Drug delivery system (DDS), which can release drugs at a specific rate and maintain the drug concentration at the target location at the optimal treatment level, has always been a research hotspot [1]. In polymer DDS, hydrogels are suitable candidates for drug delivery due to their high-water content and three-dimensional structure. In recent years, hydrogels have been widely used in biomedical and pharmaceutical fields, especially transdermal drug delivery. Hydrogel is basically a three-dimensional network structure composed of specific natural and synthetic polymers [2]. Many of the most widely used materials are based on polysaccharide hydrogels (such as agarose, chitosan, alginate and hyaluronic acid) [[3], [4], [5]], polypeptide hydrogels (such as gelatin and elastin) [6] and synthetic hydrogels (such as polyacrylic acid and polyacrylamide) [7]. At the same time, the ideal hydrogel should have good permeability, biocompatibility, flexibility and viscoelasticity. The large amount of water in hydrogels plays an important role in skin elasticity and moisturizing, making them suitable for local dosage forms [8].

The regulation of drug release from hydrogels is an important issue in medical applications. In order to improve the performance of materials in this field, the in-depth study of drug molecular diffusion in the matrix is essential. In the past few decades, some experimental studies on drug delivery systems have focused on mathematical models [9], including Fick diffusion [10], and also considered the contribution of degradation (volume or erosion) and expansion [11]. However, especially at typical drug concentrations, drug polymer interactions and other mechanisms may affect drug transport, and should not be ignored in the optimal formulation design [12,13]. Although there have been some recent studies on interactions, the effect of water on them has not been taken into account [14]. The state of water in hydrogel leads to different thermodynamic and mechanical behaviors of water, which will significantly affect the performance of hydrogel and drug release in various aspects. In hydrogel systems, water molecules are in three different states with different flow properties and crystallization capacity: non-freezable water (does not freeze even at −100 °C), intermediate water and free water [6]. The non-freezable water molecules interact directly with the polar functional groups on the polymer surface through hydrogen bonds to form the first layer of hydrogel hydration, and therefore have very small mobility and cannot crystallize even at extremely low temperatures [15]. Secondly, the intermediate water is more loosely combined with polar groups or non-freezable water molecules on the polymer surface to form the second hydration layer of the hydrogel system. It has low interaction with hydrogel polymer, high fluidity and crystallization temperature below 0 °C. Finally, the free water showed characteristics close to normal water, including high mobility and crystallization peak at about 0 °C, so there was almost no direct interaction with hydrogel polymer. The addition of water will affect the drug polymer interaction, and this relationship will also reflect the distribution of different states of water. Therefore, in-depth understanding of the drug release mechanism of hydrogel is very important for optimizing the release kinetics and building a good mathematical model to correctly predict the release spectrum.

Because of the hydrophilic functional groups on the main chain of the polymer, the main force between the hydrogel and the drug is hydrogen bond interaction [16]. However, hydrogen bonds are limited due to their saturation. The ion-dipole interaction is a kind of supramolecular interaction, and the acting elements are dipoles and ions with opposite charges [[17], [18], [19]]. The advantage of ion-dipole interaction is that it has high dynamics without directivity and saturation, which makes it possible for fewer ions to interact with multiple dipole groups [20,21]. If the “multivalent design” of ion-dipole interaction is used in polymers, the interaction between drugs and polymers can be enhanced. In supramolecular chemistry, multivalent bonds are powerful tools for obtaining dynamic bonds with high binding constants, including hydrogen bonds and metal coordination bonds [22]. The single dynamic interaction may be weak; However, multivalent double or triple dynamic interactions can have high binding constants. In this way, drug release can be regulated from two directions. The catechol group in mussel has been proved to have excellent adhesion and has been widely used in hydrogels [[23], [24], [25]]. Balavigneswaran et al. prepared a laponite based polydopamine hydrogel patch for drug-controlled release [23]. Hu et al. prepared a smart hydrogel inspired by double cross-linked mussel with enhanced antibacterial and angiogenic properties for the treatment of chronic infected diabetic wounds [26]. It leads to rapid drug release through pH response. Tang et al. prepared a series of mussel inspired pH responsive self-healing hydrogels based on oxidized tannic acid crosslinked gelatin and used them as controlled drug delivery systems [27]. But at present, most studies are to control the drug release, or to promote the release by destroying the structure of hydrogel. And there are few studies on the drug release mechanism in the related PDA articles. The main factors affecting drug release of hydrogel are the mesh size and drug polymer interaction [28]. This strategy is particularly important when small molecule drugs (i.e., adjustable ranges below the mesh size) are to be delivered [28]. Our previous study investigated the effect of mesh size on drug release from PDA hydrogels [7]. However, because most drugs suitable for transdermal delivery are small molecule drugs, drug polymer interaction is more important for drug release. In order to achieve high affinity interaction, there are a variety of chemical and physical interactions, from covalent coupling to secondary interaction. At the same time, catechol group has the ability to absorb electrons, which can provide sites for ion-dipole interaction [29].

Therefore, this study aims to develop a catechol-based hydrogel transdermal drug delivery system (PAHDP), which can regulate drug release through hydrogen bond interaction and ion-dipole interaction to achieve specific release performance of different drugs (Fig. 1a). Firstly, the structure and morphology of the hydrogel were characterized, and its adhesion performance and safety were evaluated. Ten model drugs were selected to explore drug polymer interactions (Fig. 1b, Table 1). Drug release, permeation and pharmacokinetics experiments were used to further study the skin delivery behavior of drugs in hydrogel. In addition, in order to further clarify its internal mechanism, the distribution of different water states was characterized by DSC. The hydrogen bond interaction and ion-dipole interaction were analyzed in detail by ATR-FTIR, XPS, molecular docking and kinetic simulation. The catechol hydrogel designed in this project provides a basis for the design of controllable drug release hydrogel patch.