Topical Ketoprofen Research Articles

Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries

Objective: To compare the ketoprofen TDS patch with diclofenac gel in the treatment of traumatic acute pain in benign sport-related soft-tissue injuries. Design: 7–14 treatment days, prospective, randomised, open study....

Greater allergenicity of topical ketoprofen in contact dermatitis confirmed by use

The use of topical non-steroidal anti-inflammatory drugs (NSAIDs) is very popular in spite of their doubtful efficacy and high number of generally not serious, but preventable, adverse effects, especially photoallergy. The allergenic potential of different topical NSAIDs was determined by performing a retrospective observational study of the period 1996-2001 and comparing the cases of allergy and photoallergy with the use of each topical NSAID. The diagnoses were obtained from a review of the clinical records of patch/photopatch testing carried out in the dermatology departments of 2 public hospitals in Bizkaia (Spain). The use of the different topical NSAIDs was obtained from invoices sent to the National Health System and the Reporting odds ratio (ROR) and Proportional reporting ratio (PRR) disproportionality estimates of the FEDRA database of the Spanish Pharmacovigilance System. A total of 139 contact reactions to topical NSAIDs were found with ketoprofen being responsible for 28% of the allergies and 82% of the contact photoallergies in spite of not being the most used topical NSAID (third in the ranking, diclofenac was the first). The ROR for ketoprofen was 3.9 (2.4-6.4) and the PRR 3.4 (2.1-5.5), thus confirming the possibility of a warning signal. The results support the need for regulatory action on topical ketoprofen.

Is There a Role for Topical Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Tendonitis?

Evaluation of: Mazieres B, Rouanet S, Guillon Y, Scarsi C, Reiner V: Topical ketoprofen patch in the treatment of tendinitis: a randomized, double-blind, placebo-controlled study. J. Rheumatol. 32(8), 1563–1570 (2005) [1]. This was a multicenter, double-blind, randomized, controlled trial to study the efficacy of the topical ketoprofen patch in the treatment of tendonitis. This trial suggests that using a ketoprofen once-daily 100 mg patch is helpful in the management of tendonitis. Topical nonsteroidal anti-inflammatory analgesics represent a promising alternative in the management of musculoskeletal pain for the aging population.

Topical Ketoprofen Patch

Although oral nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of a variety of acute and chronic pain conditions, their use may be associated with serious systemic adverse effects, particularly gastrointestinal disorders. In order to minimise the incidence of systemic events related to such agents, topical NSAIDs have been developed. Topical NSAIDs, applied as gels, creams or sprays, penetrate the skin, subcutaneous fatty tissue and muscle in amounts that are sufficient to exert a therapeutic effect on peripheral and central mechanisms in the absence of high plasma concentrations. Data indicate that topical NSAIDs are effective at relieving pain in a number of acute and chronic pain indications. This review article discusses the pharmacokinetics, efficacy and tolerability of a new formulation of ketoprofen available as a topical patch. The topical patch containing ketoprofen 100mg as the active principle has been developed using a novel delivery system that dispenses therapeutic doses of the drug directly to the site of injury. Pharmacokinetic data indicate that although plasma levels of ketoprofen are higher when the drug is administered as a patch versus a gel, the total systemic bioavailability of ketoprofen 100 mg administered via a patch is no more than 10% of that reported for ketoprofen 100 mg administered orally. Because the patch facilitates ketoprofen delivery over a 24-hour period, the drug remains continually present in the tissue subjacent to the site of application. High tissue but low plasma ketoprofen concentrations mean that while tissue concentrations are high enough to exert a therapeutic effect, plasma concentrations remain low enough to not result in systemic adverse events caused by elevated serum NSAID levels. Phase III clinical trials in patients with non-articular rheumatism and traumatic painful soft tissue injuries showed that the topical ketoprofen patch was significantly more effective than placebo at reducing pain during daily activities and spontaneous pain after 7 days' treatment. Moreover, the topical ketoprofen patch was well tolerated; adverse events were primarily cutaneous in nature and occurred in a similar number of ketoprofen and placebo recipients suggesting that these events were related to the patch itself rather than the active ingredient. The incidence of gastrointestinal adverse events was low (<8% of all patients), and occurred in a similar proportion of patients receiving ketoprofen and placebo. Thus, the topical ketoprofen patch appears to be a simple, effective and safe therapeutic option for the treatment of local painful inflammation.

