Flufenamic Acid-Loaded Self-Nanoemulsifying Drug Delivery System for Oral Delivery: From Formulation Statistical Optimization to Preclinical Anti-Inflammatory Assessment.

This research work aimed to prepare and optimize "self-nanoemulsifying drug delivery system (SNEDDS)" by applying full factorial design (FFD) to improve solubilization and subsequently antiinflammatory efficacy of flufenamic acid (FLF). Suitable excipients were screened out based on the maximum solubility of FLF. FFD was applied using lipid (X1) and surfactant (X2) as independent variables against droplet size (Y1, nm), zeta potential (Y2, mV) and polydispersity index (PDI, Y3). Desirability function identified the main factors influencing the responses and possible interactions. Moreover, the optimized formulation (OFS1) was characterized and compared with pure FLF suspension. The prepared formulations (FS1-FS9) showed the size, PDI and zeta potential of 14.2-110.7 nm, 0.29-0.62 and -15.1 to -28.6 mV, respectively. The dispersion and emulsification of all formulations meted out within 2 min suggesting immediate release and successful solubilization. The optimized formulation OFS1 demonstrated ~ 85% drug release within 1 h which was significantly higher (p ˂ 0.05) than FLF suspension. The hemolysis study negated the probable interaction with blood cells. Eventually, improved anti-inflammatory efficacy was envisaged which might be attributed to increased drug solubility and absorption. The present nanocarrier could be a promising approach and alternative to conventional dosage form.

Hairy cell leukaemia diagnosed in a polysensitized patient with atypical haemorrhagic skin lesions / Atípusos haemorrhagiás bortünetek hátterében igazolt hajas sejtes leukaemia poliszenzibilizált betegen.

As the topical use of non-steroidal anti-inflammatory drugs (NSAIDs) has gained popularity recently, adverse reactions related to their application have also become more common. The authors present the case of a 49-year-old man, who used etofenamate gel to treat leg pain. Following sun exposure, haemorrhagic, atypical lesions appeared and after rapid spread of the symptoms, the patient was hospitalized. In the area of the etofenamate application as well as on both legs, arms, trunk and face, confluent, erythematous sero-papules and macules were found, along with petechiae on the oral mucosa. Splenomegaly and thrombocytopenia accompanied the skin symptoms, which prompted an oncohematological workup, and the patient was diagnosed with hairy cell leukaemia. Epicutaneous testing (ET) was performed and found a positive reaction to etofenamate gel as well wood tar, propylen glycol, fragrance mix I, methylisothiazolinone, benzoic acid and balsam of Peru. The lymphocyte transformation test (LTT) and CD69 expression were negative for etofenamate. Orv Hetil. 2020; 161(38): 1646-1651.

Enhancing Anti-Tumor Activity of Sorafenib Mesoporous Silica Nanomatrix in Metastatic Breast Tumor and Hepatocellular Carcinoma via the Co-Administration with Flufenamic Acid.

INTRODUCTION: Because tumor-associated inflammation is a hallmark of cancer treatment, in the present study, sorafenib mesoporous silica nanomatrix (MSNM@SFN) co-administrated with flufenamic acid (FFA, a non-steroidal anti-inflammatory drug (NSAID)) was investigated to enhance the anti-tumor activity of MSNM@SFN. METHODS: Metastatic breast tumor 4T1/luc cells and hepatocellular carcinoma HepG2 cells were selected as cell models. The effects of FFA in vitro on cell migration, PGE2 secretion, and AKR1C1 and AKR1C3 levels in 4T1/luc and HepG2 cells were investigated. The in vivo anti-tumor activity of MSNM@SFN co-administrating with FFA (MSNM@SFN+FFA) was evaluated in a 4T1/luc metastatic tumor model, HepG2 tumor-bearing nude mice model, and HepG2 orthotopic tumor-bearing nude mice model, respectively. RESULTS: The results indicated that FFA could markedly decrease cell migration, PGE2 secretion, and AKR1C1 and AKR1C3 levels in both 4T1/luc and HepG2 cells. The enhanced anti-tumor activity of MSNM@SFN+FFA compared with that of MSNM@SFN was confirmed in the 4T1/luc metastatic tumor model, HepG2 tumor-bearing nude mice model, and HepG2 orthotopic tumor-bearing nude mice model in vivo, respectively. DISCUSSION: MSNM@SFN co-administrating with FFA (MSNM@SFN+FFA) developed in this study is an alternative strategy for improving the therapeutic efficacy of MSNM@SFN via co-administration with NSAIDs.

