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.
Introduction
Additive Manufacturing (AM) is the quintessence of customization. The shape freedom that AM offers is essential for the fabrication of the, often highly complex, architectures that are required for the realization of unusual properties and advanced functionalities. Despite the fact that the ball of AM (also known as “rapid prototyping” and “3D printing”) has been rolling in the pharmaceutical field since 1996, it is only recently that research has turned its focus on valuable materials and atypical geometries, in the attempt of creating drug-loaded products with unusual features and hard-to-reach therapeutic objectives. (1−4)
AM holds the promise of digitalizing the drug industry while enabling decentralized manufacturing at point-of-care (PoC) printing hubs. (5−8) A recent study demonstrated, for the first time, the bioequivalence of 3D printed sildenafil tablets to their large-scale-produced marketed originator. After administration to twelve (12) healthy volunteers, the results are laying the groundwork for at PoC production of 3D printed medicines and testing in clinical trials with human participants. (9) Well-established quality assurance (QA) and quality control (QC) protocols are pivotal for the realization of such a fundamental shift toward small-batch production on demand at PoC. To that end, recent research studies investigate mathematical modeling (e.g., Artificial Intelligence) for the prediction, and nondestructive analytical methods, for the evaluation of printed products’ properties. (10−16) In a recent study, a data set of 170 different formulations was used for the development of Machine Learning models that predict the printability of pharmaceutical formulations by means of the selective laser sintering (SLS) process. The inputs included data retrieved from Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC). (17) In another study, Fourier-Transform Near Infrared Spectroscopy (FTNIR) was evaluated as a nondestructive method, able to predict the density and drug release from tablets fabricated with SLS printing. (18)
Among numerous other advantages (e.g., tunable release profiles, personalized shape and size, multidrug combinations, preferable solid-state properties) SLS is a technique capable of producing relatively large batches of dosage forms due to the instrument’s usually large printing volume. SLS printing comprises exposure of fine powder particles to a narrow laser beam resulting in high resolution (down to hundreds of micrometers) and a high potential for fabricating complex architectures. As a powder bed technique, SLS has the unique characteristic that the printed structures remain immersed within and supported by the powder pool, allowing printing of extreme overhangs without additional supportive structures, as typically required during Fused Deposition Modeling (FDM) or Stereolithography (SLA) 3D printing. (11,16,18−22)
The oral route is the most common route of administration. However, drug absorption of orally administered dosage forms is being challenged by several obstacles, especially since the development of novel compounds that emerge from modern drug discovery (e.g., peptides, proteins etc.). Colon-targeted drug delivery enables a wide range of therapeutic benefits, with the most prominent ones being the direct access to local targets, reduction in systemic drug exposure and improvement of bioavailability. (23,24) During the past decades, several devices have been proposed for addressing the challenges of oral delivery and targeting intestinal areas. (25) With the traditional powder technology methods, particulate formulations are being compressed into tablets, with most of them comprising a central drug-loaded reservoir covered by protective polymeric materials that provide resistance in the harsh stomach environment and facilitate release upon intestinal triggers. However, due to their shape, these formulations are typically characterized by short residence times and poor contact with the intestinal wall. Lately, microfabricated drug-carrying polymeric devices have been proposed as promising systems for intestinal delivery, offering mucoadhesive properties and allowing unidirectional release of the active pharmaceutical ingredient (API). (26−29) Recent studies demonstrate the ex vivo and in vivo potential of microcontainers, highlighting the influence of their geometry on retention time and bioavailability. (30−34) Recently, a custom stereolithography 3D printer was used for the development of radiopaque microdevices with enhanced mucoadhesive geometries. After administration to rodents, the performance of three different designs was assessed. The results suggest that enhanced mucoadhesion might have occurred in some intestinal sites, but the overall retention time was not significantly increased. In addition, no preferred spatial orientation was observed, although the microcontainers had been designed in manners that would facilitate unidirectional distribution. (35,36)
The current study explores the fabrication capabilities of SLS 3D printing and its utilization for the development of drug-loaded dosage forms with mucoadhesive properties. Poly(vinyl alcohol) was used as a polymeric matrix and loperamide hydrochloride (LOP) was incorporated as the API. In this work, we designed and fabricated, for the first time, spiked formulations inspired by historical weapons using SLS. This approach highlights the challenges associated with this method, (37) notably achieving successful fabrication without the use of a sintering agent or prior-printing heating of the powder bed. The materials and printed products were thoroughly studied for their physicochemical and drug-release characteristics. Upon oral administration via a gastro-resistant capsule, the spiked geometries were hypothesized to prolong retention time in the intestinal tract and enhance bioavailability, thereby demonstrating the second aspect of the study’s novelty. Their behavior and performance were further evaluated using an ex vivo intestinal model. This functional application underscores the potential of SLS 3D printing as a fabrication method for colonic drug delivery systems with controlled properties (Figure 1).
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Materials
Poly(vinyl alcohol) 4-88 (PVA, Parteck MXP), poly(vinyl alcohol) 3-82 (Parteck MXP), hydroxypropyl methylcellulose (HPMC), polycaprolactone and Eudragit L100 were obtained from Merck KGaA (Darmstadt, Germany). Vivapharm HPMC E50, Vivapharm HPMC E6, Vivapharm PVA 05 and Vivapharm PVP/VA were obtained from JRS Pharma GmbH (Rosenberg, Germany). Vinylpyrrolidone-vinyl acetate Kollidon VA64 was obtained from BASF (Ludwigshafen, Germany). Microcrystalline cellulose Pharmacel 102 was obtained from DFE Pharma (Goch, Germany). Loperamide Hydrochloride (LOP) was obtained from Xi’an Faithful Biotech Co., Ltd. (Xi’an, China). All other chemicals were of analytical grade and used as obtained.
Angelos Gkaragkounis, Konstantina Chachlioutaki, Orestis L. Katsamenis, Fernando Alvarez-Borges, Savvas Koltsakidis, Ioannis Partheniadis, Nikolaos Bouropoulos, Ioannis S. Vizirianakis, Dimitrios Tzetzis, Ioannis Nikolakakis, Chris H. J. Verhoeven, Dimitrios G. Fatouros, and Kjeld J. C. van Bommel, Spiked Systems for Colonic Drug Delivery: Architectural Opportunities and Quality Assurance of Selective Laser Sintering, ACS Biomaterials Science & Engineering Article ASAP, DOI: 10.1021/acsbiomaterials.4c02038
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