Ketorolac, an injectable nonnarcotic analgesic

Clinical studies of the injectable nonsteroidal anti-inflammatory agent (NSAIA) ketorolac tromethamine are reviewed, and the chemistry, pharmacology, pharmacokinetics, drug interactions, and adverse effects of ketorolac are described. Ketorolac exhibits anti-inflammatory, analgesic, and antipyretic activity. Although the exact mechanisms of action have not been determined, its effects appear to be associated principally with the inhibition of prostaglandin synthesis. After oral, i.m., or i.v. administration, ketorolac and its metabolites are excreted mainly in urine. Ketorolac tromethamine has been used for the symptomatic relief of moderate to severe postoperative pain, including that associated with abdominal, gynecologic, oral, orthopedic, or urologic surgery. Ketorolac has also been used for the relief of acute renal colic, pain associated with trauma, and visceral pain associated with cancer. When administered i.m., ketorolac produced analgesia comparable to that of i.m. doses of meperidine, pentazocine, or morphine. The most common adverse effects associated with short-term administration are nervous system and gastrointestinal effects; these are usually mild and occur in about 39% of patients. Unlike opiate analgesics, ketorolac does not appear to cause tolerance or physical dependence in patients receiving long-term therapy. Ketorolac tromethamine has been administered concomitantly with morphine or meperidine without apparent adverse interaction. For short-term pain management, an initial i.m. ketorolac tromethamine loading dose of 30 or 60 mg is recommended. Ketorolac tromethamine appears to be as effective as morphine or meperidine for short-term management of moderate to severe postoperative pain. It lacks the respiratory depressant effects of opiate analgesics but shares the toxic potentials of other NSAIAs.     

Ketorolac tromethamine floating beads for oral application: Characterization and in vitro/in vivo evaluation

The floating beads have been employed to make a sustained release of the drug in the stomach and to decrease the dose of the drug and hence overcome its side effects. The common benefits of the floating beads were it is easy preparation, without the need of a high temperature, and high percentage of the drug entrapment. In the present work, the Ketorolac tromethamine (KT) floating beads were prepared by extrusion congealing method utilizing calcium carbonate as a gas forming agent. The physical characters of the produced beads were investigated such as KT yield, KT loading, and entrapment efficiency of the drug. In addition, floating behavior, swelling, particle size, morphology and KT stability were also evaluated. In vitro drug release study was carried out, and the kinetics of the release was evaluated using the linear regression method. Furthermore, the in vivo analgesic effect of KT after oral administration of the selected formula of floating beads (F10) was carried out using hot plate and tail flick methods. Oral commercial KT tablets and KT solution were used for the comparison. The prepared beads remained floated for more than 8 h. The optimized formulation (F10) exhibited prolonged drug release (more than 8 h) and the drug release follows the Higuchi kinetic model, with a Fickian diffusion mechanism according to Korsmeyer-Peppas (n = 0.466). Moreover, F10 showed a sustained analgesic effect as compared to the commercial tablet.     

酮咯酸氨丁三醇治疗外科疾病疼痛118例

目的;探讨酮咯酸氨丁三醇对外科疾病疼痛的镇痛效果.方法;外科疾病疼痛患者118例,给予酮咯酸氨丁三醇注射液30 mg,im,口服剂10～20 mg,po,每天最大剂量不超过120 mg,对剧烈疼痛给药30 min后无效者,可再肌内注射30 mg.结果;起效时间5～60 min,平均35 min,止痛时间为0.5～24 h,平均8.2 h.总有效率97.5%.结论;酮咯酸氨丁三醇镇痛抗炎作用显著,并且起效迅速,可用于临床各种外科性疼痛.     

