Development of essential oils as skin permeation enhancers: penetration enhancement effect and mechanism of action

Context: Essential oils (EOs) have shown the potential to reversibly overcome the stratum corneum (SC) barrier to enhance the skin permeation of drugs.

Objective: The effectiveness of turpentine, Angelica, chuanxiong, Cyperus, cinnamon, and clove oils were investigated for the capacity and mechanism to promote skin penetration of ibuprofen.

Materials and methods: Skin permeation studies of ibuprofen across rat abdominal skin with the presence of 3% w/v EOs were carried out; samples were withdrawn from the receptor compartment at 8, 10, 22, 24, 26, 28, 32, 36, and 48?h and analyzed for ibuprofen content by the HPLC method. The mechanisms of penetration enhancement of EOs were further evaluated by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) analysis and determination of the properties of EOs. Moreover, the toxicities of EOs on skin cells were also measured.

Results: The enhancement ratio (ER) values of turpentine, Angelica, chuanxiong, Cyperus, cinnamon, clove oils and azone were determined to be 2.23, 1.83, 2.60, 2.49, 2.63 and 1.97, respectively. Revealed by ATR-FTIR analysis, a linear relationship (r?=?0.9045) was found between the ER values and the total of the shift of peak position of SC lipids. Furthermore, the results of HaCaT skin cell toxicity evaluation revealed that the natural EOs possessed relatively lower skin irritation potential.

Conclusion: Compared with azone, the investigated EOs possess significantly higher penetration enhancement effect and lower skin toxicity. EOs can promote the skin permeation of ibuprofen mainly by disturbing rather than extracting the SC lipids.     

Novel transdermal delivery of Timolol maleate using sugar esters: Preclinical and clinical studies

The feasibility of matrix controlled transdermal patch based on sugar fatty acid ester (SE) as penetration and absorption enhancer containing Timolol maleate (TM) was investigated. The influence of fatty acid type, chain length and hydrophile-lipophile balance (HLB) on the in vitro drug release as well as its permeation across hairless rat skin were studied and compared aiming to select a patch formula for clinical performance. Skin irritation induced by SE patch was evaluated by visual scoring, color reflectance measurements and non-invasive transepidermal water loss (TEWL) technique. The results indicated that among different SEs tried, laurate SE with shorter fatty acid chain length and higher HLB value significantly increased the amount of TM liberated from the patch (99 ± 2.1%) and its permeation across rat skin (86 ± 4.3%). The total drug permeation and flux values were approximately 5-fold greater compared to SE free patch. The extent of absorption of TM-SE patch expressed by AUC was 64% larger as compared to the oral solution with steady plasma concentration over 18 h and relative bioavailability (F_rel) of 163%. The developed patch was well tolerated by all the subjects with only moderate skin irritation, which was recovered in 24 h after patch removal. The results are very encouraging and offer an alternative approach to maintain higher, prolonged and controlled blood level profile of the drug over 18-24 h.     

Oleodendrimers: A novel class of multicephalous heterolipids as chemical penetration enhancers for transdermal drug delivery

This paper reports synthesis and evaluation of Janus type generation G-1 and G-2 dendrimers. The dendrimers have been constructed by linking two building blocks, dendrons and oleic acid, through ester and amide bonds and were well characterized by Fourier-transform infrared (FT-IR), ¹H NMR, ¹³C NMR and electrospray ionization mass spectrometry (ESI-MS). The dendrimers have been evaluated for in vitro cytotoxicity using sulforhodamine B assay (SRB assay) and in vivo skin irritation potential. The ester linked dendrimers did not exhibit any cytotoxicity even up to 80 μg/ml while G-1 and G-2 generations dendrimers with amide linkage exhibited toxicity above 70 μg/ml and 21 μg/ml, respectively, none of the dendrimers showed any skin irritation. All the dendrimers, tested for their skin permeation enhancement potential using diclofenac sodium (DS) as a model drug at a concentration of 1% in gels, showed significant increase in steady-state flux (ER_flux) of the drug as compared to control (without enhancer), and oleic acid. Amongst the dendrimers, the ester linked G-1 and G-2 dendrimers showed highest ER_flux, 3.33 ± 0.31 and 3.39 ± 0.21, respectively.     