Efficiency of Multiparticulate Delivery Systems Loaded with Flufenamic Acid Designed for Burn Wound Healing Applications.

Burns are soft tissue injuries that require particular care for wound healing. Current tissue engineering approaches are aimed at identifying the most efficient treatment combinations to restore the tissue properties and function by using adapted scaffolds or delivery platforms for tissue repair and regeneration by triggering molecules. To reduce the inflammation associated with skin burns, the addition of an anti-inflammatory factor in these scaffolds would greatly increase the quality of the therapy. Therefore, this study is aimed at obtaining and validating a novel multiparticulate system based on a collagen matrix with controlled delivery of flufenamic acid anti-inflammatory drug for burn wound healing applications. In this work, we have characterized the properties and biocompatibility of these multiparticulate drug delivery systems (MDDS) and we have demonstrated their efficiency against burns and soft tissue lesions, particularly when the drug was microencapsulated, and thus with a controlled release. This study contributes to the advancement in therapy of burns and burn wound healing applications.

Crystal anisotropy explains structure-mechanics impact on tableting performance of flufenamic acid polymorphs.

Anisotropic features with other crystallographic properties like d-spacing, and attachment energy (Eatt) can predict material performance during the secondary pharmaceutical processing. A newly developed state-of-the-art compression cell lodged in a powder X-ray diffractometer was used to measure anisotropic Young's moduli (YM) of flufenamic acid (FFA) polymorphs in this study. Methodology is based on the generation of a single crystal deformation in this cell, which reflects as a change in the d-spacing in the PXRD pattern. Anisotropic YM was calculated from such information gathered along different FFA planes. Measured FFA crystallographic molecular features were concatenated to understand macroscopic compaction (Heckel and Shapirao's parameters) and tableting performance. Block shaped crystals of FFA form I, and III after initial characterization with SEM, DSC, PXRD, and FTIR were compressed normal to X, Y, and Z-planes, identified from calculated PXRD pattern using the reported single crystal structure. YM of X and Y planes of form I was significantly higher than corresponding planes of form III. Z plane of form III showed significantly higher YM than that for form I. Low YM of form III can be attributed to its large d-spacing regardless of their high Eatt than form I, as well as orientation of supramolecular acid dimer (OH⋯O) homosynthon chains in the FFA planes. FFA form I stiffness was further confirmed with lower densification and higher yield pressure of deformation than form III. Clearly, form III exhibited better compressibility, compactibility, and tableting performance than form I due to favorable molecular and macroscopic features. Thus, developed anisotropic measurement approach can be used to distinguish material performance in the early development stage of the pharmaceutical processes.

Flufenamic acid inhibits secondary hemorrhage and BSCB disruption after spinal cord injury.

Acute spinal cord injury (SCI) induces secondary hemorrhage and initial blood-spinal cord barrier (BSCB) disruption. The transient receptor potential melastatin 4 (Trpm4) together with sulfonylurea receptor 1 (Sur1) forms the Sur1-Trpm4 channel complex. The up-regulation of Sur1-Trpm4 after injury plays a crucial role in secondary hemorrhage, which is the most destructive mechanism in secondary injuries of the central nervous system (CNS). The matrix metalloprotease (MMP)-mediated disruption of the BSCB leads to an inflammatory response, neurotoxin production and neuronal cell apoptosis. Thus, preventing secondary hemorrhage and BSCB disruption should be an important goal of therapeutic interventions in SCI. Methods: Using a moderate contusion injury model at T10 of the spinal cord, flufenamic acid (FFA) was injected intraperitoneally 1 h after SCI and then continuously once per day for one week. Results: Trpm4 expression is highly up-regulated in capillaries 1 d after SCI. Treatment with flufenamic acid (FFA) inhibited Trpm4 expression, secondary hemorrhage, and capillary fragmentation and promoted angiogenesis. In addition, FFA significantly inhibited the expression of MMP-2 and MMP-9 at 1 d after SCI and significantly attenuated BSCB disruption at 1 d and 3 d after injury. Furthermore, we found that FFA decreased the hemorrhage- and BSCB disruption-induced activation of microglia/macrophages and was associated with smaller lesions, decreased cavity formation, better myelin preservation and less reactive gliosis. Finally, FFA protected motor neurons and improved locomotor functions after SCI. Conclusion: This study indicates that FFA improves functional recovery, in part, due to the following reasons: (1) it inhibits the expression of Trpm4 to reduce the secondary hemorrhage; and (2) it inhibits the expression of MMP-2 and MMP-9 to block BSCB disruption. Thus, the results of our study suggest that FFA may represent a potential therapeutic agent for promoting functional recovery.

Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice.

Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protection assay and a multiple-cycle growth assay showed that the antiviral activity of zanamivir was enhanced when combined with clarithromycin or FFA. A mouse challenge model was used here for the evaluation of the in vivo efficacy of the triple combination treatment. We found that mice receiving the triple combination of FFA, zanamivir, and clarithromycin had a significantly better survival rate than those receiving the double combination of zanamivir and clarithromycin (88% versus 44%, P = 0.0083) or zanamivir monotherapy (88% versus 26%, P = 0.0002). Mice in the FFA-zanamivir-clarithromycin triple combination group also exhibited significantly less body weight loss than those in the zanamivir-clarithromycin double combination group. There was no significant difference in the lung viral titers among the different groups from day 2 to day 6 postinfection. However, the levels of IL-1ß, TNF-α and RANTES in the FFA-zanamivir-clarithromycin triple combination group were significantly lower than those in the zanamivir-clarithromycin double combination group, zanamivir monotherapy group, or solvent group on day 2 postinfection. Our findings showed that the FFA-zanamivir-clarithromycin triple combination improved the inflammatory markers and survival of severe influenza A(H1N1) infection in mice.

Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy Volunteers.

Little is known about the course of the plasma concentration and the bioavailability of non-steroidal anti-inflammatory drugs (NSAIDs) contained in dermal patches. We compared an etofenamate prototype patch (patent EP 1833471) and a commercially available diclofenac epolamine patch regarding the bioavailability of the active ingredients relative to respective i.m. applications and regarding their plasma concentration-time course. Twenty-four healthy human volunteers were treated using a parallel group design (n = 12 per group) with a single dermal patch (removed after 12 hr) followed (after a latency of 48 hr) by eight consecutive dermal patches every 12 hr to reach steady-state conditions. The patches were generally well tolerated, but one volunteer treated with etofenamate developed an allergic contact dermatitis. After the first patch, Cmax was 0.81 ± 0.11 (mean ± S.E.M.) ng/mL (reached 12 hr after patch removal) for diclofenac and 31.3 ± 3.8 ng/mL for flufenamic acid (reached at patch removal), the main metabolite of etofenamate. Etofenamate was not detectable. After repetitive dosing, trough plasma concentrations after the eighth dose were 1.72 ± 0.32 ng/mL for diclofenac and 48.7 ± 6.6 ng/mL for flufenamic acid. Bioavailabilities (single dose) relative to i.m. applications were 0.22 ± 0.04% for diclofenac and 1.15 ± 0.06% for flufenamic acid. In conclusion, the relative bioavailability (compared to the respective i.m. application) of both drugs is low. The maximal plasma concentrations after topical administration of these drugs are well below the IC50 values for COX-1 and COX-2, explaining the absence of dose-dependent toxicities.

Transdermal iontophoresis of flufenamic acid loaded PLGA nanoparticles.

The objective of this study was to test in vitro a drug delivery system that combines nanoencapsulation and iontophoresis for the transdermal delivery of lipophilic model drug using poly(lactic-co-glycolic acid) (PLGA) as the carrier polymer. Negatively charged fluorescent nanoparticles loaded with negatively charged flufenamic acid were prepared. The colloidal properties of the particles were stable under iontophoretic current (constant, pulsed and alternating) profiles and in contact with skin barrier. The release of the drug from the particles was not affected by iontophoresis and remained always limited (≈50%), leading to significantly lower transdermal fluxes across human epidermis and full thickness porcine skin compared to respective free drug formulation. From nanoparticles, pulsed current profile resulted in comparable or higher fluxes compared to constant current profile although fluorescence imaging was not able to confirm deeper distribution of nanoparticles in skin. Based on our results, there is no clear advantage with respect to drug permeation from nanoencapsulating flufenamic acid into PLGA nanoparticles compared to free drug formulation, either in passive or iontophoretic delivery regimens. However, pulsed current iontophoresis could be an effective alternative instead of traditional constant current iontophoresis to enhance transdermal permeation of drugs from nanoencapsulated formulations.

