Formulation and Evaluation of Ketorolac Transdermal Systems

Abstract

Hairless mouse 피부를 이용하여 여러 용제와 투과촉진제의 ketorolac tromethamine(KT) 투과도 효과를 실험하고 이 결과를 토대로Pressure-sensitive Adhesives와 용제의 in vitro 상의 투과도와 in vivo의 약물동태학을 연구하였다. 실험한 용제 중에서 propylene glycol monolaurate (PGML) 가 94.3 ± 17.3 μg/cm2/hr 로 가장 높은 투과 flux를 나타내었다. propylene glycol monocaprylate (PGMC) 단독으로는 높은 투과력을 보이지 않았지만 diethylene glycol monoethyl ether (DGME)의 첨가에 의해 투과factor는 20,40 % 에서 각각19.0과 17.1로 두드러지게 증가하였다. PGML과 DGME의 배합시 PGML 단독 투과력 보다 DGME 20-60%에서 거의 두배 가까운 투과력을 나타냈다. propylene glycol (PG)-oleyl alcohol계 공용제 배합 비율 실험에서 투과율은 PG 증가비 만큼 증가되었고, 모든 용제에서 약물농도가 증가될수록 투과력은 높아졌다. 또한 약물농도가 용해도보다 높은 경우 투과력은 괄목할만하게 증가되는 결과가 나타났다. 5가지 지방산- caprylic acid, capric acid, lauric acid, oleic acid, linoleic acid을 1,3,5,10 %의 농도로 PG에 첨가하였다. 지방산류의 투과 촉진효과는 종류와 농도에 따라서 다르게 나타났다. PG - 10% caprylic acid 배합이 permeation flux 113.6 ± 17.5 μg/cm2/hr 로 가장 높은 투과 촉진 결과를 보였고 ketorolac tromethamine 의 lag time은 caprylic acid를 제외하고 지방산 농도의 증가에 따라 감소되었다. In vitro 상태에서 감압접착제와 용제의 ketorolac tromethamine 투과력과 in vivo의 약물동태학 실험에서는 Duro-Tak 87-2196？？ 가 in vitro에서 가장 높은 투과력을 나타냈고 propylene glycol monolaurate-diethylene glycol monoethyl ether (DGME) (60 : 40, v/v) 와 propylene glycol monocaprylate-DGME (60 : 40, v/v)가 in vitro와 in vivo에서 가장 좋은 결과를 보였다. Ketorolac경피 흡수제제는 경구투여제와 비교시 Cmax는 감소하고 Tmax, half-life는 연장되어지는 결과를 얻었다. 이는 Ketorolac경피 흡수시스템이 부작용은 감소하면서 효과는 더욱 연장되는 결과를 가질 수 있음을 보여주는 것이다. In vitro상태의 투과 flux와 in vivo의 AUC0-∞ 사이엔 뛰어난 상관 관계가 있는 것으로 나타난다.|The effects of vehicles and penetration enhancers on the in vitro permeation of ketorolac tromethamine (KT) across excised hairless mouse skins were investigated. By this results, effects of pressure-sensitive adhesives and vehicles on the in vitro permeation of ketorolac and in vivo pharmacokinetics were studied. Among pure vehicles examined, propylene glycol monolaurate (PGML) showed the highest permeation flux, which was 94.3 ± 17.3 μg/cm2/hr. Even though propylene glycol monocaprylate (PGMC) alone did not show high permeation rate, the skin permeability of KT was markedly increased by the addition of diethylene glycol monoethyl ether (DGME); the enhancement factors were 19.0 and 17.1 at 20 and 40 % of DGME, respectively. When DGME was added to PGML, the permeation fluxes were almost two times at 20-60% of DGME compared to PGML alone. In the co-solvent system consisting of propylene glycol (PG)-oleyl alcohol, the permeation rate increased as the ratio of PG increased. In the study to investigate the effect of drug concentration on the permeation rate of KT, the permeation rates increased as the drug concentration increased in all vehicles used, and the dramatic increase in permeation rate was obtained when the drug concentration was higher than its solubility. For the effects of fatty acids on the permeation of KT, five fatty acids were added to PG at the concentrations of 1, 3, 5 and 10%-caprylic acid, capric acid, lauric acid, oleic acid, and linoleic acid. The enhancing effects of fatty acids were different depending on the concentration as well as the sort of fatty acids. The highest enhancing effect was attained with 10% caprylic acid in PG; the permeation flux was 113.6 ± 17.5 μg/cm2/hr. The lag time of KT was reduced as the concentration of fatty acids increased except for caprylic acid. Duro-Tak 87-2196？？ showed the highest in vitro permeation profiles, and propylene glycol monolaurate-diethylene glycol monoethyl ether (DGME) (60 : 40, v/v) and propylene glycol monocaprylate-DGME (60 : 40, v/v) revealed the most favorable in vitro and in vivo results. The decreased Cmax and prolonged Tmax and half-life were obtained with the ketorolac transdermal systems compared to oral administration, indicating that the ketorolac transdermal systems may have prolonged effect with reduced toxic event. There was an excellent relationship between in vitro permeation flux and in vivo AUC0-∞ found.