Passive and iontophoretic transport of pramipexole dihydrochloride across human skin microchannels created by microneedles in vitro

https://doi.org/10.1016/j.ijpharm.2021.121092Get rights and content

Highlights

  • Drug transport across microchannels was analyzed using a simple diffusion model.

  • Drug delivery across microchannels was concentration or drug-loading dependent.

  • Iontophoresis coupled with MN patch enhanced drug transport across microchannels.

  • MN-created skin microchannel is promising to achieve therapeutic PXCl plasma level.

Abstract

Skin microchannels (MCs) created by microneedles (MNs) provide a promising route for enhancing transdermal drug delivery. This study investigated passive and iontophoretic transport of pramipexole dihydrochloride (PXCl) across skin MCs created by polymer MN patches made of 1:2 polymethyl-vinyl-ether-co-maleic acid (PMVEMA) to polyvinyl alcohol (PVA) ratio. Permeation studies were performed in vitro using excised human skin under the conditions of (i) “poke-and-patch” and “poke-and-release” delivery approaches with varying concentration of PXCl in the formulations, (ii) drug-loaded dissolving MN (DMN) and hydrogel-forming MN (HGMN) type patches and (iii) combination of MNs and iontophoresis. The results showed that DMN patch greatly enhanced transdermal delivery of PXCl for both “poke-and-patch” and “poke-and-release” approaches as compared with the conventional delivery method. PXCl flux mainly resulted from the contribution of MC pathway created in skin and increased with increasing drug amounts in the formulations. Compared to DMN patch, HGMN patch provided more linear sustained drug delivery over 72 h. Electromigration was the main mechanism of PXCl iontophoresis through MCs and flux enhancement was found to be larger for HGMN patch than DMN patch. These results demonstrated the potential application of MN patches individually or combined with iontophoresis as an alternative method for PXCl administration.

Introduction

Microneedles (MNs) are a painless, self-administration and highly efficient means for enhancing transdermal drug delivery (Ripolin et al., 2017). They effectively pierce through the stratum corneum (SC) and create microchannels (MCs) in the skin resulting in skin penetration enhancement of a broad range of therapeutic small molecules and macromolecules (Nguyen et al., 2018, Yu et al., 2017). Currently, MNs can be divided into five categories: solid MNs, dissolving MNs (DMNs), hydrogel-forming MNs (HGMNs), coated MNs and hollow MNs. There are four major approaches of MN-mediated transdermal drug delivery: poke-and-patch, poke-and-release, poke-and-flow and coat-and-poke approaches (Al-Japairai et al., 2020).

Polymer MNs (DMNs and HGMNs) have gained attention for transdermal drug delivery because of their low cost, easy fabrication, degradability and safety (Arya et al., 2017, Chen et al., 2020). The polymer MNs that contain no drug can be fabricated and used as the substitution for solid metal MNs to disturb the skin barrier before transdermal drug delivery (poke-and-patch approach). In addition, drug can be loaded into the polymer solution during the fabrication process to form a drug-loaded MN patch that can be used for transdermal drug delivery in a single-step process after skin insertion (poke-and-release approach). A wide range of polymers has been used to fabricate DMNs such as polymethyl-vinyl-ether-co-maleic acid (PMVEMA) (Pamornpathomkul et al., 2018), polyvinyl alcohol (PVA) (Nguyen et al., 2018), maltose (Kolli and Banga, 2008) and polyvinylpyrrolidone (Ronnander et al., 2019). PMVEMA has also been used to fabricate HGMNs through thermal crosslinking with polyethylene glycol (PEG) (Migdadi et al., 2018) or pectin (Demir et al., 2017). For DMNs, when the MNs are embedded into the skin, they dissolve rapidly by the skin interstitial fluid and subsequently release the drugs into the skin and then the dermal microcirculation. For HGMNs, they swell by drawing the skin interstitial fluid into the MNs and then release the drugs from the swollen MN matrices allowing drug delivery into the skin (Al-Japairai et al., 2020).

Iontophoresis is a technique that enhances the delivery of charged and uncharged molecules across a membrane by the application of a low electric current (typically 0.1–0.5 mA/cm2) (Alkilani et al., 2015, Li et al., 2013). Different from MNs, iontophoresis primarily influences the transport of drug molecules by electromigration (EM) and electrosmosis (EO), and to some extent by electropermeabilization, rather than mainly altering the skin barrier. Recent studies have reported the combination of iontophoresis with MNs (either DMNs or HGMNs) to provide an additional or synergistic effect on the delivery of charged compounds across the skin compared to MN-mediated or iontophoretic delivery alone (Donnelly et al., 2012, Kumar and Banga, 2012, Ronnander et al., 2019).

