Microemulsion-based hydrogel formulation of ibuprofen for topical delivery

The purpose of this study was to construct microemulsion-base hydrogel formulation for topical delivery of ibuprofen. Ethyl oleate (EO) was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulison systems and excellent skin permeation rate of ibuprofen. The pseudo-ternary phase diagrams for microemulsion regions were constructed using ethyl oleate as the oil, Tween 80 as the surfactant, propylene glycol as the cosurfactant. Various microemulsion formulations were prepared and the abilities of various microemulsions to deliver ibuprofen through the skin were evaluated in vitro using Franz diffusion cells fitted with porcine skins. The in vitro permeation data showed that microemulsions increased the permeation rate of ibuprofen 5.72-30.0 times over the saturated solution. The optimum formulation consisted of 3% ibuprofen, 6% EO, 30% Tween 80/PG (2:1) and water, showed a high permeation rate of 38.06 microg cm(-2) h(-1). Xanthan gum as a gel matrix was used to construct the microemulsion-based hydrogel for improving the viscosity of microemulsion for topical administration. The studied microemulsion-based hydrogel showed a good stability. These results indicate that the studied microemulsion-based hydrogel may be a promising vehicle for topical delivery of ibuprofen.     

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.     

Novel microemulsion-based gel formulation of tazarotene for therapy of acne

The objective of this study was to develop and evaluate a novel microemulsion based gel formulation containing tazarotene for targeted topical therapy of acne. Psudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and co-surfactant for microemulsion formation. The optimized microemulsion formulation containing 0.05% tazarotene was formulated by spontaneous microemulsification method consisting of 10% Labrafac CC, mixed emulsifiers 15% Labrasol–Cremophor–RH 40 (1:1), 15% Capmul MCM, and 60% distilled water (w/w) as an external phase. All plain and tazarotene-loaded microemulsions were clear and showed physicochemical parameters for desired topical delivery and stability. The permeation profiles of tazarotene through rat skin from optimized microemulsion formulation followed the Higuchi model for controlled permeation. Microemulsion-based gel was prepared by incorporating Carbopol®971P NF in optimized microemulsion formulation having suitable skin permeation rate and skin uptake. Microemulsion-based gel showed desired physicochemical parameters and demonstrated advantage over marketed formulation in improving the skin tolerability of tazarotene indicating its potential in improving its topical delivery. The developed microemulsion-based gel may be a potential drug delivery vehicle for targeted topical delivery of tazarotene in the treatment of acne.     

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.     

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.     

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。     

Enhance transdermal delivery of flurbiprofen via microemulsions: Effects of different types of surfactants and cosurfactants

Background and the purpose of the study

Microemulsions are thermodynamically stable, clear dispersions of water, oil, surfactant, and cosurfactant. This study was aimed to develop flurbiprofen microemulsion for enhanced transdermal delivery and investigate the effects of different surfactants and cosurfactants on its delivery and phase behavior.

Method

Various surfactant-cosurfactant mixtures in ratio of 2:1 (Smix) along with oleic acid (oil) were selected and phase diagrams were constructed. Six microemulsions each containing 5% drug, 5% oil, 56% Smix and 34% water, were prepared and compared for their permeation and phase behaviors to determine the effects of the type of Smix.

Results

In vitro transdermal permeation through rabbit skin of all microemulsions was high than saturated aqueous drug solution. Tween 20 and ethanol as Smix produced the highest flux amongst all the Smix, and were used to prepare formulations with different values of oil and Smix. While the type of surfactant did not affect the droplet size, propylene glycol as cosurfactant produced the largest droplets and highest viscosity. Decrease in oil or Smix concentration resulted in decrease of the droplet size and increase in permeation flux while decrease in viscosity also increased the permeation flux of microemulsions. Finally the selected microemulsion formulation comprising 5% flurbiprofen, 5% oleic acid, 46% Tween 20:ethanol (2:1) and 44% water, showed the highest transdermal flux and caused no skin irritation.

Conclusion

Type of surfactant and cosurfactant affect both the phase behavior and transdermal drug delivery of microemulsion; and results of this study showed that they are promising vehicles for improved transdermal delivery and sustained action of flurbiprofen.     

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.     

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.     

