[Thin layer chromatography for the analysis of certain anti-inflammatory medicines].

This work was devoted to the elucidation of conditions for isolation of ketorolac and diclofenac from biological fluids. A method is proposed for the extraction of these compounds from solutions with organic solvents at different pH values. Other methods permit to optimize identification of analytes by thin layer chromatography while the densitometric technique may be used for qualitative and quantitative analysis of their composition in biological fluids.

Long-term stability of an infusion containing paracetamol, alizapride, ketorolac and tramadol in glass bottles at 5±3°C.

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.

Alternative Drug Delivery for Patients Undergoing Cataract Surgery as Demonstrated in a Canine Model.

PURPOSE: (1) To determine ketorolac concentrations in selected ocular tissues following the intracameral administration of phenylephrine and ketorolac injection 1%/0.3% (OMIDRIA®) delivered in irrigation solution during lens replacement surgery in beagle dogs. (2) To compare the ketorolac initial dose and resultant concentrations from the above study to those achieved in aqueous and vitreous by topical administration in patients undergoing cataract surgery or vitrectomy, respectively. METHODS: Lens replacement surgery with phacoemulsification was performed in 20 female beagle dogs. A fixed combination of phenylephrine and ketorolac injection 1%/0.3% was diluted 125-fold into the balanced salt solution and delivered intracamerally during the phacoemulsification procedure. Ketorolac concentration was determined by liquid chromatography/mass spectrometry. RESULTS: Concentrations of ketorolac when administered by the intracameral route in the dosing solution in dogs were found to be considerably higher in both aqueous and vitreous compared to what is achieved with topical dosing in patients. CONCLUSIONS: Adequate therapeutic concentrations of ketorolac in aqueous and vitreous humor were achieved even at 10 h postdose. Critical concentrations in the aqueous that envelopes the iris/ciliary body, which are sites of prostaglandin E2 synthesis, and the vitreous are not achieved by topical dosing in clinical studies after the surgery, but are by direct intracameral dosing as determined in this study. Based on these studies and clinical data, phenylephrine and ketorolac injection 1%/0.3% delivered during surgery as an irrigation solution may preclude the need for topically administered pre- and postoperative NSAIDs.

Stability indicating HPLC-DAD method for analysis of Ketorolac binary and ternary mixtures in eye drops: Quantitative analysis in rabbit aqueous humor.

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).

Analysis of ketorolac and its related impurities by capillary electrochromatography.

Capillary electrochromatography (CEC) was employed for the assay of ketorolac (KT) and its known related impurities [1-hydroxy analog of ketorolac (HK), 1-keto analog of ketorolac (KK), ketorolac decarboxylated (DK)] in both drug substance and coated tablets. Detection was made at 323 nm and flufenamic acid was selected as internal standard. The experiments were performed in a 100 microm i.d. capillary packed with RP-18 silica particles (33.0, 24.5, 23.0 cm total, effective and packed lengths, respectively). The composition of the mobile phase was optimised by changing pH of the buffer and acetonitrile (ACN) content and by addition of other organic modifiers (methanol, ethanol, isopropanol, n-propanol) in order to evaluate the effect of these factors on the method performance (efficiency, retention and resolution). The optimum mobile phase consisted of a mixture of 50 mM ammonium formate buffer pH 3.5-water-acetonitrile (10:20:70, v/v/v), while voltage and temperature were set at 30 kV and 20 degrees C, respectively. Applying these conditions, all peaks were baseline resolved and the analysis was performed in less than 9 min. Selectivity, repeatability of retention time and peak area, detection and quantitation limits, linearity and range, precision and accuracy were also investigated. R.S.D. and bias values obtained for all the analytes were below 5% and sensitivity was satisfactory, thus the method was deemed suitable for pharmaceutical quality control. Applying the method to coated tablets, a recovery of 98.5+/-0.8% and an R.S.D. of 0.5% were found.

Identification and structural characterization of in vivo metabolites of ketorolac using liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS).

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.

Nasal ketorolac challenge using acoustic thinometry in patients with aspirin-exacerbated respiratory disease

Background: Safer and less time-consuming alternatives to single-blind placebo-controlled oral challenge (SBPCOC) have been sought for the diagnosis of aspirin-exacerbated respiratory disease (AERD). Nasal challenges with various nonsteroidal anti-inflammatory drugs and assessment methods have been developed. Objective: Our objective was to evaluate the utility and safety of nasal ketorolac challenge (NKC) using acoustic rhinometry in patients with suspected AERD. Methods: The study population comprised 36 patients with suspected AERD. NKC was performed with placebo (saline) and 13 mg of ketorolac sprayed as aerosol into both nostrils. A positive challenge result was defined as an increase of ≥30% in nasal symptoms (recorded using a visual analog scale) and a 30% drop in the sum of the volumes of both nasal cavities at 2-8 cm. Patients with a negative NKC result underwent SBPCOC with aspirin (cumulative dose of 750 mg). Results: A naso-ocular reaction during NKC was detected in 21 patients. Four patients also developed mild asthma exacerbations (although only 1 experienced a decrease in FEV1 >15%). No other significant adverse events occurred. The remaining 15 patients with a negative NKC result had a negative response during aspirin SBPCOC. Conclusion: NKC assessed using acoustic rhinometry is a reliable method for the study of patients with AERD. We suggest that NKC assessed with acoustic rhinometry was useful and safe for selection of candidates for safe oral aspirin challenge (AU)

