Development of controlled release dexketoprofen tablets and prediction of drug release using Artificial Neural Network (ANN) modelling

Dexketoprofen trometamol (DT) is an active S (+) enantiomer of ketoprofen, and a non-steroidal anti-inflammatory agent. DT has a short biological half-life and the dosing interval is quite short when there is a need to maintain the desirable effect for longer time periods. Consequently, a controlled release DT tablet was designed for oral administration aiming to minimize the number of doses and the possible side effects. Calculations of the parameters for controlled release DT tablets were shown clearly. Controlled release matrix-type tablet formulations were prepared using hydroxypropyl methylcellulose (HPMC) (low and high viscosity), Eudragit RS and Carbopol, and the effects of different polymers on DT release from the tablet formulations were investigated. The dissolution rate profiles were compared and analyzed kinetically. An Artificial Neural Network (ANN) model was developed to predict drug release and a successful model was obtained. Subsequently, an optimum formulation was selected and evaluated in terms of its analgesic and anti-inflammatory activity. Although the developed controlled release tablets did not have an initial dose, they were found to be as effective as commercially available tablets on the market. Dissolution and in vivo studies have shown that the prepared tablets were able to release DT for longer time periods, making the tablets more effective, convenient and more tolerable.

Effectiveness and safety of continuous ultrasound-guided femoral nerve block versus epidural analgesia after total knee arthroplasty. / Eficacia y seguridad del bloqueo femoral continuo guiado con ecografía frente a la analgesia epidural en el postoperatorio de artroplastia total de rodilla.

OBJECTIVES: Total knee arthroplasty is associated with severe postoperative pain. The aim of this study was to compare continuous ultrasound-guided femoral nerve block with continuous epidural analgesia, both with low concentrations of local anaesthetic after total knee arthroplasty. MATERIAL AND METHODS: A prospective, randomised, unblinded study of 60 patients undergoing total knee replacement, randomised into two groups. A total of 30 patients received continuous epidural block, while the other 30 received continuous ultrasound-guided femoral nerve block, as well as using 0.125% levobupivacaine infusion in both groups. Differences in pain control, undesirable effects, and complications between the two techniques were assessed, as well as the need for opioid rescue and the level of satisfaction with the treatment received during the first 48hours after surgery. RESULTS: No differences were found in demographic and surgical variables. The quality of analgesia was similar in both groups, although in the first six hours after surgery, patients in the epidural group had less pain both at rest and with movement (P=.007 and P=.011). This difference was not observed at 24hours (P=.084 and P=.942). Pain control at rest in the femoral block group was better at 48hours after surgery than in the epidural group (P=.009). The mean consumption of morphine and level of satisfaction were similar. Epidural analgesia showed the highest rate of side effects (P=.003). CONCLUSIONS: Continuous ultrasound-guided femoral nerve block provides analgesia and morphine consumption similar to epidural analgesia, with the same level of satisfaction, but with a lower rate of side effects after total knee arthroplasty.

A Dose-Finding Study of Dexketoprofen in Patients Undergoing Laparoscopic Cholecystectomy: A Randomized Clinical Trial on Effects on the Analgesic Concentration of Oxycodone.

