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Enhancement of Galantamine HBr Skin Permeation Using Sonophoresis and Limonene-Containing PEGylated Liposomes

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Abstract

This study aimed to investigate the effect of low-frequency sonophoresis (SN) and limonene-containing PEGylated liposomes (PL) on the transdermal delivery of galantamine HBr (GLT). To evaluate the skin penetration mechanism, confocal laser scanning microscopy (CLSM), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) were employed. The application of SN led to more GLT penetration into and through the skin than GLT solution alone. The liposomes also improved GLT permeation, and 2% limonene-containing PL (PL-LI2%) exhibited the highest GLT permeation, followed by PL-LI1%, PL-LI0.1%, and PL. The CLSM images of PL-LI2% resulted in the highest fluorescence intensity of fluorescent hydrophilic molecules in the deep skin layer, and the rhodamine PE-labeled liposome membrane was distributed in the intercellular region of the stratum corneum (SC). PL-LI2% induced significant changes in intercellular lipids in the SC, whereas SN had no effect on intercellular lipids of the SC. DSC thermograms showed that the greatest decrease in the lipid transition temperature occurred in PL-LI2%-treated SC. SN might improve drug permeation through an intracellular pathway, while limonene-containing liposomes play an important role in delivering GLT through an intercellular pathway by increasing the fluidity of intercellular lipids in the SC. Moreover, a small vesicle size and high membrane fluidity might enhance the transportation of intact vesicles through the skin.

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Abbreviations

Chol:

cholesterol

CLSM:

confocal laser scanning microscopy

DPH:

1,6-diphenyl-1,3,5-hexatriene

DSC:

differential scanning calorimetry

ED:

epidermis and dermis

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

FTIR:

Fourier transform infrared spectroscopy

GLT:

galantamine HBr

NaFI:

sodium fluorescein

PC:

egg phosphatidylcholine

PEG2000-DSPE:

Na-salt N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine

PL:

PEGylated liposomes

PL-LI:

limonene-containing PEGylated liposomes

Rhodamine PE:

rhodamine B 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt

SC:

stratum corneum

SD:

standard deviation

SN:

sonophoresis

Tm:

transition midpoint temperature

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Funding

We gratefully acknowledge the Thailand Research Funds through the Royal Golden Jubilee PhD Program (Grant No. PHD/0091/2554) for the financial support and thank for the Faculty of Pharmacy and Graduate School, Silpakorn University, Nakhon Pathom, Thailand and Department of Pharmaceutics, Hoshi University, Tokyo, Japan for all facilities and support. This work was supported by the MEXT-Supported Program for the Strategic Research Foundation at Private University, 2014-2018, S1411019.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand

    Worranan Rangsimawong, Praneet Opanasopit & Tanasait Ngawhirunpat

  2. Department of Pharmaceutics, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan

    Yasuko Obata

  3. Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, 350-0295, Japan

    Kozo Takayama

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  1. Worranan Rangsimawong
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Correspondence to Worranan Rangsimawong.

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Rangsimawong, W., Obata, Y., Opanasopit, P. et al. Enhancement of Galantamine HBr Skin Permeation Using Sonophoresis and Limonene-Containing PEGylated Liposomes. AAPS PharmSciTech 19, 1093–1104 (2018). https://doi.org/10.1208/s12249-017-0921-z

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