Selection of high efficient transdermal lipid vesicle for curcumin skin delivery

Curcumin shows effective anti-inflammatory activities but is seldom used in clinic because of its poor solubility in water and vulnerablity to sunshine ultraviolet effect. Novel lipid vesicles have been developed as carriers for skin delivery. In this paper, lipid vesicles—propylene glycol liposomes (PGL), Ethosomes and traditional liposomes, were prepared as curcumin carriers respectively. Their morphology, particle size and encapsulation efficiency and drug release behavior in vitro were evaluated. Transdermal efficiency and deposition quantity in abdominal skin were also measured with Franz diffusion device. Carrageenan-induced paw edema was established to evaluate the anti-inflammatory effect. From the result, the particle size order of lipid vesicles was: PGL (182.4 ± 89.2 nm) < Ethosomes (289 ± 132.1 nm) < traditional liposomes (632.9 ± 184.1 nm). The order of particle dispersion coefficient was as the same as that of particle size. The sequence of encapsulation efficiency was: PGL > Ethosomes > traditional liposomes. PGL had the best encapsulation efficiency of 92.74 ± 3.44%. From anti-inflammatory experiment, PGL showed the highest and longest inhibition on the development of paw edema, followed by Ethosomes and Traditional liposomes. With the elevated entrapment efficiency, good transdermic ability and sustained-release behavior, PGL may represent an efficient transdermal lipid vesicle for skin delivery.     

介质和有机酸对来曲唑体外经皮透过性的影响(英文)

采用水平双室扩散池,以离体鼠皮为透过屏障,考察介质和有机酸对来曲唑体外经皮透过性的影响。在肉豆蔻酸异丙酯(IPM)中加入乙醇后能明显地增加来曲唑的经皮透过量,尤其以含有20%(w/w)乙醇的IPM混合溶液促进作用最为显著。在此溶液系统中,加入的有机酸和来曲唑形成了复合物明显地增加了来曲唑的经皮透过性。由于加入有机酸的结构不同,因此其对来曲唑经皮通透具有不同的促进作用。本实验的结果表明在含有20%乙醇的IPM溶液系统中加入有机酸是促进来曲唑经皮透过性更为有效的方法。     

Transdermal delivery of venlafaxine hydrochloride: the effects of enhancers on permeation across pig ear skin

Venlafaxine representing a new class of antidepressants is a potent serotonin/ norepinephrine reuptake inhibitor. Transdermal delivery of venlafaxine hydrochloride (VHCl) may result in proper patient compliance by reducing the incidence of the undesirable GI problems generally associated with its plural oral dosing. The present study is an attempt to investigate the improvement of the transdermal flux of the hydrophilic VHCl by certain permeation enhancers viz. glycerin, urea, propylene glycol and mixture of propylene glycol and ethanol across pig ear skin. The cumulative drug release was the highest from the formulation F5 consisting of the mixture of propylene glycol and ethanol in sodium alginate gel with a load of 25% w/w VHCl with 96% permeation enhancement. The steady state flux observed with F5 was 0.203 mg cm(-2) hr and an area of 15.27 cm(2) would suffice to arrive at a required therapeutic concentration of VHCl in the blood.     

Design & development of nanosponge loaded topical gel of curcumin and caffeine mixture for augmented treatment of psoriasis

BackgroundCombination of curcumin with anti-inflammatory drug like caffeine shows augmented antipsoriatic action compared to curcumin alone and reduce the time taken for treatment of Psoriasis.ObjectiveThe objective of the present study was to develop nanosponge (NS) based topical gel of curcumin (CUR) and caffeine (CFN) combination that acts as a potential system for the treatment of psoriasis.MethodsNS composed of dimethyl carbonate (DMC) as crosslinker and beta-cyclodextrin (β-CD) as polymer were prepared by hot melt method and incorporated in topical gels. Factorial design (3²) was constructed in a fully randomized manner to study all nine possible experimental runs. The gels were prepared by varying the content of carbopol-934 (gelling agent) (X1) and guar gum (polymer) (X2). The effect of these two independent variables on viscosity (Y1) and in vitro percent drug release (Y2) of prepared gels was evaluated. Other evaluation studies for NS and nanogels were conducted. In vivo animal studies were carried out for optimized formulation using mouse model of imiquimod-induced psoriasis.ResultsThe physical and chemical characteristics exhibited by the prepared NS and gels (F1-F9) were found to be optimal. The optimization resulted in achieving formulation N10 with 69.72% in vitro drug release and 12,329.78cp viscosity. Histopathology studies revealed that prepared nanogel has promising anti-psoriatic activity. The results concluded that CUR and CFN combination has reduced the time required for showing anti-psoriatic activity to 10 days when compared to CUR alone that took around 20 days. Moreover, the nanogel has depicted sustained drug release till 12 h.ConclusionsFrom the experimental findings it has been concluded that CUR and CFN combination significantly augmented the anti-psoriatic efficacy with respect to individual components and also reduced the time required for onset of effect. Thus, the proposed nanogel would be an imperative drug delivery system for more effective anti-psoriatic therapy. Open in a separate windowGraphical abstract     

