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The Molecular Mechanism of Propylene Glycol Monocaprylate on Skin Retention: Probing the Dual Roles on the Molecular Mobility and Collagen Connection in Roflumilast Cream

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Abstract

The present work was to construct a roflumilast (ROF) cream for the treatment of psoriasis and clarify the dual roles of propylene glycol monocaprylate (PGM) in both molecular mobility of the cream, and drug-skin miscibility via drug-PGM-ceramide and drug-PGM-collagen intermolecular interaction. The cream formulation was screened through the stability study and in vitro skin administration study, optimized by Plackett–Burman and Box-Behnken design, and finally verified by the in vivo tissue distribution study. PGM demonstrated a significant drug skin retention enhancement effect (Rmax in vivo = 19.5 μg/g). It increased the molecular mobility of the oil phase of the cream by decreasing the molecular interaction of oil molecules proven by the rheology study (Ec = 3.73 × 10−4 mJ·m−3). More importantly, because of the good stratum corneum (SC) compatibility (∆H =  − 403.88 J/g), PGM promoted an orderly flow of SC lipids (X-ray scattering, ΔLPP = 1.18 nm) and entered the viable epidermis/dermis (VE/DE) in large quantities (RPGM = 1186 μg/g), acting as a bridge to connect the drug to collagen through two H-bonds (LengthH-bond = 2.846 Å and 3.313 Å), thus increasing the miscibility of drug and VE/DE significantly (∆H =  − 310.10 J/g, Emix = 21.66 kcal/mol). In this study, a ROF cream was developed successfully and the effect of PGM on the skin retention was clarified at molecular level.

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Funding

This work was supported by Liaoning Province Science and Technology Plan Project (No: 2020JH2/10300075).

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Author notes

  1. Yuxue Liu and Chao Liu contributed equally to this work and should be considered as co-first authors.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China

    Yuxue Liu, Chao Liu, Wenxuan Jia, Wenwen Xu, Peng Quan & Liang Fang

Authors
  1. Yuxue Liu
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  2. Chao Liu
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  3. Wenxuan Jia
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  4. Wenwen Xu
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  5. Peng Quan
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  6. Liang Fang
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Contributions

Yuxue Liu: methodology, investigation, formal analysis, data curation, writing original draft. Chao Liu: supervision, writing, review, editing. Wenxuan Jia: resources. Wenwen Xu: investigation, formal analysis. Peng Quan: investigation, formal analysis, validation. Liang Fang: conceptualization, resources, project administration, funding acquisition.

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Correspondence to Liang Fang.

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Liu, Y., Liu, C., Jia, W. et al. The Molecular Mechanism of Propylene Glycol Monocaprylate on Skin Retention: Probing the Dual Roles on the Molecular Mobility and Collagen Connection in Roflumilast Cream. AAPS PharmSciTech 23, 136 (2022). https://doi.org/10.1208/s12249-022-02284-y

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