Preparation and evaluation of aceclofenac microemulsion for transdermal delivery system

To develop novel transdermal formulation for aceclofenac, microemulsion was prepared for increasing its skin permeability. Based on solubility and phase studies, oil and surfactant was selected and composition was determined. Microemulsion was spontaneously prepared by mixing ingredients and the physicochemical properties such was investigated. The mean diameters of microemulsion were approximately 90 nm and the system was physically stable at room temperature at least for 3 months. In addition, the in vitro and in vivo performance of microemulsion formulation was evaluated. Aceclofenac was released from microemulsion in acidic aqueous medium, and dissolved amounts of aceclofenac was approximately 30% after 240 min. Skin permeation of aceclofenac from microemulsion formulation was higher than that of cream. Following transdermal application of aceclofenac preparation to delayed onset muscle soreness, serum creatine phosphokinase and lactate dehydrogenase activity was significantly reduced by aceclofenac. Aceclofenac in microemulsion was more potent than cream in the alleviation of muscle pain. Therefore, the microemulsion formulation of aceclofenac appear to be a reasonable transdermal delivery system of the drug with enhanced skin permeability and efficacy for the treatment of muscle damage.     

坎地沙坦与氯沙坦治疗原发性高血压的疗效及对肾脏的保护作用

目的比较坎地沙坦与氯沙坦治疗原发性高血压的临床疗效及对肾脏的保护作用。方法将本院诊治的72例轻中度原发性高血压病患者随机分为坎地沙坦组与氯沙坦组,两组分别给予坎地沙坦口服,8 mg/d,氯沙坦50 mg/d,疗程8周。比较两组治疗前后24 h动态血压改变、心率震荡初始值(TO)、心率震荡斜率(TS)及肾功能指标的变化。结果坎地沙坦组与氯沙坦组治疗有效率分别为84.2%和82.4%,两组比较差异无统计学意义(P>0.05);坎地沙坦组治疗后24 h收缩压(SBP)及24 h舒张压(DBP)分别为(121.45±10.23)mmHg和(76.24±6.03)mmHg,氯沙坦组分别为(122.39±10.16)mmHg和(76.53±6.21)mmHg,两组比较差异无统计学意义(P>0.05),但坎地沙坦组清晨血压SBP及DBP下降值分别为(13.90±3.32)mmHg和(9.80±2.17)mmHg,显著优于氯沙坦组(10.23±2.87)mmHg和(7.33±2.01)mmHg(P<0.05);坎地沙坦组与氯沙坦组治疗后TO分别为(0.38±0.23)%、(0.40±0.25)%,TS为(5.16±0.83)ms/RRI、(5.09±0.78)ms/RRI,差异无统计学意义(P>0.05);坎地沙坦组治疗后24 h尿蛋白及尿β2-MG分别为(134.90±19.21)mg和(1.88±0.43)mmol/L,氯沙坦组分别为(136.73±18.70)mg和(1.87±0.41)mmol/L,两组均显著优于治疗前(P<0.05);两组治疗后BUN、SCr与治疗前比较差异无统计学意义(P>0.05);氯沙坦组治疗后尿酸水平显著低于坎地沙坦组(312.20±18.93)vs(339.84±18.74)μmol/L,P<0.05。结论坎地沙坦与氯沙坦治疗轻中度高血压均有较好疗效,对肾脏具有保护作用。但坎地沙坦控制清晨血压效果更为理想,氯沙坦可显著降低尿酸水平,临床可根据患者病情选用药物。     

Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies

Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (∼7%) since Vin undergoes a marked first-pass effect (∼75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation.All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 μm to 2.52 μm which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula - containing laurate SE with shorter fatty acid chain length and high HLB - was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F_rel) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release.     