BACKGROUND: Dexketoprofen has been shown to provide efficient analgesia and an opioid-sparing effect after orthopedic surgery. In this dose-finding study, we evaluated the analgesic efficacy and opioid-sparing effect of dexketoprofen administered intravenously (i.v.) after laparoscopic cholecystectomy (LCC). METHODS: Twenty-four patients undergoing LCC were randomized to receive dexketoprofen 10 or 50 mg i.v. 15 min before the end of the surgery. Subjects were provided with 0.2 mg/kg of oxycodone at anesthesia induction. In the recovery room, pain was assessed with an 11-point numerical rating scale (NRS; score of 0 = no pain, score of 10 = most severe pain) every 10 min. When the NRS score was ≥3/10 at rest or ≥5/10 at wound compression, a plasma sample was taken for analysis of oxycodone [to determine the minimum effective concentration (MEC)], its metabolites, and dexketoprofen. After that, subjects were titrated with oxycodone 2 or 3 mg i.v. every 10 min until the NRS score was <3/10 at rest and <5/10 at wound compression. At this point, a second plasma sample was taken for analysis of oxycodone [minimum effective analgesic concentration (MEAC)], its metabolites, and dexketoprofen. RESULTS: At the onset of pain, the plasma oxycodone concentrations (MEC) were similar in the two groups: median 60 ng/mL (range 37-73) in the 10 mg group and median 52 ng/mL (range 24-79) in the 50 mg group. At the time of pain relief, the MEACs were 98 ng/mL (range 59-150) in the 10 mg group and 80 ng/mL (range 45-128) in the 50 mg group. The total doses of oxycodone needed to achieve pain relief were similar: 0.11 mg/kg (range 0-0.33) in the 10 mg group and 0.08 mg/kg (range 0-0.24) in the 50 mg group. Eleven subjects developed mild desaturation or a decreased respiratory rate after oxycodone titration. CONCLUSION: In the present double-blinded, randomized clinical trial, the need for a rescue opioid analgesic, oxycodone, was similar with the two dose levels of dexketoprofen-10 and 50 mg i.v.-after LCC.

Intravenous dexketoprofen induces less injection pain than racemic ketoprofen.

WHAT IS KNOWN AND OBJECTIVE: Ketoprofen has high analgesic efficacy against inflammatory and nociceptive pain. Additionally, when ketoprofen is administered in conjunction with an opioid during pain management, it prevents the development of opioid-induced hyperalgesia. The main limitation for racemic ketoprofen IV administration is venous irritation. Dexketoprofen is the active enantiomer of racemic ketoprofen and has a similar analgesic efficacy in a dose proportion of 1 : 2, but it causes fewer adverse effects than racemic ketoprofen. It has been claimed that dexketoprofen may cause less frequent and less severe injection pain than racemic ketoprofen. In this study, we compared the injection pain of IV administered racemic ketoprofen and dexketoprofen in elective surgical patients. METHODS: The ethics committee of our institution approved this randomized, double-blinded, two-treatment, two-period, crossover clinical comparison of ketoprofen and dexketoprofen. A total of 221 ASA I-III adult patients, aged 20-75 years, were initially IV administered either 0·5 mg/kg racemic ketoprofen followed 2 h later with 0·25 mg/kg dexketoprofen (group 1) or vice versa (group 2). Both compounds were diluted in 20 mL of normal saline and were injected over 6 min. Patients reported injection pain on an 11-point numerical rating scale (NRS) (0 = no pain, 10 = most pain). RESULTS AND DISCUSSION: Significantly less injection pain was reported after dexketoprofen administration. A total of 201 of 209 patients reported pain during racemic ketoprofen injection, and 157 of 210 patients reported pain during dexketoprofen injection, respectively. Moderate or severe pain was reported by 90 (41%) patients during racemic ketoprofen administration and by 43 (20%) during dexketoprofen injection (P = 0·001). The mean of injection pain during racemic ketoprofen injection was 4·2 (SD 2·5) and was 2·5 (2·4) during dexketoprofen injection (P = 0·001). No serious or unexpected adverse events were reported. WHAT IS NEW AND CONCLUSION: Dexketoprofen causes significantly less injection pain than racemic ketoprofen; therefore, it may be a more suitable IV non-steroidal anti-inflammatory than the racemate.

Esophagitis due to dexketoprofen trometamol: a rare case report.

Various drugs are known to cause pill esophagitis. Antimicrobial drugs and nonsteroidal anti-inflammatory drugs are the most common causes of pill-induced esophagitis. Most patients suffer only self-limiting pain, but serious complications can occur. A 21-year-old man was admitted to our outpatient clinic with retrosternal chest pain, dysphagia, and odynophagia complaints, which occurred within 2 weeks after starting dexketoprofen trometamol. An upper endoscopy system examination revealed three well-demarcated ulcers in the esophagus at 35 cm from the incisors. Dexketoprofen trometamol may cause esophageal lesions. This rare disorder should be considered in patients presenting with sudden-onset retrosternal pain in addition to dysphagia and odynophagia.

