PREPARATION AND CHARACTERIZATION OF TOPICAL FORMULATIONS CONTAINING 6-O-ALKYL DERIVATIVES OF ASCORBIC ACID

Alkyl vitamin C derivatives (ASCn) are amphiphilic molecules having physicochemical properties that depend on the alkyl chain length. The derivatives with low molecular weight (n < 11) have enough aqueous solubility to produce self-assemblies at room temperature (≈25°C), while those with longer alkyl chains possess a critical micellar temperature (CMT) higher than 30°C. Above CMT aqueous ASCn derivatives suspensions turn into either micellar solutions or gel phases, depending on the length of the alkyl side chain. On cooling, liquid crystal structures, called coagels, are produced. The semisolid consistency of such coagels is an interesting property that makes ASCn coagel a promising pharmaceutical platform for drug delivery. Coagels could be able to solubilize insoluble and unstable drugs, protect them from any possible aggressive environment and enhance their permeation through skin. Furthermore the rheological properties of coagels would be adequate for topical administration. Aim of the study was the evaluation of L-ascorbic acid lipophilic derivatives as permeation enhancers for two non-steroidal antinflammatory drugs, ibuprofen (IBU) and diclofenac (DICH), through hairless rat skin and ocular structures of rabbit eye, respectively, by means of in vitro, ex vivo and in vivo studies. Among lipophilic derivatives the lauroyl-6-O-ascorbic acid or ascorbyl-laurate (ASC12) and the palmitoyl-6-O-ascorbic acid or ascorbyl palmitate (ASC16) were chosen and different vehicles for both IBU and DICH were prepared and compared with the commercially available formulations. The rheological characterization of each formulation was performed. Moreover, in order to better define the physicochemical properties of ASC12 and ASC16, the effect of the co-solvent on their drug-loading capacity was evaluated using two insoluble model drugs, anthralin (ANTH) and griseofulvin (GRIS). Preliminary studies on the stability of ASC16 were conducted in the presence or absence of vitamin E (Vit E), used as antioxidant. Results showed that both ASC12 and ASC16 increased IBU transdermal permeation through hairless rat skin, producing a low depot in the skin of the same order of magnitude for both epidermis and dermis. Furthermore, a synergistic enhancement effect between ASCn and PEG400 was observed, more evident for ASC12PEG400/CIbu coagel. In vivo studies on rabbit eyes demonstrated that even if coagels did not increase the retention time of DICH in the tear fluid with respect to the commercial formulation, they were capable to raise drug concentration in the aqueous humour of two and three folds for ASC16 and ASC12, respectively. The incorporation of both IBU and DICH in the system did not produce changes on the characteristic crystalline structure of coagel, as observed from rheological measurements. The solubility profiles showed that the solubility of the model-drugs (ANTH and GRIS) was higher when the amount of the co solvent increased and a synergistic effect of PEG 400 and ASC16 coagel on the solubility of such drugs was observed. Finally, preliminary stability studies demonstrated that the presence of Vit E as antioxidant did not improve the stability of ASC16, which showed a quicker degradation at 60°C with respect to room temperature. In conclusion, ASCn coagels may be considered promising pharmaceutical systems for drugs utilizing by topical administration, even if further studies would be performed to increase their stability.