Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles

Abstract

We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles (KET nano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KET nano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83 nm. In the in vitro skin penetration experiment, the penetration rate (J c ) and penetration coefficient through the skin (K p ) values of the KET nano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KET micro gel ointment; mean particle size 7.7 µm). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (k a ) and the areas under the KET concentration-time curve values in the skin of rats receiving the KET nano gel ointment were significantly higher than those of rats receiving the KET micro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KET nano gel ointment were also significantly higher than those of rats receiving the KET micro gel ointment. In addition, the application of the KET nano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KET micro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET.Key words nanoparticle; ketoprofen; gel ointment; drug delivery; adjuvant-induced arthritis Ketoprofen (KET) is a reversible inhibitor of cyclooxygenases 1 and 2 whose action leads to a reduction in the formation of prostaglandin precursors. 1) Thus, KET acts as an antiinflammatory agent, and is used in the treatment of rheumatoid arthritis (RA) and osteoarthritis. However, its usefulness is limited due to its low water solubility and the fact that oral administration of KET tends to cause gastrointestinal lesions in 10-30% of patients. These gastrointestinal lesions lead to an interruption of drug therapy in about 5-15% patients. 2,3)Topical and transdermal delivery routes of drug administration reduce the incidence of gastrointestinal lesions and improve patient compliance. Furthermore, the transdermal route of application avoids hepatic first pass metabolism, meaning that therapeutic serum drug concentrations can be applied with a reduced risk of nephrotoxicity and drug-drug interactions.2) However, the transdermal route of application is limited by the barrier properties of the skin. Therefore, it is necessary to develop enhancement techniques to assist the skin penetration of KET, and extensive research has been done to find both topical and transdermal KET formulations.

Pharmacokinetic Studies of Gel System Containing Ibuprofen Solid Nanoparticles

“…However, the plasma concentration following the administration of the TL nano -and KET nano -gel formulations was higher than that following the administration of the TL micro and KET micro -gel formulations. In addition, the plasma concentration following the administration of the TL nano -and KET nano -gel formulations was lower than that following the administration of the ointments containing the dissolved drugs commercially available ointments 11,13 . It has been reported that drug solubility can be expected to be enhanced at particle sizes less than 100 nm 28 .…”

“…These results were the same as the current results for the IBU-gel formulations. In addition, in the in vitro skin penetration experiments, the penetration rate of the IMC nano -186 nm , KET nano -83 nm gel formulations mean particle size was higher than that of an ointment containing dissolved IMC, KET commercially available IMC-gel formulations IDOMETHINE KOWA gel 1 , KET-gel formulations SECTOR gel ® 3 12,13 , Taken together, we hypothesize that drug infiltration into the skin tissue is enhanced for particles in the size range of approximately 80-200 nm in comparison with drugs in the liquid state, and this increase in drug infiltration may cause the high skin penetration and drug accumulation in the skin tissue for the nano gel formulations. In contrast to the results in skin penetration and drug accumulation in skin tissue, the plasma concentration behavior of the TL nano -, KET nano -gel formulations differed from that of the IMC nanogel formulation in in vivo percutaneous absorption experiments 11 13 .…”

Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

“…A sheet of CLZ gel patches (0.3 g) and gel ointment was fixed on the shaved abdominal skin with an adhesive and immediately occluded with adhesive tape. Venous blood (100 µl) was collected from the jugular vein through the cannula between 0 and 48 h after the application of the CLZ gel patches and gel ointment (18). The blood was centrifuged at 15,000 rpm for 20 min at 4˚C to obtain, plasma, which was stored at -80˚C until analysis.…”

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“…Lecithin is disorganize the structure of the skin, transiently it opens the pores of the skin and increase the penetration of drugs Fig. 1 10 . But the exact mechanism how lecithin alters the skin is not yet understood clearly.…”