Pharmacokinetics of Ketorolac and p-Hydroxyketorolac Following Oral and Intramuscular Administration of Ketorolac Tromethamine

Ketorolac tromethamine (KT), a potent analgesic with cyclooxygenase inhibitory activity, was administered in an open, randomized, single-dose study of Latin-square design to 12 healthy male volunteers. Doses of 30 mg oral (po) and 30, 60, and 90 mg intramuscular (im) KT were administered in solution. Plasma samples were analyzed for ketorolac (K) and its inactive metabolite, p-hydroxyketorolac (PHK), by reversed-phase high-performance liquid chromatography (HPLC). The 30-mg im dose was found to be similar to the 30-mg po dose with respect to total AUC values for both K and PHK. The amount of PHK circulating in plasma was very low as judged by AUC ratios (PHK/K × 100) of 1.9 and 1.5% for the 30-mg po and im doses, respectively. The rate of absorption of K and formation of PHK, as determined by C _max and T _max values, was significantly slower following the im doses. Total AUC and C _max for K and PHK increased linearly with dose after im administration of 30, 60, and 90 mg of KT. The mean plasma half-life of K was remarkably consistent between po and im administration and was independent of dose, ranging from 5.21 to 5.56 hr. The plasma metabolic profile was similar following both routes of administration and graded im doses.     

Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases

Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue.     

Evaluation of ketorolac tromethamine microspheres by chitosan/gelatin B complex coacervation

Microspheres (MS) of Ketorolac Tromethamine (KT) for oral delivery were prepared by complex coacervation (method-1) and simple coacervation (method-2) methods without the use of chemical crossalinking agent (glutaraldehyde) to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate (Na-TPP) as cross linking agent. Chitosan and gelatin B were used as polymer and copolymer respectively. All the prepared microspheres were subjected to various physico-chemical studies, such as drug-polymer compatibility by Thin Layer Chromatography (TLC) and Fourier Transform Infra Red Spectroscopy (FTIR), surface morphology by Scanning Electron Microscopy (SEM), frequency distribution, encapsulation efficiency, in-vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by Differential Scanning Calorimetry (DSC) and X-ray powder Diffractometry (XRD). TLC and FTIR studies indicated no drug-polymer incompatibility. All the MS showed release of drug by a fickian diffusion mechanism. DSC and XRD analysis indicated that the KT trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. It is possible to design a controlled drug delivery system for the prolonged release of KT, improving therapy by possible reduction of time intervals between administrations.     

Clinical evaluation of novel buccoadhesive film containing ketorolac in dental and post-oral surgery pain management

Ketorolac tromethamine (KT), a non-steroidal anti-inflammatory drug, was formulated in buccoadhesive film to overcome the limitations in the currently available routes of administration which in sequence will increase patients' compliance. The film was formulated using aqueous solvents by means of two bioadhesive polymers namely: hydroxylpropyl methyl cellulose (HPMC) and Carbopol 934. The prepared film was subjected to investigations for its physical and mechanical properties, swelling behavior, in vitro bioadhesion, and in vitro, in situ and in vivo release. Anti-inflammatory efficacy and analgesic activity of the prepared buccoadhesive film were investigated in rats using the hind-paw oedema test and the hot plate method. The analgesic efficacy and tolerability of a single 30 mg dose of KT formulated into the buccoadhesive film was clinically evaluated using a standard, widely accepted post-oral surgery pain model. In this study, the prepared film has been administrated to dental post-operative patients for relieving pain in dental hospital clinic. Results indicate that the concentration of KT in the oral cavity was maintained above 4.0 microg/ml for a period of at least 6 h. The buccal KT film was excellently tolerated in all patients and no complains of GI side effects were reported. It is concluded from this clinical evaluation that KT formulated into a buccoadhesive film is effective as a potent analgesic in dental and postoperative oral surgery in a single dose of 30 mg with minimal GI side effects.     

Biphasic anaphylactic reaction to Ketorolac tromethamine

Ketorolac tromethamine is a recent injectable non-steroidal anti-inflammatory drug (NSAID) with analgesic properties approved for short-term pain management. In spite of its increasing use both in adults and children, relatively few allergic-like reactions have been reported. Reactions are often severe, and a death occurred following an intramuscular injection of ketorolac.     

