3D-printed Gabapentin-loaded Implants for Sustained Release: Leveraging 3D Printing and Hot Melt Extrusion (HME) for Customizable Drug Delivery

Abstract

Pediatric neuropathy poses significant challenges in pain management due to the limited availability of approved pharmacological options. Gabapentin, commonly used for neuropathic pain, offers therapeutic potential but necessitates careful dosing due to its variable bioavailability. This study investigates the integration of Hot Melt Extrusion and Fused Deposition Modeling in the development of polycaprolactone-based implants for sustained release of Gabapentin. A preliminary screening using Vacuum Compression Molding optimized formulations for Hot Melt Extrusion, enhancing material efficiency and process streamlining. Filaments with a diameter of 1.75 mm were successfully extruded and used for 3D printing of Gabapentin implants. Several tests were undertaken to characterize the prepared filaments and implants. Energy-Dispersive X-ray spectroscopy confirmed the uniform distribution of Gabapentin within the implant matrix. Solid-state characterization techniques were employed to assess the compatibility of implant components and to verify the solid-state of Gabapentin within the implant structure. In vitro drug release studies were conducted. Filaments with varying drug loadings were examined, revealing that a 20% w/w drug loading achieved an optimal balance between rapid and sustained release. Additionally, implants with different infill densities were analyzed, demonstrating that varying infill densities allow control over the amount and percentage of drug released. The 100% infill density resulted in the most sustained release effect, achieving approximately 40% drug release by day 28. These findings underscore the feasibility of 3D printing for producing personalized implants, emphasizing the potential for tailored drug release profiles to meet specific needs of pediatric patients.

Introduction

Pediatric neuropathy is a condition present in children, where there is peripheral nerve malfunction. These nerves play a very significant role in transmitting signals between the central nervous system and the rest of the body [1]. Effects of neuropathy can be entirely different according to the sensory, motor, or autonomic nerves involved and hence lead to a highly varied set of symptoms [2]. Pediatric neuropathic pain is very challenging for treatment in many ways, as there are few medications approved for this condition [3, 4]. When determining appropriate dosage adjustments, the child’s age, weight, and developmental stage must be carefully considered [5].

Gabapentin, a freely water-soluble medication [6], has shown effectiveness as an adjunctive treatment for partial epileptic seizures [7]. Additionally, it is widely used off-label for the management of neuropathic pain [8]. In pediatric patients, Gabapentin has emerged as a valuable option for treating neuropathic, pre-and post-operative pain [9]. It works by modulating the release of specific neurotransmitters involved in pain signaling, leading to relief from neuropathic pain [10]. Numerous studies and clinical trials have demonstrated positive results with Gabapentin use in pediatric patients. It has been found to provide pain relief in burn survivors, and it prevents postoperative pain [11, 12]. Based on American Pain Society, Gabapentin should be included in pediatric neuropathic pain condition, especially when other relievers render a sedation effect. The recommended dose is an initial of 2 mg/kg/day, and the average dose ranges from 8 to 35 mg/kg/day in divided doses a day [13, 14]. Having a structural similarity to natural amino acids, such as L-leucine, Gabapentin crosses the small intestine through the active, saturable L-amino acid transport mechanism. This transport mechanism has been identified as a major determinant of the dose-dependent bioavailability of Gabapentin. In this case, it has been determined that the bioavailability of Gabapentin is inversely proportional to dosing. That is, the higher the dose, the lower the bioavailability of Gabapentin. For example, while at doses as low as 900 mg/day, its bioavailability is around 60%, the bioavailability at a higher dose of 4800 mg/day is significantly reduced to about 27% [11, 15]. There were also reports that repeated administration of Gabapentin leads to oscillations in plasma levels which, in turn, causes impairment in memory in mice [16, 17].

Additive manufacturing, widely called 3D printing, is an additive process of building an object layer by layer, using thermoplastic polymers [18]. The relevance of 3D printing technology in formulating long-acting medicinal implants lies in their capability to customize personalized implants with specified designs in their constituents according to a patient’s preference [19,20,21]. 3D printing enables customization, incorporating multiple medications, and controlling drug release kinetics [22,23,24]. Fused Deposition Modeling (FDM) is one such commonly used form of 3D printing technology where a melted polymer is deposited through a heated nozzle into the desired object shape. The extrusion nozzle melts the polymer, which is deposited with precision on the build plate and allowed to solidify. This layering procedure allows for deposition of the softened polymer, with the softened polymer solidifying before adding a new layer to build up a 3D structure [25, 26]. This comes with several distinct advantages, including ease of operation, low-cost manufacturing, and the ability to create intricate structures without using any form of solvent [20, 27].

A drug-loaded polymer filament can be manufactured using Hot Melt Extrusion technology [28, 29]. HME, a continuous manufacturing technique, enables the uniform incorporation of active pharmaceutical ingredients (APIs) into a polymer matrix, ensuring precise dosage control and enhanced drug release profiles [30]. During the Hot Melt Extrusion process, the magnitude of material loss is substantial, characterized by a significant proportion of the material being dissipated during the startup phase or retained within the non-operational region of the extrude [31]. Vacuum Compression Modeling serves as a valuable preliminary technique to be employed before Hot Melt Extrusion, functioning as a small-scale screening tool that offers advantages such as minimizing material consumption and time savings. By implementing Vacuum Compression Modeling in the initial stages, material usage can be optimized, and the total processing time can be considerably shortened. This approach aids in efficiently evaluating the feasibility and performance of various formulations, enabling researchers to make informed decisions and streamline the subsequent Hot Melt Extrusion process [31, 32]. Polycaprolactone is among the most widely used polymers in the Hot Melt Extrusion process. It is biocompatible, biodegradable, not soluble in water, and has a relatively low melting point, between approximately 50 and 60°C [33]. Existing literature has identified PCL as a viable polymer carrier for 3D printing facilitated by FDM technology [34, 35].

Pediatric implants have shown efficacy in treating various medical conditions in children. One notable example is the histrelin implant, used to treat central precocious puberty (CPP). This subcutaneous implant, marketed as Supprelin LA, releases histrelin acetate, a GnRH agonist, over 12 months, effectively delaying early puberty. The minimally invasive procedure for implant insertion, typically performed under local anesthesia, underscores the feasibility and safety of such interventions in pediatric patients. The histrelin implant helps children develop in line with their age, showing how pediatric implants can improve health and quality of life [36]. Our goal is to develop PCL implants for the localized delivery of Gabapentin. This aims to overcome the bioavailability challenges associated with oral administration while reducing the need for high doses and frequent dosing. Additionally, the implants will help maintain stable plasma levels of Gabapentin, minimizing side effects.

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Materials

Gabapentin (GABA) was obtained from TCI America (Tokyo Chemical Industry Co., Portland, Oregon, USA). Polycaprolactone (PCL) MW 50000 was provided by Polysciences, Inc. (Warrington, PA, USA). Polyethylene glycol (PEG) 3350 and HPLC grade acetonitrile were provided from Sigma-Aldrich Inc (St. Louis, Missouri, USA). KH2PO4, KOH, and all other chemicals are of analytical grades.

Daihom, B.A., Abdelhakk, H.M. & Maniruzzaman, M. 3D-printed Gabapentin-loaded Implants for Sustained Release: Leveraging 3D Printing and Hot Melt Extrusion (HME) for Customizable Drug Delivery. AAPS PharmSciTech 26, 224 (2025). https://doi.org/10.1208/s12249-025-03215-3

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