Pramipexole dihydrochloride (PXCl), a low molecular weight (MW 284.2 g/mol) and highly water-soluble therapeutic agent, is a selective dopamine D2 agonist with antiparkinsonian activity (Bennett and Piercey, 1999). Long-term oral administration of PXCl to control motor dysfunction of Parkinson’s disease is inconvenient for elderly patients with dysphagia. This is likely a common reason for poor patient compliance. The development of transdermal administration of PXCl as an alternative drug delivery approach is highly attractive because of its ease of administration independent of the patients’ physical condition. Although transdermal administration of PXCl is favorable, skin permeability of PXCl is limited by the SC and the hydrophilicity and ionic nature (pKa = 5.0 and 9.6) of PXCl at physiological pH (Pu et al., 2017, Saepang et al., 2021). Therefore, the development of an effective transdermal delivery system for PXCl is challenging. Recently, enhanced transdermal delivery of PXCl has been studied using chemical penetration enhancer (Pu et al., 2017), iontophoresis (Kalaria et al., 2014, Kalaria et al., 2018, Saepang et al., 2021), nanocrystals (Li et al., 2018) and MN roller (Hoang et al., 2015). Considering the enhancement mechanisms of MNs and iontophoresis, PXCl can take advantage of both the aqueous MCs created by the MNs and transport enhancement provided by the externally applied electric current due to the hydrophilicity and ionic nature of PXCl. However, to our knowledge, there have been no reports on transdermal transport studies of PXCl across MN-created MCs using polymer MNs and the combined application of MNs and iontophoresis.

The present study examined the transport of PXCl across skin MCs created by polymer MN patches and the resultant transdermal delivery from the MN patches individually or in combination with iontophoresis. Transport studies were performed in vitro using the MN patch made of 1:2 weight ratio of PMVEMA to PVA as DMN with and without drug incorporation using the “poke-and-release” and “poke-and-patch” approaches, respectively. In addition to the DMN, drug-loaded HGMN patch was also prepared to compare for PXCl delivery. Iontophoresis of 0.5 mA/cm2 was assessed for its potential to further enhancing and controlling the transport of PXCl from the MN patches. The contributions of EM and EO to iontophoretic transport of PXCl across the skin MCs were determined to examine the transport mechanisms when MN was coupled with iontophoresis in transdermal PXCl delivery.

Section snippets

Materials and skin

PX and acetaminophen (AP) were purchased from Xi’an Lyphar Biotech Co. (Shaanxi, China) and Bengbu Bayi Pharmaceutical Co., Ltd. (Anhui, China), respectively. The process of Balicki et al. (Balicki et al., 2009) after modifications was used to prepare PXCl. The prepared PXCl monohydrate (MW 302.06 g/mol) after confirmation by elemental analysis and high performance liquid chromatography (HPLC) was used in this study. Sodium chloride (NaCl) was supplied by Carlo Erba Reagents (Milan, Italy).

Characterization and selection of nondrug-loaded DMN patch for enhanced transdermal transport of PXCl

The morphological characteristics, mechanical strength and skin insertion performance of MN patches fabricated from different weight ratios of PMVEMA to PVA (Table S1) were first evaluated to select the MN patch for the skin permeation studies of PXCl. The MN patches obtained from PMVEMA-PVA blends or pure PVA, but not pure PMVEMA, were acceptable (Table S2). These MN patches had flexible baseplates, which enable adapting to the skin curvature during administration (Lau et al., 2017, Xue et

Conclusion

The present study demonstrated the potential of MN patch fabricated from the 1:2 weight ratio of PMVEMA to PVA blend to deliver PXCl across the skin efficiently. With the application of these MN patches using the “poke-and-patch” and “poke-and-release” approaches, a considerable amount of PXCl was delivered across human skin through the created MCs in vitro. PXCl transport across skin MCs linearly increased with the concentration of the applied PXCl solution (1.0, 2.5 and 5.0 mg/ml) and the

CRediT authorship contribution statement

Kamchai Saepang: Conceptualization, Methodology, Investigation, Visualization, Writing – original draft. S. Kevin Li: Formal analysis, Writing – review & editing. Doungdaw Chantasart: Supervision, Formal analysis, Writing – review & editing, Resources, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This research was financially supported by the Thailand Research Fund (TRF) through the Royal Golden Jubilee (RGJ) Ph.D. Program (Grant No. PHD/0210/2559) to Doungdaw Chantasart and Kamchai Saepang. The research project was also supported by Mahidol University under the New Discovery and Frontier Research Grant.

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