Pharmacokinetics and analgesic effect of ketorolac floating delivery system

Abstract

Objectives: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form.

Methods: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay.

Results: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8?h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the C_max (2.2?±?0.3?µg/ml) was achieved at ～2?h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets.

Conclusion: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.     

Development and in vitro evaluations of gelatin A microspheres of ketorolac tromethamine for intranasal administration

Gelatin A microspheres (MS) of ketorolac tromethamine (KT) for intranasal systemic delivery were developed with the aim to avoid gastro-intestinal complications, to improve patient compliance, to use as an alternative therapy to conventional dosage forms, to achieve controlled blood level profiles, and to obtain improved therapeutic efficacy in the treatment of postoperative pain and migraine. Gelatin A microspheres were prepared using the emulsification-crosslinking technique. The drug was dispersed in polymer gelatin and formulated into a w/o emulsion with liquid paraffin, using glutaraldehyde as a crosslinking agent. The formulation variables were drug loading and the concentrations of polymer (gelatin), co-polymer (chitosan) and the crosslinking agent. All the prepared microspheres were evaluated for physical characteristics, such as particle size, incorporation efficiency, swelling ability, in vitro bioadhesion on rabbit small intestine and in vitro drug release characteristics in pH 6.6 phosphate buffer. All the microspheres showed good bioadhesive properties. Gelatin A and chitosan concentrations, percentage of the crosslinking agent and also the drug loading affected significantly the rate and extent of drug release. The data indicated that the KT release followed Higuchi's matrix model.     

Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium

ABSTRACT

Objective: To compare the cyclooxygenase (COX) activity and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) ketorolac tromethamine (ketorolac) and bromfenac sodium (bromfenac).

Methods: Cyclooxygenase activity and selectivity was determined in vitro by measuring prostaglandin E₂ (PGE₂) production following incubation of varying concentrations of NSAID with human recombinant COX‐1 or COX‐2 and arachidonic acid. Anti-inflammatory effects were evaluated in a rabbit model in which an ocular inflammatory response was induced by intravenous injection of 10?µg/kg lipopolysaccharide (LPS). In study animals, one eye was treated with 50?µL (+/–) ketorolac 0.4% (Acular LS) or bromfenac 0.09% (Xibrom) and the other eye with 50?µL buffered saline. In control animals, both eyes were treated with vehicle. All animals were treated twice: 2 hours and 1 hour before LPS.

Main outcome measures: PGE₂ production in vitro, measured by enzyme immunoassay; fluorescein isothiocyanate (FITC)-dextran leakage into the anterior chamber, measured by fluorophotometry; aqueous PGE₂ levels in vivo, measured by ELISA immunoassay.

Results: Ketorolac was six times more active against COX‐1 (?IC₅₀ = 0.02?µM) than COX‐2 (?IC₅₀ = 0.12?µM) while bromfenac was ≈ 32 times more active against COX‐2 (?IC₅₀ = 0.0066?µM) than COX‐1 (?IC₅₀ = 0.210?µM). In the animal model, both drugs resulted in nearly complete inhibition of FITC-dextran leakage and PGE₂ production in the anterior chamber of treated eyes. There was also a 79% inhibition (?p < 0.001) of FITC-dextran leakage in the contralateral eyes of bromfenac-treated rabbits, and a 22.5% inhibition (not statistically significant) in the contralateral eyes of ketorolac-treated rabbits.

Conclusions: Ketorolac is relatively COX‐1 selective while bromfenac is potently selective for COX‐2 over COX‐1. In the animal model, both ketorolac 0.4% and bromfenac 0.09% demonstrated maximal anti-inflammatory activity in treated eyes. Only bromfenac 0.09% had a significant effect on the contralateral eye, suggesting possible systemic absorption of this drug.     

