Characterization of forced degradation products of ketorolac tromethamine using LC/ESI/Q/TOF/MS/MS and in silico toxicity prediction.

Ketorolac, a nonsteroidal anti-inflammatory drug, was subjected to forced degradation studies as per International Conference on Harmonization guidelines. A simple, rapid, precise, and accurate high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (LC/ESI/Q/TOF/MS/MS) method has been developed for the identification and structural characterization of stressed degradation products of ketorolac. The drug was found to degrade in hydrolytic (acidic, basic, and neutral), photolytic (acidic, basic, and neutral solution), and thermal conditions, whereas the solid form of the drug was found to be stable under photolytic conditions. The method has shown adequate separation of ketorolac tromethamine and its degradation products on a Grace Smart C-18 (250 mm × 4.6 mm i.d., 5 µm) column using 20 mM ammonium formate (pH = 3.2): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 1.0 ml/min. A total of nine degradation products were identified and characterized by LC/ESI/MS/MS. The most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the [M + H](+) ions of ketorolac and its degradation products. In silico toxicity of the drug and degradation products was investigated by using topkat and derek softwares. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization guidelines.

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation.

Ketorolac tromethamine is a potent analgesic and moderately effective anti-inflammatory drug approved for treatment of moderately severe acute pain as an intravenous/intramuscular injectable solution and an oral tablet. ROXRO PHARMA, Inc has developed an intranasal formulation, SPRIX, that delivers the drug with a similar pharmacokinetic profile to that obtained with intramuscular administration. Local tolerance and systemic toxicology studies were performed in rats and rabbits and showed that intranasal administration of SPRIX exhibits toxicity similar to that of other routes of administration and does not result in any adverse effects on the nasal passage and upper and lower respiratory system.

Ketorolac trometamol topical formulations: release behaviour, physical characterization, skin permeation, efficacy and gastric safety.

OBJECTIVES: The objective of this study was to improve systemic delivery of the highly analgesic ketorolac trometamol (ketorolac tromethamine) via the transdermal route, through cost-effective topical formulations, to avoid most of the problems associated with ketorolac trometamol therapy. METHODS: In-vitro release behaviour of the drug from different microemulsion and emulgel formulations was evaluated. E2 emulgel (based on isopropyl myristate as penetration enhancer) and E7 emulgel (based on Brij 92 as penetration enhancer) were evaluated for their physical properties, rat skin permeation, in-vivo analgesic effect (hot-plate test and the paw pressure test), acute and chronic anti-inflammatory activity and gastric safety. KEY FINDINGS: Isopropyl myristate and the synergistic effect of the two known penetration enhancers (propylene glycol and Brij 92) significantly modulated drug permeation and may be a promising approach for the transdermal delivery of ketorolac trometamol and other drugs. Selected in-vivo tested formulae (E2 and E7) caused significantly less ulcer score and less gastric erosion compared with oral ketorolac trometamol. E7 showed significantly higher analgesic and anti-inflammatory activity compared with E2 with no significant difference compared with oral ketorolac trometamol. CONCLUSIONS: The developed ketorolac trometamol E7 emulgel appeared promising for dermal and transdermal delivery of ketorolac trometamol, which would circumvent most of the problems associated with drug therapy.

Intravitreal toxicity of ketorolac tris salt and flurbiprofen.

BACKGROUND AND OBJECTIVE: To determine the retinal toxicity of intravitreal ketorolac tris salt and flurbiprofen. MATERIALS AND METHODS: Thirty-two New Zealand rabbits were injected intravitreally with 125, 250, or 500 microg or 1 mg of ketorolac tris salt or flurbiprofen in one eye and 8 fellow eyes were injected with 5% dextrose as a control. All animals underwent indirect ophthalmoscopy and slit-lamp biomicroscopy before injection and on days 1, 7, and 14 after the intravitreal injection. Electroretinography was performed on all animals before injection and on day 14 after the injection before the animals were killed. The enucleated eyes were prepared for histology. RESULTS: Clinical examination, electroretinography results, and histological evaluation demonstrated no signs of retinal toxicity for either drug at any dose. CONCLUSIONS: Intravitreal doses up to 1 mg of ketorolac tris salt and 1 mg of flurbiprofen did not cause retinal toxicity in the rabbit eye.

Retinal toxicity of commercially available intravitreal ketorolac in albino rabbits.