以油包水型微乳为载体促进氟尿嘧啶的经皮渗透

以磺化琥珀酸二辛酯钠 (AOT) 为主要表面活性剂,制备氟尿嘧啶油包水型微乳制剂,以促进药物的经皮渗透。以伪三元相图为基础,依据微乳区域大小, 初步筛选微乳处方;用改进的Franz扩散池和离体小鼠皮肤研究氟尿嘧啶的透皮速率,以单位面积的透皮累积渗透量 (Q_n) 为指标, 考察微乳处方中助表面活性剂的种类、水相比例、混合表面活性剂比例、表面活性剂和助表面活性剂质量比和载药量对离体鼠皮透皮吸收的影响, 优化处方。结果表明,氟尿嘧啶微乳的优化处方为含药0.5%（w/v）,水30%,混合表面活性剂（AOT/Tween 85, K_m = 2）20%, 油相（IPM）49.5%,经皮渗透符合一级速率方程,12 h累积渗透量为（1 355.5 ± 41.1）μg·cm^-2, 分别为0.5%药物水溶液和2.5%（w/w）市售乳膏（O/W）的19.1和7倍。水/AOT/Tween 85/IPM微乳系统能促进5-氟尿嘧啶的透皮吸收, 可以作为氟尿嘧啶等亲水性但水溶性差和渗透性差的药物的新型经皮给药载体。

     

Formulation,characterization, and in vitro/ex vivo evaluation of quercetin-loaded microemulsion for topical application

The aim of this study was to develop a new microemulsion formulation for topical application of poorly soluble drug named quercetin. In order to design suitable microemulsion system, the pseudo-ternary phase diagrams of microemulsion systems were constructed at different surfactant/co-surfactant ratios using tween 80 as surfactant, transcutol^® P as a co-surfactant and oleic acid as an oil phase. Some physicochemical properties such as droplet size, density, refractive index, electrical conductivity, pH, surface tension, and viscosity of the microemulsion systems were measured at 298.15 K. The average hydrodynamic droplet size of the optimized microemulsions was obtained by dynamic light scattering method. Morphology assessment of the optimized quercetin-loaded microemulsion by transmission electron microscopy analysis indicated that the particles have the size of about 25?nm and spherical with narrow size distribution. Equilibrium solubility, in vitro drug release at a 24?h time period, release kinetic evaluation as well as ex vivo permeation and retention of quercetin-loaded microemulsions through rat skin has been investigated. The obtained results showed a slow release behavior without any transdermal delivery. Most of the formulations fitted best with zero-order kinetic model with a non-Fickian mechanisms. This study illustrated that the proposed QU-microemulsion has a good potential for use in sunscreen formulations.

     

Aerosol OT microemulsions as carriers for transdermal delivery of hydrophobic and hydrophilic local anesthetics

The skin permeation enhancement of many kinds of drugs and cosmetic substances by microemulsions has been widely known; however, the correlations between microemulsion microstructures and the efficiency of skin permeation are not fully elucidated. Therefore, the aim of our study was to investigate the influence of microemulsion types on in vitro skin permeation of model hydrophobic drugs and their hydrophilic salts. The microemulsion systems were composed of isopropyl palmitate (IPP), water, a 2:1 w/w mixture of Aerosol OT (AOT) and 1-butanol, and a model drug. The concentrations of surfactant mixture and model drug were maintained at 45% and 1% w/w, respectively. The concentrations of IPP and water were 15% and 39% w/w, respectively, for oil-in-water (o/w) type and vice versa for water-in-oil (w/o) type. The samples were prepared by simple mixing and characterized by visual appearance, pH, refractive index, electrical conductivity, viscosity, and determination of the state of water and IPP in the formulations using differential scanning calorimetry. Transdermal flux of lidocaine, tetracaine, dibucaine, and their respective hydrochloride salts from the drug-loaded AOT-based microemulsions through heat-separated human epidermis was investigated in vitro using modified Franz diffusion cells. The o/w microemulsions resulted in the highest fluxes of the model drugs in base form as compared with the other formulations within the same group of drugs. Moreover, the skin permeation of drug from microemulsions depended on drug molecular structure and interaction between drug and surfactant.     

