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Ketoprofen (KTF) and ketorolac (KTL) are among the most primarily used non-steroidal anti-inflammatory drugs (NSAIDs) in humans to alleviate moderate pain and to treat inflammation. Their binding affinity with albumin (the main globular protein responsible for the biodistribution of drugs in the bloodstream) was previously determined by spectroscopy without considering some conventional pitfalls. Thus, the present work updates the biophysical characterization of the interactions of HSA:KTF and HSA:KTL by 1 H saturation-transfer difference nuclear magnetic resonance ( 1 H STD-NMR), ultraviolet (UV) absorption, circular dichroism (CD), steady-state, and time-resolved fluorescence spectroscopies combined with in silico calculations. The binding of HSA:NSAIDs is spontaneous, endothermic, and entropically driven, leading to a conformational rearrangement of HSA with a slight decrease in the α-helix content (7.1% to 7.6%). The predominance of the static quenching mechanism (ground-state association) was identified. Thus, both Stern-Volmer quenching constant ( K SV ) and binding constant ( K b ) values enabled the determination of the binding affinity. In this sense, the K SV and K b values were found in the order of 10 4 M -1 at human body temperature, indicating moderate binding affinity with differences in the range of 0.7- and 3.4-fold between KTF and KTL, which agree with the previously reported experimental pharmacokinetic profile. According to 1 H STD-NMR data combined with in silico calculations, the aromatic groups in relation to the aliphatic moiety of the drugs interact preferentially with HSA into subdomain IIIA (site II) and are stabilized by interactions via hydrogen bonding and hydrophobic forces. In general, the data obtained in this study have been revised and updated in comparison to those previously reported by other authors who did not account for inner filter corrections, spectral backgrounds, or the identification of the primary mathematical approach for determining the binding affinity of HSA:KTF and HSA:KTL.

Osteoarthritis (OA) is a prevalent chronic health condition necessitating effective treatment strategies. Globally, there were 86 million people with incident knee osteoarthritis in 2020. Pain management remains the primary approach to OA as the nature of cartilage poses challenges for drug delivery. An emulsion-based delivery system, using a class of positively charged and hydrolysable polymers (poly-beta-amino-esters) to coat oil droplets containing drugs, has been shown to enhance and prolong drug localization in ex vivo cartilage models. As the properties of the polymers used in this technology strongly depend on the monomers used in the synthesis, this study presents the screening of a wide range of PBAEs as droplet coating agents and using ketorolac as a model of nonsteroidal anti-inflammatory drugs. The emulsions prepared with this PBAE library were characterized, and drug localisation and retention were evaluated in both native and glycosaminoglycan (GAG) depleted cartilage ex vivo models. Optimal candidates were identified and tested in an ex vivo model showing the ability to protect chondrocyte cell viability and increase both GAG and collagen contents in cartilage exposed to cytokine (IL-1α) simulating acute cartilage damage. This work demonstrates the potential of PBAE coated emulsion as a delivery system for effective drug delivery in OA treatment.

P21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1-6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges - 8.6 to - 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure-activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity., (© 2021. The Author(s).)

The report presents the results of the development of dental films with ketorolac trometamine based on the natural biodegradable polymers from the groups of sodium alginates and xanthan gums in combination with lightly crosslinked acrylic polymer carbopol. Physicochemical properties, such as moisture, mucoadhesion, thickness, tensile strength, disintegration in phosphate buffer were determined in obtained samples of this dosage form. A comparison of physicochemical properties of experimental samples and commercial model of dental film has allowed establishing the perspective composition of complex matrix of films with ketorolac trometamine for use in dentistry., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Eye drops and ointments are the most prescribed methods for ocular drug delivery. However, due to low drug bioavailability, rapid drug elimination, and low patient compliance there is a need for improved ophthalmic drug delivery systems. This study provides insights into the design of a new drug delivery device that consists of an ocular coil filled with ketorolac loaded PMMA microspheres. Nine different ocular coils were created, ranging in wire diameter and coiled outer diameter. Based on its microsphere holding capacity and flexibility, one type of ocular coil was selected and used for further experiments. No escape of microspheres was observed after bending the ocular coil at curvature which reflect the in vivo situation in human upon positioning in the lower conjunctival sac. Shape behavior and tissue contact were investigated by computed tomography imaging after inserting the ocular coil in the lower conjunctival fornix of a human cadaver. Thanks to its high flexibility, the ocular coil bends along the circumference of the eye. Because of its location deep in the fornix, it appears unlikely that in vivo, the ocular coil will interfere with eye movements. In vitro drug release experiments demonstrate the potential of the ocular coil as sustained drug delivery device for the eye. We developed PMMA microspheres with a 26.5 ± 0.3 wt% ketorolac encapsulation efficiency. After 28 days, 69.9% ± 5.6% of the loaded ketorolac was released from the ocular coil when tested in an in vitro lacrimal system. In the first three days high released dose (48.7% ± 5.4%) was observed, followed by a more gradually release of ketorolac. Hence, the ocular coil seems a promising carrier for ophthalmic drugs delivery in the early postoperative time period., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objective: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C., Method: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection., Results: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days., Conclusion: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 19b-c/20b-c, the anti-inflammatory effect was the same as that of the reference compound (indomethacin) and was dose-dependent. These compounds have an aryl ring at the C-1 position and a methoxycarbonyl group at the C-2 position of the pyrrolizine framework, which represent plausible pharmacophore groups with anti-inflammatory activity. The anti-inflammatory activity of 1-substituted analogs containing a five- or six-membered heterocycles was lower but still good, while that of the pyrroles was only moderate. Although the docking studies suggests that the effect of analogs 19a-c/20a-c is associated with the inhibition of cyclooxygenase-2, experimental assays did not corroborate this idea. Indeed, a significant inhibition of NO was found experimentally as a plausible mechanism of action., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Ketorolac (KTR) is used as an analgesic drug with an efficacy close to that of the opioid family. It is mainly used for the short term treatment of post-operative pain. It can inhibit the prostaglandin synthesis by blocking cyclooxygenase (COX)., Methods: In this investigation, the inherent stability and biochemical interaction of Ketorolac (KTR) and its degradation products have been studiedon the basis of quantum mechanical approaches. Density functional theory (DFT) with B3LYP/ 6-31G (d) has been employed to optimize the structures. Thermodynamic properties, frontier molecular orbital features, dipole moment, electrostatic potential, equilibrium geometry, vibrational frequencies and atomic partial charges of these optimized structureswere investigated. Molecular docking has been performed against prostaglandin H2 (PGH2) synthase protein 5F19 to search the binding affinity and mode(s). ADMET prediction has performed to evaluate the absorption, metabolism and carcinogenic properties., Results: The equilibrium geometry calculations support the optimized structures. Thermodynamic results disclosed the thermal stability of all structures. From molecular orbital data, all the degradents are chemically more reactive than parent drug (except K3). However, the substitution of carboxymethyl radicalin K4 improved the physicochemical properties and binding affinity. ADMET calculations predict the improved pharmacokinetic and non-carcinogenic properties of all degradents., Conclusion: Based on physicochemical, molecular docking, and ADMET calculation, this study can be helpful to understand the biochemical activities of Ketorolac and its degradents and to design a potent analgesic drug.

