# Cationic Moieties in Polystyrene Gels Swollen with D-Limonene Improved Transdermal Delivery System
## 1 Introduction  
Transdermal drug delivery (TDD), the transportation of drugs across the skin, has been an attractive research area because of its obvious advantages over other routes of delivery [1; 2]. Transdermal delivery systems provide convenient, pain-free and self-administrated use for the patient. It avoids the gastrointestinal side effects, usually entailed by many oral preparations. TDD also avoids fluctuations in plasma drug concentration, which helps minimizing adverse effects and therapeutic failure. The main challenge in TDD, however, is to overcome the inherent barrier of the skin. It has been reported that the rate limiting step in transdermal delivery is the \(\sim\)30 \(\mathrm{\SIUnitSymbolMicro m}\) thick stratum corneum which acts as a protective barrier against exogenous molecules including drugs [3]. For this reason, a variety of molecules [4] and materials [5] have been investigated as candidates to enable or facilitate skin permeation. Chemical penetration enhancers have been widely used to increase the skin permeability of many therapeutic molecules and anesthetics [6] by interacting with the stratum corneum (SC)lipid or keratin [7], or by increasing the solubility of drug into SC lipid [8; 9]. Extensive research during the past two decades has led to the formulation of several different classes of penetration enhancer such as terpene compound. Many reports have already provided substantial evidence that terpene [10; 11] are capable of enhancing percutaneous transportation, especially d-limonene. [PERSON] and co-workers [12] has been reported the d-limonene was the most effective permeation enhancer (PE) to enhance skin permeation of bufalin among other terpene compound and different synthetic PEs. D-limonene, is a neutral-derived terpene compound which is well known as permeation enhancer in transdermal delivery system [13; 14]. It is listed in the Code of Federal Regulations as generally recognized as a safe (GRAS) [15]. Moreover, it has low toxicity, so it is appropriate to boost up the transdermal delivery system  
Regarding the material side, organogels are promising candidates for drug delivery system including dermal and transdermal application [16; 17], because of their intrinsic properties. They are lipophilic, non-irritating easy-to-use and moisture insensitive. In an earlier work, [PERSON] and co-workers reported the preparation of limonene PG1/propylene glycol organogels as a physical gel [18]. However, it has a limitation on increasing the amount of limonene because it affects the stability of organogels. [PERSON] and co-workers reported transdermal delivery of ibuprofen using microemulsion as a vehicle [19]. Microemulsions are spreadable materials requiring a specific ratio of the oil-surfactant-water system. In order to open the door to facile preparation, we suggest that the convenient use and stability against various conditions, organogels as a chemical gel swollen with limonene [20] are an auspicious approach to solve the limitation of TDD in both of applications and permeability. Actually, it is known that the d-limonene is the excellent solvent for polystyrene (PS) [21] which is well known aromatic polymer. In addition, it can use as eco-friendly solvent for dissolving wasted expanded PS [22]. According to this advantage, the network structure consists of cross-linked PS gel is possible to swollen in d-limonene. Since PS has hydrophobic and biocompatible properties [23], it can be widely used in a variety of applications such as adsorbent materials in pollutant recovery [24; 25], drug storage to control release for lipophilic compounds [26] and transdermal delivery systems [27; 28]. In this work, the cross-linked polystyrene swollen in d-limonene as reservoir-type transdermal system was studied.