Revealing Three-Dimensional Printing Technology Advances for Oral Drug Delivery: Application to Central-Nervous-System-Related Diseases

Abstract

Background/Objectives. Central nervous system (CNS)-related diseases such as Alzheimer’s and Parkinson’s, Attention Deficit Hyperactive Disorder (ADHD), stroke, epilepsy, and migraines are leading causes of morbidity and disability worldwide. New solutions for drug delivery are increasingly needed. In this context, three-dimensional (3D) printing technology has introduced innovative alternatives to produce more efficient medicines with diverse features, patterns, and consistencies, particularly oral medications. Even though research in this area is growing rapidly, no study has thoroughly analyzed 3D printing oral drug delivery progress for the CNS. To fill this gap this study pursues to determine a technological landscape in this field.

Methods. For this aim, a Competitive Technology Intelligence (CTI) methodology was applied, examining 747 publications from 1 January 2019 to 20 May 2024 published in the Scopus database.

Results. The main advances identified comprise six categories: 3D printing techniques, characteristics and applications, materials, design factors, user acceptance, and quality processes. FDM was identified as the main technique for pharmaceutical use. The main applications include pills, polypills, caplets, gel caps, multitablets, orodispersible films, and tablets, featuring external patterns and internal structures with one or more active substances. Insights show that the most utilized materials are thermoplastic polymers like PLA, PVA, PCL, ABS, and HIPS. A novel design factor involves release patterns using compartments of varying thicknesses and volumes in the core. Additionally, advances in specialized software have enabled the creation of highly complex designs. In the user acceptance category, oral drugs dosages are tailored to the specific needs and preferences of neurological patients. Finally, for the quality aspect, the precision in Active Pharmaceutical Ingredient (API) dosage and controlled-release mechanisms are critical, given the narrow margin between therapeutic doses and toxicity for CNS diseases.

Conclusions. Revealing these advancements in 3D printing for oral drug delivery allows researchers, academics, and decision-makers to identify opportunities and allocate resources efficiently, promising enhanced oral medicaments for the health and well-being of individuals suffering from CNS disorders.

Introduction

This study starts exploring the role of 3D printing in pharmaceutical manufacturing, particularly in the development of personalized oral drug delivery systems for central nervous system (CNS) diseases. By enabling precise dosage control and tailored formulations, 3D printing addresses key challenges in conventional drug production.

1.1. Context

Three-dimensional printing technology has revolutionized various sectors of the biomedical industry. It is a highly flexible manufacturing method with the potential to significantly innovate drug administration in living biological systems [1]. This technology has facilitated the creation of drug delivery systems, particularly in pharmaceuticals, where its application to traditional diseases has been explored [2,3]. Various administration routes exist for medications, including oral, nasal, vaginal, and rectal, with the oral route being the most effective in terms of patient adherence to treatments across all age ranges [4].

Drugs are prescribed according to different ages, from newborn to elderly [5]. During their lives, people face different challenges by taking medicines and adhering to their treatments. As individuals transition to geriatric ages, they often experience difficulties in swallowing medicines, memory impairment, cognitive decline, vision loss, and reduced dexterity, affecting their medical treatments. On the other hand, many patients require complex polypharmacy regimens that are difficult to follow with traditional medications. Individuals with neurological diseases that cause visual impairments, approximately 1.5 billion people worldwide, encounter challenges in distinguishing the name, dosage, and expiration dates of medications, which are usually printed graphically on conventional packaging [6].

These factors present a significant opportunity for the development of products that cater to the diverse needs of this population. With 3D printing, patients of all ages are increasingly favoring oral medications in the form of orodispersible films, gummies, and sublingual orodispersible tablets for the ease of self-administration and the perception of safer digestion and effectiveness [7]. Personalizing doses of active substances is crucial to achieving therapeutic effects, and the treatment of CNS diseases has a main role in the global market.

CNS-related diseases are a leading cause of morbidity and disability worldwide. As detailed in ‘Global, Regional and National Burden of Disorders Affecting the Nervous System’ (The Lancet, 2024), between 1990 and 2021, these diseases affected 43% of the global population—approximately 3.4 billion people—with 443 million experiencing a poor quality of life [8]. Additionally, patients represent a significant global market share, as will be described in the next section. Conditions such as stroke, neonatal hypoxic ischemic encephalopathy, migraine, dementia, diabetic neuropathy, meningitis, epilepsy, and neurological complication in preterm birth and being on the autism spectrum were identified as the most prevalent [9].

Oral medications are fundamental for the control of these diseases as this type of drug delivery has been recognized as the fastest, simplest, and most comfortable route, often outperforming other methods [10]. The process used to fabricate medications is determined by several factors including the characteristics of the APIs and the specific requirements of the excipients, aiming to achieve the desired therapeutic effects. The effectiveness of the Active Pharmaceutical Ingredient (API) in oral medications depends on several factors, including the physical state of the APIs (e.g., pulverized solid, semi-solid, or gel), the route of entry, and transportation, distribution, and absorption within the gastrointestinal surface, which also influence the drug’s performance [11].