Comparison of the efficacy and safety of intravenously administered dexketoprofen trometamol and ketoprofen in the management of pain after orthopaedic surgery: A multicentre, double-blind, randomised, parallel-group clinical trial.

OBJECTIVE: This study aimed to evaluate the analgesic efficacy and tolerability of dexketoprofen trometamol, a nonsteroidal anti-inflammatory drug, in comparison with that of racemic ketoprofen (both administered by intravenous infusion), in patients with postoperative pain. METHODS: This was a multicentre, randomised, double-blind, parallel-group study. 252 patients with moderate to severe pain following hip or knee replacement surgery performed under general anaesthesia were randomly assigned to receive either dexketoprofen trometamol 50 mg or ketoprofen 100 mg, both administered by intravenous infusion every 8 hours over 2 days. A level of > or =40 mm on a 100 mm visual analogue scale (VAS) for pain was required for inclusion in the study. Pain intensity on the VAS at different time-points after the administration of the first dose was assessed and the sum of pain intensity differences (SAPID(0-8 h)) was calculated as the primary efficacy variable. The use of rescue medication, maximum pain intensity difference (PID(max)), time to PID(max) and safety were also evaluated. RESULTS: The mean (+/- SE) adjusted SAPID(0-8 h) scores in the per-protocol population were 310.9 +/- 19.2 and 326.3 +/- 19.0 mm x h after dexketoprofen trometamol and ketoprofen treatment, respectively. The 95% CI for the difference between treatments (-59.1 to 28.3) was fully included within the range of equivalence of +/-65.3 mm x h. There were no significant differences with regard to secondary variables. The need for rescue analgesia was high in both groups; 81.3% of patients receiving dexketoprofen trometamol treatment and 87.1% receiving ketoprofen treatment required rescue analgesia. The time to achieve PID(max) was 284.7 and 308.5 min after dexketoprofen and ketoprofen, respectively. Treatment- related adverse events were experienced by 16% of patients in the dexketoprofen trometamol group compared with 21.3% in the ketoprofen group. Most patients were concomitantly treated with low-molecular-weight heparin (94.4%), and no haemorrhagic events related to the surgical procedure were reported. No adverse events related to renal function were detected during the study. CONCLUSION: The two medications were equivalent in terms of analgesic activity in the management of postoperative pain after orthopaedic surgery. The high use of rescue analgesics indicates a need for a multimodal approach to analgesia in this type of surgery. Dexketoprofen trometamol appeared to show a trend towards a better tolerability profile compared with the racemic compound.

Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain.

The analgesic efficacy and safety of dexketoprofen trometamol (the active enantiomer of the racemic compound ketoprofen) (25mg q.i.d.) vs. ketorolac (10mg q.i.d.) was assessed in 115 patients with bone cancer pain included in a multicenter, randomized, double-blind, parallel group study. A level of >/=40 mm on the 100 mm visual analog scale (VAS) and >/=10 in the pain rating index were required for inclusion. At the end of treatment on day 7 (+1 day), mean values of VAS were 32+/-24 mm for dexketoprofen and 40+/-30 mm for ketorolac (P=0.12) but the pain rating index was significantly lower in patients given dexketoprofen (8.5+/-2.3 vs. 9.7+/-2.9, P=0.04). Moreover, most of the patients reached a pain intensity difference from baseline >/=20 mm (75% of patients for dexketoprofen and 65% of patients for ketorolac). Around half of patients in both treatments had a pain intensity <30 mm on VAS at the end of treatment (55% for dexketoprofen and 47% for ketorolac). In the overall assessment of efficacy, a higher percentage of both patients and physicians rated dexketoprofen as 'quite effective' or 'very effective' compared to ketorolac. The percentage of patients withdrawn from the study for any reason as well as for insufficient therapeutic effect or due to adverse events was lower in the dexketoprofen group than in the ketorolac group. Treatment-related adverse events occurred in 16% of patients given dexketoprofen and in 24% given ketorolac. Serious adverse events occurred in 3.5% of patients from both groups but only one case of gastrointestinal hemorrhage was considered related to ketorolac. We conclude that dexketoprofen trometamol 25 mg q.i.d. oral route is a good analgesic therapy in the treatment of bone cancer pain, comparable to ketorolac 10 mg q.i.d., with a good tolerability profile.