Introducción: El test de exposición simple ciego controlado con placebo (TEC) con aspirina es el patrón-oro para el diagnóstico de la enfermedad respiratoria exacerbada por aspirina (EREA), aunque presenta un riesgo elevado de reacciones durante su realización. Por este motivo, se han desarrollado diferentes procedimientos de provocación nasal con aspirina, lisina y ketorolaco. Objetivo: Evaluar la utilidad y la seguridad del test inhalatorio nasal con ketorolaco (TNK) usando un rinómetro acústico en pacientes con sospecha de EREA. Métodos: Se incluyeron 36 pacientes con sospecha de EREA. El TNK se realizó con placebo (solución salina) y 13 mg de ketorolaco instilado como aerosol en ambas fosas nasales. Un test de exposición positivo se definió como un aumento del 30% o más de los síntomas nasales registrados mediante una escala analógica visual y un descenso mayor del 30% en la suma de ambos volúmenes de las cavidades nasales entre 2 a 8 cm del vestíbulo nasal. Si el TNK era negativo, los pacientes se sometían a un TEC con 750 mg de aspirina (en dosis acumulativas). Resultados: Veintiún pacientes presentaron una reacción nasoocular durante el TNK. Cuatro de ellos presentaron síntomas de asma bronquial (aunque solo uno mostró un descenso del FEV1> 15%), pero no se produjeron otros acontecimientos adversos significativos. Los 15 pacientes restantes que tuvieron un TNK negativo, tuvieron una respuesta negativa durante el TEC con aspirina. Conclusión: El TNK evaluado mediante rinómetro acústico es un método fiable para el estudio de pacientes con sospecha de EREA (AU)

Acid and base degraded products of ketorolac.

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).

Mixture design in the optimization of a microemulsion system for the electrokinetic chromatographic determination of ketorolac and its impurities: method development and validation.

Microemulsion EKC (MEEKC) was used for the determination of ketorolac and its three impurities. The microemulsion system was optimized, for the first time in the literature, using a multivariate strategy involving a mixture design. A 13-run experimental plan covering an experimental domain defined by the components aqueous phase (10 mM borate buffer pH 9.2), oil phase (n-heptane) and surfactant/cosurfactant (SDS/n-butanol) was carried out. Good results were obtained with all microemulsions tested considering as responses analysis time and resolution, and according to the desirability function the best microemulsion system was constituted by 90.0% 10 mM borate buffer, 2.0% n-heptane, 8.0% of SDS/n-butanol in 1:2 ratio. Finally, with the aim of reducing analysis time, a response surface study was carried out in the experimental domain defined by the process variables temperature and voltage and the best values were 17 degrees C and -17 kV, respectively. Applying the optimised conditions, a complete resolution among the analytes was obtained in about 3 min using the short-end injection method. The method was validated for both drug substances and drug product and was applied to the quality control of ketorolac in coated tablets. A comparison of MEEKC, MEKC and CEC for assaying ketorolac and its related substances has been made.

Relación entre anti-inflamatorios no esteroideos (AINEs) y queratolisis. A propósito de un caso / Corneal melting and topical nonsteroidal anti-inflammatory drug (NSAID). A case report

Objetivo: Establecer la posible relación entre eluso de los antiinflamatorios no esteroideos (AINEs)tópicos y la queratolisis.Caso clínico: Se presenta un caso de queratolisistras cirugía vitreorretiniana y uso tópico de ketorolacotrometamol (Acular®).Discusión: Se plantea la etiología multifactorial enlos casos de queratolisis asociados al uso de AINEsy recomendando un uso de los mismos adecuado acada situación, valorando la posible comorbilidad de otros agentes(AU)

Purpose: To study the relationship between the useof nonsteroidal anti-inflammatory drug (NSAID)and the corneal melting.Case report: We report a case of keratolysis aftervitreoretinal surgery and topical use of ketorolactromethamine (Acular®).Discussion: It is proposed the multifactorial etiologyin the cases of corneal melting related to theuse of NSAID and it is recommended an reasonableuse of them in each situation and to check the possiblecomorbility of other agents(AU)