The conventional production of oral medications for CNS diseases includes methods such as direct compression, dry granulation, and wet granulation. These methods use raw materials such as APIs, excipients, diluents, disintegrants, binders like povidone (PVP), lubricants, and coatings like hydroxypropyl methylcellulose (HPMC) [12].

The three-dimensional printing of oral medications for CNS diseases offers numerous advantages over conventional manufacturing methods, such as those previously discussed. These advantages include greater customization and precision, and the ability to design medications with advanced properties, as clinical trials have shown [13]. Traditional methods face limitations; for example, direct compression can only be used with APIs in powder form that have good flowability and compactability, with limited capacity for the customization of shapes and release profiles. Meanwhile, dry granulation allows the production of products with lower homogeneity compared to other conventional methods, making it less effective for formulating complex release profiles—an area where 3D printing excels. Finally, wet granulation is costly, time consuming, and unsuitable for ingredients sensitive to moisture or heat [14], where 3D printing provides unique solutions.

For CNS medications, 3D printing provides significant advantages, as therapies often need to be tailored to individual patient needs and optimized for controlled drug release to maximize efficacy while minimizing adverse effects [15]. Moreover, 3D printing addresses the high costs associated with CNS disease treatments. By enabling smaller doses and faster production times, and reducing material waste, this technology significantly lowers manufacturing expenses. On-demand production further cuts costs by eliminating the need for large-scale manufacturing, extensive inventory storage, and costly logistics such as transportation and cold chain requirements for temperature-sensitive medications. These benefits collectively position 3D printing as a cost-effective alternative for CNS treatment production [4].
In particular, this technology offers an effective means of oral drug delivery, enabling the production of complex designs [16]. It allows the creation of oral vehicles in various forms, such as orodispersal films, pills, polypills, and multi-compartmental tablets, that optimize the effectiveness of the active substances they contain. The goal is to reduce patient mortality and morbidity, slow the progression of symptoms, and decrease therapeutic failures caused by poor adherence to medications [17]. This issue is particularly relevant because oral treatments involve conventional dosing, as presented in the Manual of Adherence to Chronic Treatments by the Pan American Health Organization, in the section on neurological medications and the lack of effectiveness of neurological medications [18]. Despite considerable research efforts in 3D printing for oral drug delivery [19,20], no study is available regarding advances around 3D printing for oral drug delivery for CNS conditions. Current research focuses on the applications of 3D printing in healthcare [1,2,7], 3D bioprinting for drug delivery [10,11,19], and 3D printing technologies for pharmaceutical manufacturing [5,11,13,14,16,17]. To fill this gap, a Competitive Technology Intelligence (CTI) methodology was implemented to reveal the 3D printing advances for oral drug delivery in CNS-related diseases, aiming to support health professionals, researchers, and scholars in the technology decision-making process.
CTI is a strategic approach based on a continuous process focused on identifying technological trends and opportunities in a specific field, offering insights for decision making in technology, innovation, product design, research, and market analysis [21]. CTI stands apart from conventional information methods by adopting a proactive approach, anticipating trends, and guiding the early adoption of transformative technologies. It provides a comprehensive, global analysis of technological, regulatory, and market landscapes, integrating multidisciplinary insights to drive innovation. Unlike traditional methods with lengthy evaluation cycles and standardized practices, CTI contributes to accelerate technology adoption and emphasizes personalization and adaptability, which are critical for addressing the unique complexities of CNS medications.

In this study, a CTI methodology comprising eight steps considering the approach of Rodriguez-Salvador and Castillo-Valdez (2021) [21] was applied as shown in a subsequent section.

1.2. Global Market for Personalized Neurological Drugs via 3D Printing

The global market for 3D-printed pharmaceuticals is experiencing significant growth, propelled by several factors, such as the use of new manufacturing technologies to achieve a more integrated healthcare ecosystem [22]. These include increased government investment in 3D printing technology, venture capital funding for startups in the field, and the pharmaceutical industry’s expanding adoption of this technology. An Organization for Economic Co-operation and Development (OECD) analysis highlights an increase in per capita government health spending in industrialized nations [23]. Personalized medicines made possible by 3D printing represent a radical shift in healthcare treatments and production processes, offering more agile and adaptable manufacturing methods. Additionally, a recent study found that approximately 63% of pharmaceutical companies are considering investing in 3D printing, with the number of professionals utilizing this technology having tripled since 2017 [24]. Currently, five pharmaceutical companies are leading the production of 3D printing technologies for pharmaceuticals: Aprecia Pharmaceuticals (Langhorne, PA, USA) pioneered the first FDA-approved 3D printing platform in 2015 for commercial-scale drug production, using its Zip Dose technology to develop Spritam, a 1000 mg levetiracetam tablet that rapidly dissolves with a sip of water. FabRx (London, UK) introduced the M3DIMAKER 3D printer, the first pharmaceutical printer for personalized medicine, capable of producing “printlets” with Braille text or dotted patterns for visually impaired patients. Merck (Darmstadt, Germany), in partnership with Additive Manufacturing Customized Machines (AMCM), a division of Electrical Optical Systems (EOS), focuses on industrial applications of 3D printing for large-scale drug manufacturing. Triastek (Nanjing, China), with 41 patents for 3D-printed pharmaceutical applications, developed an FDA-accepted 3DMED platform, enabling tablets with diverse shapes and geometries for controlled API release. The company also introduced chronotherapeutic drugs for rheumatoid arthritis and neurovascular disorders and collaborated with Eli Lilly to produce 3D-printed polypills with enhanced bioavailability and targeted release for the central nervous system. GlaxoSmithKline (London, UK), in collaboration with the University of Nottingham, has pioneered commercial-scale inkjet 3D printing with ultraviolet curing for solid medications, becoming the first in 2017 to 3D print ropinirole tablets for Parkinson’s disease while also exploring curable API inks for 3D printing [25].

