Role for Carboxylic Acid Moiety in NSAIDs: Favoring the Binding at Site II of Bovine Serum Albumin.

The molecular structures of nonsteroidal anti-inflammatory drugs (NSAIDs) vary, but most contain a carboxylic acid functional group (RCOOH). This functional group is known to be related to the mechanism of cyclooxygenase inhibition and also causes side effects, such as gastrointestinal bleeding. This study proposes a new role for RCOOH in NSAIDs: facilitating the interaction at the binding site II of serum albumins. We used bovine serum albumin (BSA) as a model to investigate the interactions with ligands at site II. Using dansyl-proline (DP) as a fluorescent site II marker, we demonstrated that only negatively charged NSAIDs such as ibuprofen (IBP), naproxen (NPX), diflunisal (DFS), and ketoprofen (KTP) can efficiently displace DP from the albumin binding site. We confirmed the importance of RCOO by neutralizing IBP and NPX through esterification, which reduced the displacement of DP. The competition was also monitored by stopped-flow experiments. While IBP and NPX displaced DP in less than 1 s, the ester derivatives were ineffective. We also observed a higher affinity of negatively charged NSAIDs using DFS as a probe and ultrafiltration experiments. Molecular docking simulations showed an essential salt bridge between the positively charged residues Arg409 and Lys413 with RCOO-, consistent with the experimental findings. We performed a ligand dissociation pathway and corresponding energy analysis by applying molecular dynamics. The dissociation of NPX showed a higher free energy barrier than its ester. Apart from BSA, we conducted some experimental studies with human serum albumin, and similar results were obtained, suggesting a general effect for other mammalian serum albumins. Our findings support that the RCOOH moiety affects not only the mechanism of action and side effects but also the pharmacokinetics of NSAIDs.

Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in topical anhydrous and aqueous gels.

BACKGROUND: Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of acute and chronic pain associated with inflammatory conditions. This study aims to evaluate the in vitro percutaneous absorption of ketoprofen 10% formulated in proprietary anhydrous and aqueous gels using the Franz skin finite dose model. MATERIALS AND METHODS: The anhydrous gel was initially characterized for cytotoxicity using EpiDerm skin tissue model by cell proliferation assay and Western blot analysis. The Ultra Performance Liquid Chromatography method for measuring ketoprofen was validated and the stability of ketoprofen 10% in the anhydrous gel formulation was evaluated at 5°C and 25°C for 181 days. The percutaneous absorption of ketoprofen was determined using donated human skin. The tissue sections were mounted within Franz diffusion cells. A variable finite dose of each ketoprofen formulation in either anhydrous or aqueous gel was applied to the skin sections and receptor solutions were collected at various time points. RESULTS: Cell proliferation assay showed minimal cell death when EpiDerm skin tissue was exposed to the anhydrous gel for 24 h; the levels of protein markers of cell proliferation were not affected after 17-h exposure. Ketoprofen was stable in the anhydrous gel when stored at 5°C and 25°C. When compounded in the anhydrous and aqueous gels, ketoprofen had mean flux rate of 2.22 and 2.50 µg/cm2 /h, respectively, after 48 h. The drug was distributed to the epidermis and dermis sections of the skin. Both the anhydrous and aqueous gels facilitated the percutaneous absorption of ketoprofen without statistically significant differences. CONCLUSION: The anhydrous gel can be used as a base to facilitate the transdermal delivery of ketoprofen. Although the anhydrous and aqueous gels can deliver a similar amount of ketoprofen, the anhydrous gel (water activity below 0.6) allows for extended default beyond-use-date of compounding preparations.

Experimental and Machine-Learning-Assisted Design of Pharmaceutically Acceptable Deep Eutectic Solvents for the Solubility Improvement of Non-Selective COX Inhibitors Ibuprofen and Ketoprofen.