Anti-hyperalgesic and anti-inflammatory effects of Ketorolac Tromethamine gel using pulsed ultrasound in inflamed rats

The aim of this study was to determine if a Ketorolac Tromethamine (KT) gel solution could be administered in vivo via phonophoretic transdermal delivery using pulsed ultrasound by examining its anti-hyperalgesic and anti-inflammatory effects in a rat carrageenen inflammation model. 1% carrageenan was injected into the plantar surface of the right hindpaw of a rat, and anti-hyperalgesic and anti-inflammatory effects of KT via phonophoretic transdermal delivery were examined. The changes in the mechanical and thermal hyperalgesia, nociceptive flexor reflex (NFR), as well as the swelling changes were determined. According to the anti-hyperagesia and anti-inflammation tests, which were used to determine the change in the pain thresh-old, NFR and swelling showed that the group given the phonophoretic transdermal delivery of KT exhibited significantly more noticeable anti-hyperalgesic and anti-inflammatory effects than those treated with the simple application of a KT gel. The transdermal application of KT gel using phonophoresis had significant anti-hyperalgesic and anti-inflammatory effects. These findings suggest that the transdermal administration of a KT gel using phonophoresis using pulsed ultrasound might be useful for treating acute inflammation and pain.     

Development, characterization, and evaluation of ketorolac tromethamine-loaded biodegradable microspheres as a depot system for parenteral delivery

Ketorolac tromethamine, a potent nonnarcotic analgesic agent and 800 times more potent than aspirin, is indicated for the short-term management of moderate to such severe painful states as post operative pain, acute musculoskeletal pain, and dental pain. It Given every 6 hr intramuscularly in patients for acute pain, to avoid frequent dosing and patient inconvenience Ketorolac from ethamine was found suitable for parenteral depot system by biodegradable microspheres for the present study. Ketorolac tromethamine-loaded microspheres were prepared by o/w emulsion solvent evaporation technique using different polymers viz. polycaprolactone, poly-dl-lactide (Resomer) and poly lactic acid (PLA). To tailor the release profile of drug for several days, blends of Resomer and PLA were prepared with polycaprolactone in different ratios. Higher encapsulation efficiency was obtained with microspheres made with pure Resomer. Surface topography was studied by scanning electron microscopy, which showed spherical shape of microspheres. Residual solvent analysis was carried out to determine the residual amount of dichloromethane in microspheres and the content was found within permissible limits. Differential scanning calorimetric studies also were carried out to study any drug polymer interactions. We concluded that with careful selection of different polymers and their combinations, we can tailor the release of ketorolac tromethamine for long periods.     

An update on the use of ophthalmic ketorolac tromethamine 0.4%

Ketorolac tromethamine 0.4% ophthalmic solution, a recent reformulation of the original ketorolac tromethamine 0.5% solution, is indicated for the reduction of ocular pain and burning/stinging following cataract and refractive surgery. Studies have demonstrated that ketorolac tromethamine 0.4% has equivalent efficacy to ketorolac tromethamine 0.5% in reducing postsurgical inflammation and controlling pain. Several studies have demonstrated that, as well as reducing pain and ocular inflammation, ketorolac tromethamine 0.4% effectively treats cystoid macular oedema, inhibits miosis and may prevent cystoid macular oedema when used both pre- and postoperatively. Ketorolac tromethamine 0.4% is a versatile agent and is effective when used as either monotherapy or as an adjunct therapy to steroids.     

