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。     

Microemulsions containing lecithin and sugar-based surfactants: nanoparticle templates for delivery of proteins and peptides

Two pseudo-ternary systems comprising isopropyl myristate, soybean lecithin, water, ethanol and either decyl glucoside (DG) or capryl-caprylyl glucoside (CCG) as surfactant were investigated for their potential to form microemulsion templates to produce nanoparticles as drug delivery vehicles for proteins and peptides. All microemulsion and nanoparticle compounds used were pharmaceutically acceptable and biocompatible. Phase diagrams were established and characterized using polarizing light microscopy, viscosity, conductivity, electron microscopy, differential scanning calorimetry and self-diffusion NMR. An area in the phase diagrams containing optically isotropic, monophasic systems was designated as the microemulsion region and systems therein identified as solution-type microemulsions. Poly(alkylcyanoacrylate) nanoparticles prepared by interfacial polymerisation from selected microemulsions ranged from 145 to 660 nm in size with a unimodal size distribution depending on the type of monomer (ethyl (2) or butyl (2) cyanoacrylate) and microemulsion template. Generally larger nanoparticles were formed by butyl (2) cyanoacrylate. Insulin was added as a model protein and did not alter the physicochemical behaviour of the microemulsions or the morphology of the nanoparticles. However, insulin-loaded nanoparticles in the CCG containing system decreased in size when using butyl (2) cyanoacrylate. This study shows that microemulsions containing sugar-based surfactants are suitable formulation templates for the formation of nanoparticles to deliver peptides.     

Microemulsions as potential ocular drug delivery systems: phase diagrams and physical properties depending on ingredients

The microemulsion systems, both o/w and w/o, composed of isopropyl myristate, soybean lecithin (Epikuron 200), Polysorbate 80, Cremophor EL, n-butanol and triacetine, taken at various amounts and in various combinations, were tested in order to assess their physical-chemical properties. Some ingredients of the microemulsions were physiologically acceptable, except one formulation containing n-butanol used as a model reference system. Phase diagrams were made for all microemulsions studied in order to test the influence of components on the boundaries of the stable microemulsion domains. The greatest area of stable microemulsion system was obtained for the formulation in which n-butanol was used, while the smallest area was obtained when soybean lecithin (Epikuron 200) was used as a surfactant. The following physical parameters were analyzed: osmotic tension, density, viscosity, refractive index. pH and particle size. Microemulsions stored at 25 degrees C for the period up to 12 months, showed physical changes depending on ingredients. The study made it possible to select the most stable microemulsion system meeting the requirements of eye drops.     

Skin-compatible lecithin drug delivery systems for fluconazole: effect of phosphatidylethanolamine and oleic acid on skin permeation

The purpose of the present study was to evaluate skin-compatible drug delivery systems for fluconazole. Pseudoternary phase diagrams were constructed, composed of different soybean lecithins/oil/isopropanol and water. The role of the various lecithin compositions was expressed in the different resulting isotropic areas. Based on these phase diagrams, two systems were chosen as drug delivery systems for fluconazole. The influence of phosphatidylethanolamine and of the oil component on the skin permeation of fluconazole was investigated. The more phosphatidylethanolamine, the greater was the fluconazole skin permeation, independent of the hydrophilicity of the system. The influence of oleic acid and isopropylmyristate as the oil component was compared and a greater penetration enhancing effect was found for the microemulsion containing oleic acid.     

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.     

Preparation of griseofulvin nanoparticles from water-dilutable microemulsions

Nanoparticles of griseofulvin, a model drug with poor solubility and low bioavailability, were prepared from water dilutable microemulsions by the solvent diffusion technique. Solvent-in-water microemulsion formulations containing water, butyl lactate, lecithin, taurodeoxycholate sodium salt (TDC) or dipotassium glycyrrhizinate (KG), 1,2-propanediol or ethanol were used. The formation of macroscopically homogeneous, stable, fluid, optically transparent, isotropic solutions (microemulsions) was investigated by constructing pseudo-ternary phase diagrams. In the presence of TDC or KG, microemulsion systems that remained transparent on water dilution could be obtained. The displacement of butyl lactate, with an excess of water, from the internal phase of the microemulsions containing the drug into the external phase, lead to successful fabrication of drug nanosuspensions. Nanoparticle size was dependent on microemulsion composition: using KG, griseofulvin nanoparticles below 100 nm with low polydispersity and an increased dissolution rate were obtained.     