Deep eutectic solvents (DESs) are commonly used in pharmaceutical applications as excellent solubilizers of active substances. This study investigated the tuning of ibuprofen and ketoprofen solubility utilizing DESs containing choline chloride or betaine as hydrogen bond acceptors and various polyols (ethylene glycol, diethylene glycol, triethylene glycol, glycerol, 1,2-propanediol, 1,3-butanediol) as hydrogen bond donors. Experimental solubility data were collected for all DES systems. A machine learning model was developed using COSMO-RS molecular descriptors to predict solubility. All studied DESs exhibited a cosolvency effect, increasing drug solubility at modest concentrations of water. The model accurately predicted solubility for ibuprofen, ketoprofen, and related analogs (flurbiprofen, felbinac, phenylacetic acid, diphenylacetic acid). A machine learning approach utilizing COSMO-RS descriptors enables the rational design and solubility prediction of DES formulations for improved pharmaceutical applications.

Fluorescent sensing of non-steroidal anti-inflammatory drugs naproxen and ketoprofen by dansylated squaramide-based receptors.

Bis-squaramide receptors L1-L4 bearing a dansyl moiety were synthesised and their potential applications as fluorescent probes towards non steroidal anti-inflammatory drugs naproxen and ketoprofen was investigated. A detailed photophysical characterization in CH3CN/DMSO solution (9 : 1 v/v) was conducted and demonstrated that the two macrocyclic receptors L1 and L2 show good sensitivity towards ketoprofen with an ON-OFF fluorescent response, while the two open chain receptors L3 and L4 behave similarly with the three guests considered. DFT theoretical calculations carried out on L2 and L4 as model receptors allowed to propose a possible coordination mode towards the guests. Finally, 1H-NMR spectroscopy in DMSO-d6/0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.

LC-MS/MS approach for simultaneous assessment of hyoscine N-butyl bromide and ketoprofen in biological fluids and pharmaceuticals.

The mixture of hyoscine N-butyl bromide (HBB) and ketoprofen (KTP) is commonly used for the handling of abdominal spasms and pain relief. There are two challenges that restrict the simultaneous assessment of HBB and KTP in biological fluids and pharmaceuticals. The first issue is the difficulty of elution of HBB and the second one is the presence of KTP as a racemic mixture in all pharmaceutical formulations, which obscures its appearance as a single peak. An ultrasensitive and highly efficient liquid chromatography-mass/mass spectrometric (LC-MS/MS) method is designed and validated for the first concurrent assessment of HBB and KTP in spiked human serum and urine, and pharmaceutical formulations. The estimated linearity ranges for HBB and KTP were respectively, 0.5-500 and 0.05-500 ng/ml, with excellent correlation coefficients. Validation results showed that the value of relative standard deviations were <2% for HBB and KTP. The mean extraction recoveries for HBB and KTP were, respectively, 91.04 and 97.83% in Spasmofen® ampoules; 95.89 and 97.00% in spiked serum; and 97.31 and 95.63% in spiked urine. The presented innovative chromatographic approach was utilized for the measurement of trace amounts of coexisting pharmaceuticals in pharmacokinetics studies and routine therapeutic medication monitoring.

Design and Development of Functionalized Single-walled Carbon Nanotube-ethosomes for Transdermal Delivery of Ketoprofen.

The purpose of this study was to combine carbon nanotube with ethosomes in order to obtain hybrid nanocarriers for transdermal delivery of ketoprofen (KP). KP-loaded functionalized single-walled carbon nanotube (f-SWCNTs) composite ethosomes (f-SWCNTs-KP-ES) were designed and were verified by a series of characterizations. The particle size of the preparation is less than 400 nm. DSC and XRD experiments showed that KP existed in an amorphous state after it was adsorbed and loaded on f-SWCNTs. TEM experiments showed that the structure of SWCNTs remained intact after oxidation and modification by PEI. FTIR results showed that PEI were successfully modified on the surface of SWCNT-COOH, and KP was successfully loaded on f-SWCNTs. In vitro release characteristics showed that the preparation had sustained release behavior and conformed to the first-order kinetic equation model. In addition, f-SWCNTs-KP-ES gel were prepared and in vitro skin permeation and in vivo pharmacokinetics were studied. The results showed that f-SWCNTs-KP-ES gel could enhance the skin permeation rate of KP and increase the drug retention of drugs in the skin. The characterization results consistently showed f-SWCNTs is a promising drug carrier. The hybrid nanocarrier prepared by the combination of f-SWCNTs and ethosomes can enhance the transdermal absorption of drugs and improve the bioavailability of drugs, which has a certain significance for the development of advanced hybrid nano-preparations.

