RELEASE OF HYDROCORTISONE ACETATE FROM HYDROPHILIC AND LIPOPHILIC FORMULATIONS

Hydrocortisone acetate (HCA) is a synthetic corticosteroid efficient against cutaneous pathology, such as inflammatory dermatitis. Commercial vehicles for systemic administration of HCA include rectal suppositories, while intra-articular injections are used for temporary relief under certain conditions. Several commercial products containing HCA are available for topical use on skin7. Topical formulations of corticosteroids are usually administered in the pharmaceutical form of ointments, creams, lotions, gels, aerosol sprays, powders and foams7. It is therefore desirable to know if and how the formulation enables a control of permeation and to design formulations where are clearly assessed promotion of the absorption properties or prolonging the residence time on the application site, while displaying poor penetrating properties. Following these suggestions, in this paper we tested four different topical formulations for their suitability in dermatology to topical administration and release of HCA, mainly to evaluate their properties to promote or not its flux across an animal membrane: formulations examined in fact possess different technological characteristics that range from an aqueous gel to an ointment, from an aqueous to a non-aqueous microemulsion. Experimental methods Hydrocortisone acetate was a commercial sample of pharmaceutical purity (Sigma, Milan, Italy); white powder (mp. 223°C, with decomposition), very poorly soluble in water. Franz cell: donor compartment (2.5 ml); animal diffusional membrane (64 mm2); receiving cell (4.8 ml - aqueous ethanol (40/60 v/v); withdrawn: 2 ml at presetted time (1, 2, 3, 4, 5, 6, 7, 8, 24 h) and replaced with fresh solution at 37°C; analysis HPLC; mobile phase was a mixture of methanol, acetonitrile and water (15:27:58, v/v/v); flow rate 0.8 ml/min. HCA flux through the porcine skin was calculated from the amount of drug permeated over 24 h. Release from the formulations – Table 1 shows also the results of the release for the different formulations as a function of time. The study presented herein demonstrated that all the formulations have the ability to release a satisfactorily amount of the active drug. The release profiles are almost parallel for all the formulations (Figure 1): the amount released increases with a characteristic profile during a first period of 8 h; and then reach the 24 h value very slowly: in the second period of 16 h the amount released represent only about 15% of the total one. The released amount after 24 h is comparable for the different formulations, ranging from 186 μg/ml from the ointment (D) to about 300 μg/ml for microemulsion systems. But when the dissolved/released amount ratio is considered, the highest value is found for the ointment, suggesting that in this system the drug displays high mobility. A linear relationship can be found between the dissolved and released amount after 24 h of Table 2 (Figure 2): the amount released is high when solubility is high, indicating that the dissolved fraction drives the release and since the released amount represents a low percentage of the dissolved one, this suggests that a dosage too much higher than that necessary to saturate the formulation could be useless. Formulation A does not obey, since its release value appears lower than expected. This fact suggests that HCA in the aqueous microemulsion attains a particular stability (also due to micelle solubilization, see below) that delays the release. On the contrary the behavior of non-aqueous microemulsion is more linear, since to high solubility corresponds high release of the drug. Permeation profiles of HCA from:  aqueous gel (B);  ointment (D). Conclusions: All the formulations are similar regarding rate and the release of the drug, while the two microemulsions display extent of the release of HCA and demonstrated not to hinder notable properties to promote also permeation across an ex-vivo membrane, examined...