Effects of permeation enhancers on flufenamic acid delivery in Ex vivo human skin by confocal Raman microscopy.

For effective topical delivery, a drug must cross the stratum corneum (SC) barrier into viable tissue. The use of permeation enhancers is a widespread approach for barrier modification. In the current study, flufenamic acid (FluA), a non-steroidal anti-inflammatory drug, is a model agent for investigating the influence of hydrophobic versus hydrophilic enhancers. In separate experiments, FluA in octanol or propylene glycol/ethanol (75/25) is applied to the SC for varying times followed by confocal Raman microscopic mapping of drug and enhancer penetration and spatial distribution. Deuterated versions of the enhancers permit us to spectroscopically distinguish the exogenous chemicals from the endogenous SC lipids without affecting penetration parameters. The FluA pathway is tracked by the CC stretching mode at ∼1618cm(-1). Discrete, small inclusions of both enhancers are observed throughout the SC. High concentrations of FluA are co-localized with octanol domains which appear to provide a pathway to the viable epidermis for the drug. In contrast, FluA concentrates in the upper SC when using the hydrophilic agent and endogenous lipids appear unperturbed in regions outside the enhancer pockets. The ability to examine perturbations to endogenous ultrastructure and molecular structure in skin while tracking penetration pathways provides insight into delivery mechanisms.

A strategy for in-silico prediction of skin absorption in man.

For some time, in-silico models to address substance transport into and through the skin are gaining more and more importance in different fields of science and industry. In particular, the mathematical prediction of in-vivo skin absorption is of great interest to overcome ethical and economical issues. The presented work outlines a strategy to address this problem and in particular, investigates in-vitro and in-vivo skin penetration experiments of the model compound flufenamic acid solved in an ointment by means of a mathematical model. Experimental stratum corneum concentration-depth profiles (SC-CDP) for various time intervals using two different in-vitro systems (Franz diffusion cell, Saarbruecken penetration model) were examined and simulated with the help of a highly optimized three compartment numerical diffusion model and compared to the findings of SC-CDPs of the in-vivo scenario. Fitted model input parameters (diffusion coefficient and partition coefficient with respect to the stratum corneum) for the in-vitro infinite dose case could be used to predict the in-use conditions in-vitro. Despite apparent differences in calculated partition coefficients between in-vivo and in-vitro studies, prediction of in-vivo scenarios from input parameters calculated from the in-vitro case yielded reasonable results.

Investigation of microemulsion microstructure and its impact on skin delivery of flufenamic acid.

Microemulsions are well known penetration enhancing delivery systems. Several properties are described that influence the transdermal delivery of active components. Therefore, this study aimed to characterize fluorosurfactant-based microemulsions and to assess the impact of formulation variables on the transdermal delivery of incorporated flufenamic acid. The microemulsion systems prepared in this study consisted of bistilled water, oleic acid, isopropanol as co-solvent, flufenamic acid as active ingredient and either Hexafor(TM)670 (Hex) or Chemguard S-550-100 (Sin) as fluorosurfactant. Characterization was performed by a combination of techniques including electrical conductivity measurements, small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) self-diffusion experiments. In vitro skin permeation experiments were performed with each prepared microemulsion using Franz type diffusion cells to correlate their present microstructure with their drug delivery to skin. Electrical conductivity increased with added water content. Consequently, the absence of a conductivity maximum as well as the NMR and SAXS data rather suggest O/W type microemulsions with spherical or rod-like microstructures. Skin permeation data revealed enhanced diffusion for Hex- and Sin-microemulsions if the shape of the structures was rather elongated than spherical implying that the shape of droplets had an essential impact on the skin permeation of flufenamic acid.

Eight-channel transceiver RF coil array tailored for ¹H/¹9F MR of the human knee and fluorinated drugs at 7.0 T.