微波及离子液体条件下香豆素类化合物的合成研究

目的：探索操作简便、环境友好的香豆素衍生物的合成方法：方法：以乙酰乙酸乙酯和苯酚类化合物为原料,通过Pechmann反应,在4种不同的反应条件（浓硫酸催化、Lewis酸三氯化铋催化、微波Lewis酸三氯化铋催化、微波离子液体催化）下催化合成多种香豆素衍生物,并对4种方法进行对比。结果：微波离子液体条件下的Pechmann反应与传统方法相比革除了有机溶剂的使用,缩短了反应时间且产率较高。结论：微波及离子液体条件下合成香豆素类化合物是一种条件简单、环境友好的合成方法。     

麻黄碱类离子液体分离5种药物及其色谱行为影响的研究

目的建立了以麻黄碱类离子液体作为流动相添加剂,分离5种药物的高效液相色谱法（HPLC）。方法通过改变离子液体的浓度、流动相的pH以及改变阴离子组成,考察离子液体对5种药物分离的影响,并在此基础上研究麻黄碱类离子液体在高效液相色谱法中的色谱行为。色谱柱Kromasil C18柱（200mm×4．6mm,5μm）,流动相为甲醇-水-60：40（v／v）,pH=4．0．离子液体5mmol·L^-1。结果所分离的5种药物是关托洛尔、比索洛尔、普萘洛尔、奥美拉唑、酮洛芬。5种药物在此备件下达到完全分离。结论离子液体的阴阳离子均可影响分析物的色谱行为。所采用的离子液体缩短了酸性药物的保留时间。本离子液体可以作为1种潜在的流动相添加剂用于高效液相色谱法中。     

Curcumin-Eudragit® E PO solid dispersion: A simple and potent method to solve the problems of curcumin

Using a simple solution mixing method, curcumin was dispersed in the matrix of Eudragit® E PO polymer. Water solubility of curcumin in curcumin-Eudragit® E PO solid dispersion (Cur@EPO) was greatly increased. Based on the results of several tests, curcumin was demonstrated to exist in the polymer matrix in amorphous state. The interaction between curcumin and the polymer was investigated through Fourier transform infrared spectroscopy and ¹H NMR which implied that OH group of curcumin and carbonyl group of the polymer involved in the H bonding formation. Cur@EPO also provided protection function for curcumin as verified by the pH challenge and UV irradiation test. The pH value influenced curcumin release profile in which sustained release pattern was revealed. Additionally, in vitro transdermal test was conducted to assess the potential of Cur@EPO as a vehicle to deliver curcumin through this alternative administration route.     

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations

Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 g·cm^–2·h^–1 and 3.2 g·cm^–2·h^–1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.     

Systemic delivery of timolol after dermal application: Transdermal flux and skin irritation potential in the rat and dog

Timolol, a beta-adrenergic antagonist, was evaluated for transdermal flux with rat skin in vitro and with the dog in vivo. Skin irritation after dermal application of timolol was assessed in the rat in vivo. Drug flux across rat skin in vitro ranged between 2 and 110 µg cm^–2 hr^–1, dependent on the formulation. The transdermal flux of timolol in the dog was greater than 10 µg cm^–2 hr^–1. This estimate was based on the degree of antagonism of isoproterenol challenge following transdermal administration of timolol relative to that obtained following intravenous administration of timolol. Irritation was observed in the rat after occluded dermal application of timolol free base but was not observed when the concentration of the drug in the formulation was decreased.     