Trypsin as a novel potential absorption enhancer for improving the transdermal delivery of macromolecules

Objectives The aim was to assess the effect of trypsin on the transdermal delivery of macromolecules by applying its specific biochemical properties to the stratum corneum of the skin. Methods Fluorescein isothiocyanate (FITC)‐labelled dextrans (FDs), with molecular weights of 4 to 250 kDa, and FITC‐insulin were used as model macromolecules and a model polypeptide, and the in‐vitro transdermal permeation experiments, with or without trypsin (0.1–2.5%), were carried out using rat skin and cultured human epidermis. The mechanism for the enhancement of trypsin was also studied using fluorescence and conventional light microscopy. Key findings Trypsin significantly increased the transdermal permeability of all FDs through the rat skin (2.0‐ to 10.0‐fold). It also markedly enhanced the permeation of FD4 through three‐dimensional cultured human epidermis (3.1‐fold), which was used to evaluate the transport pathways other than the transfollicular route. Furthermore, the permeation flux of FITC‐insulin was increased by 10.0‐fold with trypsin pretreatment (from 0.02 ± 0.00 to 0.20 ± 0.07 μg/cm² per h). Mechanistic studies indicated that trypsin affects both the intercellular pathway and the hair follicular route, and may alter stratum corneum protein structures, thereby affecting skin barrier properties. Conclusions This study suggests that trypsin could be effective as a biochemical enhancer for the transdermal delivery of macromolecules including peptide and protein drugs.     

Formulation and in vivo evaluation of membrane-moderated transdermal therapeutic systems of nicardipine hydrochloride using carvone as a penetration enhancer

A membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride was developed using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 8%w/w of carvone as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38, or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28%w/w vinyl acetate) or EVA 2825 membrane/skin composite also was studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED and 2%w/w HPC gel as reservoir containing 8%w/w of carvone as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 23 hr with improved bioavailability in comparison with the immediate-release capsule dosage form.     

Enhancing effect of pyrrolidone derivatives on transdermal drug delivery II. Effect of application concentration and pre-treatment of enhancer

We compared the enhancing effects of 1-methyl- (I), 1-hexyl- (II) and 1-lauryl-2-pyrrolidone (III) on the penetration of phenolsulfonphthalein (Phenol red) as a model for a non-absorbable drug. Using the in vitro penetration technique and excised rat skin, the enhancers were applied at various concentrations. An increase in enhancer concentration was found to increase the flux and skin accumulation, and shorten the lag time for steady-state penetration of Phenol red. The enhancing effects of II and III ceased at 0.1 mmol/ml. Penetration for enhancers was found to increase with their own concentrations. Pre-treatment with enhancer for 5 h shortened the lag time for steady-state penetration of Phenol red. Removal of II from the donor side after pre-treatment decreased its enhancing effect. Enhancer III still showed an effect after removal.     

Antioxidant and antibacterial activities of the leaf essential oils of Himalayan Lauraceae species

The leaf essential oils from seven Himalayan Lauraceae species viz. Neolitsea pallens, Lindera pulcherrima, Dodecadenia grandiflora, Persea duthiei, Persea odoratissima, Persea gamblei and Phoebe lanceolata exhibited potent antioxidant and antibacterial activities. The in vitro antioxidant activity was assessed by using β-carotene bleaching assay, reducing power, DPPH radical scavenging and inhibition of lipid peroxidation methods. The oils of D. grandiflora and L. pulcherrima showed a potent free radical scavenging activity as evidenced by low IC₅₀ value for DPPH radical (0.032 mg/ml and 0.087 mg/ml, respectively) and inhibition of lipid peroxidation (in between IC₅₀ = 0.44 mg/ml and IC₅₀ = 0.74 mg/ml, respectively). The oils were tested against three Gram negative (Escherichia coli, Salmonella enterica enterica and Pasturella multocida) and one Gram positive (Staphylococcus aureus) bacteria at different concentrations using disc diffusion and tube dilution methods. The inhibition zones (IZ) and MIC values for bacterial strains were in the range of 8.7–22.0 mm and 3.90–31.25 μl/ml, respectively.     