The purpose of this study was to evaluate the feasibility of an eight-channel dual-tuned transceiver surface RF coil array for combined (1)H/(19)F MR of the human knee at 7.0 T following application of (19)F-containing drugs. The (1)H/(19)F RF coil array includes a posterior module with two (1)H loop elements and two anterior modules, each consisting of one (1)H and two (19)F elements. The decoupling of neighbor elements is achieved by a shared capacitor. Electromagnetic field simulations were performed to afford uniform transmission fields and to be in accordance with RF safety guidelines. Localized (19)F MRS was conducted with 47 and 101 mmol/L of flufenamic acid (FA) ­ a (19)F-containing non-steroidal anti-inflammatory drug ­ to determine T1 and T2 and to study the (19)F signal-to-dose relationship. The suitability of the proposed approach for (1)H/(19)F MR was examined in healthy subjects. Reflection coefficients of each channel were less than -17 dB and coupling between channels was less than -11 dB. Q(L)/Q(U) was less than 0.5 for all elements. MRS results demonstrated signal stability with 1% variation. T1 and T2 relaxation times changed with concentration of FA: T1 /T2 = 673/31 ms at 101 mmol/L and T1 /T2 = 616/26 ms at 47 mmol/L. A uniform signal and contrast across the patella could be observed in proton imaging. The sensitivity of the RF coil enabled localization of FA ointment administrated to the knee with an in-plane spatial resolution of (1.5 × 1.5) mm(2) achieved in a total scan time of approximately three minutes, which is well suited for translational human studies. This study shows the feasibility of combined (1)H/(19)F MRI of the knee at 7.0 T and proposes T1 and T2 mapping methods for quantifying fluorinated drugs in vivo. Further technological developments are necessary to promote real-time bioavailability studies and quantification of (19)F-containing medicinal compounds in vivo.

Effect of monoacyl phosphatidylcholine content on the formation of microemulsions and the dermal delivery of flufenamic acid.

The choice of appropriate excipients is crucial for the success of a dermal drug delivery system. Especially surfactants should be chosen carefully, because of their possible interactions with the skin or the applied drug. Since monoacyl phosphatidylcholine (MAPL) exhibits great emulsification properties and can be derived from natural sources, it is of great interest as surfactant in microemulsions. Therefore, the aim of the present study was to investigate the effect of the MAPL content on the formation of microemulsions. The great emulsification power of MAPL was confirmed by increased isotropic areas with increasing MAPL content. Moreover, a decrease in particle size, particle size distribution and viscosity with increasing MAPL content was determined. Besides its effects on microemulsion structure, MAPL exhibited a significant influence on the skin permeation of flufenamic acid. Interestingly, the higher the MAPL content, the lower was the skin permeation of flufenamic acid. A possible explanation might be that the hydrophilic MAPL could hinder the permeation of the lipophilic drug. In contrast, the skin permeation enhancing effects of the microemulsion with the lowest MAPL content might be attributed to formation of a patch-like structure and therefore better contact between the formulation and the skin.

Topical gels of etofenamate: in vitro and in vivo evaluation.

Non-steroid anti-inflammatory drugs (NSAIDs), such as etofenamate, are among the most prescribed drugs used for their analgesic, anti-rheumatic, antipyretic and anti-inflammatory properties. Topical formulations have the main advantage of targeted delivery. However, drugs must overcome the skin due to its role as a physical and chemical barrier against the penetration of chemicals and microorganisms. This barrier must be altered to allow the permeation of drugs at a suitable rate to the desired site of activity. Permeation modulators can intercalate the skin outer layers causing structure disruption, opening an energetically favourable route for the drug to diffuse through. The aim of this work was the development of hydroalcoholic gels containing 5.0% (w/w) of etofenamate for topical administration with anti-inflammatory activity and enhanced drug delivery. The physical and chemical characterization, in vitro release and permeation studies and in vivo anti-inflammatory activity were assessed. The gel with 30% ethanol showed in vivo anti-inflammatory activity with suitable physical chemical and microbiologic characteristics. In vitro release and permeation studies revealed that the different amounts of ethanol used influenced the release profiles of etofenamate. Moreover, it was demonstrated that this formulation is an adequate vehicle for the etofenamate skin permeation.

Development of etofenamate-loaded semisolid sln dispersions and evaluation of anti-inflammatory activity for topical application.