Relative bioavailability of ketoprofen 20% in a poloxamer-lecithin organogel

The bioavailability of a single, topically applied, 200-mg dose of ketoprofen (delivered in a ketoprofen 20% gel) relative to a single 50-mg oral dose in healthy volunteers was studied. This was an open-label crossover study. The subjects were randomized to receive an oral 50-mg ketoprofen capsule or a single topical dose of ketoprofen 20% in a poloxamer-lecithin organogel (PLO). Treatment was followed by a one-week washout period. Blood samples were collected at intervals up to 10 hours after administration, and plasma ketoprofen concentrations were determined by high-performance liquid chromatography with ultraviolet or mass spectrometry detection. Noncompartmental pharmacokinetic values were obtained after each dose, and relative bioavailability was calculated. Eight healthy volunteers enrolled in and completed the study. Topical absorption of ketoprofen was highly variable among the subjects over the 10-hour sampling period. The median oral maximum plasma concentration (Cmax) exceeded the topical Cmax by nearly 200-fold (4.15 versus 0.021 microg/mL) (p = 0.001). The median relative bioavailability of topical ketoprofen was 0.48%, with individual subjects' values ranging from 0.18% to 2.1%. The relative bioavailability of ketoprofen was low and highly variable when the drug was administered as a single dose in a PLO-based ketoprofen 20% gel.

Comparison of performance of C18 monolithic rod columns and conventional C18 particle-packed columns in liquid chromatographic determination of Estrogel and Ketoprofen gel

The performance of monolithic HPLC columns Chromolith™ (made by Merck, Germany) and conventional C18 columns Discovery (Supelco, Sigma–Aldrich, Prague, Czech Republic) was tested and the comparison for two topical preparations Ketoprofen gel and Estrogel gel was made. The composition of mobile phases – for Ketoprofen analysis a mixture of acetonitrile, water and phosphate buffer adjusted to pH 3.5 (40:58:2) and for Estrogel analysis a mixture of acetonitrile, methanol, water (23:24:53) – was usually not optimal for analyses at all types of columns. Thus an adjustment of components ratio was necessary for sufficient resolution of the compounds analysed. Various flow rates (1.0–5.0 ml/min) and mobile phases (usually increasing ratio of water content) were applied. Determination of active substances, preservatives and impurities and comparison of retention times and system suitability test parameters was accomplished. For Estrogel gel, following chromatographic conditions were found: using Chromolith Flash RP-18e monolith column, mobile phase was acetonitrile, methanol, water (13:24:63, v/v/v) and flow-rate 3.0 ml/min. Using monolith column ChromolithSpeedROD RP-18e, the mobile phase was acetonitrile, methanol, water (18:24:58, v/v/v) and flow-rate 4.0 ml/min. For the monolith column Chromolith Performance RP-18e, the mobile phase was acetonitrile, methanol, water (23:24:53, v/v/v), flow-rate 3.0 ml/min. Analysis of Ketoprofen gel gave the best results using following analytical conditions: for monolith column Chromolith Flash RP-18e, mobile phase as a mixture of acetonitrile, water, phosphate buffer pH 3.5 (30:68:2, v/v/v) was used, at flow-rate 2.0 ml/min. For ChromolithSpeedROD RP-18e monolith column, acetonitrile, water, phosphate buffer pH 3.5 (35:63:2, v/v/v) was used as a mobile phase at flow-rate 3.0 ml/min. Chromolith Performance RP-18e gave the best results using mobile phase acetonitrile, water, phosphate buffer pH 3.5 (30:68:2, v/v/v) at the flow-rate 5.0 ml/min. It was proved that monolith columns, due to their porosity and low back-pressure, can save analysis time by about a factor of three with sufficient separation efficiency. Thus, for example 11 min long analysis can be performed in 4 min with comparable results.