The role of ketorolac in decreasing length of stay and narcotic complications in the postoperative pediatric orthopaedic patient.

The control of postoperative pain in the pediatric orthopaedic patient is a challenging endeavor. Several studies have shown the efficacy of ketorolac tromethamine in the pediatric general surgical population, but its efficacy in the pediatric orthopaedic population remains unproven. Twenty-seven consecutive patients (age 6 months to 18 years) who underwent long-bone osteotomies or foot procedures by a group of three pediatric orthopaedic surgeons were given a ketorolac protocol (1 mg/kg loading, 0.5 mg/kg every 6 h for 24 h). Breakthrough pain was managed with morphine until the patient was able to take oral pain medication, as was any pain after the 24-h period for ketorolac expired. Thirty-seven age- and case-matched patients were used as retrospective controls. The patients in the study who received ketorolac required significantly fewer doses of morphine than did the control group (2.29 +/- 3.98 vs. 10.02 +/- 3.39; p < 0.05). In addition the patients on the ketorolac protocol experienced fewer gastrointestinal side effects (4% vs. 32%; p < 0.05). Finally, the patients in the ketorolac group had a significantly shorter length of stay (3.63 +/- 1.64 days vs. 4.74 +/- 1.76 days; p < 0.05). There were no bleeding complications in either group. Ketorolac is thus a safe and effective means of controlling postoperative pain in the pediatric orthopaedic population while avoiding the troubling maleffects seen with the exclusive use of morphine.

Postoperative hemorrhage after tonsillectomy: use of ketorolac tromethamine.

Recent reports have associated an increased incidence of bleeding after tonsillectomy with the perioperative use of ketorolac tromethamine. To review this association, we examined the hospital and office records of 310 pediatric patients who underwent tonsillectomy with or without adenoidectomy at our institution during a 2-year period. Of these patients, 213 received ketorolac administered as a single dose at the conclusion of the procedure. The remaining 97 patients did not receive ketorolac. The frequency of postoperative hemorrhage was not found to differ significantly between these 2 groups (2.3% vs. 3.1% respectively, P = 0.71). Furthermore, the average time to discharge after surgery was significantly shorter in those patients who received ketorolac than in those who did not (8.5 hours vs. 12.5 hours, respectively, P < 0.0001). The frequency of overnight hospital stays was also significantly lower in those patients who received ketorolac (16.0% vs. 31.6%, respectively, P < 0.01). Concern over the potential for increased hemorrhage after tonsillectomy has led several authors to caution against the use of ketorolac in this setting. In our study, however, the use of ketorolac was not found to increase the incidence of posttonsillectomy hemorrhage and furthermore was associated with a significant decrease in the length of hospital stay as well as a decreased likelihood of overnight hospital stay after surgery.

Efficacy and safety of nonpreserved ketorolac ophthalmic solution in postoperative ocular pain following radial keratotomy.

