(T1430-01-05) Influence of Kollicream^® OD on Ibuprofen Skin Permeation and Retention

Purpose: Kollicream^® OD (octyldodecanol) is a cGMP-manufactured, compendial grade solvent and emollient based on non-petrolatum resources. As a medium spreadability oil, this lipophilic excipient has been shown to provide medium emollience and may enhance skin penetration of some active pharmaceutical ingredients (APIs). Due to its chemical structure as a branched chain primary alcohol, Kollicream^® OD is stable against hydrolysis and can therefore be used in an exceptionally wide pH range, suitable for alkaline and acidic topical, transdermal, and vaginal applications. Previous spectral analytical studies have shown that Kollicream^® OD can increase stratum corneum lipid disordering. An investigation into the effect of adjusting the concentration of Kollicream^® OD on ibuprofen-containing semi-solid formulations was conducted to understand how this lipidic penetration enhancer influences API skin permeation and retention.

Methods: Six creams composed of Kolliwax^® CSA 50 (cetostearyl alcohol, BASF), Kolliwax^® GMS II (mono- and di-glycerides, BASF), Kolliphor^® PS 60 (polysorbate 60, BASF), Kolliwax^® MCT 70 (medium chain triglycerides, BASF), mineral oil (Spectrum Chemical), Kollicream^® OD (BASF), ibuprofen (BASF), glycerin (Avantor Performance Materials), and Euxyl^® PE 9010 (phenoxyethanol-ethylhexylglycerin, Ashland) were formulated. Creams were composed of variable amounts of Kollicream^® OD (0%, 3%, 5%, 7%, 9%, and 12%) with other excipients held constant. The formulations were hot processed under the conventional direct method. The creams underwent in vitro permeation testing (IVPT) with the following conditions: diffusion area of 0.64 cm², receptor media of PBS (pH 7.4), equilibration time of 15 minutes, receptor chamber mixing rate of 600 rpm, and sampling volume of 400 µL. Samples were pulled at the following time points: 0, 1, 2, 4, 8, 12, 16, 20, and 24 hours. Ibuprofen was quantified using a high performance liquid chromatography (HPLC) with UV detection. The HPLC system was an Agilent 1100 Series liquid chromatograph with Agilent Chemstation software. A mobile phase consisting of 40% pH 2.5 buffer and 60% acetonitrile was pumped through an Agilent Eclipse XDB-C18, 3.5 µm, 4.6 x 150 mm column at a flow rate of 1.0 mL/minute, and an injection volume of 30 µL. The column temperature was maintained at 25.0 + 0.2°C with UV detection at 221nm. To determine the ibuprofen concentration in the epidermis and dermis after IVPT, the donor compartment was removed, and the skin gently wiped to remove excess formulation. The skin was then rinsed with an appropriate volume of PBS to remove residual formulation and then wiped dry with a Q-tip. The dermis and epidermis were separated using forceps and transferred into pre-weighted homogenization tubes. The final weight of the homogenization tube was recorded. 1 mL of PBS was added into each tube and the samples was homogenized for 9 minutes using a BeadBug homogenizer. Samples were then centrifuged at 4000 rpm for 4 minutes followed by filtration of the supernatant using a 0.45 um Nylon syringe filter. Samples were analyzed using the validated HPLC method described previously.

Results: The amount of ibuprofen that permeated across human cadaver skin into the receptor compartment was found to be lower for the Kollicream^® OD-containing formulations in comparison to the control (Figure 1). The calculated mean flux at a given time was also lower for the Kollicream^® OD-containing formulations when compared to the control (Figure 2). Skin distribution studies showed that amount of ibuprofen detected in the dermal layer was not significantly different between the formulations. However, there was a clear trend where the amount of ibuprofen detected in the epidermal layer decreased as the concentration of Kollicream^® OD was increased in the formulation. The total amount of ibuprofen detected in the skin after 24 hours was similar across all formulations.

Conclusion: Kollicream^® OD containing formulations can influence the amount ibuprofen that is retained in the skin. While the control formulation released more ibuprofen into the receptor compartment over time in comparison to Kollicream^® OD-containing formulations, skin distribution studies showed that similar amounts of ibuprofen were detected in the skin at 24 hours for all formulations. These results indicate that Kollicream^® OD allows for reduced ibuprofen to be available for entry into systemic circulation. Kollicream^® OD provides a retardant effect to enhance localized delivery of ibuprofen. IVPT and skin distribution study results are not predictive of each other and should be considered as complimentary tests.