AimsThe study was designed to evaluate the relative bioavailability of diclofenac in plasma, subcutaneous adipose and skeletal muscle tissue after repeated topical administration using MIKA Diclofenac Spray Gel (4%), a novel formulation, and after oral dosing using VOLTAREN " 50 mg enteric coated tablets. MethodsDiclofenac (48 mg) was administered topically three times daily for 3 days onto a defined area of the thigh of 12 healthy males. After a 14-day wash out period, subjects were orally treated with 50 mg diclofenac three times daily for 3 days. In vivo microdialysis in subcutaneous and muscle tissues was per formed immediately after the final doses from both treatments on day 4, and 48 h later. Plasma samples were taken simultaneously. ResultsThe relative bioavailability of diclofenac in subcutaneous adipose and skeletal muscle tissue was substantially higher after topical compared with oral dosing (324% and 209%, respectively) whereas relative plasma bioavailability was 50-fold lower. Plasma C max values were approximately 250-fold lower after topical compared with oral drug administration (i.e. median values = 4.89 ng mL -1 ; 95% CI: 3.37-7.68 and 1240 ng mL -1 ; 95% CI: 787-1389 ng mL -1 ). Both treatments were well tolerated. ConclusionsOwing to its favourable penetration characteristics and low systemic availability, MIKA Diclofenac Spray Gel 4% is a rational alternative to oral diclofenac formulations for the treatment of inflammatory soft tissue conditions.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Therapy with topical non‐steroidal anti‐inflammatory drugs (NSAIDs) relies on the ability of the active drug to penetrate the skin in sufficiently high amounts to exert a clinical effect, which is linked to the specific galenic properties of the formulation. WHAT THIS STUDY ADDS • This phase 1 study characterizes the transdermal penetration and plasma exposure of different dose levels with galenic differences of a novel topical diclofenac formulation under development and indicates greater diclofenac penetration through the skin when compared with a commercially available formulation. AIMS To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid‐based delivery system under development (DCF100C). METHODS This was a single‐centre, open‐label, three‐period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren® Emulgel® gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4. RESULTS All four DCF100C formulations demonstrated a three‐ to fivefold, dose‐dependent increase in systemic diclofenac availability compared with Voltaren® Emulgel® and were approximately 30–40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren® Emulgel® (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation. CONCLUSION DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development.
1. The swimming activity of 6 specimens of the Pachon cave form of Astyanax mexicanus was tested with regard to its time control under various light-dark(LD)cycles and constant conditions, and it is compared to that of a river form. 2. In general, activity is entrainable by all applied LDs, but even if the amplitude of a forcing signal increases the signal energies are lower than in the river fish. 3. In case of entrainment the maximum values of surface activity correspond to the dark phases, those of bottom activity to the light phases of a LD. Flexible patterns -as often observed in the river form in the range of resonance about 24 h - are very seldom. Furthermore, disturbances of ten occur in the entrainment of one activity form, or one form runs arrhythmic while the other is still entrained. 4. The activity answers to changing environmental conditions are not as uniformly quick as in the river fish. But the system hardly needs a swing-in time to become entrained when a LD starts. 5. After transition from LD to DD (= constant darkness) the entrained rhythms disappear immediately. 6. In no LD with a period length differing from 24 h a circadian rhythm can be observed in addition to the entrained frequency. 7. These results show that the passive system of the river form has developped into an extremely passive one being unable to oscillate and thus has become simplified during regressive evolution. Concerning the circadian oscillator of the epigean ancestor, it was also subjected to regression, but it has not been completely lost. After a LD with a period length about 24 h the circadian oscillator is able to act as a stable system, clearly shown by the freerunning circadian rhythms of surface activity. But out of this range the oscillator is unable to control activity. In DD after all other LDs activity patterns are arrhythmic.
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