Fabrication of osmotic pump tablets utilizing semisolid extrusion three-dimensional printing technology

Abstract

The utilization of three-dimensional (3D) printing technology is prevalent in the fabrication of oral sustained release preparations; however, there is a lack of research on 3D-printed osmotic pump tablets. A 3D-printed core–shell structure bezafibrate osmotic pump tablet was developed based on the characteristics of rapid absorption and short half-life of bezafibrate, utilizing semisolid extrusion (SSE) 3D printing technology. First, the properties of different shell materials were investigated to define the composition of the shell, and ultimately, the optimal formulation was found to be ethyl cellulose:cellulose acetate:polyethylene glycol = 2:1:2. The formulation of the tablet core was defined based on the printing performance and release behavior. The formulation consisted of bezafibrate, lactis anhydrous, sodium bicarbonate, sodium alginate, polyethylene oxide, and sodium dodecyl sulfate at a ratio of 400:400:300:80:50:50. The tablet was capable of achieving zero-order release. The physicochemical properties were also characterized. The pharmacokinetic data analysis indicated that there were no statistically significant differences in the pharmacokinetic parameters between the 3D-printed tablets and the reference listed drugs. There was a strong correlation between the in vitro and in vivo results for the 3D-printed tablets. The results showed that SSE printing is a practical approach for manufacturing osmotic pump tablets.

Introduction

The main clinical manifestations of hyperlipidemia, also known as dyslipidemia, are abnormal blood lipid levels, such as high levels of plasma triglycerides, total cholesterol, and low-density lipoprotein (Antza et al., 2024, Knopp et al., 2006, Yao et al., 2020). It is particularly prevalent among individuals aged 50–69 years old(Shou et al., 2024, Yen et al., 2024). The prevalence of hyperlipidemia is increasing among younger individuals due to the changing modern dietary patterns(Hu et al., 2016).

Bezafibrate is frequently prescribed for the treatment of primary hyperlipidemia(Floreani and De Martin, 2021, Goldenberg et al., 2008, Wang et al., 2020). Specifically, it is primarily utilized for treating hypertriglyceridemia and hypercholesterolemia(Khakoo et al., 2023, Yanai et al., 2023). Bezafibrate exhibits poor water solubility; however, it demonstrates rapid and complete oral absorption with a short half-life (1.6 h) (Vens-Cappell et al., 1993, Yang et al., 2008). The primary factors that restrict the rate of absorption following oral administration are the solubility and the dissolution rate of the drug. Due to the properties of bezafibrate, it was prepared as a sustained release preparation to facilitate its clinical application(Goldenberg et al., 2008). The commercial sustained-release tablet was gel matrix sustained-release tablets, a single unit of 400 mg and one tablet per day.

Osmotic pump preparations, as a type of classical controlled release preparation, can consistently release drugs at a constant rate across various dissolution media(Vens-Cappell et al., 1993). The release kinetics of osmotic pump formulations can typically be described by a zero-order release model(Chen et al., 2016). The use of osmotic pump preparations can effectively mitigate fluctuations in blood drug concentrations and avoid common large blood concentration fluctuations with oral fast-release preparations(Verma et al., 2004, Zhang et al., 2020). The external layer of the osmotic pump preparation is a semipermeable membrane composed of water-insoluble substances with pore-forming agents formed by the coating. Water enters the interior of the preparation through the pores formed by pore-forming agents, but the drug cannot pass through these pores. Drug release orifices are prepared by methods such as laser drilling on coating films. The drug is released through a drug release orifice. Osmotic pressure can generate significant osmotic pressure within the tablet core to allow water to continue to enter and push the drug out of the drug release orifice. With the development of technology, various kinds of osmotic pumps, such as multilayer and multichamber osmotic pumps, have been developed(Zhao et al., 2016). However, there are relatively few studies on the fabrication of osmotic pump preparations using three-dimensional (3D) printing technology.

The invention of 3D printing technology dates back to the 1980 s. The continuous advancement of technology and the introduction of treatment concepts such as personalized drug delivery have led to the gradual exploration of the immense potential of 3D printing technology in the pharmaceutical field(Cui et al., 2021, Muhindo et al., 2023, Norman et al., 2017). The 3D printing technology used extensively in the pharmaceutical industry encompasses stereo lithography apparatuses, powder bonding, fused deposition modeling and semisolid extrusion(Alhijjaj et al., 2016, Gioumouxouzis et al., 2019, Kotta et al., 2018).