Eutectic phase transition during tablet manufacture: effect of melting point of eutectic forming drug.

The aim was to investigate eutectic transition during tableting and storage. Mixtures of lidocaine and series of NSAIDs with increasing melting point were used as model systems to guide formulators to scaleup eutectic forming materials gaining enhanced dissolution while avoiding deleterious physical changes. Physical mixtures of NSAIDs with lidocaine were prepared at eutectic forming ratio. These were directly compressed, dry co-ground before compression, or compressed after wet granulation. Dissolution of tablets was compared to corresponding dry co-ground mixture. Thermograms of direct compressed tablet were compared to co-ground mixture and pure compound. Stability of direct compressed tablets was assessed. Tableting initiated eutexia which enhanced dissolution of NSAIDs. Eutexia was associated with tablet softening in case of low melting point ketoprofen and aceclofenac. Wet granulation hastened eutexia developing unacceptable tablet in case ketoprofen and aceclofenac. Tablets prepared by direct compression of physical mixtures underwent gradual eutectic transition upon storage with the magnitude of eutectic transition reducing with increased melting point of NSAIDs. Ketoprofen was physically unstable but aceclofenac degraded chemically as well. Tenoxicam and meloxicam tablets were physically and chemically stable. Direct compression after physical mixing is the best tableting technique, but low melting point drugs should consider different strategy before compression.

Modeling of Adhesion in Tablet Compression at the Molecular Level Using Thermal Analysis and Molecular Simulations.

The molecular basis of adhesion leading to sticking was investigated by exploring the correlation between thermal analysis and molecular simulations. It is hypothesized that intermolecular interactions between a drug molecule and a punch face are the first step in the adhesion process and the rank order of adhesion during tablet compression should correspond to the rank order of the energies of these interactions. In the present study, the sticking propensity was investigated using ibuprofen, flurbiprofen, and ketoprofen as model substances. At the intermolecular level, a thermal analysis model was proposed as an experimental technique to estimate the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen in a DSC aluminum pan. The linear relationship was established between the enthalpy of vaporization and sample mass to demonstrate the accuracy of the instruments used. The threshold mass for ibuprofen, flurbiprofen, and ketoprofen was determined to be 107, 112, and 222 µg, respectively, after three replicate measurements consistent with the experimental results. Ketoprofen showed a 2-fold higher threshold mass compared to ibuprofen and flurbiprofen, which predicts that ketoprofen should have the highest sticking propensity. Computationally, the rank order of the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen with the metal surface was simulated to be -75.91, 44.75, and -96.91 kcal/mol, respectively, using Materials Studio. The rank order of the interaction between the drug molecule and the iron superlattice decreases in the order ketoprofen > ibuprofen > flurbiprofen. The results indicate that the thermal model can be successfully implemented to assess the sticking propensity of a drug at the molecular level. Also, a new molecular simulation script was successfully applied to determine the interaction energy of the drug molecule upon contact with iron.

One Hundred Carboxylate Receptors.

This work presents a compilation of binding constant (logKass) values in DMSO-d6/H2O (0.5% m/m) for a variety of receptors with 12 carboxylate anions (formate, acetate, lactate, pivalate, sorbate, hexanoate, benzoate, glyphosate, glucuronate, ibuprofen, naproxen, and ketoprofen). A total of 489 logKass values are listed for 100 anion receptor molecules. Most logKass values originate from previously published articles, along with some values for previously unpublished receptor molecules, spanning a workflow of 8 years. The purpose of this study is to serve as a comprehensive information source for selecting suitable receptor candidates to be used in practical carboxylate sensing applications, such as constructing ion-selective electrodes (ISE-s). To support such decision making, all receptors are presented together with lipophilicity (logPo/w) data.

A new case of photoallergic contact dermatitis caused by benzophenones in magazine covers.

