(W1230-10-55) In Vivo Evaluation of Cocoyl Caprylocaprate on API Skin Permeation and Bioavailability

Purpose: Kollicream^® 3 C (AKA Cocoyl caprylocaprate, UNII 8D9H4QU99H) is a lipid-based excipient with beneficial properties for topical semisolid drug formulations. The objective of the study reported here was to conduct in vivo studies to assess whether the presence of Kollicream^® 3 C in a formulation would impact API skin permeation and bioavailability.

Methods: Five similar semi-solid cream formulations were prepared with the following variations: F1: With 3 w/w% cocoyl caprylocaprate + 2 w/w% mineral oil and 1% Ketoprofen, F2: Without cocoyl caprylocaprate + 5 w/w% mineral oil and 1% Ketoprofen, F3: With 3 w/w% cocoyl caprylocaprate + 2 w/w% mineral and 1% Sodium diclofenac, F4: Without 3 w/w% cocoyl caprylocaprate + 5 w/w% mineral oil and 1% Sodium diclofenac and F5: Placebo control with 3 w/w% cocoyl caprylocaprate + 2 w/w% mineral oil and no API. The stability of the five formulations during the expected duration of the study (3 months) at room temperature was determined and confirmed by monitoring pH, emulsion droplet size distribution and specific gravity. Sprague-Dawley rats were topically treated with each of the formulations (n=6 for each sampling time point for formulations with API plus or minus cocoyl caprylocaprate, n=3 for each time point for placebo formulations). Blood samples were drawn and analyzed at 2, 4, 6 and 8 hours after cream application to the skin. Rats were sacrificed at plasma sampling intervals and the treated skin on each sacrificed animal was removed and analyzed for drug content. Studies were performed as per CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals) guidelines.

Results: Ketoprofen: The plasma concentration profile demonstrated a typical profile as generally observed in topical drug absorption cases from a finite dose (see Figure 1). For Ketoprofen (see Table 1) statistical analysis (T-test) indicated that the plasma concentrations were significantly higher with the cocoyl caprylocaprate containing creams versus the creams without cocoyl caprylocaprate up to 6 hours. At 8 hours plasma samples were not significantly different. The plasma concentration-time profile of the 8th hour group was used to calculate pharmacokinetic parameters including AUC (area under the curve), C_max, and T_max as the number of samples (n = 6) remained the same at all time points. The difference in the area under the curve and the C_max between the test and the control products was statistically significant (P=0.001 and 0.002 respectively). The T_max did not differ significantly. Particularly at 2 hours, the amount of drug in the skin (Table 2) was >3x higher in case of cream with cocoyl caprylocaprate compared to the control. The amount of drug in the skin was comparable at 6 and 8-hour time points across the two creams. Diclofenac sodium: The plasma concentration was statistically significantly different between the creams with and without cocoyl caprylocaprate up to 6 hours, but not different at 8 hours (see Table 1). The difference in area under the curve and the C_max between the test and the control products was statistically significant (P < 0.05). While the T_max visually appeared to be different, the T_max did not differ significantly (4.33±0.82 h versus 3.0±1.67 h in the case of the cream without and with cocoyl caprylocaprate, respectively, likely due to the variability). The diclofenac sodium skin content (Table 2) also showed an initial increase followed by a decline. The amount of drug in the skin was significantly higher in the cream that incorporated cocoyl caprylocaprate in comparison to the control cream at 2 and 4 hours. At 2 hours, the amount of drug in the skin was about 3x higher in the cocoyl caprylocaprate cream vs control.

Conclusion: Incorporation of Kollicream^® 3 C in topical semi-solid formulations had a significant effect on bioavailability and skin retention:The drug concentration time profiles exhibited a skewed bell curve likely because of two phenomena: Depletion of drug at the site of absorption over time and the transient permeability enhancement effect of cocoyl caprylocaprate. This is evident in the way the amount of drug in the skin and the plasma drug concentration gradually converged at later time points. Kollicream^® 3 C accelerated the rate of drug penetration into and through the skin. The enhanced permeation appears to be driven by the concentration gradient between the skin and systemic circulation per Fickian diffusion.

Figure 1. API Plasma Levels (with and without cocoyl caprylocaprate)

Table 1. API Plasma Levels at (ng/ml) at time intervals after topical application

Table 2. API content in skin (ng/ml), from treatment area, at time intervals after topical application