Bioequivalence determination of topical ketoprofen using a dermatopharmacokinetic approach and excised skin penetration

Ketoprofen is a photolabile drug. The aim of the present study was to compare the bioavailability of ketoprofen in a photo-stabilised formulation with a gel without photoprotection using a new dermatopharmacokinetic tape-stripping model and an established ex vivo penetration method using human skin. Analyses of the stratum corneum showed that during the first 45 min about 12 μg/cm 2 ketoprofen was absorbed into the skin from the formulations. The area under the ketoprofen content–time curve (AUC 0–6 h ) for the ratio photo-stabilised gel/transparent gel was 73% with a 90% confidence interval (CI) 65–83. The rate of penetration of ketoprofen through isolated skin was approximately 0.2 μg/cm 2 h for both formulations. AUC 0–36 h for the ratio was 84% with 90% CI 64–105. Thus, the two methods did not disagree in terms of relative efficacy of the two gels. However, the difference obtained in vivo was statistically significant, whereas no significant data arise from the ex vivo study. Comparing the amount of ketoprofen in the skin after 45 min with the amount penetrated through the excised skin during 36 h, suggests a change in the thermodynamic activity of ketoprofen during the exposure. A supersaturated formulation may well have been formed initially due to evaporation of ethanol.

Contact and photocontact allergy to ketoprofen. The Belgian experience.

Topical ketoprofen (KP) is widely used because of its anti-inflammatory effect. However, photocontact dermatitis is a side-effect. Between May 2001 and June 2002, the Belgian Contact & Environmental Dermatitis Group conducted a prospective, open patch and photopatch test study in 20 patients suspected of KP dermatitis. Severe skin symptoms requiring systemic corticotherapy occurred in 47%. 5 patients were hospitalized. 1 patient showed prolonged photosensitivity. All patients were tested with KP and the other constituents of KP gel. Attribution to KP was demonstrated in all cases. Patch and photopatch tests with KP 2% in petrolatum showed contact photoallergy in 17 patients, contact allergy in 1 patient and photoaggravated contact allergy in 2 patients. 5 patients also reacted to the fragrance components lavender (Lavandula augustifolia) oil and/or neroli (Citrus aurantium dulcis) oil 5% in alcohol. However, in 4 of these, irritant reactions to the ethanolic dilutions could not be ruled out. Additional tests with 3 non-steroidal anti-inflammatory drugs without benzophenone structure ibuprofen, naproxen and diclofenac identified only 1 contact allergic reaction to diclofenac. Cross-reactivity to the substituted benzophenones, oxybenzone and sulisobenzone occurred only to the first in less than 30% of the patients. A high frequency (69%) of contact allergy to fragrance mix was found. Dermatologists should be aware of the severity of photoallergic reactions to KP and the risk of cross-sensitization.

Analgesic profile of peroral and topical ketoprofen upon low pH-induced muscle pain

Topical analgesics are widely marketed for treatment of muscle and joint pain. We have recently developed a model of muscle pain and have used this model to evaluate the efficacy of commercially available topical and peroral ketoprofen in order to evaluate the time- and dose-dependence of analgesia. In the present study, we examined the dose- (0, 50, and 100 mg) and time-dependence (hourly to 8 h) of commercially available peroral and topical ketoprofen. In order to achieve infusion times of 8 h (and thus study the time course of analgesic action), we adapted the model of low pH-induced muscle pain in humans to these requirements by applying the infusions continuously for 10 min every hour for 8 h. We found that the 10 min infusion produced reliable and consistent pain levels that were reproducible over the 8 h of the study. The study was performed double-blind, randomized, and with a 1-week interval between each of five different sessions (cross-over). Altogether six volunteers underwent intramuscular infusions of isotonic phosphate-buffered saline solution of pH 5.2; during each 8 h session the infusion was switched on eight times with a duration of 10 min at 50 min intervals (there was no infusion during the 50 min interval). The intramuscular infusion of low pH phosphate buffer induced a localized dull-aching or stinging muscle pain sensation; the flow rate of the pH infusion was individually adjusted to induce pain of a magnitude of 20% on a visual analogue scale (ranging from ‘no pain’ (0%) to ‘unbearable pain’ (100%)). Twenty minutes after starting the infusion the volunteers received a capsule with either a placebo or 50 or 100 mg ketoprofen perorally and, in addition, either placebo gel or 50 or 100 mg of a 2.5% commercial ketoprofen gel was applied topically to the skin. One of the sessions included a placebo gel and an oral placebo. The intensity of the recurrent pain stimulus was significantly reduced by 59% following administration of 100 mg peroral ketoprofen within the first 3 h ( P<0.03, Wilcoxon test); this analgesia lasted up to the sixth hour of the experimental protocol. Oral ketoprofen (50 mg) was less effective and reduced the pain intensity by 45% ( P<0.05) from only the second to the third hour. In contrast, pain reduction after topical ketoprofen application was not of the same magnitude but appeared to be faster to develop (with a maximum effect within 1 h) on average. The maximum pain suppression with 100 mg topical 2.5% ketoprofen gel was by 51% (significant with P<0.03), while 50 mg topical ketoprofen produced a non-significant reduction of 29%. The apparent analgesia was rapid to develop but transient and pain ratings increased back to baseline values within 3 h for the 100 mg dose and within 2 h for the 50 mg dose. This data suggests that topical application of commercial gel-based systems does not provide long-lasting analgesia in the muscle when compared to perorally-dosed ketoprofen. In addition, the data show that even doses of 100 mg peroral ketoprofen do not provide complete relief of muscle pain.

