(W1130-06-39) Development of In Vitro Release Testing and In Vitro Permeation Testing Methods to Study the Impact of Quantitative Differences in Carbomer on the Performance of Diclofenac Sodium Topical Gels

Purpose: Differences in the formulation composition and/or the manufacturing process may influence the physicochemical and structural (Q3) properties, and thereby, the performance of topical products. The aim of the current study is to develop and validate a discriminatory in vitro release test (IVRT) method and an in vitro permeation test (IVPT) method to assess the impact of quantitative differences in carbomer on the performance of diclofenac sodium gels.

Methods: Five diclofenac sodium gels, 0.5% w/w containing propylene glycol, methylparaben, propylparaben, sodium hydroxide and water were prepared by varying the amount of gelling agent, carbomer homopolymer type C (Carbopol 980). The reference formulation contained 0.5% w/w Carbopol 980. Four modified formulations contained 0.55%w/w (reference+10%), 0.45% w/w (reference-10%), 0.625%w/w (reference+25%) and 0.375%w/w (reference-25%) of Carbopol 980. The Q3 properties of the gels including appearance, pH, water activity, microstructure, and rheology were evaluated. IVRT and IVPT studies were performed using vertical diffusion cells in accordance with the relevant FDA guidances [1,2]. The receptor solution, dose amount, study duration and sampling intervals were carefully chosen. Pivotal IVRT and IVPT studies were performed for all five formulations.

Results: All Q3 properties except rheology were similar across the 5 gels. The microscopic images showed that diclofenac sodium was fully dissolved in the gels. The zero-shear viscosity increased as the amount of the gelling agent increased in the formulations (Table 1). The IVRT method was developed using the reference gel, and the method was found to be linear, precise, and reproducible with an average R²=0.9989, intra-run coefficient of variation (CV) of 5.53% and inter-run CV of 4.45% (n=6). The diclofenac sodium release from the five carbomer gels are shown in Figure 1a. The gel containing 0.375%w/w (reference-25%) carbomer appears to have a higher release rate compared to other gels, however, the 90% confident intervals (CI) were within the limits of 75-133.33% (Figure 1b), indicating that there is no statistical difference in the diclofenac sodium release rates for the modified gels compared to the reference gel. Similarly, the permeation and flux profiles (Figure 2) for all the gels appeared to be similar with no significant differences in the permeation and/or flux.

Conclusion: All modified gels showed similar Q3 properties to the reference gel, except rheology. Furthermore, the in vitro release rates and flux profiles of diclofenac sodium were comparable across the 5 gels. This suggests that altering carbomer homopolymer type C (Carbopol 980) concentration by up to 25% compared to the reference gel does not significantly impact the in vitro performance of the diclofenac sodium gels evaluated in this study.

References: 1. Draft Guidance for Industry: In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs
2. Draft Guidance: In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs

Acknowledgements: This work was funded by the Broad Agency Announcements (BAA) # 75F40123C00213 from the U.S. Food and Drug Administration (FDA).


Table 1. Physicochemical and structural (Q3) properties of diclofenac sodium gels containing different amounts of Carbopol 980 (data are presented as Mean ± SD, n=3)


Figure 1. (a) IVRT profiles of diclofenac sodium gels (data are presented as Mean ± SD, n = 6) (b) Comparison of release rates across the 4 gels (T) and the reference gel (R)


Figure 2. IVPT flux profiles for diclofenac sodium gels (data are presented as Mean ± SE, 3 donors, 3 replicates per donor)