Transdermal delivery of oxybutynin chloride proniosomal gels for the treatment of overactive bladder

Abstract

Context: Overactive bladder (OAB) is a common problem and anticholinergic drugs are first-line therapy, but they have side effects.

Objective: Development of oxybutynin chloride (OC) proniosomal gels and analyses of its efficacy for OAB treatment.

Materials and methods: Phase separation coacervation was used to prepare proniosomal gels using various non-ionic surfactants, lipids, soy lecithin and isopropyl alcohol. Gels were characterized with regard to entrapment efficiency (EE), vesicle size, surface morphology (using environmental scanning electron microscopy [E-SEM]), stability, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, in vivo animal studies and histopathology.

Results and discussion: EE was 87–92%, vesicle size was 0.38–5.0?μm, and morphology showed some loosened pores in proniosomes after hydration. ATR-FTIR spectroscopy showed no significant shifts in peaks corresponding to OC and excipients. Most formulations exhibited >50% permeation but the cholesterol-containing formulations P3 (Span 20:Span 60 [1:1]) and P4 [Tween 20:Tween 80 (1:1)] had the highest percent cumulative permeation. P3 and P4 also showed faster recovery of cholinergic effects on salivary glands than oral formulations. P3 and P4 had pronounced therapeutic effects in reduction of urinary frequency and demonstrated improvements in bladder morphology (highly regenerative surface of the transitional epithelium).

Conclusion: These results suggest that OC could be incorporated into proniosomal gels for transdermal delivery in the treatment of OAB.     

Potential pitfalls in skin permeation experiments: Influence of experimental factors and subsequent data evaluation

There is a growing demand for skin penetration and permeation data considering toxicological and potential drug delivery aspects for an increasing number of substances. Although there are official guidelines available, results from different skin diffusion studies are often inconsistent and sometimes even controversial. The aim of our study is to address and to investigate the influence of experimental parameters as well as mathematical problems for subsequent evaluation of the permeation raw data. To create a reliable database diffusion experiments across human stratum corneum were performed under highly standardized conditions. The experimental data were evaluated using linear and non-linear regression analysis to determine the influence on the permeability coefficient and the lag-time. Additionally, the influence of two critical experimental parameters, temperature and unstirred water layers, on the permeability was investigated in silico. Based on our results we suggest that the influence of temperature on the permeability coefficient is small compared to the effect of other experimental parameters. Thickness of unstirred water layers has a tremendous effect on the permeation and may lead to underestimation of the permeability by more than 90%. Non-linear regression analysis seems to be superior compared to linear algorithms hence is advisable for evaluation of the experimental data. Our findings may help to optimize the experimental set-up and to reduce total costs for future skin diffusion testing. With regards to EU’s REACH-Initiative this will also help to create more and reliable data on safety issues of industrial materials.     

高氧液提高乏氧血氧含量及相关基础研究

目的　旨在探索高氧液体治疗缺血缺氧性疾病的部分基础药理特性 ,为临床应用提供可靠的理论依据。方法　用光量子溶氧技术将O2 高浓度的溶解在复方林格氏液体中 ,称为高氧液体或晶体携O2 液 ,并探讨高氧液体对静脉血氧分压、红细胞脆性和失血性休克的PaO2 、SaO2 与血液粘滞度等指标的影响。结果　高氧液体的LD50 、红细胞脆性和热原质试验与溶液氧前林格比较无改变 (P >0 0 5 )。溶氧后高氧液体的氧分压由 2 1kPa上升到 90 - 10 0kPa ,能容量依赖性的提高静脉血氧分压和氧饱和度 ,能明显提高急性失血性休克家兔的PaO2 和SaO2 ,并降低血液粘滞度。结论　高氧液体不改变基液的基本特性 ,符合人体输注的各项要求 ,对缺血缺氧性疾病的治疗具有一定的药理学基础     

An evaluation of the potential of linear and nonlinear skin permeation models for the prediction of experimentally measured percutaneous drug absorption

