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Manvelian G.,Iroko Pharmaceuticals | Daniels S.,Premier Research Group International LLC | Gibofsky A.,Hospital for Special Surgery
Pain Medicine (United States) | Year: 2012

Background. Safety concerns associated with nonsteroidal anti-inflammatory drugs (NSAIDs) have prompted the development of new formulations that minimize adverse events (AEs) and maintain efficacy. Objectives. To determine the analgesic efficacy and safety of an investigational, proprietary, nano-formulated, oral diclofenac (nano-formulated diclofenac) compared with placebo in subjects with acute dental pain. Methods. A Phase 2, multisite, randomized, double-blind, single-dose, parallel-group, active- and placebo-controlled study was carried out in 202 subjects (18-50 years old) who had extraction of ≥2 third molars (≥1 had to be a fully or partially impacted mandibular third molar) and experienced moderate to severe pain intensity ≤6 hours postsurgery (NCT00985439). Subjects received nano-formulated diclofenac 35mg or 18mg, celecoxib 400mg, or placebo. The primary efficacy variable was the sum of total pain relief (TOTPAR) over 0-12 hours (TOTPAR-12) after Time 0. Secondary end points included TOTPAR over 0-4 hours (TOTPAR-4), TOTPAR over 0-8 hours (TOTPAR-8), and time to onset of analgesia. Results. Mean±standard deviation TOTPAR-12 for nano-formulated diclofenac 35mg and 18mg, celecoxib, and placebo were 16.81±12.76, 17.76±13.76, 14.61±15.05, and 5.65±11.53, respectively (P<0.001, nano-formulated diclofenac compared with placebo). Similar improvements were observed for TOTPAR-4, TOTPAR-8, mean time to first perceptible pain relief (P<0.001), and peak relief (P<0.05). Celecoxib treatment was not statistically different than placebo for these latter two parameters. Treatment-emergent AEs were similar across all treatment groups. Conclusions. Lower dose, nano-formulated diclofenac demonstrated good overall efficacy, prompt pain relief, and was well tolerated. These data suggest lower dose nano-formulated NSAIDs could be effective for acute pain and may potentially improve safety and tolerability as a result of using a lower overall dose. © 2012 American Academy of Pain Medicine. Source


Manvelian G.,Iroko Pharmaceuticals | Daniels S.,Premier Research Group International LLC | Altman R.,University of California at Los Angeles
Postgraduate Medicine | Year: 2012

Background: Safety and tolerability concerns associated with nonsteroidal anti-inflammatory drugs (NSAIDs) have prompted the development of lower-dose formulations. This phase 1 clinical study characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano-formulated, lower-dose oral indomethacin (nano-formulated indomethacin) compared with standard oral indomethacin in healthy subjects. Methods: Forty healthy subjects were enrolled in a single-dose, randomized, 5-period, 5-treatment crossover study. Subjects received nano-formulated indomethacin 20 mg (fasted), or nano-formulated indomethacin 40 mg or standard indomethacin 50 mg (fed and fasted). Pharmacokinetic parameters, including maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), elimination half-life (T1/2), and area under the concentration-time (AUC) curve, along with safety and tolerability, were assessed. Results: There was a more rapid mean (± standard deviation) Tmax for nano-formulated indomethacin 20 mg (1.11 ± 0.55 h) and 40 mg (1.25 ± 0.60 h) compared with indomethacin 50 mg (1.97 ± 0.81 h) under fasting conditions, demonstrating faster absorption for the nano-formulated indomethacin. The T1/2 was similar for nano-formulated indomethacin 40 mg and indomethacin 50 mg. The Cmax for nano-formulated indomethacin 40 mg was higher compared with indomethacin 50 mg in fasted subjects (3115 ± 900 ng/mL vs 2759 ± 936 ng/mL, respectively), and slightly lower in fed subjects (1360 ± 424 ng/mL vs 1408 ± 469 ng/mL, respectively). There was a 26% reduction in drug exposure (AUC0-∞) when subjects received nano-formulated indomethacin 40 mg compared with indomethacin 50 mg under fasting conditions (6861 ± 1585 h*ng/mL vs 9306 ± 2234 h*ng/mL, respectively). Safety and tolerability were comparable between formulations. Conclusion: The nano-formulated, lower-dose indomethacin had an improved PK profile compared with indomethacin. Under the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may support use of lower-dose NSAID formulations that improve safety/tolerability while maintaining pain relief similar to standard NSAID formulations. © Postgraduate Medicine. Source


Altman R.,University of California at Los Angeles | Bosch B.,iCeutica | Brune K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Patrignani P.,University of Chieti Pescara | Young C.,Iroko Pharmaceuticals
Drugs | Year: 2015

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility. © 2015 The Author(s). Source