Silver nanoparticles (AgNPs) have been widely recognized as antibacterial agents. However, its stability and activity over time have been poorly studied. In this work, the properties and characteristics of differently stabilized AgNPs were evaluated during a span of time. The surface capping agents were diclofenac (d), and ketorolac (k), which currently are used as anti-inflammatory in human medicine. On evaluating the size variation over time, it was observed that the AgNPs-k are the most stable, unlike the non-capped nanoparticles agglomerate and precipitate. UV-Vis spectroscopy analysis showed that the absorbance during time decreases for the three types of nanoparticles, but the decrease is less marked for the two types of anti-inflammatory-capped AgNPs. The rapid loss of the optical prop- erties of bare AgNPs, is mainly due to oxidation, agglomeration, and precipitation of this nanoparticles. The potential cytotoxicity of the AgNPs, evaluated through the formation of the superoxide anion using XXT, showed that both, AgNPs-k and AgNPs-d, generate the radical anion when the samples are irradiated with UV light at 365 nm. This effect appears associated with the capping agents, since the bare nanoparticles did not promote the formation of the superoxide anion. The antibacterial activity of the AgNPs throughout time, against two microorganisms (Escherichia coli and Staphylococcus aureus), was also evaluated. The results showed that capping agents played a decisive role in the antibacterial ability of AgNPs and also in enhancing the antibacterial activity over time., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cataract is highly prevalent among old population worldwide and replacement of the opacified crystalline lens by an intraocular lens (IOL) is the safest and the most effective treatment. Although not very frequently (0.02-0.33% of the cases), the patients who undergo cataract surgery may develop endophthalmitis, which is a serious problem eventually leading to blindness. To avoid this complication, the postoperative instillation of antibiotics and anti-inflammatories is almost universally used in clinical practice. The aim of this work was to study the possibility of loading an IOL material with an antibiotic and an anti-inflammatory, which could be simultaneously released and successfully substitute the frequent instillation of topical drops for the prevention of endophthalmitis. The IOL material commercially available under the name of CI26Y (Contamac Products) was chosen and two pairs of drugs consisting of one antibiotic and one anti-inflammatory were tested: moxifloxacin + ketorolac and moxifloxacin + diclofenac. The drug loading was done by soaking under optimized conditions. Simultaneous drug loading improved the release profiles, especially in the case of moxifloxacin + ketorolac. The effect of sterilization by steam heat (carried out on the first day of loading) and by gamma-radiation upon the release profiles was negligible. The optical and mechanical properties of the sterilized, double-loaded IOL materials were kept at adequate levels. Application of a mathematical model to predict the in vivo released concentrations suggested that the most efficient system complied with the therapeutic needs: the lens loaded with moxifloxacin + ketorolac was effective against S. aureus and S. epidermidis up to 15 days, and the amount of released ketorolac remained active against inflammation for a minimum of 16 days., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: The aim of this study was to investigate ketorolac (KT) systemic absolute bioavailability after sublingual (SL) administration in vivo to conscious rabbits. Furthermore, the study investigated the potential use of chitosan nanoparticles as a delivery system to enhance the systemic bioavailability of KT following SL administration., Methods: Ketorolac-loaded chitosan nanoparticles were prepared through ionotropic gelation of chitosan with tripolyphosphate anions. The KT-nanoparticles were administered SL as a spray to rabbits and KT plasma concentration at predetermined time points was compared to SL spray administration of KT in solution. The concentrations of KT in plasma were analyzed by ultra-performance liquid chromatography mass spectroscopy (UPLC/MS)., Results: KT-loaded chitosan nanoparticles significantly (p < .05) enhanced systemic absorption with 97% absolute bioavailability as compared to 70% after SL administration of KT solution., Conclusions: The results of the present study suggest that SL absorption of KT illustrated flip-flop kinetics with prolonged persistence in the body compared to intravenous administration. Formulation of KT as chitosan nanoparticles has increased its systemic bioavailability after SL spray administration. The new delivery system could be an attractive approach for the delivery of KT.