Antipsoriatic microemulsion gel formulations for topical drug delivery of babchi oil (Psoralea corylifolia)

The aim of this study was to investigate and evaluate a microemulsion gel-based system of babchi oil (Psoralea corylifolia) for the treatment of psoriasis, which could provide improved permeation of the drug through the skin and increased patient compliance. Babchi oil is used because its chief constituent psoralen is a photoactive furocoumarin that binds to DNA when exposed to UV light to form photoproducts with pyrimidine base. This action inhibits DNA synthesis and causes decrease in cell proliferation. Moreover, babchi oil, in addition to providing psoralen, also acts as an oily phase for microemulsion system. The presence of surfactant and cosurfactant increases the permeation. On the basis of qualitative and quantitative estimation of all eight brands of babchi oil, Bakuchi Tail was selected for microemulsion formulation. Microemulsions were prepared by aqueous phase-titration method. Pseudoternary phase diagrams were constructed for the identification of microemulsion existence zones. Prepared microemulsions were subjected to different thermodynamic stability tests and characterized for droplet size, viscosity and refractive index. In vitro skin permeation of babchi oil through rat abdominal skin was determined by the Franz diffusion cell. The in vitro skin permeation profile of formulation F2, which consisted of 1.67% v/v of babchi oil, 8.33% v/v of oleic acid, S(mix) 55% v/v of Tween 80 Transcutol-P (S/Co ratio 1:1) and 35% v/v of distilled water, was significant when compared with other microemulsion formulations (p < 0.05). Formulation F2 was converted into microemulsion gel by adding 1% Carbopol-940 and coded as MGF2. Formulation MGF2 was selected for its in vivo antiinflammatory effects determined by footpad edema. The results suggested that microemulsion gel is a potential vehicle for improved topical delivery of psoralen and that microemulsion gels are potential vehicles for improved topical delivery of babchi oil.     

遗传算法在经皮给药微乳载体处方优化中的应用

以萘普生为模型药物，用遗传算法优化经皮给药微乳载体的处方。用伪三元相图法确定由Tween 80、IPM、乙醇和水组成的微乳区域。用3因素3水平的中心设计法制备载药量为1.12%的萘普生模型微乳，并进行离体兔皮的体外渗透实验。以稳态渗透速率的二次回归模型为目标函数，用遗传算法对中心设计结果进行优化，筛选出具有最大透皮速率的萘普生微乳载体处方。所得优化处方的组成为：21.41% Tween 80、15.17%乙醇、4.14% IPM和59.28%水，预计的稳态渗透速率为183.57 μg·cm^-2·h^-1。回代试验表明，以优化处方制备的萘普生微乳，其稳态渗透速率的平均值为189.43 μg·cm^-2·h^-1，高于预测值。结果表明，用遗传算法筛选微乳经皮给药载体处方，方法可行，结果合理、可靠。     

Formulation design of microemulsion for dermal delivery of penciclovir

The purpose of the present study was to evaluate the potential application of microemulsions as a dermal drug delivery loading penciclovir. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of oleic acid (oil phase), Cremorphor EL (surfactant) and ethanol (cosurfactant). Composition of microemulsion systems was optimized using simplex lattice mixture design including the concentrations of surfactant, cosurfactant and water (independent variables) and the solubility and the cumulative amount of penciclovir permeated through excised mouse skins per unit area (response variables). The physicochemical properties of the optimized microemulsion and the permeating ability of penciclovir from microemulsions were also investigated. The results showed that the optimized microemusion formulation was composed of oleic acid (5%, w/w), Cremorphor EL (20%, w/w), ethanol (30%, w/w) and water (45%, w/w). The mean particle diameter was 36.5nm and solubility of penciclovir in the emulsion was 7.41 mg g(-1). The cumulative amount of penciclovir permeated through excised mouse skins from microemulsion was about 3.5 times that of the commercial cream. The conclusion was that the permeating ability of penciclovir was significantly increased from the microemulsion formulation compared with commercial cream.     

Lecithin microemulsions for the topical administration of ketoprofen: percutaneous adsorption through human skin and in vivo human skin tolerability

The potential application of highly biocompatible o/w microemulsions as topical drug carrier systems for the percutaneous delivery of anti-inflammatory drugs, i.e. ketoprofen, was investigated. Microemulsions were made up of triglycerides as oil phase, a mixture of lecithin and n-butanol as a surfactant/co-surfactant system and an aqueous solution as the external phase. To evaluate the percutaneous enhancing effect of oleic acid, this compound was used as a component of some o/w microemulsions. The topical carrier potentialities of lecithin-based o/w microemulsions were compared with respect to conventional formulations, i.e. a w/o emulsion, a o/w emulsion and a gel. Physicochemical characterisation of microemulsions was carried out by light scattering and zeta potential analyses. Microemulsions showed mean droplet size < 35 nm and a negative zeta potential, that is -39.5 mV for the oleic acid-lecithin microemulsion and -19.7 mV for the lecithin-based microemulsion. The percutaneous adsorption of the various topical formulations was evaluated through healthy adult human skin, which was obtained from abdominal reduction surgery. Ketoprofen-loaded microemulsions showed an enhanced permeation through human skin with respect to conventional formulations. No significant percutaneous enhancer effect was observed for ketoprofen-loaded oleic acid-lecithin microemulsions. The human skin tolerability of various microemulsion formulations was evaluated on human volunteers. Microemulsions showed a good human skin tolerability.     

