(W0930-11-71) Development of Multiple Structured Pulsatile Release Tablets via Hot Melt Extrusion and Dual-Nozzle Fused Deposition Modeling 3D Printing

Purpose: Pulsatile drug delivery systems (PDDS) are designed to release drugs in a programmed pattern, which is particularly useful for drugs that must be released at specific times or in specific locations within the body [1]. However, the oral PDDS produced through the traditional method is associated with some challenges of low drug loading capacity, the incomplete release of the drug, and multiple manufacturing steps[2]. To fabricate complex structure PDDS with fewer manufacturing steps, fused deposition modeling (FDM) 3D printing technology was applied. The present study is intended to utilize hot-melt extrusion (HME) and dual-nozzle FDM 3D printing technology to develop and manufacture three different types of pulsatile release tablets. Type I is a “delay-release” structure, type II is a “rapid-sustained release” structure, and type III is a “release-lag-release” structure.

Methods: A ThermoFisher Scientific Process 11 twin screw co-rotating extruder was used in this study to develop filaments. The formulation composition and operation parameters of the HME filaments are shown in Table 1. Three types of pulsatile release tablets with different release models were designed using Fusion 360 software in this project. The tablets were produced by extruding filaments with a dual-nozzle Bowden FDM 3D printer. The in vitro release study was carried out using a USP dissolution apparatus II in 900 mL pH 6.8 phosphate buffer. The temperature was maintained at 37 ± 0.5℃ and a paddle rotation speed set at 50 rpm.

Results: Figure 1 shows the development process of pulsatile release tablets. Type I is the “delay-release” model. In this model, the drug starts to release after a lag time. The out layer of this structure is PVA with a uniform thickness of 1mm, and the core is the C-PVA or C-IR tablet with a diameter of 10mm, and a height of 4 mm. Type II is the “rapid-sustained release” model. In this model, the drug is initially released rapidly and then switches to a sustained-release mode. This structure is wrapped with a layer of C-PVA or C-IR with a uniform thickness of 0.913mm as a rapid-release layer, and inside is a C-15LV sustained-release core with a diameter of 10.174 and a height of 4.174mm. The volume of the rapid release layer and sustained release layer is 1:1. Type III is the “release-lag-release” model. In this model, the drug is initially released, followed by a pause period, and then completed drug release. In this structure, the thickness of the outer drug-containing layer is 0.467 mm, the middle contains a 1 mm-thick PVA spacer layer, and the inner core is a tablet with a diameter and height of 9.066 mm and 3.066 mm, respectively. The ratio of the outer drug-containing layer to the inner core is 1:1. Figure 2 shows the dissolution profiles of various pulsatile release tablets. Type I exhibited a lag time of over 30 minutes at the beginning of the dissolution. Type II showed a clear inflection point where a switch from rapid to sustained release occurs at 50% release. Type III exhibited a plateau period of approximately 45 minutes during the dissolution process.

Conclusion: In this study, different pulsatile release tablets were successfully formulated and produced using HME and dual-nozzle FDM 3D printer. The dissolution results are consistent with the expectations.

References: [1] L. Kalantzi, E. Karavas, E. Koutris, D. Bikiaris, Recent Advances in Oral Pulsatile Drug Delivery, Recent Pat. Drug Deliv. Formul. 3 (2009) 49–63. https://doi.org/10.2174/187221109787158337.
[2] D. Jain, R. Raturi, V. Jain, P. Bansal, R. Singh, Recent technologies in pulsatile drug delivery systems., Biomatter. 1 (2011) 57–65. https://doi.org/10.4161/biom.1.1.17717.

Table .1 Formulation composition and operation parameter of the hot melt extruded filaments.

Figure 1: The development process of pulsatile release tablets.

Figure 2. The dissolution profiles for all types of pulsatile release tablets.