Although the possibility of using drug-loaded ophthalmic lens to promote sustained drug release has been thoroughly pursued, there are still problems to be solved associated to the different alternatives. In this work, we went back to the traditional method of drug loading by soaking in the drug solution and tried to optimize the release profiles by changing the temperature and the time of loading. Two materials commercially available under the names of CI26Y and Definitive 50 were chosen. CI26Y is used for intraocular lenses (IOLs) and Definitive 50 for soft contact lenses (SCLs). Three drugs were tested: an antibiotic, moxifloxacin, and two anti-inflammatories, diclofenac and ketorolac. Sustained drug release from CI26Y disks for, at least 15 days, was obtained for moxifloxacin and diclofenac increasing the loading temperature up to 60 °C or extending the loading time till two months. The sustained release of ketorolac was limited to about 8 days. In contrast, drug release from Definitive 50 disks could not be improved by changing the loading conditions. An attempt to interpret the impact of the loading conditions on the drug release behavior was done using solid-state NMR and differential scanning calorimetry. These studies suggested the establishment of reversible, endothermic interactions between CI26Y and the drugs, moxifloxacin and diclofenac. The loading temperature had a slight effect on the mechanical and optical properties of drug loaded CI26Y samples, which still kept adequate properties to be used as IOL materials. The in vivo efficacy of CI26Y samples, drug loaded at 60 °C for two weeks, was predicted using a simplified mathematical model to estimate the drug concentration in the aqueous humor. The estimated concentrations were found to comply with the therapeutic needs, at least, for moxifloxacin and diclofenac., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ketorolac tromethamine (KTC) with phenylephrine hydrochloride (PHE) binary mixture (mixture 1) and their ternary mixture with chlorpheniramine maleate (CPM) (mixture 2) were analyzed using a validated HPLC-DAD method. The developed method was suitable for the in vitro as well as quantitative analysis of the targeted mixtures in rabbit aqueous humor. The analysis in dosage form (eye drops) was a stability indicating one at which drugs were separated from possible degradation products arising from different stress conditions (in vitro analysis). For analysis in aqueous humor, Guaifenesin (GUF) was used as internal standard and the method was validated according to FDA regulation for analysis in biological fluids. Agilent 5 HC-C18(2) 150×4.6mm was used as stationary phase with a gradient eluting solvent of 20mM phosphate buffer pH 4.6 containing 0.2% triethylamine and acetonitrile. The drugs were resolved with retention times of 2.41, 5.26, 7.92 and 9.64min for PHE, GUF, KTC and CPM, respectively. The method was sensitive and selective to analyze simultaneously the three drugs in presence of possible forced degradation products and dosage form excipients (in vitro analysis) and also with the internal standard, in presence of aqueous humor interferences (analysis in biological fluid), at a single wavelength (261nm). No extraction procedure was required for analysis in aqueous humor. The simplicity of the method emphasizes its capability to analyze the drugs in vivo (in rabbit aqueous humor) and in vitro (in pharmaceutical formulations)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to develop and evaluate the effectiveness of biodegradable nanofibrous lidocaine/ketorolac-loaded anti-adhesion membranes to sustainably release analgesics on abdominal surgical wounds. The analgesic-eluting membranes with two polymer-to-drug ratios (6:1 and 4:1) were produced via an electrospinning technique. A high-performance liquid chromatography (HPLC) assay was employed to characterize the in vivo and in vitro release behaviors of the pharmaceuticals from the membranes. It was found that all biodegradable anti-adhesion nanofibers released effective concentrations of lidocaine and ketorolac for over 20 days post surgery. In addition, a transverse laparotomy was setup in a rat model for an in vivo assessment of activity of postoperative recovery. No tissue adhesion was observed at 2 weeks post surgery, demonstrating the potential anti-adhesion capability of the drug-eluting nanofibrous membrane. The postoperative activities were recorded for two groups of rats as follows: rats that did not have any membrane implanted (group A) and rats that had the analgesic-eluting membrane implanted (group B). Rats in group B exhibited faster recovery times than those in group A with regard to postoperative activities, confirming the pain relief effectiveness of the lidocaine- and ketorolac-loaded nanofibrous membranes. The experimental results suggested that the anti-adhesion nanofibrous membranes with sustainable elution of lidocaine and ketorolac are adequately effective and durable for the purposes of postoperative pain relief in rats., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Protein chemical shift perturbations (CSPs), upon ligand binding, can be used to refine the structure of a protein-ligand complex by comparing experimental CSPs with calculated CSPs for any given set of structural coordinates. Herein, we describe a fast and accurate methodology that opens up new opportunities for improving the quality of protein-ligand complexes using nuclear magnetic resonance (NMR)-based approaches by focusing on the effect of the ligand on the protein. The new computational approach, 1 H empirical chemical shift perturbation (HECSP), has been developed to rapidly calculate ligand binding-induced 1 H CSPs in a protein. Given the dearth of experimental information by which a model could be derived, we employed high-quality density functional theory (DFT) computations using the automated fragmentation quantum mechanics/molecular mechanics approach to derive a database of ligand-induced CSPs on a series of protein-ligand complexes. Overall, the empirical HECSP model yielded correlation coefficients between its predicted and DFT-computed values of 0.897 ( 1 HA), 0.971 ( 1 HN), and 0.945 (side chain 1 H) with root-mean-square errors of 0.151 ( 1 HA), 0.199 ( 1 HN), and 0.257 ppm (side chain 1 H), respectively. Using the HECSP model, we developed a scoring function (NMRScore&#95;P). We describe two applications of NMRScore&#95;P on two complex systems and demonstrate that the method can distinguish native ligand poses from decoys and refine protein-ligand complex structures. We provide further refined models for both complexes, which satisfy the observed 1 H CSPs in experiments. In conclusion, HECSP coupled with NMRScore&#95;P provides an accurate and rapid platform by which protein-ligand complexes can be refined using NMR-derived information.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. While the role of NSAIDs as cyclooxygenase (COX) inhibitors is well established, other targets may contribute to anti-inflammation. Here we report caspases as a new pharmacological target for NSAID family drugs such as ibuprofen, naproxen, and ketorolac at physiologic concentrations both in vitro and in vivo. We characterize caspase activity in both in vitro and in cell culture, and combine computational modeling and biophysical analysis to determine the mechanism of action. We observe that inhibition of caspase catalysis reduces cell death and the generation of pro-inflammatory cytokines. Further, NSAID inhibition of caspases is COX independent, representing a new anti-inflammatory mechanism. This finding expands upon existing NSAID anti-inflammatory behaviors, with implications for patient safety and next-generation drug design., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An old anti-inflammatory/analgesic drug called Toradol is a racemic form of Ketorolac (50% R-form and 50% S-form) that blocks the oncogenic RAC-PAK1-COX-2 (cyclooxygenase-2) signaling, through the direct inhibition of RAC by the R-form and of COX-2 by the S-form, eventually down-regulating the production of prostaglandins. However, due to its COOH moiety which is clearly repulsive to negatively-charged phospholipid-based plasma membrane, its cell-permeability is rather poor (the IC 50 against the growth of human cancer cells such as A549 is around 13 μM). In an attempt to boost its anti-cancer activity, hopefully by increasing its cell-permeability through abolishing the negative charge, yet keeping its water-solubility, here we synthesized a 1,2,3-triazolyl ester of Toradol through "Click Chemistry". The resultant water-soluble "azo" derivative called "15K" was found to be over 500 times more potent than Toradol with the IC 50 around 24 nM against the PAK1-dependent growth of A549 cancer cells, inactivating PAK1 in cell culture with the apparent IC 50 around 65 nM, and inhibiting COX-2 in vitro with the IC 50 around 6 nM. Furthermore, the Click Chemistry boosts the anti-cancer activity of Ketorolac by 5000 times against the PAK1-independent growth of B16F10 melanoma cells. Using a multi-drug-resistant (MDR) cancer cell line (EMT6), we found that the esterization of Ketorolac boosts its cell-permeability by at least 10 folds. Thus, the Click Chemistry dramatically boosts the anti-cancer activity of Ketorolac, at least in three ways: increasing its cell-permeability, the anti-PAK1 activity of R-form and anti-COX-2 activity of S-form. The resultant "15K" is so far among the most potent PAK1-blockers, and therefore would be potentially useful for the therapy of many different PAK1-dependent diseases/disorders such as cancers., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common type of medication used in the treatment of acute pain. Ketorolac trometamol (KT) is a nonnarcotic, peripherally acting nonsteroidal anti-inflammatory drug with analgesic effects comparable to certain opioids., Objective: The aim of this study was to compare the efficacy of KT and naproxen (NA) in the treatment of acute low back pain (LBP) of moderate-to-severe intensity., Patients and Methods: In this 10-day, Phase III, randomized, double-blind, double-dummy, noninferiority trial, participants with acute LBP of moderate-to-severe intensity as determined through a visual analog scale (VAS) were randomly assigned in a 1:1 ratio to receive sublingual KT 10 mg three times daily or oral NA 250 mg three times daily. From the second to the fifth day of treatment, if patient had VAS >40 mm, increased dosage to four times per day was allowed. The primary end point was the reduction in LBP as measured by VAS. We also performed a post hoc superiority analysis., Results: KT was not inferior to NA for the reduction in LBP over 5 days of use as measured by VAS scores (P=0.608 for equality of variance; P=0.321 for equality of means) and by the Roland-Morris Disability Questionnaire (P=0.180 for equality of variance test; P=0.446 for equality of means) using 95% confidence intervals. The percentage of participants with improved pain relief 60 minutes after receiving the first dose was higher in the KT group (24.2%) than in the NA group (6.5%; P=0.049). The most common adverse effects were heartburn, nausea, and vomiting., Conclusion: KT is not inferior in efficacy and delivers faster pain relief than NA.