In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs

The aim of the present work was to generate an index to predict topical efficiency of a series of nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin, diclofenac, ketoprofen, piroxicam, tenoxicam and ketorolac. This index took into account both biopharmaceutic and pharmacodynamic aspects. The biopharmaceutic aspect, based on the maximal flux ( J m ), was determined experimentally from transdermal studies carried out with human skin in previous work. The pharmacodynamic aspect, based on the ability to inhibit cyclooxygenase-2 (COX-2) in vitro, was determined by incubating human dermal fibroblasts in culture, pre-treated with phobol-12-myristate-13-acetate (PMA) for 6 h, with 25 μM [ 14C]-arachidonic acid (AA) in the presence of several drug concentrations. The most potent inhibitor of COX-2 activity in induced fibroblasts was diclofenac while indomethacin, ketoprofen and ketorolac were approximately equipotent. Piroxicam and tenoxicam were inhibitors at higher concentrations. Based on the proposed index of the topical anti-inflammatory activity (ITAA) diclofenac, ketorolac, ketoprofen and indomethacin exhibited acceptable efficiency for external use. However, piroxicam and tenoxicam showed the lowest topical anti-inflammatory activity of the series assayed. In conclusion, indomethacin ketorolac, ketoprofen and diclofenac have shown good intrinsic feasibility for formulation into topical pharmaceutical forms. However, for dermatological formulations of oxicams, use of penetration enhancers may be unavoidable.

Five cases of photocontact dermatitis due to topical ketoprofen: photopatch testing and cross-reaction study.

In parallel with the popular usage of topical ketoprofen, the number of reported cases of ketoprofen-induced photoallergic contact dermatitis has been increasing. It is clinically important to know the cross-reactivity of ketoprofen in order to avoid cross-sensitization caused by several structurally similar non-steroidal anti-inflammatory drugs (NSAID) on the market. To evaluate the spectrum of cross sensitization, photopatch testing was performed on five patients with ketoprofen-induced photoallergic contact dermatitis using ketoprofen and other structurally similar chemicals, such as oxybenzone, tiaprofenic acid and suprofen. All five patients reacted positively to ketoprofen or ketoprofen plaster on photopatch testing. All four patients photopatch tested with related chemicals showed cross-photosensitization with tiaprofenic acid and suprofen. However, none of the patients reacted positively to oxybenzone. Either the diphenylketone moiety or a structurally similar tiophene-phenylketone moiety is important as the antigenic determinants of ketoprofen photoallergy. The arylpropionic acid side chain would not be involved.

Efficacy of Topical Ketoprofen Cream for Chronic Knee Pain.

Efficacy of Topical Ketoprofen Cream for Chronic Knee Pain.

Acute renal failure induced by topical ketoprofen

Acute renal failure is a known complication with oral non-steroidal anti-inflammatory drugs.1 2 In contrast, topical application of such drugs is usually considered safe because of marginal percutaneous absorption (5-8%).3...

Photocontact dermatitis from ketoprofen and tiaprofenic acid: cross-reactivity study in 12 consecutive patients.

