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DOI:10.1111/j.1365-2125.2005.02484.x Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation Martin Brunner,1 Pejman Dehghanyar,1 Bernd Seigfried,2 Wolfgang Martin,3 Georg Menke4 & Markus Müller1
1Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria; 2MIKA Pharma
GmbH, Limburgerhof, Germany;
3Pharmakin GmbH, Ulm, Germany; 4Biostatistician, Frankfurt/Main, Germany.
The 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.
Krankenhaus – AKH, Waehringer-Guertel 18–20, A-1090 Vienna, Diclofenac (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 weretaken simultaneously.
The 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. PlasmaCmax values were approximately 250-fold lower after topical compared with oraldrug administration (i.e. median values = 4.89 ng mL-1; 95% CI: 3.37–7.68 and1240 ng mL-1; 95% CI: 787–1389 ng mL-1). Both treatments were well tolerated.
Owing to its favourable penetration characteristics and low systemic availability, MIKA Accepted
Diclofenac Spray Gel 4% is a rational alternative to oral diclofenac formulations for the treatment of inflammatory soft tissue conditions.
care costs [1]. To increase the effect–risk ratio of NSAIDs, Nonsteroidal anti-inflammatory drugs (NSAIDs) are topical formulations have been developed [2, 3].
widely used throughout the world. Generally, they are The stratum corneum of the human skin, however, is well tolerated, but the occurrence of sometimes life- known to be an effective and selective barrier to drug threatening adverse events limits their use and results in permeation [4, 5]. Therefore, to improve local drug substantial morbidity, mortality and increasing health delivery to deeper tissue layers, penetration enhancers and novel drug vehicles have been designed [6].
brown glass bottles containing 1 g diclofenac sodium in Recently, a new topical pharmaceutical form of 25 g of solution. The bottles were fitted with a mechan- diclofenac sodium, i.e. MIKA Diclofenac Spray Gel ical pump spray which delivered 8 mg diclofenac 4%, has been patented. The spray gel consists of water, isopropyl alcohol and propylene glycol as basic solvents VOLTAREN® 50 mg enteric coated tablets (Novartis and soy bean lecithin, ethanol, disodium phosphate Pharma AG, Basel, Switzerland), were obtained from dodecahydrate, sodium dihydrogen phosphate dihy- drate, peppermint oil and ascorbyl palmitate as excipi- Subjects received the topical drug first, followed by ents. Sprayed onto to the skin, the solution changes its the oral form, with a 14-day washout period between viscosity by evaporation of the alcoholic components them. A dose of 48 mg diclofenac sodium (i.e. six spray and forms a low-viscous gel sticking to the skin. Pene- actuations) was administered onto a shaved area of the tration of diclofenac into deeper skin layers has been thigh three times a day. Oral drug application was given demonstrated in vitro using the spray gel formulation at a dose of 50 mg three times a day at fixed time points [7]. Based on the physico-chemical characteristics of the irrespective of meals. In vivo microdialysis employing spray gel it was hypothesized that diclofenac tissue con- centrations after spray gel application would be compa- Microdialysis AB, Stockholm, Sweden) was performed rable if not higher than after administration of an after the administration of the 10th dose (on day 4 of each regimen) after an overnight fast. Microdialysates The present study was designed to compare the bio- and blood samples were collected every hour for 10 h availibility of diclofenac with respect to subcutaneous post dosing and again at 48 h after the last dose, as adipose and skeletal muscle tissue after repeated topical described previously [3]. Probes were calibrated in vivo and oral (VOLTAREN® 50 mg enteric coated tablet) at the end of each study day according to a no net flux administration of equivalent daily doses. Microdialysis, method [11]. All samples were stored at -80 ∞C prior to a minimally invasive technique for the measurement of unbound drug concentrations in target tissues was used.
Microdialysis is recognized by regulatory authorities as a potential tool for bioequivalence evaluation of topical All drug analyses were conducted according to GLP dermatological dosage forms [9, 10].
guidelines. Diclofenac concentrations in plasma andmicrodialysates were determined by a validated LC- Materials and methods
MS/MS method (Pharmakin SOP NMM_0037–0001, The study was approved by the local Ethics Committee Version 1). After thawing, either 100 mL plasma (sam- and was performed in accordance with the Declaration pled after oral diclofenac administration, diluted to of Helsinki and the Good Clinical Practice Guideline of 1 mL with blank plasma) or 1 mL plasma (sampled after the European Commission (EC-GCP guideline). Sub- topical diclofenac administration) were mixed with jects were given a detailed description of the study and 50 mL internal standard solution (containing 147 ng 6]-diclofenac). Acidification by addition of 500 L 0.1 M HCl was followed by extraction with 6 mL cyclo- hexane: tert. butylmethyl ether (1 : 2 (v/v)), centrifuga- An open, prospective, single-centre, nonrandomized, tion, recovery of the organic layer, evaporation to fixed sequence Phase I study was performed.