BACKGROUND: Allergic contact dermatitis (ACD) and photoallergic contact dermatitis (PACD) to benzophenone present in printing ink have been reported. However, precise chemical analyses and extended photo-patch tests have not been performed in these cases. OBJECTIVES: To determine which components present in a magazine cover are responsible for a patient's skin reaction, to determine the primary sensitizer, and precisely diagnose ACD and PACD. METHODS: After initial photo-patch tests were performed on a patient with a history of reaction to magazine covers after sun exposure, gas chromatography-mass spectrometry and high-performance liquid chromatography analyses of the magazine covers, and additional photo-patch tests were performed. RESULTS: The first photo-patch test results confirmed PACD to ketoprofen and fenofibrate and evoked PACD to the magazine covers. 4-methyl benzophenone (4-MBP) and 1-hydroxy-cyclohexyl-phenyl-ketone (1-HCPK) were found in the magazine cover. Additional photo-patch tests confirmed PACD to 1-HCPK and to benzophenone, and photo-aggravated ACD to 4-MBP. The primary sensitizer was ketoprofen. CONCLUSIONS: Benzophenones are present in a wide variety of products, without always being listed on the packaging. Patients previously sensitized to other ketones, such as ketoprofen, may react to benzophenones without being able to avoid contact with these molecules. New regulations may be needed for more efficient eviction advice.

Removal of Non-Steroidal Anti-Inflammatory Drugs from Drinking Water Sources by GO-SWCNT Buckypapers.

Pharmaceutical products such as antibiotics, analgesics, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) are new emerging pollutants, often present in wastewater, potentially able to contaminate drinking water resources. Adsorption is considered the cheapest and most effective technique for the removal of pollutants from water, and, recently, membranes obtained by wet filtration method of SWCNT aqueous solutions (SWCNT buckypapers, SWCNT BPs) have been proposed as self-standing porous adsorbents. In this paper, the ability of graphene oxide/single-walled carbon nanotube composite membranes (GO-SWCNT BPs) to remove some important NSAIDs, namely Diclofenac, Ketoprofen, and Naproxen, was investigated at different pH conditions (pH 4, 6, and 8), graphene oxide amount (0, 20, 40, 60, and 75 wt.%), and initial NSAIDs concentration (1, 10, and 50 ppm). For the same experimental conditions, the adsorption capacities were found to strongly depend on the graphene oxide content. The best results were obtained for 75 wt.% graphene oxide with an adsorption capacity of 118 ± 2 mg g-1 for Diclofenac, 116 ± 2 mg g-1 for Ketoprofen, and 126 ± 3 mg g-1 for Naproxen at pH 4. Overall, the reported data suggest that GO-SWCNT BPs can represent a promising tool for a cheap and fast removal of NSAIDs from drinking water resources, with easy recovery and reusability features.

Synthesis, In Vitro Anti-Inflammatory Activity, and HRMS Analysis of New Amphetamine Derivatives.

Herein, we report the obtaining of new hybrid molecules of amphetamine with different profens (amfens). The obtained amfens are characterized by their melting points, UV, 1H-, 13C-NMR, and HRMS spectra. A complete and detailed mass spectral analysis of the newly obtained derivatives of amphetamine with ibuprofen, flurbiprofen, ketoprofen, naproxen, and carprofen was performed. In vitro inhibition of albumin denaturation of each new compound was assessed, and they showed significant activity. The IC50 values of the obtained amphetamine-profen derivatives ranged from 92.81 to 159.87 µg/mL. This indicates that the new hybrids inherit the anti-inflammatory properties of profens. Using in silico method, the toxicity was also calculated. The obtained results are given in LD50 values. Depending on the route of administration, the amfens are less toxic compared to the standard amphetamine.

Triplet stabilization for enhanced drug photorelease from sunscreen-based photocages.

Recently, sunscreen-based drug photocages have been introduced to provide UV protection to photoactive drugs, thus increasing their photosafety. Here, combined experimental and theoretical studies performed on a photocage based on the commercial UVA filter avobenzone (AB) and on the photosensitizing non-steroidal anti-inflammatory drug ketoprofen (KP) are presented unveiling the photophysical processes responsible for the light-triggered release. Particular attention is paid to solvent stabilization of the drug and UV filter excited states, respectively, which leads to a switching between the triplet excited state energies of the AB and KP units. Most notably, we show that the stabilization of the AB triplet excited state in ethanol solution is the key requirement for an efficient photouncaging. By contrast, in apolar solvents, in particular hexane, KP has the lowest triplet excited state, hence acting as an energy acceptor quenching the AB triplet manifold, thus inhibiting the desired photoreaction.