The development of 3D printing technology in the field of oral solid preparations has a long history(Jamroz et al., 2020, Singh et al., 2022, Wang et al., 2021). In the field of pharmaceutical research, the primary application of 3D printing technology lies in addressing the limitations associated with certain conventional manufacturing processes(Chen et al., 2023, Eleftheriadis et al., 2019). For example, 3D printing is frequently used in the production of customized drugs with precise dosage standards(Chen et al., 2024, Sarvan and Nori, 2021). The dosage of the preparation can be adjusted by modifying the preparation model using 3D printing technology(Englezos et al., 2023, Whitaker et al., 2023, Yang et al., 2023). The utilization of multihead printing technology has facilitated the development of multilayer preparations, enabling the synergistic administration of multiple drugs(Dumpa et al., 2021, Vynckier et al., 2016). Researchers have developed the special release behavior of the preparation by adjusting the structure(Geraili et al., 2020). Tablets incorporating the reticular formation have been developed to enhance the specific surface area of preparations and facilitate rapid drug release(Ayyoubi et al., 2023, Mandati et al., 2022). The core–shell structure is used extensively in the preparation of controlled release systems(Alzahrani et al., 2022, Wang et al., 2023). The enteric-coated material has also been developed into a shell to achieve delayed release of the preparation and facilitate targeted drug delivery in the intestines(Li et al., 2022). Additionally, water-insoluble materials such as ethyl cellulose can serve as a block layer to regulate the release orientation of films and patches(Eleftheriadis et al., 2019).

Semisolid extrusion (SSE) is a type of extrusion-based 3D printing technology(Al-Maaitah, 2022, Jamroz et al., 2017). The advantages of SSE include a high drug loading rate, low cost, and simple operation(Al-Maaitah, 2022, Rahman and Quodbach, 2021). The principle of SSE is not complex(Cui et al., 2019). Initially, the wetting agent is introduced into the raw material, causing it to transform into a semisolid paste. Subsequently, the paste is introduced into the printing chamber. The paste is extruded from the print head as a filament through the action of the extrusion screw. The suitability of the printing properties of the raw materials defines their applicability for SSE printing. The utilization of SSE 3D printing eliminates the necessity of incorporating excessive dosages of disintegrant, glidants, fillers, and other excipients commonly found in traditional preparations, thereby enhancing the drug loading efficiency(Suárez-González et al., 2021, Tagami et al., 2019). After the wetting agent volatilizes, a porous structure can be formed inside the preparation prepared by SSE technology(Seoane-Viaño et al., 2021, Yi et al., 2023). The application of SSE technology is prevalent in the field of pharmaceutical preparation. Researchers have developed numerous preparations utilizing SSE 3D printing, such as large-dose immediate-release preparations, controlled release preparations, and double-layer preparations, to address challenges that are not easily resolved with conventional formulations.

In the present study, bezafibrate was utilized to develop a 3D-printed osmotic pump tablet using SSE 3D printing technology. The tablet had a core–shell structure. The shell acted as a semipermeable membrane. The optimal formulation of the tablet core was investigated based on the printing performance and release behavior. The release mechanism and potential impact of dissolution conditions on tablet release were then investigated by dissolution tests. The physicochemical properties of the raw material and tablet were also investigated. An in vivo study of 3D-printed osmotic pump tablets was performed using commercial sustained-release tablets as a reference listed drug (RLD). The pharmacokinetic parameters were subjected to statistical analysis to investigate the bioequivalence between the 3D-printed tablets and RLDs. The in vivo absorption fraction was defined using the Loo-Riegelman equation. The in vivo-in vitro correlation was assessed by conducting linear regression analysis on cumulate release rate and absorption fraction. This study aimed to innovatively fabricate osmotic tablets using SSE 3D printing. It is a filed that has not yet been studied at present. The study can provide some reference for the follow-up research in this filed.

Materials

Bezafibrate sustained release tablet (400 mg, batch no. 04309) was purchased from Stada Arzneimittel AG., Germany. Bezafibrate (purity ≥ 99 %, batch no. 487999) and cellulose acetate (CA) were purchased from Shanghai Yien Chemical Technology Co., Ltd., China. Lactis anhydrous (Lac) was purchased from Shanghai Aladdin Reagent Co., Ltd., China. Mannitol and NaCl were purchased from Shanghai Aladdin Reagent Co., Ltd., China. Sodium carbonate (Na2CO3) and sodium carbonate (NaHCO3) were purchased.

Hao Chen, Dongyang Fang, Xiangyu Wang, Ye Gong, Yang Ji, Hao Pan, Fabrication of osmotic pump tablets utilizing semisolid extrusion three-dimensional printing technology, International Journal of Pharmaceutics, 2024, 124668, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124668.