To investigate quantitatively the percutaneous absorption of dexamethasone acetate (DA) and palmitate (DP), gel and petrolatum ointments were prepared and applied to rat skin. DA in the presence of absorption enhancers (AzoneR and sorbitan monooleate) was rapidly absorbed, in the form of dexamethasone, through the skin, whereas the absorption after application of DA ointment without enhancers was relatively poor. DP was also efficiently absorbed in the presence and absence of enhancers, with bioavailability of 5.3 and 4.1%, respectively. The absorbed DP was slowly hydrolyzed in the systemic circulation. The percutaneous absorption of drugs from the petrolatum ointments with enhancers was slower than that from the gel ointments. The in vitro release rates of DA and DP from the gel ointments with enhancers were 7.3 and 6.1 mg/h1/2, respectively and were much higher than those from the petrolatum ointments. The partition coefficient of DP was much larger than that of DA. Thus, it is suggested that DA and DP gel ointments with enhancers are effective in terms of high absorption into the circulation.Systemic administration of cortisone and its synthetic analogs gives excellent results in clearing inflammatory skin lesions. Unfortunately, corticosteroids carry the risk of side effects such as peptic ulceration, hypokalemic alkalosis and edema.1) Corticosteroids have been frequently used in topical dosage forms for cutaneous diseases. It has been found that the esterification of the 17-and 21-hydroxy groups produces increased efficacy and improved penetration through skin, as shown in the case of betamethasone dipropionate and hydrocortisone butyrate propionate.2,3) The changes of molecular structure and technical advances in drug delivery systems have thus allowed increased utilization of transdermal formulations in corticosteroid therapy. Consequently, a kinetic study of esterified steroids in the systemic circulation would provide important information for practical application. Despite many studies on dermatologic preparations of corticosteroids, surprising little work has been carried out to define quantitatively the percutaneous absorption based on measuring plasma concentration. In this work, the in vivo percutaneous absorption of dexamethasone acetate and palmitate was investigated in rats, using gel and petrolatum ointments with or without absorption enhancers (AzoneR and sorbitan monooleate). In addition, various factors (the drug release rate, partition coefficient and hydrolysis in skin) which influence the penetration of drugs were investigated in relation to the percutaneous absorption.
Experimental
MaterialsDexamethasone acetate (DA, pharmaceutical grade) and dexamethasone palmitate (DP) and stearate were generous gifts of Nippon Merck-