Poloxamer gel as vehicle for transdermal iontophoretic delivery of arginine vasopressin: evaluation of in vivo performance in rats

The present study describes the formulation and evaluation for pharmacokinetic and pharmacodynamic activity of arginine vasopressin (AVP), a nanopeptide with antidiuretic activity on being delivered by transdermal iontophoresis. Poloxamer 407 was used to form stable gels that did not reduce the release of AVP. The release rate from the gel followed Higuchi kinetics indicating that the dominant mechanism of release is diffusion. Iontophoresis alone and in combination with chemical enhancers was used to augment the transdermal permeation of AVP. The results of both pharmacokinetic and pharmacodynamic studies emphasize the dimension of 'rapid onset' achieved by iontophoresis. The correlation between pharmacokinetic data and pharmacodynamic activity was only qualitative. Histopathological studies revealed that skin toxicity caused by either iontophoresis or chemical enhancers when used alone could be reduced by using a combination of both the techniques in tandem.     

氯沙坦钾氢氯噻嗪片治疗老年原发性高血压的临床效果观察

目的分析老年原发性高血压患者应用氯沙坦钾氢氯噻嗪片治疗的效果。方法 96例老年原发性高血压患者,随机分为对照组和观察组,每组48例。对照组采用氢氯噻嗪片治疗,观察组采用氯沙坦钾氢氯噻嗪片治疗。比较两组患者治疗效果及治疗前后血压水平。结果观察组患者的治疗总有效率97.92%高于对照组的85.42%,差异具有统计学意义(P<0.05)。治疗前,两组患者的清晨收缩压(SBP)、舒张压(DBP)及24 h动态SBP、DBP水平比较差异无统计学意义(P>0.05);治疗后,两组患者的清晨SBP、DBP及24 h动态SBP、DBP水平均较治疗前降低,且观察组患者的清晨SBP(135.14±7.04)mm Hg(1 mm Hg=0.133 kPa)、DBP(86.53±6.78)mm Hg及24 h动态SBP(134.24±9.61)mm Hg、DBP(84.81±8.80)mm Hg低于对照组的(140.26±8.17)、(92.06±7.36)、(142.36±9.16)、(89.03±8.05)mm Hg,差异具有统计学意义(P<0.05)。结论老年原发性高血压患者应用氯沙坦钾氢氯噻嗪片治疗的效果比较好,可以明显改善血压水平,具有较高的应用价值。     

Human skin penetration of the major components of Australian tea tree oil applied in its pure form and as a 20% solution in vitro

The safety of topical application of Australian tea tree Oil (TTO) is confounded by a lack of transdermal penetration data, which adequately informs opinions and recommendations. In this study we applied TTO in its pure form and as a 20% solution in ethanol in vitro to human epidermal membranes from three different donors, mounted in horizontal Franz-type diffusion cells, using normal ‘in use’ dosing conditions (10 mg/cm²). In addition, we examined the effect of partially occluding the application site on the penetration of TTO components. Our data showed that only a small quantity of TTO components, 1.1–1.9% and 2–4% of the applied amount following application of a 20% TTO solution and pure TTO, respectively, penetrated into or through human epidermis. The largest TTO component penetrating the skin was terpinen-4-ol. Following partial occlusion of the application site, the penetration of terpinen-4-ol increased to approximately 7% of the applied TTO. Measurement of the rate of evaporation of tea tree oil from filter paper (7.4 mg/cm²) showed that 98% of the oil evaporated in 4 hours. Overall, it is apparent that the penetration of TTO components through human skin is limited.     

