In the current market, oral administration remains the desirable route for many drugs [1]. Due to their easy preparation, stability in storage, and dosage accuracy, tablets are still the most widely used formulation. Oral tablets can be categorized into three types: immediate-release (IR) systems, sustained-release (SR) systems, and biphasic-release (BR) systems. Compared to IR systems that can rapidly achieve effective blood levels and SR systems that prolong curative effects, BR systems have distinct advantages in treating pain management and bacterial diseases [2,3]. In BR systems, the IR part releases drugs to quickly achieve the therapeutic concentration in blood plasma, while the SR part prolongs the drug release time to maintain plasma concentration [4]. Therefore, BR systems are the better choice for non-steroidal anti-inflammatory drugs and certain antibiotics.

Ofloxacin is a synthetic quinolone drug that is widely used in clinical practice for treatment of various bacterial diseases including respiratory, throat, tonsil, and urinary tract infections [5]. Ofloxacin, a concentration-dependent antibiotic with bactericidal activity proportional to its drug concentration (or dosage), is suitable for biphasic-release systems [6]. The safety and therapeutic efficacy of ofloxacin can be attributed to its favorable absorption, high bioavailability, and low systemic toxicity. Notably, the solubility of ofloxacin decreases as the pH increases [7]. Ofloxacin has the maximum solubility in the stomach because the N–Me piperazine ring of the drug protonates at the pH = 1.2 dissolution medium and is primarily absorbed in the upper digestive tract, making it suitable for preparing BR formulations that deliver drugs directly to the stomach [8,9]. For improved treatment outcomes, the daily dosage of ofloxacin typically ranges from 300 mg to 600 mg, administered in 2–3 doses. However, the availability of only 100 mg ofloxacin IR tablets is extremely inconvenient for patients. Therefore, there is an urgent need to explore novel formulations of ofloxacin that enhance patient compliance.

Bilayer tablets are the most convenient form for achieving a BR system [10]. However, manufacturing bilayer tablets using the traditional pelleting method poses challenges and can lead to inadequate hardness, imprecise individual mass control, and decreased yield [11]. The most important issue is the insufficient adhesion between adjacent layers, which is mainly caused by the different nature of the materials in the upper and lower layers. Adjusting the pressure may be the best method to solve this problem. Moreover, if the pressure is too high or low, the layers can't adhere firmly. Furthermore, other issues need to be taken care of, such as the selection of layer sequence, layer weight ratio, and cross-contamination between layers [[12], [13], [14]].

With the increasing demand for bilayer tablets, three-dimensional (3D) printing technology offers a novel alternative solution due to its greater flexibility in building products layer by layer [15,16]. In 2015, the Food & Drugs Association (FDA) granted a levetiracetam IR tablet (SPRITAM®) using 3D printing technology. Furthermore, in 2021, T19 obtained clinical trials approval from the FDA, demonstrating the success of 3DP technology in the field of pharmaceutical fabrication [17]. 3DP technology has unique advantages in preparing formulations with complex structures and drug compositions. Subsequently, it has been employed successfully to produce various dosage forms, including compound tablets [18], hewable tablets [19], gastro-floating SR tablets [20], high drug-loading IR tablets [21], bone implants [22], microneedle patches [23], and nasal implants [24]. Also, 3DP technology can accelerate the release of drugs or alter the drug's behavioral conditions in vivo by adjusting the internal structure of tablets [25,26].

Despite a few reports on preparing bilayer tablets using Fused Deposition Modeling (FDM) technology [[27], [28], [29], [30]], the absence of suitable excipients for FDM remains a significant developmental limitation. In addition, the heating process involved in FDM wire preparation renders it unsuitable for temperature-sensitive drugs and excipients. Semi-solid extrusion (SSE) technology, however, operates at room temperature without necessitating a heating process, thereby extending its applicability to a wider array of materials, including temperature-sensitive drugs and excipients. The whole process of SSE technology involves several steps, including the manufacturing of a printable and extrudable paste, extrusion of the paste into the desired object via a needle, and solidification and post-processing of the object, which includes solvent evaporation and desiccation [31,32]. This efficient production method holds promise for application in pharmaceutical manufacturing by reducing the time needed before the final tablets could be used and expediting product launch.

Building on the mentioned context, our team conducted an investigate into the feasibility of using SSE technology for preparing bilayer tablets with various structures. Ofloxacin was selected as an active pharmaceutical ingredient (API) for fabricating BR bilayer tablets. Through the optimization of the formulation and structure of the IR and SR sections, a series of BR tablets with different release profiles specific to various disease conditions were developed.