(T1430-11-63) Development of Accelerated Transdermal Diffusion model for In Vitro Permeation Testing of Topical Pharmaceuticals

Purpose: In Vitro Permeation Testing (IVPT) is a sensitive in vitro tool to demonstrate the bioequivalence of topical drug products and current test methodology is a time-consuming process. The objective of this study was to develop an accelerated transdermal diffusion model for IVPT with a reasonable time frame, without compromising skin tissue integrity.

Methods: IVPT experiments were performed using Perme Gear vertical Franz diffusion cells, ex-vivo human skin samples and Dapsone gel 7.5 % as a model drug product (1). The testing parameters used for the IVPT study are provided in Table 1.  Human skin samples were used as is or after treatment with different permeation enhancers (PEs), namely Chloroform, Oleic acid, or Dimethyl sulfoxide (DMSO)) for 30 minutes. The skin barrier integrity was assessed by measuring Trans epidermal water loss (TEWL) (2). Drug concentrations were measured using a validated HPLC method. To assess the selectivity of the developed IVPT model, two different formulations were compared. Cumulative drug release (ng/cm²) with respect to time and Flux Profiles (ng/cm²/hr.) were compared to assess the effectiveness of PEs in accelerating the drug permeation through the skin.

Results: Cumulative drug release (ng/cm²) with respect to time and rate of Flux Profiles (ng/cm²/hr.) are provided in Figures 1 and 2, respectively. Among the three PEs used, Skin treated with DMSO showed approximately 126-fold increase in cumulative drug release per cm² and 45-fold increase in Flux Profiles (ng/cm²/hr.), relative to untreated skin. Effect of PEs on skin permeation was in the order of DMSO > Oleic Acid >Chloroform >Untreated skin. Integrity of skin samples was confirmed. TEWL values were < 20gm/m³/hr. for all the skin samples (2). Similarly, the model proved selective when different formulations were evaluated and compared for diffusion parameters.

Conclusion: IVPT study can be accelerated using PEs without compromising skin tissue integrity. Skin samples treated with PEs demonstrated desired flux profiles with significant reduction of time.

References: 1. Shin SH, Rantou E, Raney SG, Ghosh P, Hassan H, Stinchcomb A. Cutaneous Pharmacokinetics of Acyclovir Cream 5% Products: Evaluating Bioequivalence with an In Vitro Permeation Test and an Adaptation of Scaled Average Bioequivalence. Pharm Res. 2020 Oct 1;37(10):210
2. Miranda M, Veloso C, Brown M, C Pais AAC, Cardoso C, Vitorino C. Topical bioequivalence: Experimental and regulatory considerations following formulation complexity. Int J Pharm. 2022 May 25; 620:121705.

Table 1. Test Parameters used for IVPT analysis



Figure 1 Cumulative amounts of Dapsone permeated (ng/cm2) through untreated and PE- treated skin tissues (Temperature 32±1°C, 600 RPM stir speed)



Figure 2. Rate of Flux profiles of Dapsone permeated through the skin treated with different PEs (ng/cm2/hr.) (Temperature 32±1°C, 600 RPM stir speed