Dermal application of various active substances is widely preferred for topical or systemic delivery. SLNs consist of biocompatible and non-toxic lipids and have a great potential for topical application in drugs. In this study, semisolid SLN formulations were successfully prepared by a novel one-step production method as a topical delivery system of etofenamate, an anti-inflammatory drug. Compritol 888 ATO and Precirol ATO 5 were chosen as lipid materials for the fabrication of the formulations. In-vitro evaluation of the formulations was performed in terms of encapsulation efficiency, particle size, surface charge, thermal behavior, rheological characteristics, in vitro drug release profile, kinetics, mechanisms, stability, and anti-inflammatory activity. The colloidal size and spherical shape of the particles were proved. According to the results of the rheological analysis, it was demonstrated that the semisolid SLN formulations have a gel-like structure. Stability studies showed that semisolid SLNs were stable at 4°C for a six month period. Zero order release was obtained with Precirol ATO 5, while Compritol 888 ATO followed the square root of time (Higuchi's pattern) dependent release. Semisolid SLNs showed higher inhibitory activity of COX in comparison with pure etofenamate. In conclusion, etofenamate-loaded semisolid SLN formulations can be successfully prepared in a novel one-step production method and useful for topical application.

Influence of the composition of monoacyl phosphatidylcholine based microemulsions on the dermal delivery of flufenamic acid.

Although microemulsions are one of the most promising dermal carrier systems, their clinical use is limited due to their skin irritation potential. Therefore, microemulsions based on naturally derived monoacyl phosphatidylcholine (MAPL) were developed. The influence of the water, oil and surfactant content on dermal delivery of flufenamic acid was systematically investigated for the first time. A water-rich microemulsion led to significantly higher in vitro skin penetration of flufenamic acid compared to other microemulsions. The superiority of the water-rich microemulsion over a marketed flufenamic acid containing formulation was additionally confirmed. Differences in drug delivery could be explained by alterations of the microemulsions after application. Evaporation of isopropanol led to crystal-like structures of MAPL on the skin surface from the surfactant- or oleic acid-rich microemulsions. In contrast, the formation of this additional barrier was hindered in case of the water-rich microemulsion. The skin penetration of MAPL was additionally analyzed by combined ATR-FTIR and tape stripping experiments, where MAPL itself penetrated only into the initial layers of the stratum corneum, independent of the microemulsion composition. Since a surfactant must penetrate the skin to cause irritation, MAPL can be presumed as a skin-friendly emulsifier with the ability to stabilize pharmaceutically acceptable microemulsions.

Bicellar systems as new delivery strategy for topical application of flufenamic acid.

In this work, bicellar systems, bilayered disc-shaped nanoaggregates formed in water by phospholipids, are proposed as a novel strategy for delivery of the anti-inflammatory flufenamic acid (FFA) to the skin. A comparative percutaneous penetration study of this drug in bicellar systems and other vehicles was conducted. The effects induced on the skin by the application of FFA in the different vehicles were analyzed by attenuated total reflectance-fourier transform infrared (ATR-FTIR). Additionally, using the microscopic technique freeze-substitution transmission electron microscopy (FSTEM) and X-ray scattering technique using synchrotron radiation (SAXS-SR), we studied the possible microstructural and organizational changes that were induced in the stratum corneum (SC) lipids and the collagen of the skin by the application of FFA bicellar systems. Bicellar systems exhibited a retarder effect on the percutaneous absorption of FFA with respect to the other vehicles without promoting disruption in the SC barrier function of the skin. Given that skin disruption is one of the main effects caused by inflammation, prevention of disruption and repair of the skin microstructure should be prioritized in anti-inflammatory formulations.

Nanocarriers for dermal drug delivery: influence of preparation method, carrier type and rheological properties.

Nanocarriers are highly interesting delivery systems for the dermal application of drugs. Based on a eudermic alkylpolyglycosid nanoemulsions, solid lipid nanoparticles (SLN) and nano-structured lipid carriers (NLC) were prepared by ultrasonic dispersion. The ultrasound preparation technique turned out to be convenient and rapid. For reasons of comparison, nanoemulsions were also prepared by high-pressure homogenisation with highly similar physicochemical properties. Cryo electron microscopy was employed to elucidate the microstructure of the ultrasound-engineered nanocarriers. Furthermore, in vitro skin experiments showed excellent skin permeation and penetration properties for flufenamic acid from all formulations. Moreover, ATR-FTIR studies revealed barrier-restorative properties for NLC and SLN. Furthermore, the rheological characteristics of all nanocarriers were determined. In order to increase the viscosity, three different polymers were employed to also prepare semi-solid NLC drug delivery systems. All of them exhibited comparable skin diffusion properties, but may offer improved dermal applicability.