PURPOSE: To investigate the efficacy and safety of nonpreserved ketorolac tromethamine 0.5% ophthalmic solution in relieving pain following radial keratotomy (RK). SETTING: Multicenter clinical trial. METHODS: Topical ketorolac was compared with its vehicle in a double-masked, randomized, parallel-group study involving 170 RK patients. Patients were treated with nonpreserved ketorolac 0.5% ophthalmic solution or the vehicle 4 times daily beginning immediately after surgery and continuing for 3 days or until they no longer had ocular pain. RESULTS: At several intervals, patients treated with ketorolac reported significantly greater pain relief and less pain intensity than patients treated with the vehicle. The time required for patients to first report "complete relief" or "no pain" was shorter in the ketorolac than in the vehicle group (P < or = .006). Patients in the ketorolac group used less escape medication (acetaminophen) (P < or = .001) and had fewer sleep difficulties (P < or = .031), fewer symptoms of ocular discomfort (P < or = .028), and less difficulty performing activities of daily living (P = .048). Patients treated with ketorolac experienced the same low rate of treatment-related adverse events as those treated with the vehicle and exhibited the same improvement in visual acuity and manifest refraction. CONCLUSIONS: Nonpreserved ketorolac tromethamine 0.5% ophthalmic solution was significantly more effective than, and as safe as, the vehicle in alleviating the postoperative pain associated with RK. This resulted in significant improvements in patient quality of life and less need for oral analgesics, suggesting that topical ketorolac is an appropriate treatment option for ocular pain following RK.

Comparative effects of ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions on inflammation after cataract surgery.

OBJECTIVE: Ketorolac tromethamine 0.5% and diclofenac sodium 0.1% ophthalmic solutions are approved for use by the U.S. Food and Drug Administration to avoid excessive postoperative inflammation after cataract surgery and implantation of an intraocular lens. This study compares the efficacy and toxicity of these nonsteroidal anti-inflammatory drugs for the first time. DESIGN: Randomized, double-masked, prospective clinical trial. PARTICIPANTS: A total of 120 patients assigned in equal numbers to 1 of the 2 treatment regimens. INTERVENTION: Treatment with either ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions instilled four times daily for 30 days beginning the first postoperative day after surgery. MAIN OUTCOME MEASURES: Objective (Kowa FC 1000 laser cell and flare meter) and subjective (slit-lamp biomicroscope) measurements of inflammation and toxicity were made and compared at three separate post-operative visits. RESULTS: The anti-inflammatory effects of the two treatment regimens were not statistically different at any of the postoperative visits. Patients tolerated both treatments equally well. CONCLUSIONS: This study shows diclofenac sodium 0.1% and ketorolac tromethamine 0.5% ophthalmic solutions are equally effective and safe for the control of postoperative inflammation after uncomplicated cataract surgery performed by phacoemulsification followed by the implantation of a foldable intraocular lens.

Analgesic efficacy and safety of nonpreserved ketorolac tromethamine ophthalmic solution following radial keratotomy. Ketorolac Radial Keratotomy Study Group.

PURPOSE: To compare the analgesic efficacy and safety of nonpreserved ketorolac tromethamine 0.5% with those of its vehicle in the treatment of postsurgical ocular pain following radial keratotomy. METHODS: This study employed a multicenter, double-masked, randomized, parallel-group design. Radial keratotomy patients were treated with either nonpreserved ketorolac tromethamine 0.5% or its vehicle four times daily for up to 3 days following surgery. Patients were provided with an escape medication (acetaminophen) for use only as needed for intolerable pain. RESULTS: Patients treated with ketorolac reported significantly greater pain relief (P < or =.023), less pain intensity (P < or =.047), less use of escape medication (P < or =.001), fewer symptoms of ocular discomfort (P=.024), and fewer sleep disturbances (P < or =.013) than did patients treated with vehicle. No treatment-related adverse events were reported in the ketorolac group, and only one treatment-related adverse event was reported in the vehicle group. Most other safety findings were equivalent in the two treatment groups except that there were significantly less eyelid erythema (P=.026) and eyelid edema (P < or =.001) in the ketorolac group. CONCLUSIONS: Nonpreserved ketorolac tromethamine 0.5% ophthalmic solution was significantly more effective than, and as safe as, vehicle in the treatment of postoperative pain associated with radial keratotomy. Therefore, topical ketorolac may be a valuable treatment option for the maintenance of patient comfort following refractive surgery.

