Microdialysis assessment of percutaneous penetration of ketoprofen after transdermal administration to hairless rats and domestic pigs.

The study was performed to evaluate the percutaneous penetration of ketoprofen after transdermal administration using a microdialysis technique in pigs, in comparison with rats. Ketoprofen release from patches was determined by analysis of the remaining drug content after application to hairless rats and pigs. Skin and knee joint penetration of ketoprofen was tested by microdialysis, and recovery was determined by retrodialysis. Residual rates in hairless rats and pigs were 68.1 ± 1.6% and 81.7 ± 4.4%, respectively, at 10h. The average recoveries of ketoprofen over 480 min in the skin and knee joint cases were 72.0 ± 3.4% and 9.8 ± 6.2% in rats and 72.3 ± 2.5% and 57.6 ± 3.1% in pigs, respectively. In rats, ketoprofen was rapidly absorbed with transdermal administration, with C(max) values of 191.7 ± 76.2 and 35.5 ± 21.7 ng/mL and AUC(0-8h) values of 918.2 ± 577.5 and 195.9 ± 137.1 ngh/mL, respectively, for the skin and knee joint. The C(max) values for the pig were 20.9 ± 18.5 and 3.7 ± 3.0 ng/mL, with AUC(0-8h) values of 73.1 ± 69.2 and 16.1 ± 16.1 ngh/mL. Ketoprofen concentrations within skin and knee joint of non-application sites in rats and pigs were less than 0.8 ng/mL. Transdermal administration of ketoprofen significantly reduced prostaglandin E2 levels in the skin of the application site and showed a tendency for inhibition in the knee joint. We thus demonstrated that topical patches containing ketoprofen can deliver the drug through the skin and knee joint of pigs and rats via direct diffusion, and microdialysis data with the pig may be useful for the prediction of human tissue penetration of drugs with transdermal administration.

Intra-articular penetration of ketoprofen and analgesic effects after topical patch application in rats.

The purpose of this study was to evaluate percutaneous penetration and pharmacological effects of ketoprofen after transdermal administration, compared to the oral route. Skin and knee joint penetration of ketoprofen was tested by a microdialysis technique in rats and in vivo recovery was determined by retrodialysis. After oral and transdermal administration of ketoprofen, dialysate was sampled at 60 min intervals up to 360 min, for determination of concentrations of ketoprofen and prostaglandin E2. Analgesic effects of ketoprofen in iodoacetate and adjuvant-induced arthritis models were evaluated using the weight bearing method. The average recoveries of ketoprofen over 360 min in the skin and knee joint were 60.2+/-3 and 15.8+/-9%, respectively. Cmax values for ketoprofen absorbed within the skin after oral and transdermal administration were 20.1+/-5 and 297.5+/-478 ng/mL, respectively, and within the knee joint, 4.4+/-0.4 and 2.7+/-0.9 ng/mL. The Cmax value for the plasma concentration of ketoprofen after oral administration was approximately 80 times higher than with the transdermal route. Both transdermal and oral administration of ketoprofen significantly decreased PGE2 production in the skin and knee joint and improved weight bearing after exposure to iodoacetate and adjuvant. These results indicate that the transdermal ketoprofen patch is a useful formulation that can deliver the drug in sufficient amounts to inhibit prostaglandin E2 production in the skin and knee joint.

Percutaneous penetration of felbinac after application of transdermal patches: relationship with pharmacological effects in rats.

We have evaluated the percutaneous penetration of felbinac following application of topical patches using a microdialysis technique, and have examined correlations with pharmacological effects. A linear microdialysis probe with a 20-mm dialysis fibre was inserted into the skin of anaesthetized rats. Probe perfusion was started at 2.0 microL min(-1) with physiological saline and after a 60-min baseline sampling of dialysate, 0.1 mL croton oil was applied to the skin surface at a concentration of 8%, v/v. A felbinac patch was then applied to the same point 60 min thereafter and dialysate was sampled at 60-min intervals up to 300 min after patch application, for determination of concentrations of felbinac and prostaglandin (PG) E2. Analgesic effects of felbinac patches in an iodoacetateinduced osteoarthritis model and an incisional pain model were evaluated using the weight bearing method. After application of patches, felbinac penetration into the skin was rapid, maximum concentrations in the dialysates with 0.07, 0.5 and 3.5% w/w felbinac patches being 0.046+/-0.02, 0.104+/-0.06 and 0.244+/-0.2 microg mL(-1), respectively. Dermal administration of croton oil caused an increment in PGE2 levels, which was significantly decreased by 0.5 and 3.5% felbinac patches 2-5 h after application. In pharmacological studies, 3.5% felbinac patches suppressed pain-associated behaviour induced by iodoacetate injection and plantar incision. These results suggested that the transdermal patch containing 3.5% felbinac may become a useful formulation.