Lecithin-based oil-in-water microemulsions for parenteral use: pseudoternary phase diagrams,characterization and toxicity studies

Pseudoternary phase diagrams have been constructed to evaluate the phase behavior of systems containing water/lecithin/polysorbate 80/isopropyl myristate at different polysorbate 80:lecithin weight ratios (K(m)). Oil-in-water microemulsion regions were accurately determined and the influence of the K(m) on the area of existence of such disperse systems was also examined. Viscosity studies as well as particle size analysis by dynamic light scattering were carried out on oil-water microemulsions, and the influence of the oil phase content, the total amount of surfactants and K(m) on the rheological behavior, viscosity, and droplet size of such disperse systems was evaluated. All systems studied showed a water-rich isotrope region (oil-in-water microemulsion area), that was seen to be highly dependent upon the surfactant/cosurfactant weight ratio. Most of the microemulsions analyzed showed a non-Newtonian rheological behavior and both, droplet size, and viscosity of the disperse systems, were found to be much more influenced by the total content of oil phase and surfactants present in the microemulsion than by the K(m). The selected system underwent both stability and in vivo acute toxicity studies, and seemed to be highly stable, even at extreme conditions, and very low toxic according to the results obtained.     

药用微乳伪三元相图的几种制备方法比较研究

目的评价目前常用的几种微乳伪三元相图制备方法的优劣。方法选择吐温-80、聚氧乙烯辛基苯基醚(OP)和大豆卵磷脂为乳化剂,乙醇为助乳化剂,肉豆蔻酸异丙酯或油酸乙酯为油相,制备伪三元相图,以相图中数据点的准确性和可靠性等为指标,评价不同方法所得微乳相图的差异。结果不同方法制备的水包油型乳化剂的伪三元相图微乳区面积差异不大,但图中不同区域数据点的准确性和可靠性差异较大;不同方法制备的油包水型乳化剂伪三元相图的各相以及相区的面积差异均较大。结论制备准确可靠的伪三元相图,应根据组分的性质及所制备的微乳类型来选择方法,并综合利用某几种方法来判断滴定终点。     

Novel dithranol phospholipid microemulsion for topical application: development, characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm2/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

Bioavailability of seocalcitol II: development and characterisation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides.

By constructing ternary phase diagrams it was possible to identify two self-microemulsifying drug delivery systems (SMEDDS) containing either medium chain triglycerides (MC-SMEDDS) or long chain triglycerides (LC-SMEDDS), with the same ratio between lipid, surfactant and co-surfactant. The SMEDDS ended up having a composition of 25% lipid, 48% surfactant and 27% co-surfactant, MC-SMEDDS: viscoleo, cremophor RH40, akoline MCM and LC-SMEDDS: sesame oil, cremophor RH40, peceol. Upon dilution with water both SMEDDS resulted in clear to bluish transparent microemulsions with a narrow droplet size of 30nm. The industrial usefulness of the developed SMEDDS was evaluated with regard to bioavailability and chemical stability using the vitamin D analogue, seocalcitol, as model compound. The absorption and bioavailability of seocalcitol in rats were approximately 45% and 18%, respectively, from both the MC-SMEDDS and LC-SMEDDS indicating similar in vivo behavior of the two formulations, despite the difference in nature of lipid component. There was no improvement in bioavailability by the use of SMEDDS, compared to the bioavailability achieved from simple MCT and LCT solutions (22-24%) (Grove, M., Pedersen, G.P., Nielsen, J.L., Mullertz, A., 2005. Bioavailability of seocalcitol. I. Relating solubility in biorelevant media with oral bioavailability in rats-effect of medium and long chain triglycerides. J. Pharm. Sci. 94, 1830-1838.). After 3 months' storage at accelerated conditions (40 degrees C/75% RH), a decrease in concentration of seocalcitol of 10-11% was found in MC-SMEDDS and LC-SMEDDS compared with a degradation of less than 3% for the simple lipid solutions of MCT and LCT. In this study the simple lipid solutions seem to be a better choice compared with the developed SMEDDS due to a slightly higher bioavailability and a better chemical stability of seocalcitol.     