Objectives The developments in combinatorial chemistry have led to a rapid increase in drug design and discovery and, ultimately, the production of many potential molecules that require evaluation. Hence, there has been much interest in the use of mathematical models to predict dermal absorption. Therefore, the aim of this study was to test the performance of both linear and nonlinear models to predict the skin permeation of a series of 11 compounds. Methods The modelling in this study was carried out by the application of both quantitative structure permeability relationships and Gaussian process‐based machine learning methods to predict the flux and permeability coefficient of the 11 compounds. The actual permeation of these compounds across human skin was measured using Franz cells and a standard protocol with high performance liquid chromatography analysis. Statistical comparison between the predicted and experimentally‐derived values was performed using mean squared error and the Pearson sample correlation coefficient. Key findings The findings of this study would suggest that the models failed to accurately predict permeation and in some cases were not within two‐ or three‐orders of magnitude of the experimentally‐derived values. However, with this set of compounds the models were able to effectively rank the permeants. Conclusions Although not suitable for accurately predicting permeation the models may be suitable for determining a rank order of permeation, which may help to select candidate molecules for in‐vitro screening. However, it is important to note that such predictions need to take into account actual relative drug candidate potencies.     

Investigating the potential of essential oils as penetration enhancer for transdermal losartan delivery: Effectiveness and mechanism of action

The effect of tea tree oil (TTO), cumin oil (CO), rose oil (RO) and aloe vera oil (AVO) on the skin permeation of losartan potassium (LP) was investigated. In vitro skin permeation studies were carried out using rat skin. The mechanism of skin permeation enhancement of LP by essential oils treatment was evaluated by FTIR, DSC, activation energy measurement and histopathological examination. Both concurrent ethanol/enhancer treatment and neat enhancer pretreatment of rat SC with all the oils produced significance increase in the LP flux over the control. The effectiveness of the oils as the penetration enhancers was found to be in the following descending order: AVO > RO > CO > TTO. However, only AVO was the only enhancer to provide target flux required to deliver the therapeutic transdermal dose of LP. FTIR and DSC spectra of the enhancer treated SC indicated that TTO, CO, RO and AVO increased the LP permeation by extraction of SC lipids. The results of thermodynamic studies and histopathological examination of AVO treated SC suggested additional mechanisms for AVO facilitated permeation i.e. transient reduction in barrier resistance of SC and intracellular transport by dekeratinization of corneocytes which may be attributed to the presence of triglycerides as constituents of AVO. It is feasible to deliver therapeutically effective dose of LP via transdermal route using AVO as penetration enhancer.     

Ascomycins: promising agents for the treatment of inflammatory skin diseases

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams currently under development for the treatment of skin diseases. The main biological effect of ascomycins is an inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells. Several compounds are being developed with SDZ ASM 981 being at the most advanced stage. It has high anti-inflammatory activity in animal models of skin inflammation and does not induce skin atrophy. Topical application of SDZ ASM 981 was shown to be effective in atopic dermatitis (AD), allergic contact dermatitis and also in psoriasis under semi-occlusive conditions. In patients with AD, SDZ ASM 981 cream led to consistently low systemic exposure even when applied on large areas of skin. SDZ ASM 981 overcomes the drawbacks of current topical therapies of inflammatory skin diseases as its safety profile is better than that of topical corticosteroids. Studies continue to investigate its efficacy and safety in the treatment of inflammatory skin diseases.     

Supramolecular solvent-liquid-liquid microextraction followed by smartphone digital image colorimetry for the determination of curcumin in food samples

Smartphone digital image colorimetry (SDIC) was coupled with supramolecular solvent-based liquid-liquid microextraction (SMS-LLME) for the determination of curcumin. Images, captured for sample solutions placed inside a homemade colorimetric box, were split into their red-green-blue channels and the intensity of the blue channel was correlated to the concentration of curcumin. Optimum SDIC performance was achieved at a distance of 9.0 cm between the sample cuvette and the detection camera, a region of interest of 1600 px² and a light source at 15% brightness. Optimum SMS-LLME efficiency was obtained with 1000 μL of tetrahydrofuran/1-undecanol (4:1, v/v) as the supramolecular extraction solvent, pH of sample solution adjusted to 7.0, and 2.0% (w/v) sodium chloride within 60 s extraction time. Limits of detection (LOD) were found in the range of 0.2–0.9 μg mL^?1 (0.04–0.18%, w/w). Calibration graphs demonstrated good linearity with coefficients of determination higher than 0.9965 and relative standard deviations lower than 8.5%. The proposed SMS-LLME-SDIC method was applied to determine curcumin in turmeric and tea samples from which percentage relative recoveries between 94.0 and 104.0% were obtained.     