PURPOSE: To determine whether intravitreal injection of a commercially available ketorolac tromethamine preparation causes retinal toxicity in albino rabbits. METHODS: Nine albino rabbits were injected intravitreally with ketorolac tromethamine (3 mg; 0.1 mL) in one eye and saline (0.1 mL) in the fellow eye. Six of the rabbits received a single injection of ketorolac, and the other three rabbits underwent biweekly injection for a total of four injections. Electroretinography testing was performed on both eyes at different time intervals during 4 weeks of follow-up in the single injection group, and during 12 weeks of follow-up in the multiple injection group. Visual evoked potentials were recorded from each rabbit using monocular and binocular stimulation at the end of the follow-up period. Animals were then killed, and the retinas were prepared for morphologic examination at the light microscope level and for immunostaining for glial fibrillary acidic protein, as a marker of retinal damage. RESULTS: The electroretinography responses from the control and experimental eyes were similar throughout the follow-up period in all rabbits of both experimental groups. There were no differences in the flash visual evoked potential responses between experimental and control eyes in the single injection group, while in the repeated injection group, statistically significant differences were found. Light microscopy did not identify significant histologic differences between the retinas from control and experimental eyes after a single dose. However, after repeated dosing, two of three eyes showed histologic evidence of local toxicity. Immunocytochemical analysis showed no glial fibrillary acidic protein staining in Muller (glial) cells throughout the retina in the single injection group. Slight glial fibrillary acidic protein staining was detected in only one of the three retinas from rabbits in the repeated injection group. CONCLUSIONS: Commercially available ketorolac tromethamine was found to be toxic to the retinas of albino rabbits following multiple intravitreal injections at a dose of 3 mg while no electrophysiologic toxicity was found. Therefore, the use of commercially available ketorolac containing alcohol, for intravitreal injection is not recommended.

The safety of intraocular ketorolac in rabbits.

PURPOSE: To assess the safety of a possible substitute treatment for intraocular steroid injections, intraocular injections of ketorolac tromethamine, one of the nonsteroidal anti-inflammatory drugs, were performed in rabbits. METHODS: Either 0.5% or 0.25% preservative-free ketorolac tromethamine ophthalmic solution (0.1 mL) was injected into the vitreous of the right eye of 15 rabbits. Physiologic saline solution (BSS; Alcon, Ft. Worth, TX) was injected into the left eye of each rabbit as a control. A standard electroretinogram and intraocular pressure measurements were obtained before injection, and repeated 1 day and 1, 2, 3, and 4 weeks after injection. After 4 weeks, the rabbits were euthanatized and the retinas examined by light and electron microscopy. Differences in the electroretinograms, intraocular pressure, and histopathology between the two eyes were recorded. Further, the elimination half-life of the drug in the vitreous was assessed. RESULTS: There were no statistically significant differences in electroretinograms, or intraocular pressure measurements obtained between the ketorolac-injected eyes and the control eyes. The half life of the drug was measured to be 2.3 hours. No histopathologic changes were observed in study eyes compared with control eyes. CONCLUSIONS: Preservative-free ketorolac tromethamine is nontoxic to the retinas of rabbits when injected intravitreally and could be considered as an alternative to intraocular steroid injections.

Antinociceptive and neurotoxicologic screening of chronic intrathecal administration of ketorolac tromethamine in the rat.

UNLABELLED: Many drugs are tested intrathecally to investigate alternatives to opioids. We aimed to explore the analgesic and possible neurotoxic effects of chronic intrathecally-administered ketorolac tromethamine in rats. Catheters were placed via atlantoaxial interval in 28 Wistar rats under anesthesia of intraperitoneally-injected thiopental 30 mg/kg. Rats were randomized into 4 groups and administered 4 repeated intrathecal doses of therapy with 5-day intervals. The control group received 10 microL of saline, and the other groups received 50, 150, and 400 microg of ketorolac tromethamine respectively. The formalin test, behavioral test, and histopathological examination of four different spinal cord levels were performed. Neither behavioral testing nor histopathological examination revealed abnormalities that would suggest neurotoxicity. Formalin tests showed that both phase I and phase II responses of ketorolac tromethamine groups were significantly less than those of the control group. Although phase I responses did not differ during comparisons among ketorolac tromethamine-administered groups, phase II responses decreased significantly in groups that received 150 and 400 microg of ketorolac tromethamine. Intrathecally administered ketorolac tromethamine reduced nociceptive responses and exhibited no untoward neurological effect even at large doses. However, its intrathecal use as a safe alternative drug for chronic pain remains to be investigated in other species. IMPLICATIONS: The present study is unique because it has demonstrated that chronic intrathecal administration of ketorolac tromethamine in rats, even at considerably large doses, showed a potent analgesic effect during the formalin test without exhibiting any neurotoxic side effect.