微乳化技术制备固体脂质纳米粒微乳化技术制备固体脂质纳米粒

目的采用微乳化技术制备固体脂质纳米粒（SLN）。方法以硬脂酸为油相，卵磷脂为乳化剂，乙醇为助乳化剂，蒸馏水为水相，按不同比例混合制备微乳。通过改变卵磷脂与乙醇的配比（K_m），绘制出不同K_m值下的三元相图。从中选择适宜的微乳，将其分散于冷水中制备SLN。考察了工艺因素和处方因素对SLN制备和SLN质量的影响。在单因素考察的基础上，采用正交设计优化工艺，并对优化所得的工艺进行重现性考察。结果水相温度（T_w）、微乳的温度（T_i）、微乳注入速度（r_d）均直接影响SLN的制备，其中水相温度是影响SLN质量的重要因素；微乳各组分的配比、微乳与水相的比例也对SLN的质量有一定影响。结论微乳化技术制备固体脂质纳米粒是可行的。     

Cow ghee fortified ocular topical microemulsion; in vitro,ex vivo,and in vivo evaluation

Abstract

Aim: Utility of cow ghee (CG) as permeation enhancer in development of topical ocular microemulsion (ME) for delivery of fluocinolone acetonide (FA) to posterior eye.

Methods: For ME preparation, oil, surfactant and cosurfactant were screened based on solubility of FA. Pseudoternary phase diagrams were constructed to determine their ratios. The developed MEs were characterised for their physicochemical properties like size, polydispersity index, zeta potential, and stability etc. They were evaluated for ex vivo permeation and irritation. In vivo pharmacokinetic studies were performed on Sprague dawley rats.

Results: Lauroglycol as oil, labrasol as surfactant and Transcutol as cosurfactant were selected. The optimised ratio of oil:surfactant:cosurfactant:water was 4:23:23:50. The developed FA loaded ME fortified with CG was characterised. Ex vivo study revealed higher permeation and non-irritancy. In vivo pharmacokinetic study showed retention of CG fortified ME in posterior rat eye.

Conclusion: Present investigation established CG as permeation enhancer for ocular topical formulation.     

Development and evaluation of a microemulsion formulation for transdermal delivery of terbinafine

The aim of the present study is to develop and evaluate microemulsion formulations for Terbinafine (TB) with a view to enhance its permeability through the skin and provide release for 24 h. Various o/w microemulsions were prepared by the spontaneous emulsification method. Oleic acid was chosen as the oil phase, Caprylo caproyl macrogol-8- glyceride (Labrasol S) and purified diethylene glycol monoethyl ether (Transcutol P) were used as surfactant and cosurfactant, respectively, on the basis of solubility studies. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, cosurfactant, and water for microemulsion formulation. The optimized microemulsion consisted of 2% w/w TB, 8% w/w oleic acid, 31% w/w labrasol S, 31% w/w transcutol P, and 30% w/w distilled water. Permeability parameters like Jss and Kp were found to be significantly higher for formulation F4 as compared to other formulations (P < 0.05). Microbiological studies of TB in microemulsion showed better anti-fungal activity against Candida albicans and Aspergillus flavus as compared to marketed product (P < 0.05).     

Transdermal delivery of ketoprofen using microemulsions

A transdermal preparation containing ketoprofen was developed using O/W microemulsion system. Of the oils tested, oleic acid 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 ketoprofen was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 3% ketoprofen, 6% oleic acid, 30% Labrasol/Cremophor RH 40 (1:1) and water. Terpenes were added to the microemulsion at the level of 5% and their effect on the skin permeation of ketoprofen from the microemulsion was evaluated. Of the four terpenes used, only limonene resulted in a powerful enhancing activity (3-fold increase over control).