盐酸羟考酮注射液复合酮咯酸氨丁三醇用于剖宫产术后镇痛的临床观察

目的：观察盐酸羟考酮注射液复合酮咯酸氨丁三醇用于剖宫产术后镇痛的效果及安全性。方法选择腰?硬联合麻醉下剖宫产手术患者75例,ASAⅠ或Ⅱ级,随机均分为盐酸羟考酮组（ O组）,盐酸羟考酮复合酮咯酸氨丁三醇组（ OT组）,酮咯酸氨丁三醇组（T组）。术后镇痛泵配方为O组羟考酮1 mg／kg ＋托烷司琼5 mg;OT组羟考酮0．5 mg／kg＋酮咯酸氨丁三醇1．5 mg／kg＋托烷司琼5 mg;T组酮咯酸氨丁三醇3 mg／kg＋托烷司琼5 mg,三组均以生理盐水稀释至100 mL。观察术后6、12、24、48 h的切口痛VAS评分、宫缩痛评分及BCS评分;记录麻醉前、术后12、24、36 h血清P物质（ SP ）浓度;记录术后48 h内的不良反应,术后12、36 h的缩宫素使用量和子宫底高度。结果与T组比较,术后6、12、24 h O组和OT组的切口痛VAS评分和宫缩痛评分明显降低、BCS评分明显升高（P＜0．05）,术后12、24、36 h O组和OT组SP浓度明显降低（P＜0．05）,O组和OT组胃绞痛发生率明显降低（P＜0．05）。与术前比较,三组患者术后12、24、36 h的SP浓度均明显升高（P＜0．05）。结论盐酸羟考酮复合酮咯酸氨丁三醇用于剖宫产术后镇痛,镇痛效果好,不影响子宫复旧,不良反应少。     

Biodegradable microspheres of ketorolac tromethamine for parenteral administration

Ketorolac tromethamine loaded microspheres were prepared using two different polyesters, namely poly (lactic acid) and poly (glycolic acid) by solvent evaporation technique. The morphology of microspheres was analysed by scanning electron microscopy. In vitro release profiles of these microspheres were studied in phosphate buffered saline pH 7.4. The release kinetics of ketorolac tromethamine from the microspheres was evaluated by fitting the release data to the zero-order, Higuchi and korsemeyer-peppas equations. All microspheres showed initial burst release, followed by fickian diffusion of drug through microspheres. These microspheres were formulated as parenterals to have controlled release system.     

Study of thermo-sensitive in-situ gels for ocular delivery

The aim of the present study was the development of thermo-sensitive in-situ gels for in-vitro evaluation of ophthalmic delivery systems of ketorolac tromethamine (KT), based on methylcellulose (MC) in combination with hydroxypropylmethyl cellulose (HPMC). The gel temperature of 1% MC solution was observed at 60°C. It was found that 6% oral rehydration salt without dextrose (ORS) was capable to reduce the gel temperature below physiological temperature. HPMC was added to increase viscosity and drug release time. The results indicated a large increase in viscosity at 37°C with addition of HPMC whch provided sustained release of the drug over a 4h period. From in-vitro release studies, it could be concluded that the developed systems were thus a better alternative to conventional eye drops.     

Enhancement of 3-Hydroxy-3-methylglutaryl–Coenzyme A (HMG–CoA) Reductase Inhibitor Efficacy Through Administration of a Controlled-Porosity Osmotic Pump Dosage Form

An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the -hydroxyacid form of simvastatin, a potent HMG–CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and C _max that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG–CoA reductase inhibitors for the treatment of hy-percholesterolemia.     

Pharmacokinetics of single-dose oral and intramuscular ketorolac tromethamine in the young and elderly

The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti-inflammatory, antipyretic investigational drug with anti-prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open-label, parallel single-dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post-dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post-dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half-life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P less than .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half-life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biodegradable microspheres of ketorolac tromethamine for parenteral administration

Ketorolac tromethamine loaded microspheres were prepared using two different polyesters, namely poly (lactic acid) and poly (glycolic acid) by solvent evaporation technique. The morphology of microspheres was analysed by scanning electron microscopy. In vitro release profiles of these microspheres were studied in phosphate buffered saline pH 7.4. The release kinetics of ketorolac tromethamine from the microspheres was evaluated by fitting the release data to the zero-order, Higuchi and korsemeyer-peppas equations. All microspheres showed initial burst release, followed by fickian diffusion of drug through microspheres. These microspheres were formulated as parenterals to have controlled release system.