New compounds for the treatment of eczematous skin diseases

Eczematous skin diseases such as atopic dermatitis and allergic contact dermatitis are common and are characterised by the appearance of oozing, erythema, crusting, papules and, in long standing lesions, lichenification. After the successful introduction of the topical immunomodulators as a new topical therapy of atopic eczema, several other therapeutic compounds have been developed in the last 2 years. These are presented in this article based on recent patents. Primarily, developments for the treatment of pruritus and inflammation are molecules affecting the H4-receptor, the cannabinoid receptors and the prostanoid receptors, but antagonists targeting PDE4, CCR-1 or -3, or chemoattractants have also been developed. The latest patents on glucocorticosteroids and their compositions are discussed, also, the antibody-derived and cytokine-targeted therapeutical agents. In the latter case, however, the number of patents has decreased due to their time-consuming and cost-intensive production. Furthermore, one interesting patent deals with improvement of the skin barrier function and enhancement of epidermal cohesion through stratum corneum acidification. Finally, new photosensitisers or pro-photosensitisers for photodynamic therapy to treat T-cell-mediated skin disorders have been claimed. However, most of the discussed developments will need application of clinical efficacy and safety in the near future.     

Embryonic and developmental toxicity of the ionic liquid 1‐methyl‐3‐octylimidazolium bromide on goldfish

The embryonic developmental toxicity of the ionic liquid (IL) 1‐methyl‐3‐octylimidazolium bromide ([C₈mim]Br) on the goldfish Carassius auratus was evaluated in this study. First, the 72 h 50% lethal concentrations (72 h‐LC₅₀) for [C₈mim]Br in goldfish embryos at the stages of cleavage, early gastrula, closure of blastopore, and heart beating were determined by preliminary acute toxicity tests. After that, fish embryos in different developmental stages (cleavage, early gastrula, closure of blastopore, and heart beating) were exposed to 10.4, 20.8, 41.6, and 104 mg/L of [C₈mim]Br until their hatching stage. The results of the acute toxicity tests showed that 72 h‐LC₅₀ values at the early cleavage, early gastrula, closure of blastopore, and heart beating stages of development were 208.96, 187.1, 245.03, and 298.33 mg/L, respectively. In the subchronic tests, [C₈mim]Br exposure prolonged the duration of embryo dechorionation and decreased the hatching rates of the treated embryos compared to control embryos. In addition, [C₈mim]Br treatment also caused remarkable increases of embryonic malformation and mortality ratio in most treatment groups. Finally, we also found that the embryonic and developmental toxicity of [C₈mim]Br on fish embryos was dose‐response and developmental stage‐specific. These results indicate that [C₈mim]Br has toxic effects on the early embryonic development of goldfish, and the risk to aquatic ecosystem by ILs leaking into the water body must be evaluated in the future. © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

Site-specific drug delivery in the skin for the localized treatment of skin diseases

ABSTRACT

Introduction: Due to the well-organized structure and barrier function of the skin, it is generally difficult for drugs applied directly on the surface of skin to reach their expected site of action. Accordingly, site-specific drug delivery in the skin has been increasingly explored to facilitate the treatment of skin diseases and reduce the systemic toxicity.

Area covered: An overview of the generally used sites for drug delivery in the skin is herein presented. Different strategies including particle-based carriers, physical technologies, and chemical approaches are discussed with regards to their potential application in site-specific drug delivery in the skin.

Expert opinion: Particle-based carriers are of particular significance for the enhancement of drug delivery in the skin. Although no recommendation can be made regarding which type of carriers can provide better skin penetration, the lipid-based colloidal systems appear to be favored due to their compatibility. In addition, the physical technologies provide unique advantages in delivering hydrophilic macromolecules for the skin immunization. As a new class of permeation enhancers, skin penetrating peptides are gaining more attention in drug delivery to skin cells. For the design of robust site-specific drug delivery systems, the impacts of diseased state and drug properties should not be disregarded.