Topical 0.5% ketorolac vs 0.03% flurbiprofen for inhibition of miosis during cataract surgery.

OBJECTIVE: To compare the effects of topical 0.5% ketorolac tromethamine ophthalmic solution (Acular, Allergen Pharmaceuticals, Irvine, Calif) with topical 0.03% flurbiprofen sodium ophthalmic solution (Ocufen, Allergen Pharmaceuticals) on the inhibition of surgically induced miosis during phacoemulsification cataract surgery. DESIGN: One hundred eighteen patients were prospectively randomized to receive 0.5% topical ketorolac or 0.03% topical flurbiprofen at 3 preoperative intervals. The flurbiprofen-treated group served as the control group. The surgeon was masked as to patient selection. Horizontal pupillary diameter measurements were obtained at the start of surgery, just before phacoemulsification, before lens implantation, and after lens implantation. RESULTS: Mean horizontal pupillary diameter measurements for both medications were similar at the start of surgery. However, a consistent trend of larger pupillary diameter was seen in all subsequent surgical intervals in the ketorolac-treated group. Changes from baseline measurements also indicated a more significant inhibition of miosis at all subsequent intervals, and a more stable mydriasis throughout the procedure in the ketorolac-treated group. CONCLUSIONS: Topical ketorolac is an effective inhibitor of miosis during phacoemulsification cataract surgery, and provides a more stable mydriatic effect throughout the surgical procedure.

Ketorolac tromethamine and hemorrhage in tonsillectomy: a prospective, randomized, double-blind study.

Ketorolac tromethamine (KT) is a nonsteroidal, antiinflammatory analgesic. Its nonsedating property makes it an attractive analgesic for sleep apnea patients undergoing uvulopharyngopalatoplasty, but its antiplatelet activity makes the potential for postoperative hemorrhage a concern. A prospective, randomized, double-blind study was designed to evaluate the bleeding risk of KT using adult tonsillectomy patients as the model. Patients were randomized into two groups receiving Meperidine (MP) (controls) or KT for the first postoperative day. Posttonsillectomy bleeding rates of 7% (3/43) in the MP group and 18.9% (7/37) in the KT group were demonstrated, but this difference was not statistically significant. The number of KT doses administered had no effect on the incidence of bleeding or the number of cases requiring return to the operative suite for hemostasis. Although this study did not attain statistical significance, the trend towards increased hemorrhage with KT is worrisome. This study and other reports in the literature support the manufacturer's warning that the use of KT is contraindicated in major surgery.

[Methods of the use of ketorolac tromethamine in patients during the early postoperative period]. / Metody primeneniia ketorolaka trometamina u bol'nykh v rannem posleoperatsionnom periode.

Analgesia with nonsteroid antiinflammatory drugs (NSAID) becomes a pressing problem today. One such drug is ketorolak tromethamine (KT), characterized by expressed analgesic activity comparable with that of opioid analgesics morphine or promedol. Our purpose was to assess KT efficacy in analgesia performed by different methods, including analgesia controlled by the patient (ACP) after surgery. In medium severe and strong pain KT was used in group I (n = 60) "as needed" in a dose of 30 mg up to 3-4 times a day, in group 2 (n = 12) by the ACP method, in group 3 (n = 16) KT was incessantly infused in a daily dose of up to 120 mg, and in group 4 (n = 11) KT was injected 3-4 times a day in a dose of 30 mg in combination with morphine ACP. The results indicate a high efficacy of KT: 83% after a single injection. Combined use of KT and promedol decreased the dose by 40-50%. Side effects were observed in 15% of patients: most often it was a sense of fever and sweating (in 4% of patients), nausea and vomiting (in 2%), insomnia (in 2%). ACP and planned injections in a daily dose of 90-120 mg is the optimal method of analgesia in patients after extensive surgical interventions.