Skin penetration of caffeine from commercial eye creams and eye creams designed and optimized based on Hansen solubility parameters.

Computer-aided formulation design can streamline and speed up product development. In this study, ingredient screening and optimizing software, Formulating for Efficacy® (FFE), was used to design and optimize creams for the topical delivery of caffeine. FFE was set up to optimize lipophilic active ingredients, therefore, this study challenged the program's capabilities. The effect of two chemical penetration enhancers, including dimethyl isosorbide (DMI) and ethoxydiglycol (EDG), were studied based on their favorable Hansen Solubility Parameter physicochemical input parameters for the skin delivery of caffeine in the FFE® software application. Four oil-in-water emulsions containing 2% caffeine were formulated, one without a chemical penetration enhancer, one with five percent of DMI, one with five percent of EDG, and one with 2.5% of DMI and EDG each (DMI + EDG). Additionally, three commercial products were used as reference products. The cumulative amount of caffeine released and permeated, and the flux across Strat-M® membranes were determined using Franz diffusion cells. The eye creams had skin-compatible pH, excellent spreadability for the application area, were opaque emulsions with 14-17 µm droplet size, and were stable at 25 °C for 6 months. All four eye creams formulated released over 85% of caffeine in 24 h, outperforming the commercial products. DMI + EDG cream provided the highest permeation in vitro in 24 h, which was significantly higher than the commercial products (p < 0.05). FFE proved to be a valuable and quick tool to aid in the topical delivery of caffeine.

Fatty acyl-CoA-acyl-CoA-binding protein complexes activate the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum.

We previously reported that fatty acyl-CoA esters activate ryanodine receptor/Ca2+ release channels in a terminal cisternae fraction from rabbit skeletal muscle [Fulceri, Nori, Gamberucci, Volpe, Giunti and Benedetti (1994) Cell Calcium 15, 109-116]. Skeletal muscle cytosol contains a high-affinity fatty acyl-CoA-binding protein (ACBP) [Knudsen, Hojrup, Hansen, H.O., Hansen, H.F. and Roepstorff (1989) Biochem. J. 262, 513-519]. We show here that palmitoyl-CoA (PCoA) in a complex with a molar excess of bovine ACBP causes a discrete Ca2+ efflux or allows Ca2+ release from the Ca2+-preloaded terminal cisternae fraction by sub-optimal caffeine concentrations. Both effects were abolished by elevating the free [Mg2+] in the system, which inhibits the Ca2+ release channel activity. Sensitization towards caffeine was a function of both the concentration of the complex and the [PCoA]-to-[ACBP] ratio. In all experimental conditions the calculated free [PCoA] was no more than 50 nM, and such concentrations by themselves were inactive on Ca2+ release channels. The KD for PCoA binding was approx. 2 nM for bovine and yeast ACBP, and slightly higher (8 nM) for rat ACBP. The PCoA-rat ACBP complex behaved in the same manner as the PCoA-bovine ACBP complex, whereas the ester complexed with yeast ACBP was more active in activating/sensitizing Ca2+ efflux. A non-hydrolysable analogue of PCoA bound to (bovine) ACBP also sensitized the Ca2+ release channel towards caffeine. These findings indicate that fatty acyl-CoA-ACBP complexes either interact directly with one or more components in the terminal cisternae membranes or, through interaction with the component(s), donate the fatty acyl-CoA esters to high-affinity binding sites of the membrane, thus affecting (and possibly regulating) Ca2+ release channel activity.