Synthesis of a PVA drug delivery system for controlled release of a Tramadol-Dexketoprofen combination.

The local administration of analgesic combinations by means of degradable polymeric drug delivery systems is an alternative for the management of postoperative pain. We formulated a Tramadol-Dexketoprofen combination (TDC) loaded in poly(vinyl alcohol) (PVA) film. Films were prepared by the solvent casting method using three different molecular weights of PVA and crosslinking those films with citric acid, with the objective of controlling the drug release rate, which was evaluated by UV-vis spectrometry. Non-crosslinked PVA films were also evaluated in the experiments. Differential scanning calorimetry (DSC) analysis of samples corroborated the crosslinking of PVA by the citric acid. Blank and loaded PVA films were tested in vitro for its impact on blood coagulation prothrombin time (PT) and partial thromboplastin time (PTT). The swelling capacity was also evaluated. Crosslinked PVA films of higher-molecular weight showed a prolonged release rate compared with that of the lower-molecular-weight films tested. Non-crosslinked PVA films released 11-14% of TDC. Crosslinked PVA films released 80% of the TDC loaded (p < 0.05). This suggests that crosslinking films can modify the drug release rate. The blank and loaded PVA films induced PT and PTT in the normal range. The results showed that the polymeric films evaluated here have the appropriate properties to allow films to be placed directly on surgical wounds and have the capacity for controlled drug release to promote local analgesia for the control of postoperative pain.

Core-shell MOF@COFs used as an adsorbent and matrix for the detection of nonsteroidal anti-inflammatory drugs by MALDI-TOF MS.

A core-shell material (UiO@TapbTp) has been developed as an adsorbent and matrix to detect nonsteroidal anti-inflammatory drugs (NSAIDS) by matrix laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in complex samples. The hybrid material is prepared by growing covalent organic framework (COF, TapbTp) layers in situ on an amino-modified metal-organic framework (MOF, UiO-66-NH2). The combination of the MOF and COF overcomes their individual shortcomings and integrates both of their advantages. Compared with the bare COF and MOF, the core-shell composite exhibits improved enrichment ability and matrix performance. With the help of pre-enrichment under optimized conditions, the limits of detection (LODs) for ketoprofen, naproxen, and aspirin are reduced by nearly 1000 times, with values of 0.001 mg L-1, 0.010 mg L-1, and 0.001 mg L-1, respectively, and the relative standard deviations (RSDs) are all below 12.35%. The good recoveries (84.8-118%) in (spiked) saliva and environmental water sample further verify the applicability of the method in complex samples.

Role of Chiral Configuration in the Photoinduced Interaction of D- and L-Tryptophan with Optical Isomers of Ketoprofen in Linked Systems.

The study of the L- and D-amino acid properties in proteins and peptides has attracted considerable attention in recent years, as the replacement of even one L-amino acid by its D-analogue due to aging of the body is resulted in a number of pathological conditions, including Alzheimer's and Parkinson's diseases. A recent trend is using short model systems to study the peculiarities of proteins with D-amino acids. In this report, the comparison of the excited states quenching of L- and D-tryptophan (Trp) in a model donor-acceptor dyad with (R)- and (S)-ketoprofen (KP-Trp) was carried out by photochemically induced dynamic nuclear polarization (CIDNP) and fluorescence spectroscopy. Quenching of the Trp excited states, which occurs via two mechanisms: prevailing resonance energy transfer (RET) and electron transfer (ET), indeed demonstrates some peculiarities for all three studied configurations of the dyad: (R,S)-, (S,R)-, and (S,S)-. Thus, the ET efficiency is identical for (S,R)- and (R,S)-enantiomers, while RET differs by 1.6 times. For (S,S)-, the CIDNP coefficient is almost an order of magnitude greater than for (R,S)- and (S,R)-. To understand the source of this difference, hyperpolarization of (S,S)-and (R,S)- has been calculated using theory involving the electron dipole-dipole interaction in the secular equation.

Comprehensive Characterisation of the Ketoprofen-ß-Cyclodextrin Inclusion Complex Using X-ray Techniques and NMR Spectroscopy.