Rho family GTPases (including Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening of the Prestwick Chemical Library® and cheminformatics we identified the R-enantiomers of two approved drugs (naproxen and ketorolac) as inhibitors of Rac1 and Cdc42. The corresponding S-enantiomers are considered the active component in racemic drug formulations, acting as non-steroidal anti-inflammatory drugs (NSAIDs) with selective activity against cyclooxygenases. Here, we show that the S-enantiomers of naproxen and ketorolac are inactive against the GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action against the GTPases, establishing the selectivity of the two identified NSAIDs. R-naproxen was first identified as a lead compound and tested in parallel with its S-enantiomer and the non-chiral 6-methoxy-naphthalene acetic acid (active metabolite of nabumetone, another NSAID) as a structural series. Cheminformatics-based substructure analyses-using the rotationally constrained carboxylate in R-naproxen-led to identification of racemic [R/S] ketorolac as a suitable FDA-approved candidate. Cell based measurement of GTPase activity (in animal and human cell lines) demonstrated that the R-enantiomers specifically inhibit epidermal growth factor stimulated Rac1 and Cdc42 activation. The GTPase inhibitory effects of the R-enantiomers in cells largely mimic those of established Rac1 (NSC23766) and Cdc42 (CID2950007/ML141) specific inhibitors. Docking predicts that rotational constraints position the carboxylate moieties of the R-enantiomers to preferentially coordinate the magnesium ion, thereby destabilizing nucleotide binding to Rac1 and Cdc42. The S-enantiomers can be docked but are less favorably positioned in proximity to the magnesium. R-naproxen and R-ketorolac have potential for rapid translation and efficacy in the treatment of several epithelial cancer types on account of established human toxicity profiles and novel activities against Rho-family GTPases.

Migraine is a chronic disorder characterized by significant headache and various associated symptoms which worsen with exertion. Zolmitriptan approved for use in the acute treatment of migraine and related vascular headaches but are limited by high pain recurrence due to rapid drug elimination. Combinationalformulationof triptans and a nonsteroidal anti-inflammatory drug may provide a quicker and longer duration of relief from the subsequent pain during the attack. In this study, we formulate a Zolmitriptan (ZT) & ketorolac tromethamine (KT) loaded thermo reversible in-situ mucoadhesive intranasal gel (TMISG) formulation which gels at the nasal mucosal temperature and contains a bioadhesive polymer (Xyloglucan) that lengthens the residence time will enhance the bioavailability of the combinational drugs. This study uses Box-Behnken design for the first time to develop, optimize the TMISG and assess factors affecting the critical quality attributes. Histopathological study of the nasal mucosa suggested that the formulation was safe for nasal administration. The statistical difference in absolute bioavailability between oral and intranasal route suggested that intranasal route had almost 21% increases in bioavailability for ZT and for KT there was 16% increase over oral formulations. Optimized formulation would help mitigate migraine associated symptoms much better over the currently available formulations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel method was developed for the simultaneous determination of guaifenesin (GUA) and ketorolac tromethamine (KET) enantiomers in plasma samples. Since GUA probably increases the absorption of coadministered drugs (e.g., KET), it would be extremely important to monitor KET plasma levels for the purpose of dose adjustment with a subsequent decrease in the side effects. Enantiomeric resolution was achieved on a polysaccharide-based chiral stationary phase, amylose-2, as a chiral selector under the normal phase (NP) mode and using ornidazole (ORN) as internal standard. This innovative method has the advantage of the ease and reliability of sample preparation for plasma samples. Sample clean-up was based on simply using methanol for protein precipitation followed by direct extraction of drug residues using ethanol. Both GUA and KET enantiomers were separated using an isocratic mobile phase composed of hexane/isopropanol/trifluoroacetic acid, 85:15:0.05 v/v/v. Peak area ratios were linear over the range 0.05-20 µg/mL for the four enantiomers S (+) GUA, R (-) GUA, R (+) KET, and S (-) KET. The method was fully validated according to the International Conference on Harmonization (ICH) guidelines in terms of system suitability, specificity, accuracy, precision, robustness, and solution stability. Finally, this procedure was innovative to apply the rationale of developing a chiral high-performance liquid chromatography (HPLC) procedure for the simultaneous quantitative analysis of drug isomers in clinical samples., (© 2014 Wiley Periodicals, Inc.)

