Research show that novel cream-gel and gel-in-oil formulations are attractive alternatives for targeted skin penetration of an API - broadening the range of choices of topical formulations.
Effective skin penetration of an active pharmaceutical ingredient is essential in developing topical drugs. This penetration can be optimized to enhance efficacy and safety by carefully selecting the appropriate dosage form.
New research conducted by R&I Seppic teams look into two emerging dosage forms: cream-gel and gel-in-oil emulsion. The goal of the study was to maximise the API concentration in the skin sublayers (stratum corneum, epidermis, and dermis), while achieving equal or lower diffusion in the receptor fluid, when compared to a market benchmark. In the dosage forms containing the API diclofenac sodium and formulated with Sepineo P 600 (3-in-1 polymer) and Sepineo SE 68 (self-emulsifying system), various penetration enhancers and emollients were tested by in vitro penetration tests on human skin. The penetration enhancers included: Propylene glycol (PG), diethylene glycol monoethyl ether (DEGEE), and a combination of the two (PG-DEGEE). The emollients included: Isopropyl myristate (IPM), coco-caprylate / caprate alone (CCC) or with liquid paraffin (CCC-MO). The benchmark product was based on the conventional semi-solid dosage form, emulgel.
What are cream-gel and gel-in-oil formulations
Cream-gel is an oil-in-water system, where the lipophilic phase is stabilised by a gel polymer network not requiring the addition of surfactants (figure 1), while gel-in-oil emulsions consists of a high concentration of closely packed gel droplets dispersed within a liquid continuous oil phase (figure 2).
Figure 1: Schematic representation of a cream-gel microstructure. R&I Seppic teams [1]
Figure 2: Schematic representation of a gel -in-oil emulsion microstructure. R&I Seppic teams [1]
The tests revealed that cream-gel formulas exhibited higher penetration into the receptor solution compared to the emulgel benchmark drug, whereas gel-in-oil emulsions led to decreased diffusion of the API into the receptor fluid. The tests also showed that addition of the enhancer DEGEE to cream-gel resulted in higher penetration into receptor fluid, however no significant difference was seen between for the gel-in-oil emulsions (fig. 3). Furthermore, the tests demonstrated that removing the penetration enhancers from the cream-gel or gel-in-oil formulations resulted in a penetration profile in receptor fluid closer to benchmark (data not shown).
Figure 3: In vitro penetration profiles of cream-gel and gel-in-oil emulsion compared to benchmark. R&I Seppic teams [1]
The penetration of diclofenac (API) into cutaneous layers after 24 hours was studied for cream-gels with penetration enhancer (Cream-Gel + PG-DEGEE) and without (Cream-Gel IPM, Cream-Gel CCC-MO, Cream-Gel CCC). The three cream–gels without enhancer showed significantly higher diclofenac content in the epidermis compared to the benchmark, in addition to higher dermis content for Cream-Gel IPM and Cream-Gel CCC (Figure 4).
Figure 4: Comparison of cream with solvent removal (PG-DEGEE vs without) and emollient changes to benchmark. Amount of diclofenac penetrated into skin layers and receptor fluid after 24 h. R&I Seppic teams [1]
The penetration of diclofenac (API) into the different layers of skin was also tested for gel-in-oil emulsion. This test demonstrated that removing propylene glycol from gel-in-oil emulsion did not change the total amount of diclofenac penetrated, but it changed skin distribution of the API, with significant higher epidermis and dermis content versus the benchmark and higher dermis content versus gel-in-oil with propylene glycol (figure 5). Furthermore, rheological characterisation revealed similar profiles of cream-gel and emulgel, whereas gel-in-oil emulsion showed characteristics suitable for massaging product into the skin.
Figure 5: Comparison of gel-in-oil emulsion with solvent removal (PG-CCC vs CCC alone. Amount of diclofenac penetrated into skin layers and receptor fluid after 24 h. R&I Seppic teams [1]
Conclusion
The novel cream-gels and gel-in-oil emulsions are attractive delivery systems for active pharmaceutical ingredients, broadening the range of choices for targeted skin application. The two formulations showed higher penetration of API into skin layers compared to benchmark, but only gel-in-oil showed reduced penetration of API in receptor fluid, opening the possibility for lower systemic exposure of APIs.
[1] Gavinet B, Sigurani S, Garcia C, Roso A. Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium. International Journal of Molecular Sciences. 2024; 25(13):7432. https://doi.org/10.3390/ijms25137432