Screening for antimicrobial activity of some essential oils by the agar overlay technique

Fifty-three essential oils were tested against five micro-organisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans) using the agar overlay technique. The essential oils were randomly selected and not on the basis of a supposed activity. It was found that all oils showed an activity against at least one micro-organism, and that substantial activities againstP. aeruginosa were scarce. Combined activities againstC. albicans, the Gram-positive bacteria andE. coli, and an activity againstC. albicans were most often observed. Secondly a combined activity againstC. albicans, B. subtilis andS. aureus was found. The differences between the inhibition zones were too small for a differentiation of the antimicrobial activities of the essential oils. A correlation matrix shows the relationships of the micro-organisms as to the activity patterns of the essential oils. High correlations were found for all the micro-organisms, except forP. aeruginosa.     

Combined effect of liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate in rat skin

In this report, we investigated the combined effect of drug liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate (ISN) in rat abdominal skin in vitro. Occlusive application of both liposomal and aqueous ISN solution, with and without addition of 5% glycerol, showed that drug liposomalization and addition of glycerol has far-reaching implications for ISN permeation and accumulation in 4 and 8 weeks old rat abdominal skin. Using 8 weeks old rat abdominal skin, the optimal concentration of glycerol to be added to liposomal ISN was found to be 5%. The ISN mean values permeated through and accumulated in stripped 8 weeks old rat abdominal skin from those formulations described above were not significant different, which might indicate the combined effect of glycerol and liposomal ISN resides solely in the stratum corneum (SC). Based on previous reports, the enhancement effect of glycerol might be due to an increase in the SC hydration, and perhaps due to subtle changes in the lipid organization caused by penetration of liposomal lipids within the SC intercellular spaces. These data might provide evidence that glycerol action on SC is useful to facilitate skin permeation and accumulation of drugs formulated in liposome.     

Enhancement of the transdermal delivery of zidovudine by pretreating the skin with two physical enhancers: microneedles and sonophoresis

BackgroundZidovudine (AZT) has been the most widely used drug for antiretroviral therapy. In order to improve the therapy with this drug, different alternatives have been proposed, such as the transdermal administration. The use of permeation enhancers is necessary to favor the passage of this drug through the skin, due to its physicochemical properties and to the natural permeation barrier imposed by the skin. ObjectivesTo evaluate the effect of two permeation enhancers, sonophoresis and microneedles, on the permeability of AZT through the skin.MethodsPermeation studies with an AZT solution were performed using pigskin clamped in Franz-type cells. Sonophoresis was applied under different conditions (i.e., amplitude, duty cycle and application time), selected according to an experimental design, where the response variables were the increase in temperature of the skin surface and the increase in transepidermal water loss. ATR-FTIR was also used to demonstrate the effect of enhancers on membrane components. ResultsThe permeability of AZT through intact skin was very poor, with a very long lag time. Pretreatment of the skin with sonophoresis increased AZT transport significantly, reducing the lag time. The maximum flux (27.52 µgcm⁻² h⁻¹) and the highest total amount permeated (about 624 µg/cm²) were obtained when applying sonophoresis in continuous mode, with an amplitude of 20%, and an application time of 2 min. Sonophoresis appears to have an impact on stratum corneum proteins. The use of microneedles further increased the flux (30.41 µgcm⁻² h⁻¹) and the total amount permeated (about 916 µg/cm²), relative to sonophoresis. ConclusionThe results are encouraging in terms of promoting AZT transport through the skin using sonophoresis or microneedles as permeation enhancers.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s40199-021-00402-y.     