Different types of ketorolac ester prodrugs incorporating tert-butyl (KT), benzyl (KB), heptyl (KH), and diketorolac heptyl (DKH) promoieties were synthesized for the comparison of percutaneous penetration. The prodrugs were characterized according to their melting point, capacity factor, lipophilicity, solubility in 30% ethanol/buffer, enzymatic hydrolysis, in vitro skin permeation, hair follicle accumulation, and in vivo skin tolerance. Interactions between the prodrugs and esterases were predicted by molecular docking. Both equimolar suspensions and saturated solutions in 30% ethanol/pH 7.4 buffer were employed as the applied dose. All of the prodrugs exhibited a lower melting point than ketorolac. The lipophilicity increased in the following order: ketorolac < KT < KB < KH < DKH. The prodrugs were rapidly hydrolyzed to the parent drug in esterase medium, skin homogenate, and plasma, with KT and KB exhibiting higher degradation rates. KT exhibited the highest skin permeation, followed by KB. The flux of KT and KB exceeded that of ketorolac by 2.5-fold and twofold, respectively. KH and DKH did not improve ketorolac permeation but exhibited a sustained release behavior. KT and KH revealed selective absorption into follicles and a threefold greater follicular uptake compared with ketorolac. KB, KH, and DKH slightly but significantly increased transepidermal water loss (TEWL) after consecutive administration for 7 days, whereas ketorolac and KT exhibited no influence on TEWL. According to the experimental results, it can be concluded that an optimal balance between lipophilicity and aqueous solubility is important in the design of a successful prodrug. The acceptable skin tolerance for safe application is also an important consideration., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Background: Ketorolac, a potent nonsteroidal anti-inflammatory drug used for pain control in children, exists as a racemate of inactive R (+) and active S (-) enantiomers., Aim: To develop a microsampling assay for the enantioselective analysis of ketorolac in children., Methods: Ketorolac enantiomers were extracted from 50 μl of plasma by liquid–liquid extraction and separated on a ChiralPak AD-RH. Detection was by a TSQ quantum triple quadrupole mass spectrometer with an electrospray ionisation source operating in a positive ion mode. Five children (age 13.8 (1.6) years, weight 52.7 (7.2) kg), were administered intravenous ketorolac 0.5mg/kg (maximum 10mg) and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h post administration. CL, VD and t1/2 were calculated based on non-compartmental methods., Results: The standard curves for R (+) and S (-) ketorolac were linear in the range 0–2000 ng/ml. The LLOQs of the method were 0.15 ng on column and 0.31 ng on column for R (+) and S (-) ketorolac, respectively. The median (range) VD and CL of R (+) and S (-) ketorolac were 0.12 l/kg (0.07–0.17), 0.017 l/h/kg (0.12–0.29) and 0.17 (0.09–0.31) l/kg, 0.049 (0.02–0.1) l/h/kg, p = 0.043), respectively. The median (range) elimination half-life (t1/2) of the R (+) and S (-) ketorolac was 5.0 h (2.5–5.8) and 3.1 h (1.8–4.4), p = 0.043), respectively., Conclusion: The development of a simple, rapid and reliable ketorolac assay suitable for paediatric PK studies is reported., (Copyright © 2013 John Wiley & Sons, Ltd.)

Six aminoethyl and aminobutyl esters of ketorolac containing 1-methylpiperazine (MPE and MPB), N-acetylpiperazine (APE and APB) or morpholine (ME and MB), were synthesized and their hydrolysis kinetics were studied. The hydrolysis was studied at pH 1 to 9 (for MPE, APE and ME) and pH 1 to 8 (for MPB, APB and MB) in aqueous phosphate buffer (0.16 M) with ionic strength (0.5 M) at 37°C. Calculation of k(obs), construction of the pH-rate profiles and determination of the rate equations were performed using KaleidaGraph® 4.1. The hydrolysis displays pseudo-first order kinetics and the pH-rate profiles shows that the aminobutyl esters, MPE, APB and MB, are the most stable. The hydrolysis of the ethyl esters MPE, APE and ME, depending on the pH, is either fast and catalyzed by the hydroxide anion or slow and uncatalyzed for the diprotonated, monoprotonated and nonprotonated forms. The hydrolysis of the butyl esters showed a similar profile, albeit it was also catalyzed by hydronium cation. In addition, the hydroxide anion is 105 more effective in catalyzing the hydrolysis than the hydronium cation. The hydrolysis pattern of the aminoethyl esters is affected by the number and pKa of its basic nitrogen atoms. The monobasic APE and ME, show a similar hydrolysis pattern that is different than the dibasic MPE. The length of the side chain and the pKa of the basic nitrogen atoms in the aminoethyl moiety affect the mechanism of hydrolysis as the extent of protonation at a given pH is directly related to the pKa.

Context: Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management., Objective: Development and evaluation of transdermal ketorolac film forming polymeric solution., Materials and Methods: Eudragits(®) RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin., Results: The use of 10% oleic acid, Lauroglycol(®) 90 or Azone(®) with 5% Eudragit(®) RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit(®) RSPO and 10% Lauroglycol(®) 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn't run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation., Conclusion: Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.

The objective of this study was to formulate novel painless combined hyaluronic acid (HA)-ketorolac (KT) membrane for the management of osteoarthritis with rapid analgesic onset, thus avoiding HA frequent invasive intra-articular injections and KT gastrointestinal complaints associated with all non-steroidal anti-inflammatory drugs. HA was chemically crosslinked with carbodiimide/glutaraldehyde to yield membrane of low water content. Different in vitro aspects (mechanical properties, water content and in vitro release) were studied leading to an optimized soft, flexible K8 HA membrane containing 30 mg KT that achieved the desired balance of excellent elasticity and low water content. Moreover, a successful retardation of KT release rate was achieved (82%) after 48 h with favored initial fast drug release in the first hour (32.7%) to attain rapid analgesic effect. The clinical assessments in arthritic rats revealed apparent improvement in joint space narrowing, highest increase in bone mineral density at the proximal tibia and distal femur joints with the absence of osteophytosis only in animal group treated with combined HA-KT membrane. Application of K8 membrane was able to preserve KT plasma concentration above its minimum effective concentration for 48 h therefore, would able to replace six commercial tablets each of 10 mg KT.

A highly sensitive, selective and rapid liquid chromatography-electrospray ionization mass spectrometry (LC-MS) method has been developed and validated for simultaneous determination of moxifloxacin (MFX) and ketorolac (KTC) in rat plasma. Gemifloxacin (GFX) was used as an internal standard (IS). A simple protein precipitation method was used for the extraction of analytes from rat plasma. Effective chromatographic separation of MFX, KTC and GFX was achieved on a Kromasil C(18) column (100 × 4.6 mm, 5 µm) using a mobile phase consisting of acetonitrile-10 mm ammonium acetate (pH 2.5)-0.1% formic acid (50:25:25) in an isocratic elution, followed by detection with positive ion electrospray ionization mass spectrometry using target ions of [M + H](+) at m/z 402 for MFX, m/z 256 for KTC and m/z 390 for GFX in selective ion recording mode. The method was validated over the calibration range of 5-100 ng/mL for MFX and 10-6000 ng/mL for KTC. The method demonstrated good performances in terms of intra- and inter-day precision (0.97-5.33%) and accuracy (93.91-101.58%) for both MFX and KTC, including lower and upper limits of quantification. The recoveries from spiked control samples were >75% for MFX and >79% for KTC. The matrix effect was found to be negligible and the stability data were within acceptable limits. Further, the method was also successfully applied to a single-dose pharmacokinetic study in rats. This method can be extended to measure plasma concentrations of both drugs in human to understand drug interaction and adverse effects., (Copyright © 2012 John Wiley & Sons, Ltd.)