dryness with nitrogen and dissolution of the dry residuein 250 mL mobile phase. Forty microlitres of microdi- alysate was mixed with 40 mL internal standard solution 12 healthy male Caucasians were studied, with a mean age (±SD) of 27.8 ± 4.1 years (range: 23–39 years), a nol. After sample work-up, 50 mL of plasma extract or mean body height of 1.83 ± 0.06 m (range: 1.75– microdialysate were injected into the LC-MS/MS.Sep- 1.94 m), a mean body weight of 77.2 ± 6.5 kg (range: aration of the analyte was achieved on a 5-mm Purospher 67.8–88.4 kg), and a mean BMI of 23.0 ± 1.8 (range: RP18 column. Ammonium carbaminate solution 75 mM (adjusted to pH 4 by formic acid) was used as the mobilephase. Chromatography was performed in the isocratic Study medication and experimental design mode and at room temperature. The column eluent was MIKA Diclofenac Spray Gel 4%, was supplied by split and eluent at a flow of 100 mL min-1 was passed MIKA PHARMA GmbH (Limburgerhof, Germany) in into the electrospray ionization source of a Micromass Quattro II triple quadrupole mass spectrometer (Micro- expressed as a percentage (95% CI) in plasma was 2.23% mass, Altrincham, UK). The nebulizing gas (nitrogen) (1.55–3.20%; P < 0.0001) indicating oral diclofenac was flow was 25 L h-1 and the instrument was programmed about 50 times more systematically bioavailable than the for a scan dwell time of 500 ms. Diclofenac responses topical form. In contrast, the relative bioavailability ratio were measured in the positive ionization mode using was higher in subcutaneous and skeletal muscle tissue multiple reaction monitoring. Mass transitions of m/z (324% (232-453%) and 209% (130-337%), respec- 296 > 214 for protonated diclofenac and m/z 302 > 219 tively) after topical compared with oral drug adminis- for hexadeuterated diclofenac as internal standard were tration, respectively (P < 0.0001 and P = 0.006).
used to selectively monitor precursor ions and corre- After topical drug administration the mean bioavail- sponding product ions. The lower limit of quantification ability ratio between subcutaneous tissue and plasma of the assay was 0.15 ng mL-1. Within-day and between- was 78.1% (95% CI: 42.2–145%; P = 0.396), and that day precision was 2.2% and 3.7% at 0.20 ng mL-1, 1.3% between muscle tissue and plasma was 52.2% (95% CI: and 0.8% at 7.97 ng mL-1 and 0.4% and 0.4% at 37.4–72.8%; P = 0.001). After oral treatment the corre- sponding bioavailability ratios were two orders ofmagnitude lower (0.536% (95% CI: 0.426–0.675%) for the subcutaneous tissue/plasma ratio and 0.556% AUC• (identical with AUC0-8 in steady state), (95% CI: 0.429–0.720%) for the muscle tissue/plasma 0-8 and Cmax data were determined using a ratio (P 0.0001 for both ratios)).
noncompartmental approach (SYSTAT™, Version 10, No serious adverse events were reported. The spray SPSS Inc, Chicago, USA). Data were ln-transformed gel was well tolerated except for slight erythema in 3 of and relative diclofenac bioavailability ratios were deter- 12 subjects after the third treatment day, most probably mined by dividing AUC values after topical administra- due to shaving the area of drug application.
tion by those after oral dosing. Values for tissue/systemic circulation ratios were calculated from these Discussion
bioavailibility ratios. Results were compared by one Repetitive treatment with the new spray gel formulation sample t-tests, and the type I error was fixed at a = 0.05.
resulted in substantial dermal absorption of diclofenac.