Racemic ketoprofen (KP) and ß-cyclodextrin (ß-CD) powder samples from co-precipitation (1), evaporation (2), and heating-under-reflux (3) were analysed using X-ray techniques and nuclear magnetic resonance (NMR) spectroscopy. On the basis of NMR studies carried out in an aqueous solution, it was found that in the samples obtained by methods 1 and 2, there were large excesses of ß-CD in relation to KP, 10 and 75 times, respectively, while the sample obtained by method 3 contained equimolar amounts of ß-CD and KP. NMR results indicated that KP/ß-CD inclusion complexes were formed and the estimated binding constants were approximately 2400 M-1, showing that KP is quite strongly associated with ß-CD. On the other hand, the X-ray single-crystal technique in the solid state revealed that the (S)-KP/ß-CD inclusion complex with a stoichiometry of 2:2 was obtained as a result of heating-under-reflux, for which the crystal and molecular structure were examined. Among the methods used for the preparation of the KP/ß-CD complex, only method 3 is suitable.

How to Obtain the Maximum Properties Flexibility of 3D Printed Ketoprofen Tablets Using Only One Drug-Loaded Filament?

The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediate- and sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics.

Treatment of oxidative stress-induced pain and inflammation with dexketoprofen trometamol loaded different molecular weight chitosan nanoparticles: Formulation, characterization and anti-inflammatory activity by using in vivo HET-CAM assay.

Angiogenesis is a fundamental process of wound healing, embryogenesis etc. but occurs in cancer and chronic inflammation pathologically. HET-CAM assay is a useful, well established and animal alternative test to screen anti-inflammatory potentials of pharmaceutical products as well as nano-formulations. Dexketoprofen trometamol (DT) belongs to the nonsteroidal anti-inflammatory drug (NSAID) group which is a rapidly acting analgesic ingredient. Because DT has a short half-life, high and frequent dosing is used in treatment. The need of design and producing a new oral prolonged-release dosage form containing DT is the major aim of the study with low dose and low side effects. Chitosan (CS) has been widely used in the pharmaceutical area because of its favorable biological properties. In this study, DT loaded CS nanoparticles (CS-NPs) were produced by spray drying method for oral drug delivery. Structures of CS-NPs were elucidated by particle size, zeta potential, SEM, DSC, FT-IR and 1H NMR. High encapsulation efficiency was obtained (73-84%) for the prepared formulations. In vitro release was examined in pH 1.2 buffer and pH 6.8 buffer. DT-loaded CS-NPs showed prolonged release, particularly at pH 6.8. Weibull kinetic model was found to fit best to DT release from CS-NPs in both release medium. The anti-inflammatory activity of optimum formulation (M-DT) was examined using the in vivo HET-CAM assay. The anti-inflammatory activity results indicated that M-DT coded NPs formulation showed significantly good anti-inflammatory potential with closer inhibition value to the standard anti-inflammatory DT at one fifth lower dosage. According to the proposed method and results it can be successfully applicable to the NP preparation containing DT and it could be concluded that DT loaded CS-NPs seem to be a promising prolonged release drug delivery system for oral administration with low dose and high efficiency.

A Novel Binary Supercooled Liquid Formulation for Transdermal Drug Delivery.

The aim of this study was to prepare binary supercooled liquid (SCL) by intermolecular interaction and apply this formulation to transdermal drug delivery. Ketoprofen (KET) and ethenzamide (ETH) were selected as binary SCL component. Thermal analysis of physical mixtures of KET and ETH showed decreases in melting points and glass transition below room temperature, thereby indicating formation of KET-ETH SCL. Intermolecular interactions between KET and ETH in the SCL were evaluated from Fourier transform (FT)-IR spectra. KET-ETH SCL maintained SCL state at 25°C with silica gel over 31 d and at 40°C/89% relative humidity (RH) over 7 d. KET SCL and KET-ETH SCL showed similar permeability of KET for hairless mice skin, which was two-fold higher than that of KET aqueous suspension. Our findings suggest that the SCL state could enhance the skin permeation of drugs and the binary SCL formed by intermolecular interaction could also improve the stability of the SCL. The binary SCL system could become a new drug form for transdermal drug delivery.