The parenteral administration of combinations of drugs is often necessary in palliative medicine, particularly in the terminal stage of life, when patients are no longer able to take medication orally. The use of infusers to administer continuous subcutaneous infusions is a well-established practice in the palliative care setting and enables several drugs to be given simultaneously, avoiding the need for repeated administrations and the effects of peaks and troughs in the doses of medication. The method is also appreciated by patients and caregivers in the home care setting because the devices and infusion sites are easy to manage. Despite their frequent use, however, the mixtures of drugs adopted in clinical practice are sometimes not supported by reliable data concerning their chemical and physical compatibility. The present study investigates the chemical compatibility of binary mixtures (morphine with ketorolac) and the physical compatibility of binary (morphine or methadone with ketorolac) or ternary mixtures (morphine with ketorolac and/or haloperidol, and/or dexamethasone, and/or metoclopramide, and/or hyoscine butylbromide) with a view to reducing the aleatory nature of the empirical use of such combinations, thereby increasing their safety and clinical appropriateness.

In vivo metabolites of ketorolac (KTC) have been identified and characterized by using liquid chromatography positive ion electrospray ionization high resolution tandem mass spectrometry (LC/ESI-HR-MS/MS) in combination with online hydrogen/deuterium exchange (HDX) experiments. To identify in vivo metabolites, blood urine and feces samples were collected after oral administration of KTC to Sprague-Dawley rats. The samples were prepared using an optimized sample preparation approach involving protein precipitation and freeze liquid separation followed by solid-phase extraction and then subjected to LC/HR-MS/MS analysis. A total of 12 metabolites have been identified in urine samples including hydroxy and glucuronide metabolites, which are also observed in plasma samples. In feces, only O-sulfate metabolite and unchanged KTC are observed. The structures of metabolites were elucidated using LC-MS/MS and MS(n) experiments combined with accurate mass measurements. Online HDX experiments have been used to support the structural characterization of drug metabolites. The main phase I metabolites of KTC are hydroxylated and decarbonylated metabolites, which undergo subsequent phase II glucuronidation pathways., (Copyright © 2012 John Wiley & Sons, Ltd.)

The objective of this investigation was to prepare mucoadhesive microspheres of ketorolac for nasal delivery to avoid gastrointestinal side effects of conventional dosage form. Mucoadhesive microspheres were prepared using carbopol, polycarbophil and chitosan as polymer by spray drying method. The process and formulation parameters were varied to study the effect on the yield and particle size. Microspheres were characterized for surface morphology, encapsulation efficiency, swelling behavior, mucoahesion properties, interaction studies using FTIR and DSC, in vitro drug release, ex vivo nasal cilio toxicity studies and in vivo anti-inflammatory and analgesic activity. Prepared microspheres were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 79-92%. The results showed that the process parameters significantly affect the particle size (10.29-16.75 μm) and yield of microspheres (36.53-56.69%). Interaction studies revealed that there were no drug to polymer interactions. Prepared microspheres exhibited good swelling and mucoadhesion strength which confined the strong mucoadhesive property of microspheres. Ketorolac release from the microspheres was extended up to 8 h and exhibited fickian drug release kinetics with best fit to higuchi model. The drug loaded microspheres were found to be nontoxic to nasal mucosa. The anti-inflammatory and analgesic effects of formulation showed a significant increase (p < 0.05) in percent inhibition value of up to 8 h when compared with ketorolac. In conclusion, spray dried microspheres based on chitosan could be suitable nasal delivery system for the administration of ketorolac.

Saturation transfer difference NMR (STD-NMR) spectroscopy has emerged as a powerful screening tool and a straightforward way to study the binding epitopes of active compounds in early stage lead discovery in pharmaceutical research. Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. Using well-studied COX inhibitors and by comparing STD signals with crystallographic structures, we show that there is a relation between the orientations of ibuprofen and diclofenac in the COX-2 active site and the relative STD responses detected in the NMR experiments. On the basis of this analysis, we propose that ketorolac should bind to the COX-2 active site in an orientation similar to that of diclofenac. We also show that the combination of STD-NMR with competition experiments constitutes a valuable tool to address the recently proposed behavior of COX-2 as functional heterodimers and complements enzyme activity studies in the effort to rationalize COX inhibition mechanisms.

Ketorolac loaded rigid and elastic vesicles were prepared by sonication and the physicochemical properties of the drug loaded-vesicle formulations were examined. Rigid and elastic vesicles were prepared from the double chain surfactant sucrose-ester laurate (L-595) and the single chain surfactant octaoxyethylene-laurate ester (PEG-8-L). Sulfosuccinate (TR-70) was used as a negative charge inducer. Evaluation of the prepared vesicle was performed by dynamic light scattering, extrusion and by (1)H NMR (T(2) relaxation studies). The vesicles mean size varied between 90 and 150 nm. The elasticity of the vesicles was enhanced with increasing PEG-8-L/L-595 ratio, while an increase in loading of ketorolac resulted in a reduction in vesicle elasticity. (1)H NMR measurements showed that the molecular mobility of ketorolac was restricted, which indicates that ketorolac molecules were entrapped within the vesicle bilayers. The T(2) values of the aromatic protons of ketorolac increased gradually at higher PEG-8-L levels, indicating that ketorolac mobility increased in the vesicle bilayer. The chemical stability of ketorolac was dramatically improved in the vesicle formulation compared to a buffer solution. The strong interactions of ketorolac with the bilayers of the vesicles might be the explanation for this increased stability of ketorolac., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To determine whether a mixture for intravenous perfusion containing tramadol (5 mg/ml), ranitidine (1.5 mg/ml), ketorolac (1.5 mg/ml) and metoclopramide (0.5 mg/ml) in a 0.9% sodium chlorides solution is compatible and stable at room temperature during a 48-hour period., Methods: We tested the mixture for stability using the HPLC technique (high performance liquid chromatography), with parallel visual assessments of any changes in colour, appearance of precipitate or phase separation indicating incompatibilities between the components., Results: At the end of the trial, chromatography data showed a mean metoclopramide concentration between 100% and 105% of the initial level, while concentrations of tramadol, ketorolac and ranitidine were between 99% and 102% of initial levels. There was no evidence of incompatibility between the drugs at any time during the study period., Conclusions: The combination is stable as a solution and its components are physically and chemically compatible in the concentrations used in the study, during at least 48 hours at room temperature., (Copyright © 2008 SEFH. Published by Elsevier Espana. All rights reserved.)