Application of Design Expert for the investigation of capsaicin-loaded microemulsions for transdermal delivery

Our previous study reported that the Design Expert® Software showed a beneficial role in the development of microemulsions (ME) for transdermal drug delivery. To fully confirm the reproducibility and the reliability of simultaneous optimal ME formulations, the optimal ME formulations predicted by the Design Expert® Software were experimentally formulated and verified for their skin permeability. Ternary phase diagrams were used to predict the optimal ME area, and the ME formulations selected from outside this area were considered as candidate ME systems. Our ME systems were formulated with isopropyl myristate (IPM) as the oil phase, cocamide diethanolamine (DEA) as the surfactant, ethanol as a co-surfactant and water as the aqueous phase. The droplet size, size distribution, electrical conductivity, pH, drug content and skin permeability of the candidate ME systems were monitored. Our findings indicated that the skin permeability of the optimal ME and all of the candidate ME formulations was significantly greater than that of the commercial capsaicin (CAP) product. Our study succeeded in predicting and developing the ME systems for the transdermal delivery of CAP. The simplex lattice design used in this study is experimentally useful for the development of pharmaceutical formulations.     

Formulation and evaluation of flurbiprofen microemulsion

The purpose of the present study was to investigate the microemulsion formulations for topical delivery of Flurbiprofen (FP) in order to by pass its gastrointestinal adverse effects. The pseudoternary phase diagrams were developed and various microemulsion formulations were prepared using Isopropyl Myristate (IPM), Ethyl Oleate (EO) as oils, Aerosol OT as surfactant and Sorbitan Monooleate as cosurfactant. The transdermal permeability of flurbiprofen from microemulsions containing IPM and EO as two different oil phases was analyzed using Keshary-Chien diffusion cell through excised rat skin. Flurbiprofen showed higher in vitro permeation from IPM as compared to that of from EO microemulsion. Thus microemulsion containing IPM as oil phase were selected for optimization. The optimization was carried out using 2(3) factorial design. The optimized formula was then subjected to in vivo anti-inflammatory study and the performance of flurbiprofen from optimized formulation was compared with that of gel cream. Flurbiprofen from optimized microemulsion formulation was found to be more effective as compared to gel cream in inhibiting the carrageenan induced rat paw edema at all time intervals. Histopathological investigation of rat skin revealed the safety of microemulsion formulation for topical use. Thus the present study indicates that, microemulsion can be a promising vehicle for the topical delivery of flurbiprofen.     

Novel dithranol phospholipid microemulsion for topical application: development,characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm²/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

Investigations into the formation and characterization of phospholipid microemulsions. IV. Pseudo-ternary phase diagrams of systems containing water-lecithin-alcohol and oil; The influence of oil

Phase studies have been performed for quaternary systems composed of egg lecithin, cosurfactant, water and oil. The lecithin used was the commercially available egg lecithin Ovothin 200 (which comprises ≥ 92% phosphatidylcholine). The cosurfactants employed were propanol and butanol, and these were used at lecithin/cosurfactant mixing ratios (K_m) of 1:1 and 1.94:1 (weight basis). Six polar oils were investigated, including the alkanoic acids, octanoic and oleic, their corresponding ethyl esters and the medium and long chain triglycerides, Miglyol 812 and soybean oil. All oils, irrespective of the alcohol and the K_m used, gave rise to systems that produced a stable isotropic region along the surfactant/oil axis (designated as a reverse microemulsion system). In addition, the systems incorporating propanol at both K_m and butanol at a K_m of 1.94: 1, generally gave rise to a liquid crystalline region and, in some cases, a second isotropic non-birefingent area (designated as a normal microemulsion system). The phase behaviour observed was largely dependent upon the alcohol and K_m used and the size and the polarity of the oil present.     

Extraction of nettle leaves using synthetic esters of fatty acids

The extractive power of synthetic esters of higher fatty acids, widely used as emollients in cosmetics, has been studied. Three popular emollients — isopropyl myristate (IPM), capryl-caprinic triglycerides (CCT) and soybean oil (SO) — were used to isolate biologically active substances from nettle leaves (Folia urtica). The qualitative compositions of lipophilic biologically active compounds in all extracts have proved to be identical, including chlorophyll derivatives, carotenoids, and some unidentified substances. The extractive power of emollients with respect to chlorophyll derivatives increases in the following order: SO < CCT < IPM. The process of two-phase extraction of nettle leaves using natural emollients and synthetic esters of fatty acids as the nonpolar phase has been studied. The nature of the polar phase involved in the two-phase extractant (TPE) has been found to strongly influence the amount of chlorophyll derivatives extracted from the plant material. The maximum concentration of chlorophyll derivatives in the nonpolar phase (soybean oil and synthetic emollients) was obtained using a water-ethanol mixture as the polar phase. It is established that the use of TPEs also enriches the qualitative composition of extracts. The best results in case of the IPM-60% ethanol TPE system were obtained using preliminary maceration of a raw plant material with the nonpolar (IPM) phase. In the case of the soybean oil-60% ethanol TPE system, the best results were obtained upon maceration with the polar (aqueous ethanol) phase. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 11, pp. 35–39, November, 2005.     