Unbound interstitial diclofenac concentrations in tissue layers underneath the application site were about Figure 1 shows that plasma diclofenac concentrations 2.5 ng mL-1, and corresponding values for total concen- were higher following oral drug administration. AUC tration in plasma were about 4.1 ng mL-1. This is in and Cmax values are summarized in Table 1. The geomet- accordance with unbound diclofenac plasma concentra- ric mean steady state relative bioavailability ratio tions of approximately 0.004 ng mL-1, if a plasma pro- Mean concentration vs. time profiles of diclofenac in plasma (closed circles), subcutaneous adipose (open triangles) and skeletal muscle tissue (closed squares) after the final dose of a 3-day regimen of either MIKA Diclofenac Spray Gel 4% applied to the skin of the thigh (left panel) or with VOLTAREN® 50 mg enteric coated tablets given orally (right panel) in 12 healthy males. Results are presented as mean ± SE. Plasma (᭹), subcutaneous tissue (᭡), skeletal muscle tissue (᭿) Diclofenac concentration (ng/mL)
0 2 4 6 8 10 48
0 2 4 6 8 10 48
Time (hrs)
Time (hrs)
Table 1
Main pharmacokinetic parameters for diclofenac obtained in plasma (total drug) and subcutaneous and skeletal muscle tissue
(free drug) of the thigh in 12 healthy males after the final dose of a 3-day multiple dose regimen of either topical application
of MIKA Diclofenac Spray Gel 4% or oral administration of VOLTAREN® 50 mg enteric coated tablets
Plasma (n = 12)AUC∞, AUCt (ng h mL-1) Subcutaneous tissue (n = 12)AUC∞, AUCt (ng h mL-1) Skeletal muscle (n = 12)AUC∞, AUCt (ng h mL-1) AUC, AUCt [ng h mL-1], Area under the plasma or tissue concentration vs. time curve of diclofenac approximated to infinity(AUC) or evaluated in the last dosage interval (0–8 h; AUCt); Cmax [ng mL-1], Maximal plasma or tissue concentration. tein binding of 99.9% is assumed [12]. Consequently, penetration of drugs. In the present work, tissue concen- the present data indicate a steep tissue-to-plasma gradi- trations of diclofenac were far less variable following ent of about 1000 for unbound diclofenac, demonstrat- oral administration. The ‘double peaks’ in plasma seen ing substantial skin penetration from the present in the concentration vs. time profiles were also reflected formulation. The findings do not support the concept of in tissue, indicating a relatively low experimental vari- local plasma-to-tissue rediffusion as described for other ability as described for other analytes in microdialysis formulations of diclofenac [13]. Following oral admin- experiments [16], and suggesting that the variability istration, unbound diclofenac tissue concentrations were encountered after transdermal application is the true similar to those estimated for unbound drug in plasma.
Thus, for the oral formulation, the plasma-to-tissue gra- Maximal tissue concentrations following topical dos- dient of 1–2 indicates free plasma-to-tissue diffusion of ing showed relatively high interindividual variability.
Substantial variability in plasma concentrations (of up Based on clinical studies demonstrating the efficacy to 400%) was also observed in some subjects, which of oral diclofenac at a daily dose of 150 mg [14, 15], indicates that transdermal penetration into the systemic our data suggest an effective target site concentration of circulation can also be variable. Differences and changes 1.1 ng mL-1 for unbound diclofenac, and that effective over time in (1) local blood flow (2) release kinetics of concentrations equivalent or better than those obtained the drug from the stratum corneum (3) skin temperature from oral dosing are attained following spray gel admin- and (4) leg movements and subsequent changes in local istration. Whereas tissue concentrations after oral dos- blood flow [17, 18] may account for this variability.
ing gradually declined after the last dose, those after Following the topical drug administration, pharmaco- repetitive topical drug administration remained rela- kinetic parameters have been reported to vary by orders tively stable over time. Furthermore, after gel adminis- of magnitude, a number of factors being responsible for tration, the relative plasma bioavailability of diclofenac this, including differences in types of subjects, and sites was approximately 50-fold lower than after oral dosing.
of drug application [19–22]. A recent review on Because maximum diclofenac plasma concentrations diclofenac pharmacokinetics concluded that its topical following spray administration were only 0.4% of those delivery is largely dependent on the nature of the drug after the oral dose, systemic side-effects after topical and vehicle, as well as skin integrity and hydration administration should be negligible.
A consistent finding of in vivo transdermal studies is In conclusion, owing to its favourable penetration the considerable interindividual variability in the skin characteristics and low systemic availability, MIKA Diclofenac Spray Gel is a rational alternative to oral 12 Davies NM, Anderson KE. Clinical pharmacokinetics of diclofenac. diclofenac for the treatment of soft tissues injuries.
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14 Zacher J, Feldman D, Gerli R, Scott D, Hou SM, Uebelhart D, 1 Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of Rodger IW, Ozturk ZE, Etoricoxib OA Study Group. A comparison nonsteroidal antiinflammatory drugs. N Engl J Med 1999; 340 of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis. Curr Med Res Opin 2 Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs 2000; 60 15 Arcangeli P, Andreotti L, Palazzini E. Effective treatment of osteoarthritis with a 150 mg prolonged-release formulation of 3 Müller M, Rastelli C, Ferri P, Jansen B, Breiteneder H, Eichler HG. diclofenac sodium. Riv Eur Sci Med Farmacol 1996; 18 (5–6): Transdermal penetration of diclofenac after multiple epicutaneous administration. J Rheumatol 1998; 25: 1833–6.
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healthy volunteers: comparison of the suction blister technique 6 Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. and cutaneous microdialysis. Acta Derm Venereol 1999; 79 (4): Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ 1998; 316 (7128): 333–8.
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20 Benfeldt E, Serup J. Effect of barrier perturbation on cutaneous 8 Link R. Placebo-controlled clinical multicentre study to verify penetration of salicylic acid in hairless rats: in vivo efficacy and safety of Diclofenac Spray Gel 4 % MK in the pharmacokinetics using microdialysis and non-invasive treatment of ankle distortions, MIKA Pharma data on file, 2000.
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