The stability of ketorolac tromethamine was investigated in acid (0.5M HCl) and alkaline conditions (0.5M NaOH), using the same procedure reported by Devarajan et al. [2]. The acid and base degradation products were identified by liquid chromatography-mass spectrometry (LC-MS)., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to D-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself.

A bioanalytical method was developed for the simultaneous determination of paracetamol and ketorolac enantiomers in human plasma using two-dimensional liquid chromatography-mass spectrometry. Separation was first achieved in a reversed-phase C18 column by using a gradient solvent system consisting of 0.1% aqueous formic acid and acetonitrile (ACN). The effluent between 8.9 and 9.9 min, corresponding to phenacetin and racemic ketorolac peaks, was transferred to a polysaccharide-based chiral column (ChiralPak AD-RH) by using a six-port switching valve. Ketorolac enantiomers were subsequently separated on the chiral column using an isocratic mobile phase composed of ACN/0.1% formic acid 50:50 (v/v). The total run-time was less than 18 min. This innovative strategy prolongs the lifetime of chiral columns by avoiding damages due to the sample matrix. The detection was carried out with an ion trap mass spectrometer equipped with an electrospray ionisation source. The tested ranges were 0.05-20 microg/ml for paracetamol and 0.005-2 microg/ml for each ketorolac enantiomer. This method was fully validated and showed good performances in terms of trueness (80-110%) and precision (6.7-13.2%). The mean extraction recoveries were 60%, 72% and 76% for paracetamol, R-ketorolac and S-ketorolac, respectively. Finally, this procedure was successfully applied to a pharmacokinetic study.

The purpose of this study was to investigate the stereospecific pharmacokinetics of ketorolac (KT) in goats following a single 2 mg/kg intravenous (i.v.) dose and a single 6 mg/kg oral dose. A stereoselective high pressure liquid chromatography assay was used to quantify ketorolac plasma concentrations. Pharmacokinetic parameters for both stereoisomers were estimated by model independent methods. Following an i.v. dose, the plasma concentration profiles for the stereoisomers were similar with half-lives of 1.05 +/- 0.62 h for R-KT and 1.05 +/- 0.61 h for S-KT. Clearance values for R- and S-KT after an i.v. dose were 0.53 +/- 0.23 and 0.54 +/- 0.23 L.h/kg, respectively. Following an oral dose, the terminal half-lives were longer with values of 34.08 +/- 11.81 and 33.97 +/- 12.19 h for R-KT and S-KT, respectively. The average bioavailability was 133 +/- 23% for R-KT and S-KT, respectively. The longer half-lives and high apparent bioavailability after oral dosing are suggestive of a slow absorption process in the gastrointestinal tract and recycling. The results indicate that interconversion of the stereoisomers of ketorolac is absent in goats. However, studies with individual isomers are needed before any conclusion can be drawn about the lack of bioinversion.

Ketorolac (KC) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of KC were synthesized by amidation with ethyl esters of amino acids, namely, glycine, l-phenylalanine, l-tryptophan, l-valine, l-isoleucine, l-alanine, l-leucine, l-glutamic acid, l-aspartic acid and beta-alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for biopharmaceutical studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, anti-inflammatory activities were obtained in all cases as compared to KC. Among synthesized prodrugs, viz. AR-11, AR-19 and AR-20 showed excellent pharmacological response and encouraging hydrolysis rate both in SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent showed enhanced partition coefficient but diminished dissolution and hydrolysis rates. Such prodrugs can be considered for sustained release purpose.

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37 degrees C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t(1/2) = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t(1/2) in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P(app) was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56- and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.

The aim was to evaluate the skin permeation and accumulation profiles of a highly lipophilic fatty ester using the combination of various permeation enhancing techniques to study the potential of highly lipophilic fatty esters as local topical agents. Permeation and accumulation profiles of ketorolac stearate (C18:0) were studied using solubility improved formulation, supersaturated solution of permeant in enhancer vehicle, lipophilic receptor solution, enhancer pretreatment, and the removal of stratum corneum and delipidization of skins. Impermeability and minimal skin accumulation of ketorolac stearate could delineate a preliminary possibility for designing safer topical agents without systemic absorption.

The objective of this investigation was to evaluate the effect of delivery strategies such as cyclodextrin complexation and liposomes on the topical delivery of ketorolac acid (KTRA) and ketorolac tromethamine. Ketorolac acid-hydroxypropyl-beta-cyclodextrin solid dispersions (KTRA-CD) were prepared by kneading method. The liposomes containing ketorolac tromethamine (KTRM) and KTRA-CD were prepared. The in vitro permeation of KTRM solution, KTRA solution, KTRA-CD, and liposomes containing KTRM or KTRA-CD through guinea pig skin was evaluated. The anti-inflammatory activity of the topically applied KTRA-CD gel (containing 1% w/w KTRA) was compared to that of orally delivered KTRM solution. The KTRA-CD demonstrated significantly higher transdermal transport of ketorolac as compared to all other systems whereas liposomes significantly reduced the transport of ketorolac. The anti-inflammatory activity of the topically applied KTRA-CD gel was similar to that of the orally administered KTRM. Thus, cyclodextrin complexation enabled effective transdermal delivery of the ketorolac.

It has long been known that singlet oxygen ((1)O2) is generated during inflammatory processes. Once formed in substantial amounts, (1)O2 may have an important role in mediating the destruction of infectious agents during host defense. On the other hand, (1)O2 is capable of damaging almost all biological molecules and is particularly genotoxic, which gives a special relevance to the scavenging of this ROS throughout anti-inflammatory treatments. Considering that the use of non-steroidal anti-inflammatory drugs (NSAIDs) constitutes a first approach in the treatment of persistent inflammatory processes (due to their ability to inhibit cyclooxygenase), a putative scavenging activity of NSAIDs for (1)O2 would also represent a significant component of their therapeutic effect. The aim of the present study was to evaluate the scavenging activity for (1)O2 by several chemical families of NSAIDs. The results suggested that the pyrazole derivatives (dipyrone and aminopyrine) are, by far, the most potent scavengers of (1)O2 (much more potent compared to the other tested NSAIDs), displaying IC(50)-values in the low micromolar range. There was a lack of activity for most of the arylpropionic acid derivatives tested, with only naproxen and indoprofen displaying residual activities, as for the oxazole derivative, oxaprozin. On the other hand, the pyrrole derivatives (tolmetin and ketorolac), the indolacetic acid derivatives (indomethacin, and etodolac), as well as sulindac and its metabolites (sulindac sulfide and sulindac sulfone) displayed scavenging activity in the high micromolar range. Thus, the scavenging effect observed for dipyrone and aminopyrine will almost certainly contribute to their healing effect in the treatment of prolonged or chronic inflammation, while that of the other studied NSAIDs may have a lower contribution, though these assumptions still require further in vivo validation.