Nanodelivery of essential oils as efficient tools against antimicrobial resistance: a review of the type and physical-chemical properties of the delivery systems and applications

This review provides a synthesis of the last ten years of research on nanodelivery systems used for the delivery of essential oils (EOs), as well as their potential as a viable alternative to antibiotics in human and veterinary therapy. The use of essential oils alone in therapy is not always possible due to several limitations but nanodelivery systems seem to be able to overcome these issues. The choice of the essential oil, as well as the choice of the nanodelivery system influences the therapeutic efficacy obtained. While several studies on the characterization of EOs exist, this review assesses the characteristics of the nanomaterials used for the delivery of essential oils, as well as impact on the functionality of nanodelivered essential oils, and successful applications. Two classes of delivery systems stand out: polymeric nanoparticles (NPs) including chitosan, cellulose, zein, sodium alginate, and poly(lactic-co-glycolic) acid (PLGA), and lipidic NPs including nanostructured lipid carriers, solid lipid NPs, nanoemulsions, liposomes, and niosomes. While the advantages and disadvantages of these delivery systems and information on stability, release, and efficacy of the nanodelivered EOs are covered in the literature as presented in this review, essential information, such as the speed of emergence of a potential bacteria resistance to these new systems, or dosages for each type of infection and for each animal species or humans is still missing today. Therefore, more quantitative and in vivo studies should be conducted before the adoption of EOs loaded NPs as an alternative to antibiotics, where appropriate.     

The application of the full factorial design and Response Surface Methodology in optimization conditions for essential oils extraction from Lavandula stoechas,Carum carvi and Eucalyptus camaldulensis: Effect of plants particle size on the extraction of essential oils

The study applies experimental design to optimize hydrodistillation (HD) parameters in essential oils (EOs) extraction from the aerial parts of three different plants: Lavandula stoechas, Eucalyptus camaldulensis and Carum carvi. Three parameters have been examined: the particle size (Ps) the distillate flow (Q) and the volume of EOs vapor in the Clevenger (V_vap).The ratio of plant mass to the water volume has been kept constant as well as the extraction time. The full factorial design (FFD) gives a first-order model with an R² > 0.99 for both plants Lavandula stoechas and Carum carvi. According to the Box–Behnken design (BBD) , the EOs yield of Eucalyptus camaldulensis seems to depend on the Vapor volume of the EOs, distillate flow and the particle size and, on the interaction between the Vapor volume and the distillate flow. A second order model obtained by the BBD application on the Eucalyptus camaldulensis plant. The analysis of variance (ANOVA) reveals that the model was significant, as evidenced from R² of 0.991 and the model F-value of 196, 42. Finally, it seems that for plants whose secretory sites are superficial glandular trichomes, such as Lavandula stoechas leaves (Lamiaceae), or secretory canals, such as Carum carvi seeds (Apiaceae), the particle size has no effect on the extraction yield. On the contrary, the particle size is a limiting parameter in the case of endogenous secretory pockets of Eucalyptus camaldulensis (Myrtaceae).     

A new approach for the evaluation of niosomes as effective transdermal drug delivery systems

The central motivation for this study was to evaluate if the increased hydrophilic drug permeation across the skin, which is always observed in presence of vesicular systems, is dependent on the structural organization of niosomes, that are used to transport the active molecules, or if it is only dependent on the surfactant dual nature. To answer this question, non-ionic surfactants belonging to the class of Pluronic and sucrose esters were used both as components of niosomal systems or in the form of sub-micellar solutions. The obtained niosomes were characterized by their entrapment efficiency, size and morphology.The enhancing effect of niosomes on the ex vivo percutaneous penetration of a model drug was investigated using a Franz-type diffusion chamber and compared to that obtained by using sub-micellar solution of surfactant or achieving pretreatment of the skin with surfactants’ sub-micellar solution or empty niosomes.The results suggest that the surfactants used in this study could be considered as percutaneous permeation enhancers only when they are in the form of drug-loaded vesicular systems: no percutaneous promotion was achieved by using sub-micellar solution containing free Sulfadiazine sodium salt or performing pretreatment with empty niosomes or sub-micellar solutions of the surfactant. In our experiments, only niosomes act as effective transdermal drug delivery systems.