Elsevier

Journal of Controlled Release

Volume 322, 10 June 2020, Pages 1-12
Journal of Controlled Release

A systematic approach to determination of permeation enhancer action efficacy and sites: Molecular mechanism investigated by quantitative structure−activity relationship

https://doi.org/10.1016/j.jconrel.2020.03.014Get rights and content

Highlights

  • The present study provided a systematic evaluation approach to determination of enhancement action efficacy and sites of CPEs.

  • The enhancement action efficacy and sites of CPEs were determined by its physicochemical parameters.

  • Hydrophilic CPEs obtained highest ERrelease indicated that its enhancement action site was polymer matrix, and CPEs with high log P, molecular weight and polarizability showed highest ERpermeation, which indicated that its enhancement action site was skin.

Abstract

The present study was to systematically evaluate the enhancement action efficacy and sites of chemical permeation enhancer (CPEs), which provided references for the reasonable application of CPEs and the formula optimization of transdermal patch. Enhancement action efficacy was characterized using an indicator of comprehensive enhancement effect (ERcom). In addition, enhancement action sites were evaluated using a novel enhancement action parameter (βR/P), which was derived from the release enhancement effect (ERrelease) and skin permeation enhancement effect (ERpermeation) using seven CPEs with different physicochemical properties. Then the molecular mechanism was revealed by quantitative structure−activity relationship. Hydrophilic CPEs obtained highest ERrelease indicated that its enhancement action site was polymer matrix according to βR/P value (>1), due to CPEs formed the strongest hydrogen bonds with polymer, thereby undermined drug-polymer interaction according to the results of FT-IR, MDSC and molecular docking. CPEs with high log P, molecular weight and polarizability showed highest ERpermeation, which indicated that its enhancement action site was skin according to its βR/P value <1, due to it interacted with skin lipid strongly and obtained the lowest diffusion rate in skin. Thus, it increased the disruption level of highly ordered arrangement of intercellular lipid bilayers, which was characterized by ATR-FTIR, Raman, confocal laser scanning microscopy and molecular dynamics simulation. In conclusion, physicochemical properties of CPEs determined its enhancement action efficacy and sites in transdermal drug delivery process, which permitted rational selection of CPEs and the development of safer and more efficacious transdermal patch.

Introduction

Chemical permeation enhancers (CPEs) were indispensable excipients in transdermal formulations, which directly affected development of safe and efficacious transdermal patch [1]. Active agents of transdermal patch were firstly released from the polymer matrix and then permeated through skin [2]. Meantime, CPEs were also involved in the whole process. However, the enhancement effects of CPEs on drug release or skin permeation was studied individually, which did not reflect comprehensive enhancement efficacy of CPEs in transdermal drug delivery process in the previous literatures [3,4]. Moreover, scientific determination of enhancement action efficacy and sites of CPEs was still lacking, which resulted in blindness and uncertainty of screening of CPEs in formula optimization of transdermal patch. As a result, a systematic evaluation approach was supposed to be proposed basing on physicochemical parameters of CPEs to describe the comprehensive enhancement action efficacy and sites by quantitative structure−activity relationship.

Nowadays, the dominating evaluation methods of CPEs included the enhancement effect on drug release or skin permeation. On one hand, it was found that Span 80 played an important role in facilitating bisoprolol tartrate release from adhesive DURO-TAK® 87–2287 mainly through weakening drug-adhesive interaction and increasing free volume of adhesive [5]. After that, it was proved that Span 80 enhanced release of oxybutynin from patch by the improvement of adhesive mobility [6]. On the other hand, the enhancement effect of Azone and menthyl decanoate on skin permeation of flurbiprofen was explored, which was caused by the perturbing effect of CPEs on intercellular lipid of stratum corneum (SC) [7]. It was also revealed that hydrophobic CPEs mainly affected SC lipids and hydrophilic CPEs were linked to SC lipid and protein, and molecular mobility of SC was confirmed as main factor affecting permeability of skin barrier [8]. However, the two enhancement approaches of CPEs were interconnected whole in transdermal drug delivery process, which were supposed to be investigated considering the connection between enhancement drug release and skin permeation. Combining these two aspects, high molecular mobility of polymer and SC was known to increasing enhancement efficacy of CPEs. In addition, degree of change in molecular mobility was often governed by strength of interaction between drug and polymer [9], which was able be described through physicochemical parameters of drug and polymer [10]. Thus, it was inferred that CPEs exhibited different enhancement efficacy, which was connected with CPEs physicochemical parameters. Meanwhile, the determination of enhancement action sites of CPEs was equal importance, which aided in the screening of types and actual dose applied of CPEs in design of transdermal formulation. Therefore, a novel enhancement action parameter (βR/P) was very necessary to be proposed to address the issue, qualitatively and quantificationally.