处方因素对亚微乳物理稳定性的影响

目的 初步探讨亚微乳处方中乳化剂及油相因素对其物理稳定性的影响.方法 采用高速剪切分散和高压均质乳化工艺制备亚微乳,单因素试验法考察处方中乳化剂与油相对亚微乳物理稳定性的影响;以平均粒径、D50值、D99值及ζ电位为指标,考察不同处方中亚微乳灭菌前后的物理稳定性,并留样观察其长期稳定性.结果 泊洛沙姆188与中链油相互配伍不能得到性质稳定的亚微乳,且单独以泊洛沙姆188为乳化剂的各处方制剂长期放置后平均粒径明显增大;聚乙二醇硬脂酸酯( HS15)与各油相结合制得的亚微乳均较稳定,长期放置后各项指标基本不变;聚山梨酯80与大豆油-中链油(1∶1)混合油或大豆油配伍制成的亚微乳在灭菌后产生较大粒径的乳滴,而与中链油相配伍可制得粒径较小且均匀分散的体系;蛋磷脂E80单独作为亚微乳乳化剂,乳化效果欠佳.结论 大豆油、中链油及混合油与不同性质的乳化剂相互作用可共同影响亚微乳的粒径,但不同制剂的处方对亚微乳ζ电位无显著影响.     

Formation of liquid crystal and other non-fluid phases in emulsions containing non-ionic surfactants.

The relation between the phase distribution of components and the nature and properties of dispersions formed in a four-component system containing dodecane, water and two homogeneous non-ionic surfactants has been investigated by phase-rule techniques. Phase equilibrium diagrams for the four ternary systems were investigated and the phase boundaries for the various regions formed in these systems were defined by synthetic and analytical methods. In some of the ternary diagrams a narrow three-phase region occurs where 'gel' or liquid crystal as well as two isotropic liquid phases are present. Dispersions containing the gel phase were very stable. The four-component system has not been fully investigated due to the presence of extensive liquid crystal phases and three-phase regions. However, some distribution data for the quaternary system was obtained. In the presence of sufficient amounts of the short chain non-ionic surfactant C10H21(O.CH2.CH2)3OH, a three-liquid phase region occurs where multiple drops readily form.     

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.     

Physicochemical characterization of a reverse micellar solution after loading with different drugs

Diclofenac sodium (DS), timolol maleate (TM) and pilocarpine hydrochloride (PHCl) were solubilized in a reverse micellar solution (RMS) consisting of lecithin and middle-chain triglycerides (MCT). The influence of these drugs on the physicochemical parameters of the RMS was investigated. Although none of the drugs influenced the size of the associates, the micellar shapes varied considerably. While DS and PHCl increased the anisometry, reverse micelles with TM were spherical. The transformation of the RMS into a lamellar mesophase on contact with water was generally not prevented by any of the drugs but all drugs led to an increased number of defect structures in the liquid crystal. Furthermore the interlayer distance of the lamellar mesophase was reduced by a higher content of DS. In comparison with an RMS containing isopropylmyristate (IPM) instead of MCT, differences in the physicochemical properties of the drug-free RMS and in the influences of solubilized drugs were noticed.     

醋酸泼尼松龙醇质体的制备及其药剂学性质考察

目的:制备醋酸泼尼松龙醇质体并考察其药剂学性质。方法:采用乙醇注入法制备醇质体。以包封率为指标,以处方中药物与大豆磷脂质量比(A)、胆固醇与大豆磷脂质量比(B)、无水乙醇占处方总量的百分比(C)为考察因素进行正交设计优化处方;考察优化后处方所制醇质体的形态、粒径、Zeta电位、包封率、稳定性等,差示量热分析法考察其热力学特性。结果:最佳处方为平均A包1:封20率,B为1(:766、.C793±0%0.2;9以)%此,处贮方藏制30备d的稳醇定质性体较外好形。圆差整示光量滑热,分平析均法粒结径果为(表2明78,.醋5±酸4泼6.7尼)松nm龙,Z以et无a电定位形为状(态-包31封.6于±醇0.0质4)体m中V,。结论:醋酸泼尼松龙醇质体制备工艺简单,优化处方所制制剂药剂学性质符合要求。