Manvelian G.,Iroko Pharmaceuticals | Daniels S.,Premier Research Group International LLC | Gibofsky A.,Cornell University
Postgraduate Medicine | Year: 2012

Introduction: There is a clinical need for new nonsteroidal anti-inflammatory drugs (NSAIDs) and/or new formulations that, at minimum, retain the established efficacy of standard NSAIDs while minimizing their associated adverse events. This phase 1 clinical trial characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano-formulated, lower-dose oral diclofenac (nano-formulated diclofenac) compared with oral diclofenac in healthy subjects. Methods: A single-center, single-dose, randomized, open-label, 5-period, 5-treatment, 10-sequence crossover study was completed in 30 healthy subjects. Subjects received either nano-formulated diclofenac 18 mg or 35 mg or diclofenac 50 mg in fed and fasting states. The maximum measured plasma concentration (C max), time to maximum measured concentration (T max), terminal elimination half-life (T 1/2), and area under the concentration time curve (AUC), along with safety and tolerability, were assessed. Results: Mean (±standard deviation) T max for nano-formulated diclofenac 18 (0.62±0.35 h) and 35mg (0.59±0.20 h) demonstrated faster absorption than diclofenac 50mg (0.80±0.50 h). The T 1/2 was similar between nano-formulated diclofenac 35 mg and diclofenac 50 mg (1.85 ±0.45 h vs 1.92±0.38 h, respectively). The C max for nano-formulated diclofenac 35mg and diclofenac 50mg was comparable in fasted subjects (1347±764ng/mL vs 1316±577ng/ mL, respectively), but lower in fed subjects (524±222ng/mL vs 951±391ng/mL, respectively). As anticipated, there was a 19% reduction in drug exposure (AUC 0-∞) when subjects received nano-formulated diclofenac 35 mg compared with diclofenac 50 mg under fasting conditions (1225±322 h*ng/mL vs 1511±389 h*ng/mL, respectively). Safety and tolerability were comparable between nano-formulated diclofenac and diclofenac. Conclusion: The novel nano-formulated, lower-dose diclofenac demonstrated lower systemic exposure, comparable C max, and faster absorption compared with diclofenac. In light of the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may permit use of lower NSAID doses that improve safety and tolerability while, at minimum, relieving pain similar to standard formulations. © Postgraduate Medicine. Source


Gibofsky A.,Cornell University | Hochberg M.C.,University of Maryland, Baltimore | Jaros M.J.,Summit Analytical LLC | Young C.L.,Iroko Pharmaceuticals
Current Medical Research and Opinion | Year: 2014

Objective: NSAIDs, such as diclofenac, are the most commonly used medications to treat osteoarthritis (OA), but they are associated with dose-related adverse events (AEs). Low-dose submicron diclofenac was developed using a new, proprietary dry milling process that creates submicron drug particles (SoluMatrix Fine Particle Technology*), enabling effective treatment at lower doses than other commercially available diclofenac drug products. This phase 3 study evaluated the efficacy and safety of low-dose submicron diclofenac 35mg three times daily (tid) and twice daily (bid) in patients with OA pain. Research design and methods: This double-blind study enrolled patients ≥40 years of age with clinically and radiographically confirmed (Kellgren-Lawrence grade II-III) hip or knee OA. Eligible patients were chronic NSAID and/or acetaminophen (APAP) users with baseline Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain subscale scores ≥40mm by visual analog scale and an OA flare (≥15mm increase in WOMAC pain subscale score following discontinuation of NSAIDs/APAP at screening). Patients were randomized to submicron diclofenac 35mg tid, submicron diclofenac 35mg bid, or placebo for 12 weeks. ClinicalTrials.gov identifier: NCT01461369. Main outcome measures: Efficacy parameters included mean change from baseline in WOMAC pain subscale score at week 12 (primary efficacy parameter) and in average total WOMAC score over 12 weeks. Results: Submicron diclofenac 35mg tid significantly improved WOMAC pain subscale scores from baseline at 12 weeks (-44.1; p=0.0024) compared with placebo (-32.5). Submicron diclofenac 35mg bid provided numerical improvement in pain at week 12 that did not reach statistical significance (-39.0; p=0.0795) compared with placebo. Submicron diclofenac 35mg tid (-35.9; p=0.0002) and 35mg bid (-30.3; p=0.0363) improved the average total WOMAC score in treated patients over 12 weeks compared with placebo (-23.2). The most frequent AEs in the submicron diclofenac-treated groups were diarrhea, headache, nausea, and constipation. The inclusion of patients with a documented requirement for analgesic therapy (OA 'flare') at baseline and the high rates of rescue medication usage in the placebo group may have impacted the study outcome for the submicron diclofenac treatment groups. Conclusions: Low-dose submicron diclofenac is an effective therapeutic option for the treatment of OA pain. © 2014 Informa UK Ltd. Source

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