In this study, seven CPEs with different physicochemical properties were selected and listed in Table 1, including Span 80 (SP), Maisine™ 35–1 (MA), Plurol® Oleique CC 497 (POCC), menthol (ME), Capryol™ 90 (CP), Transcutol® P (TP) and propylene glycol (PG). Their chemical structures were shown in Fig. 1. Loxoprofen (LOX) was chosen as model drug and acrylic pressure sensitive adhesive (PSA) containing carboxyl group, with superior drug loading capacity and physical stability, was selected as a model polymer matrix. Enhancement effect on drug release (ERrelease) was investigated by in vitro drug release of patch. Enhancement effect on skin permeation (ERpermeation) was investigated by in vitro skin permeation of drug solution. And comprehensive enhancement effect (ERcom) was investigated by in vitro skin permeation of patch and confirmed by pharmacokinetic study. The regression analyses were used to establish quantitative structure−activity relationship. The molecular mechanisms of enhancement action were affirmed using Fourier transform infrared spectroscopy (FT-IR), modulated temperature differential scanning calorimetry (MDSC), molecular docking, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, Raman spectra, confocal laser scanning microscopy (CLSM) and molecular dynamics (MD) simulation.

Section snippets

Chemicals

LOX and ME (Purity: 98.0%) were purchased from Shanghai Bide Pharmaceutical Co., Ltd. (Shanghai, China). PG (Purity: 98.0%) and SP (Purity: 99.0%) were purchased from Bodi Chemical Co., Ltd. (Tianjin, China). POCC, MA, CP and TP (Purity >98.0%) were supplied by Gattefossé (Lyon, France). Caprylic capric triglyceride (ODO) was purchased from Shandong Yousuo Chemical Technology Co., Ltd. (Shandong, China). Thioflavin T and ibuprofen were purchased from Shanghai Macklin Biochemical Co., Ltd.

In vitro drug release of patch

In order to investigate enhancement effect of CPEs on drug release in patch, in vitro drug release study was performed (Fig. 2). The ERrelease of seven CPEs were listed in Table 2, which demonstrated that only TP and PG significantly increased drug release percent, thereby improved drug concentration gradient and facilitated drug skin permeation in patch.

In vitro skin permeation of drug solution

The enhancement effect of CPEs on drug skin permeation was showed in Fig. 3. The ERpermeation of seven CPEs were summarized in Table 2, which

Discussions

The present study provided a systematic evaluation approach to determination of enhancement action efficacy and sites of CPEs. As expected, the enhancement action efficacy and sites of CPEs were determined by its physicochemical parameters, including: log P, M.W and polarizability. Furthermore, this study represented the first systematic structural study of CPEs, which lay a solid theoretical basis for successful application of CPEs in transdermal patch.

From the viewpoint of enhancement action

Conclusion

In this work, a systematic evaluation approach and novel enhancement action parameter (βR/P) were successfully developed to determine enhancement action efficacy and sites of CPEs in transdermal drug delivery process. And molecular mechanism of enhancement action was revealed by quantitative structure−activity relationship. Hydrophilic CPEs owned highest ERrelease, which indicated that its enhancement action site was polymer matrix according to βR/P value (>1). CPEs with high log P, molecular

Declaration of Competing Interest

The authors declare no competing financial interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China [grant number 81773665].

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