(T1530-08-50) Chemical Profiling and Single-Solvent System Effects in Topical Cimetidine Formulations

Purpose: Cimetidine, a histamine-2 receptor antagonist, demonstrates immunomodulatory properties with potential applications in treating cutaneous warts. While traditionally administered orally or intravenously, topical delivery offers advantages by directly targeting affected tissues and avoiding first-pass metabolism. This study aimed to (1) characterize the pH-dependent lipophilicity of cimetidine by determination of the Log D_{1-octanol/buffer} at different pH values as this has not been reported in the literature and (2) evaluate the in vitro skin permeation and retention profiles of model cimetidine single-solvent systems using Franz diffusion cell studies with porcine ear skin.

Methods: Log D_{1-octanol/buffer} values of cimetidine were determined using the shake flask method in accordance with OECD guidelines¹ at pH 4.8 (citric acid/trisodium citrate buffer), 6.8 (sodium phosphate buffer), 7.4 (PBS), and 8.8 (tris/HCl buffer) at 23 ± 1°C. For permeation studies, 5% (w/v) cimetidine formulations were prepared in propylene glycol (PG), Transcutol^® (TC), and 1,2-pentanediol (1,2-PeD). Franz diffusion cell experiments were conducted under both infinite (250 μL) and finite (10 μL) dose conditions at 32 ± 1°C for 24 h. All samples for Log D determinations, permeation and mass balance determination were quantified using a validated HPLC method.

Results: The Log D_{1-octanol/buffer} values of cimetidine were determined as -2.07 ± 0.23 at pH 4.8, -0.09 ± 0.01 at pH 6.8, 0.33 ± 0.02 at pH 7.4, and 0.43 ± 0.01 at pH 8.8 (n = 9, mean ± SD). Franz diffusion cell studies showed limited cimetidine permeation through porcine ear skin for PG (3.54 ± 0.51 μg/cm² for infinite dosing, 2.80 ± 0.86 μg/cm² for finite dosing) and TC (0.97 ± 0.34 μg/cm² for infinite dosing, 0.82 ± 0.25 μg/cm² for finite dosing) after 24 h (4 ≤ n ≤ 5, mean ± SD). No permeation of cimetidine from 1,2-PeD was observed for either dosing condition. The skin retention of cimetidine varied between finite and infinite dose conditions for different solvents. For PG, the retention was 10.65 ± 2.03 μg under infinite dose conditions and 13.13 ± 1.42 μg under finite dose conditions. TC showed a more significant difference, with 1.60 ± 0.49 μg for infinite dose conditions and 11.37 ± 2.57 μg for finite dose conditions (p  < 0.001). In contrast, 1,2-PeD resulted in similar retention amounts for both dosing conditions: 4.32 ± 0.45 μg for infinite dose conditions and 4.57 ± 0.92 μg for finite dose conditions (4 ≤ n ≤ 5, mean ± SD). Notably, for TC, the skin retention amounts were significantly higher under finite dose conditions compared to infinite dose conditions. Under finite dose conditions, cimetidine skin retention for PG and TC was significantly higher compared with 1,2-PeD (p < 0.01), with no statistical difference between the values for PG and TC (p > 0.05).

Conclusion: The relatively low Log D_{1-octanol/buffer} values of cimetidine across the tested pH range (4.8, 6.8, 7.4, and 8.8) confirm the hydrophilic character of the molecule. This comprehensive pH-dependent lipophilicity characterization is the first reported at these specific pH values. As hydrophilic substances have limited interaction with the lipid-rich environment of the stratum corneum², this likely contributes to the poor skin permeation observed. Despite this, the observed skin retention, especially under finite dose conditions, indicates the potential for achieving localized cutaneous delivery through appropriate formulation strategies. This study, comparing permeation studies under both finite and infinite dose conditions, illustrates the importance of dosing regimens on skin retention. PG and TC promoted significantly greater cimetidine skin retention compared to 1,2-PeD, likely due to their solubilizing properties and ability to modify stratum corneum lipid organisation^3,4. These findings suggest PG and TC as promising candidates for cimetidine topical formulations and emphasize the importance of vehicle selection in topical formulation design. The observed skin retention, despite poor permeation, indicates potential for a localized delivery strategy that could minimize systemic exposure while maximizing therapeutic efficacy at the target site. To our knowledge, this is the only report of cimetidine permeation through intact porcine ear skin. This research provides a foundation for developing effective cimetidine-based treatments for cutaneous warts and potentially other skin conditions.

References: 1. OECD. Test No. 107: Partition Coefficient (n-Octanol/Water): Shake Flask Method. (OECD, 1995).
2. Margalit, R. et al. Liposomal drug delivery: thermodynamic and chemical kinetic considerations. J. Controlled Release 17, 285–296 (1991).
3. Osborne, D. W. & Musakhanian, J. Skin Penetration and Permeation Properties of Transcutol®—Neat or Diluted Mixtures. AAPS PharmSciTech 19, 3512–3533 (2018).
4. Carrer, V. et al. Effect of propylene glycol on the skin penetration of drugs. Arch. Dermatol. Res. 312, 337–352 (2020).

Figure 1. Recovery (%) of cimetidine from the applied dose during the mass balance experiments after 24 h infinite dose permeation studies (4 ≤ n ≤ 5; mean ± SD) (*p < 0.05, **p < 0.01).

Figure 2. Recovery (%) of cimetidine from the applied dose during the mass balance experiments after 24 h finite dose permeation studies (4 ≤ n ≤ 5; mean ± SD) (*p < 0.05, **p < 0.01).