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Construction of Imatinib Controlled Release Film-Forming System Based on Drug Ion-Pair and Oligomeric Ionic Liquids for the Long Local Therapy of Cutaneous Melanoma

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Abstract

An imatinib controlled release film-forming system (FFS) was developed based on the drug ion-pair and newly designed oligomeric ionic liquids (OILs) for the topical therapy of cutaneous melanoma, which avoided the systemic side-effect of oral administration and maintained a long local therapy effect. The OILs significantly improved the drug release capacity about 1.5-fold, and the formability and stability of FFSs (verified by AFM/PLM). The in vivo anti-tumor efficacy studies in melanoma tumor bearing mice showed that compared with the oral capsules, the topical application of the optimized imatinib FFS significantly (p < 0.01) increased tumor inhibition rate (67.54 ± 2.72%) and the amount of apoptotic cells. As confirmed by FT-IR and NMR, the partial protonation of OILs were demonstrated to have high hydrogen bond forming capacity, thus showing low polarity and good biocompatibility. More importantly, based on 13C-NMR study, OILs demonstrated higher hydrogen bond forming capacity, and formed bridge between drug ion-pair (O–H of counter-ion) and PVA (O–H), increased the molecular mobility of PVA, thus maintaining a long drug release capacity. Therefore, an imatinib FFS was developed with good therapeutic effect and the effect of drug ion-pair and OILs on increasing the drug skin retention and controlled release of imatinib FFS for topical therapy was clarified at the molecular level, which provided a safe and effective way for the treatment of cutaneous melanoma.

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Data will be made available on request.

Abbreviations

IM:

Imatinib

ILs:

Ionic liquids

OILs:

Oligomeric ionic liquids

SC:

Stratum corneum

FFS:

Film-forming system

TDDS:

Transdermal drug delivery system

IM-LA:

Imatinib-lactic acid

GE:

Geranic acid

OLE:

Oleic acid

LA:

Lactic acid

ERU:

Erucic acid

LAU:

Lauric acid

DEC:

Decanoic acid

BEN:

Benzoic acid

LIN:

Linoleic acid

TIR:

Tumor inhibition rate

FT-IR:

Fourier transform infrared

ODO:

Caprylic/capric triglyceride

CH-GE:

Oligomeric ionic liquids prepared from choline and geranic acid

PVA:

Polyvinyl alcohol

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No: 81803468).

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Authors and Affiliations

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

    Junzhu Wang, Han Sun, Wenxuan Jia, Yilin Song, Peng Quan, Liang Fang & Chao Liu

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  3. Wenxuan Jia
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Contributions

Junzhu Wang: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing—original draft, Writing—review & editing. Han Sun: Methodology, Investigation. Wenxuan Jia: Methodology, Investigation. Yilin Song: Validation, Investigation. Peng Quan: Validation, Formal analysis. Liang Fang: Resources, Supervision. Chao Liu: Conceptualization, Resources, Writing—original draft, Writing—review & editing, Supervision, Funding acquisition.

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Correspondence to Chao Liu.

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Wang, J., Sun, H., Jia, W. et al. Construction of Imatinib Controlled Release Film-Forming System Based on Drug Ion-Pair and Oligomeric Ionic Liquids for the Long Local Therapy of Cutaneous Melanoma. AAPS PharmSciTech 24, 87 (2023). https://doi.org/10.1208/s12249-023-02546-3

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