**1. Introduction**

Pellets, as multiple unit preparations, offer a lot of clinical benefits compared with single unit dosage forms, such as reduced intra- and inter-subject variability on drug plasma, decreased local irritations, less dose dumping risk, and stable plasma concentrations [1,2]. To prepare sustained release pellets, film coating is an ideal method. With the development of aqueous-based dispersion systems, film coating technologies have shifted from organic-based polymeric solutions to aqueous-based polymeric dispersion systems [3]. As one of the aqueous ethyl cellulose dispersions, Surelease® (ADEC) could be used alone or combined with other polymers to obtain satisfactory release profiles [4–7]. Additionally, most of these release profiles showed a diffusion-controlled release mechanism, which meant a predictable release pattern could be achieved by altering the ADEC coating weight gain [8,9].

Loxoprofen sodium (LXP), as a 2-phenylpropinate non-steroidal anti-inflammatory drug (NSAD), was first introduced by Sankyo Company in Japan. It has been widely used for the treatment of osteoarthritis, scapulohumeral periarthritis, rheumatoid arthritis, arthritis, toothache, and post-operation pain [10]. As a pro-drug, LXP is converted to its active metabolite (trans-OH LXP) in vivo to inhibit the activity of cycloosygenase (COX), which mediates the production of inflammatory prostaglandins [11]. Due to the short elimination half-life of approximately 65 min [12], the commercial tablet of LXP has to be administrated three times a day to maintain the therapeutic concentration in plasma, which might cause high risks of gastrointestinal (GI) lesions and systemic side effects [13,14]. Several studies have been reported on the preparation of LXP sustained release dosage forms [15–17]. However, due to its high solubility, most of the preparations, especially for the matrix-based formulations, showed a burst release (drug release >30%) during the first2h[18], which could cause unexpected GI mucosal injury for patients. Therefore, a sustained release dosage form with decreased initial release would be necessary.

As a weakly acidic drug, loxoprofen shows good solubility at high pH, while poor solubility at low pH. Several strategies have been developed to prepare sustained release formulations of the pH-sensitive drugs [19–22]. Among them, incorporation of pH-modifiers into the preparation was a common approach in matrix or coating systems. These pH modifiers could significantly modify the micro-environmental pH (pHM) inside the systems, and result in a decrease or increase of the drug solubility, leading to a modified drug dissolution rate [22–24]. In addition, their extent and duration played an important role on the drug release rate [25]. Approaches like using coated pH-modifier as the starting core [23], blending pH-modifier with drugs into the core with a subsequent coating [26], or incorporating pH-modifiers into the matrix formulations [20], have been proposed and studied to achieve the sustained release of pH-sensitive drugs. However, for the maintenance of an appropriate pHM inside the dosage forms, more than 20% pH-modifiers in the preparations were often needed [20,23,26], which might cause undesired GI irritations, especially for patients with GI ulcers. In order to reduce the usage of pH-modifiers and maintain an appropriate pHM in the dosage form, citric acid (CA) as the pH-modifier was first proposed to be incorporated into the dissolution-rate controlling layer to decrease the dissolution rate of LXP.

Drug delivery systems (DDS), based on their system design or rate-controlling mechanism, can be divided into models such as dissolution, diffusion, erosion, osmosis, and swelling [27]. As for the film coating systems, the diffusion or osmosis mechanisms were often applied to elucidate the drug release profiles [5,28–30], while the influence of drug dissolution rate was often omitted or just attributed to the drug diffusion rate [27]. In the most common cases, only one of these mechanisms was applied to control the drug release rate in DDS, except for the bio-erodible or hydrogel matrix systems, where the drug release rate was controlled by two or three of these release mechanisms [31,32]. Although theoretical approaches regarding the dissolution-diffusion mechanism have been extensively reported [33,34], a combination of the dissolution and diffusion release mechanisms as a rate-controlling strategy was seldom reported.

In this study, a novel concept of two-step control of the drug release rate is proposed. A schematic diagram of this hypothesis is illustrated in Figure 1. In this system, the first-step control was to reduce the dissolution rate of LXP by creating a sub-coating layer containing pH-modifier CA, while the second-step control was to decrease the diffusion rate of LXP by creating a non-soluble polymeric film. Furthermore, a three-level, three-factor Box-Behnken experiments design was conducted to optimize and evaluate the effects of different parameters on the drug release. Additionally, the pharmacokinetic studies of the optimal formulation were performed in fasted beagles to compare its in vivo performance with the conventional tablet.

**Figure 1.** Schematic diagram of the sustained release pellets.

### **2. Materials and Methods**
