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Investigation of the Compatibility of the Skin PAMPA Model with Topical Formulation and Acceptor Media Additives Using Different Assay Setups

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Abstract

The Skin Parallel Artificial Membrane Permeability Assay (PAMPA) is a 96-well plate–based skin model with an artificial membrane containing free fatty acid, cholesterol, and synthetic ceramide analogs to mimic the stratum corneum (SC) barrier. The current study evaluates the compatibility of lipophilic solvents/penetration enhancer, topical emulsions containing different emulsifier systems, and organic acceptor media additives with the artificial membrane of the assay. Additionally, different assay setups (standard setup: donor in bottom plate versus modified setup: donor in top plate) were compared. Methylparaben (MP), ethylparaben (EP), and propylparaben (PP) were used as model permeants and internal standards for proper assay execution. The permeation order of the parabens (MP > EP > PP) remained the same with different lipophilic solvents, and the ranking of lipophilic solvents was comparable under standard and modified conditions (isopropyl myristate, IPM > dimethyl isosorbide, DMI ≥ propylene glycol, PG > diisopropyl adipate, DIPA). Pre-incubation of the Skin PAMPA plates with IPM, DIPA, and DMI, as well as with formulations that contain non-ionic emulsifiers, and acceptor solutions containing DMSO or EtOH (≤ 50%) for 4 h did not increase the percentage of permeated parabens in the main experiment, suggesting that those compounds do not make the artificial membrane more permeable. High-resolution mass spectrometry confirmed that acceptor solutions with ≤ 50% DMSO or EtOH do not extract stearic acid, cholesterol, and certramides at standard assay conditions. Hence, if certain constraints are considered, the Skin PAMPA model can be used as a pre-screening tool for topical formulation selection.

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Abbreviations

API:

Active pharmaceutical ingredient

DIPA:

Diisopropyl adipate

DMI:

Dimethyl isosorbide

DMSO:

Dimethyl sulfoxide

EtOH:

Ethanol

IPM:

Isopropyl myristate

MP, EP & PP:

Methyl-, ethyl- & propylparaben respectively

PAMPA:

Parallel Artificial Membrane Permeability Assay

PG:

Propylene glycol

SC:

Stratum corneum

UPLC:

Ultra-performance liquid chromatography

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Acknowledgements

The authors thank Elvira Balaguer, Almirall SA, Sant Feliu, Spain, for technical support.

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Authors and Affiliations

  1. Almirall Hermal, R&D Dermatology, Scholtzstrasse 3, 21465, Reinbek, Germany

    Melanie Köllmer, Parinaz Mossahebi, Elena Sacharow, Sascha Gorissen, Nicole Gräfe, Dirk-Heinrich Evers & Michael E. Herbig

  2. RaDes GmbH, Schnackenburgallee 114, 22525, Hamburg, Germany

    Melanie Köllmer, Sascha Gorissen, Dirk-Heinrich Evers & Michael E. Herbig

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  1. Melanie Köllmer
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  2. Parinaz Mossahebi
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Correspondence to Melanie Köllmer.

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Köllmer, M., Mossahebi, P., Sacharow, E. et al. Investigation of the Compatibility of the Skin PAMPA Model with Topical Formulation and Acceptor Media Additives Using Different Assay Setups. AAPS PharmSciTech 20, 89 (2019). https://doi.org/10.1208/s12249-019-1305-3

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