Ketorolac is a non-steroidal anti-inflammatory drug. Dextran conjugates of ketorolac (KD) were synthesized and characterized to improve ketorolac aqueous solubility and reduce gastrointestinal side effects. An N-acylimidazole derivative of ketorolac (KAI) was condensed with a model carrier polymer, dextran of different molecular masses (40000, 60000, 110000 and 200000). IR spectral data confirmed formation of ester bonding. Ketorolac contents were evaluated by UV-spectrophotometric analysis. The molecular mass was determined by measuring viscosity using the Mark-Howink-Sakurada equation. In vitro hydrolysis studies were performed in aqueous buffers (pH 1.2, 7.4, 9) and in 80% (V/V) human plasma (pH 7.4). At pH 9, a higher rate of ketorolac release from KD was observed as compared to aqueous buffer of pH 7.4 and 80% human plasma (pH 7.4), following first-order kinetics. In vivo biological screening in mice and rats indicated that conjugates retained analgesic and anti-inflammatory activities with significantly reduced ulcerogenicity compared to the parent drug.

The purpose of this study was to evaluate the physicochemical properties, skin permeation and accumulation profiles of model lipophilic ketorolac fatty ester (esters) prodrugs. Ketorolac linoleate (C18:2), oleate (C18:1) and stearate (C18:0) were evaluated for their solubility, capacity factor, enzymatic hydrolysis, chemical stability, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of supersaturated solution of permeants in the enhancer vehicle, lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc. Esters were highly lipophilic, chemically stable for the duration of observation, enzymatically unstable in hairless mouse skin/liver homogenates and plasma, and impermeable into the receptor solution. Absence of skin permeation, relative enzymatic stability during permeation and chemical stability of these esters could delineate preliminary possibilities for designing safer topical agents without systemic absorption.

Full details are provided for a recently invented method to couple indoles and pyrroles to carbonyl compounds. The reaction is ideally suited for structurally complex substrates and exhibits high levels of chemoselectivity (functional group tolerability), regioselectivity (coupling occurs exclusively at C-3 of indole or C-2 of pyrrole), stereoselectivity (substrate control), and practicality (amenable to scaleup). In addition, quaternary stereocenters are easily and predictably generated. The reaction has been applied to a number of synthetic problems including total syntheses of members of the hapalindole family of natural products, ketorolac, acremoauxin A, and oxazinin 3. Mechanistically, this coupling protocol appears to operate by a single electron-transfer process requiring generation of an electron-deficient radical adjacent to a carbonyl which is then intercepted by an indole or pyrrole anion.

The purpose of this study was to establish the stereospecific pharmacokinetics of ketorolac (KT) in calves following a single 2 mg/kg intravenous (i.v.) and a single 8 mg/kg oral dose. Plasma concentrations were determined using a stereoselective HPLC assay. Pharmacokinetic parameters for both the stereoisomers were estimated by model-independent methods. Following an i.v. dose, the plasma concentration profiles of the stereoisomers were similar with half-lives of 5.9 +/- 5.1 h for R-KT and 6.0 +/- 4.9 h for S-KT. Clearance values for R- and S-KT after an i.v. dose were 0.0470 +/- 0.0370 and 0.0480 +/- 0.0370 L/h/kg respectively. After an oral dose, the terminal half-lives were longer than following i.v. administration with values of 14.77 +/- 3.08 and 14.55 +/- 2.95 h for R-KT and S-KT respectively. The average oral bioavailability was 86.5 +/- 20.6% for R-KT and 86.7 +/- 20.3% for S-KT. The results indicate that the stereoisomers of KT have similar pharmacokinetic profiles in calves. Although, unlike humans, bioinversion between KT stereoisomers appears minimal in calves, studies with individual isomers are needed before any firm conclusions can be drawn about this lack of KT bioinversion.

Six new 1-alkylazacycloalkan-2-one esters of ketorolac (1-6) were synthesized and evaluated as potential dermal prodrugs. In vitro experiments were carried out to evaluate their chemical and enzymatic stability and permeation through excised human skin. Furthermore, partition coefficients n-octanol-water of ketorolac and its esters were determined to obtain information about their lipophilicity. Esters 1-6 showed increased lipophilicity compared to the parent drug, good stability in phosphate buffer pH 7.4, and were readily hydrolyzed in human plasma. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 2 and 4 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketorolac.

Purpose: Classic penetration enhancement/retardation methods for improved dermal drug delivery primarily focus on co-applied chemicals aided alterations in skin accumulation/permeation profile, and in many cases, this has been achieved by compromising the systemic absorption/toxicities of penetrant/enhancer/retarder. In this study, higher dermal accumulation without systemic absorption of ketorolac and its fatty esters (esters) will be achieved by synthesizing lipophilic fatty ester soft prodrugs of ketorolac., Methods: Ketorolac decenoate (C10:1), dodecenoate (C12:1) and palmitoleate (C16:1) were synthesized and evaluated for their lipophilicity, enzymatic hydrolysis, chemical stabilities, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc., Results: Esters were highly lipophilic, chemically stable, enzymatically unstable in hairless mouse skin/liver homogenates and impermeable into the receptor solution., Conclusion: Higher dermal accumulation, absence of skin permeation, relative enzymatic stability in whole skins during permeation study and the pharmaceutical stability of esters could delineate a preliminary possibility for designing safer dermal agents with minimum potential for systemic absorption without the co-application of permeation enhancers or retarders.

In the present study, 2 alternative strategies to optimize ketorolac transdermal delivery, namely, prodrugs (polyoxyethylene glycol ester derivatives, I-IV) and nanostructured lipid carriers (NLC) were investigated. The synthesized prodrugs were chemically stable and easily degraded to the parent drug in human plasma. Ketorolac-loaded NLC with high drug content could be successfully prepared. The obtained products formulated into gels showed a different trend of drug permeation through human stratum corneum and epidermis. Particularly, skin permeation of ester prodrugs was significantly enhanced, apart from ester IV, compared with ketorolac, while the results of drug release from NLC outlined that these carriers were ineffective in increasing ketorolac percutaneous absorption owing to a high degree of mutual interaction between the drug and carrier lipid matrix. Polyoxyethylene glycol esterification confirmed to be a suitable approach to enhance ketorolac transdermal delivery, while NLC seemed more appropriate for sustained release owing to the possible formation of a drug reservoir into the skin.