as an oil phase and water as an external phase. The effect of composition of microemulsion including the ratio of oil phase/surfactant/aqueous phase, various cosurfactant and polymer on the character and permeability of microemulsion were evaluated. The mean droplet size of SNA microemulsions ranged from 64 to 208 nm. Microemulsions showed potent enhancement effect for SNA transdermal delivery by a 3.7-7.1-fold increase when compared with the control group. Microemulsion containing ethanol as cosurfactant had the highest enhancement effect. With incorporated polymer, the viscosity of microemulsions increased resulting in the decrease in penetration rate of SNA. However, the permeability of SNA delivered from microemulsion was higher than SNA from volatile vehicles (pH 4.2 buffer containing 25% ethanol) reported in an earlier study, therefore microemulsions could be an effective vehicle for topical delivery of SNA.     

Pseudo-ternary Phase Diagrams of Lecithin-based Microemulsions: Influence of Monoalkylphosphates

The formation of macroscopically homogeneous, stable, fluid, optically transparent, isotropic solutions (microemulsions) was delineated, at 25°C, for systems containing water, soybean lecithin, sodium monoalkylphosphate (hexyl or octyl), alcohol and isopropyl myristate. Six straight or branched alcohols (1-butanol, 2-butanol, isobutanol, 1-pentanol, 2-pentanol, 3-pentanol) were investigated as co-surfactants. A constant lecithin/alcohol mixing ratio was used, while the aqueous phase consisted of a solution of alkylphosphates at different concentrations. An increase of the microemulsion domain was seen by increasing the concentration of the alkylphosphate. With 0·2 m hexylphosphate, as aqueous phase, the microemulsion domain consisted of a single, region, that, in the presence of butylic alcohols, spanded the greater portion of the phase diagram. In the presence of amyl alcohols the area of this region was much smaller. With 0·2 m octylphosphate the realm of existence of the microemulsions, except for 1-pentanol, consisted of two regions separated by a liquid-crystal region. With all the alcohols examined, the liquid-crystal phase solubilized a larger amount of oil in the presence of octylphosphate than in the presence of hexylphosphate. The stability ranges of microemulsions in systems containing soybean lecithin, alcohol, water, and isopropyl myristate can be greatly increased by using a second hydrophobic amphiphile, such as hexylphosphate, to adjust the hydrophilic-lipophilic balance or the spontaneous peaking properties of lecithin-alcohol systems.     

Amphotericin B in oil-water lecithin-based microemulsions: formulation and toxicity evaluation

A novel lecithin-based microemulsion containing AmB was developed to reduce the toxic effects of the drug, comparing it with the commercial formulation Fungizone. Phase diagrams containing the microemulsion region were constructed for pseudoternary systems composed of isopropil myristate (IPM)/Brij((R)) 96V/lecithin/water. The incorporation of AmB to the microemulsions was done following the Phase Inversion Temperature (PIT) method or by diluting the drug in the aqueous phase of the disperse system before forming the microemulsion. The percentage of drug entrapped in the microemulsion was analyzed by an HPLC method obtaining recoveries > 98%. Mean droplet size of the microemulsions chosen for the acute toxicity evaluation was of 45 nm, and the rheological studies showed that those microemulsions mentioned followed a Newtonian behavior. Different studies are described in this work to prove the stability of these new dosage forms. Acute toxicity results, determined by a graphic method, the probit binary model and the Reed and Muench method showed that lethal dose 50 (LD(50)) for AmB microemulsions was of 2.9 mgkg(-1) compared to 1.4 mgkg(-1) for the commercial deoxycholate suspension, Fungizone. The overall results indicate that treatment with AmB microemulsions was less toxic than Fungizone, suggesting a potential therapeutic application.     

胸腺五肽油包水型口服微乳的处方设计与评价

目的对胸腺五肽油包水(W/O)型口服微乳进行处方设计及评价。方法 Km值(Km=m乳化剂∶m助乳化剂)滴定法制备伪三元相图,考察油相、乳化剂、助乳化剂、Km值、温度和药物对W/O微乳区域面积和载水量的影响,求出W/O型微乳的最佳处方组合。结果物理化学性质稳定且W/O区域面积和载水量均较高的W/O型微乳的最佳处方组合为蒸馏水/豆磷脂/无水乙醇/辛癸酸三甘油酯(Km=1∶1),制备温度为室温(20±1)℃。根据最佳处方组合,将水溶性药物胸腺五肽溶于水相中,制备了含药微乳的伪三元相图。结论蒸馏水/豆磷脂/无水乙醇/辛癸酸三甘油酯(Km=1∶1)组合具有较大W/O区域面积和载水量,可成功地将水溶性肽类药物包载于水相,并可将其应用于口服药物传递载体。