The arylpropionic acid derivatives (APADs) ketoprofen and tiaprofenic acid can provoke photoallergic dermatitis. Possible cross-reactivity between APADs is of importance in patients using nonsteroidal anti-inflammatory drugs. Because of the similarities in chemical structures, we investigated patients with photoallergy to ketoprofen or tiaprofenic acid, in order to study cross-reactivity between APADs and a possible pattern of cross-reactivity between benzophenone-containing molecules, so as to determine the molecular basis of photoallergy to ketoprofen or tiaprofenic acid. 10 patients with photoallergy to topical ketoprofen, 2 with photoallergy to oral tiaprofenic acid, and 15 control subjects with no history of contact dermatitis from APADs, nor from benzophenone-containing molecules, were photopatch tested in triplicate with ketoprofen, tiaprofenic acid, other APADs (alminoprofen, fenoprofen, flurbiprofen, ibuprofen and naproxen), benzophenone-containing molecules (fenofibrate, oxybenzone, sulisobenzone), and unsubstituted benzophenone. 1 set was irradiated with UVA light, 1 with solar-simulated irradiation and 1 dark control. Tests were read at 2, 3 and 4 days. Patients reacted to both ketoprofen and tiaprofenic acid (12/12), fenofibrate (8/12), oxybenzone (3/12) and unsubstituted benzophenone (11/12), but not to other APADs, nor to sulisobenzone. Tests remained negative in control patients. Photoallergy is due to the benzophenone moiety of ketoprofen, or to the very similar thiophene-phenylketone of tiaprofenic acid, but not to their arylpropionic function. This induces cross-reactivity to fenofibrate and oxybenzone but not to APADs without a benzophenone moiety, which may therefore probably be used in such patients. Unsubstituted benzophenone should be added to standard phototesting series.

Contact and photocontact allergy to ketoprofen: clinical and experimental study

In the last 3 years, we have studied 10 patients with allergic reactions to topical ketoprofen. We have investigated the sensitization and irritant potential of the drug and the possibility of cross-reactivity with other aryl-propionic non-steroidal anti-inflammatory drugs (ibuproxam, ibuprofen, naproxen, fenoprofen, flubiprofen and tiaprofenic acid). 2 of our patients had contact dermatitis, and the other 8 photocontact dermatitis. One of our patients showed cross-reactivity between ketoprofen and ibuproxam on patch testing. In the photopatch tests, we observed cross-reactivity between ketoprofen and tiaprofenic acid in 2 patients, and cross-reaction between ketoprofen and ibuproxam and flurbiprofen in another case. Experimental studies, including human maximization and photomaximization tests, performed in 20 healthy volunteers, showed a complete absence of sensitization, 3 volunteers showed a marked irritant reaction to ketoprofen (20% pet.) during either maximization (2 cases) or photomaximization (1 case) tests. Although ketoprofen appears not to be a sensitizing agent in human volunteers, the fact that photosensitization to this drug seems to be quite common after topical use suggests that there are some local or individual factors, at present unknown, facilitating the development of allergy.

Allergic and photoallergic contact dermatitis from topical ketoprofen

Allergic and photoallergic contact dermatitis from topical ketoprofen

Topical Ketoprofen is Absorbed Through the Skin

Topical Ketoprofen is Absorbed Through the Skin

Anti-inflammatory effects of ketoprofen in rabbit corneal epithelial wound model

Ocular anti-inflammatory effects of ketoprofen were assessed and compared with indomethacin in the rabbit corneal epithelial wound model. Intraperitoneally (5 mg kg-1 and 50 mg kg-1) and topically (0.01%) administered ketoprofen and topical indomethacin (0.5%) prevented the release of polymorphonuclear leukocytes (PMNs) into the tear fluid of rabbits following partial de-epithelialization. However, 0.001% ketoprofen applied topically potentiated the PMN response. Topical ketoprofen at all doses tested equally inhibited prostaglandin (PG) synthesis in both conjunctiva and iris-ciliary body. In contrast, indomethacin was more effective in inhibiting PG synthesis in conjunctiva than in the iris-ciliary body. In addition, anti-inflammatory doses of ketoprofen did not interfere with wound healing after complete corneal de-epithelialization in rabbits.