Spiked Systems for Colonic Drug Delivery: Architectural Opportunities and Quality Assurance of Selective Laser Sintering

Abstract

Additive manufacturing has been a breakthrough therapy for the pharmaceutical industry raising opportunities for long-quested properties, such as controlled drug-delivery. The aim of this study was to explore the geometrical capabilities of selective laser sintering (SLS) by creating spiked (tapered-edged) drug-loaded specimens for administration in colon. Poly(vinyl alcohol) (PVA) was used as the binding material and loperamide hydrochloride was incorporated as the active ingredient. Printing was feasible without the addition of a sintering agent or other additives. Innovative printing protocols were developed to help improve the quality of the obtained products. Intentional vibrations were applied on the powder bed through rapid movements of the printing platform in order to facilitate rigidity and consistency of the printed objects. The drug-loaded products had physicochemical properties that met the pharmacopoeia standards and exhibited good biocompatibility. The behavior of spiked balls (spherical objects with prominent spikes) and their retention time in the colon was assessed using a custom ex vivo intestinal setup. The spiked balls showed favorable mucoadhesive properties over the unspiked ones. No movement on the tissue was recorded for the spiked balls, and specimens with more spikes exhibited longer retention times and potentially, enhanced bioavailability. Our results suggest that SLS 3D printing is a versatile technology that holds the potential to revolutionize drug delivery systems by enabling the creation of complex geometries and medications with tunable properties.

Keywords: 3D printing; colonic drug delivery; extended retention time; loperamide; mucoadhesion; selective laser sintering; spiked drug delivery systems.

Figure 1

Conceptualization of the study: (a.) Traditional loperamide delivery results in a delayed onset of action because the drug dissolves in the ileum, which is not the intended target site. (b.) As a proof-of-concept, sharp-edged 3D-printed objects were designed using selective laser sintering. (c.) Mucoadhesive drug delivery systems were developed to increase retention time and adhesion to the target site. The spikes incorporated into the 3D-printed formulations enhance retention, extending the overall release of loperamide at the site of action. Created with BioRender.com.

Figure 2

(a) Schematic representation of the components of the SLS setup which was used during this study. The printing platform moves on the X and Y axes, the printing bed moves on the Z axis and the rest of the parts are static. (b) A modern representation of a flail weapon, (c) CAD dimensions in mm, (d) 3D printed spiked balls, (e) Dimensional assessment using “ray-tracing thickness”. Color map [0.0 10.0] mm.

Figure 3

(a) Schematic representation of powder bed compaction through intentional vibrating steps. (b) Printed objects before and after optimization of printing parameters. (c) A–E: the preprint concept and printing at different orientations (0°, 15°, 30°, 45°, 90°) with respect to the printing platform; F: the arrows indicate the different sides and surfaces of the tablet.

Figure 4

Spiked balls with 5-spikes (top) and 6-spikes (bottom): (A and E) 3D photorealistic representations of the printed objects; (B and F) 3D volume rendering displaying the local thickness; (C and G) “clipped” volume rendering illustrating the thickness in the object’s core. Core-color scales range: up [0.02–0.07], down [0.01–0.07]; (D and H) histogram depicting the distribution of local thickness values.

Figure 5

Thickness distribution of the pore phase in both the 5-spikes (top) and 6-spikes (bottom) objects, along with their respective local thickness maps; scale bar at 3 mm, color bar from 0.01 mm to 0.10 mm.

Figure 6

(a) FTIR spectra; (b) DSC spectra; (c) X-ray diffractograms; (d) cell viability; (e) in vitro drug release profiles from 3D printed tablets and 6-spiked balls.

Figure 7

3D representation of flow velocity streamlines resulting from the FE-based permeability analysis, in both longitudinal and transverse directions, normalized by 1,000 μm/s; target spike solids shown in purple, analysis cuboid solids rendered in blue.

Figure 8

(a) Mucoadhesion performance of the unspiked and spiked balls on an ex vivo intestinal model. (b) Photos capturing the retention time of the unspiked and spiked balls on porcine intestinal tissue during ex vivo performance. (c) Illustration of the setup for determining the disintegration time of the sharp-edged objects. (d) In vitro disintegration test: Photos capturing the balls (without spikes), 2-spiked balls, 4-spiked balls, and 6-spiked balls over time during disintegration test.