Financial backing has played a crucial role in driving this market expansion, with countries such as the United States, Canada, Germany, the United Kingdom, France, Austria, Japan, India, China, and South Korea offering incentives to support investments in advanced digital technologies, including 3D printing [26,27].

In recent years, there has been a growing interest in personalized medicine, with 3D printing playing an increasingly vital role. This technology enables tailored dosages, enhances medication retention rates, and facilitates easier swallowing through various medication forms [28].

3.3. Printing Materials

The use of materials to produce different consistencies of excipients is fundamental to innovation within 3D printing, particularly in the production of personalized oral medications, including the use of APIs for managing diseases of the central nervous system. In this context, 3D prints with soft consistencies, such as gel caps, orodispersible firms, or films with different 3D printing patterns, generate a precise seal with dimensional harmony, overcoming traditional production defects like surface coverage issues, defective sealing, or asymmetry, and reducing production costs [83].
These processes use thermoplastic polymers such as PLA, PVA, PCL, ABS, and HIPS, which exhibit versatile applications in pharmaceutical 3D printing. Initially used in neural conduit fabrication, these materials later advanced to the production of oral vehicles like hydrogels and are now being adapted for manufacturing gel capsules [84]. These capsules feature polymeric networks with high water absorption capacity, emphasizing their role in sustained drug release [57]. PLA is employed in implants, scaffolds, and drug delivery systems. Its thermoplastic properties enable processing via FDM, allowing tailored degradation rates for prolonged release. Conversely, PVA’s water solubility, biocompatibility, and mechanical enhancement properties make it suitable for oral caplets, tablet casings enabling zero-order release, and controlled-release shells [5]. Additionally, these polymers can form complex geometries, facilitating the design of nanotechnological medicines [85] to address specific delivery challenges [86].
During printing, the polymer filament has the ability to, if required, combine with the active ingredients of the medication, a process that can be carried out through immersion in a solution. The traditional process involves passive diffusion, where the filament is immersed in a solution saturated with the drug’s active ingredient, such as caffeine orodispersible films [79].

According to the analysis of the materials mentioned above, PLA and PVA are the most used in pharmaceutical production due to their characteristics, which are described below.

PLA is a natural, organic, biodegradable, and biocompatible polymer. However, it has hydrophobic properties, which is a biomedical disadvantage, as it poses difficulties in dissolution and disintegration, affecting the optimal release of active substances. It may also trigger inflammatory responses. PLA is used in venlafaxine production for treating depression [87]. PVA, on the other hand, is a hydrophilic, biodegradable, biocompatible, and non-toxic synthetic polymer, though it is only slightly soluble in ethanol and insoluble in organic solvents. It is used in pharmaceuticals due to its suitable viscosity and low melting temperature. However, its hygroscopicity can alter the release and action of the drug. PVA is used in medications such as haloperidol, pramipexole, levetiracetam, and aripiprazole [57].

Currently, polymer mixtures are used to create filaments necessary for printing oral vehicles for oral drugs such as levetiracetam and lamotrigine [11]. These mixtures enhance their rheological properties, enabling the printing of specific three-dimensional structures, thus providing stability to the composition of the active ingredients for optimal function and ensuring compliance with pharmacological quality standards.

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Table 1. Categories and topics in 3D printing for oral drug delivery.

Category	Topic
3D Printing Techniques	Fused Deposition Modeling (FDM).
	Semi-Solid Extrusion (SSE).
	Stereolithography (SLA).
	Digital Light Processing (DLP).
	Selective Laser Sintering (SLS).
	Binder Jetting (BJ).
Applications	Pills.
	Polypills.
	Caplets.
	Gel Caps.
	Multitablets.
	Orodispersible Films.
	Tablets with one or more API(s).
Materials	Polylactic Acid (PLA).
	Polyvinyl Alcohol (PVA).
	Polycaprolactone (PCL).
	Acrylonitrile Butadiene Styrene (ABS).
	High-Impact Polystyrene (HIPS).
Design Factors	Geometric Pattern for Drug Release Control.
	Multi-Compartment Designs.
	Release Profiles.
User Acceptance	Personalized Drug Dosages.
	Customized Shapes and Textures.
	Improved Adherence.
Quality Processes	Precision in API Dosage.
	Biosafety and Regulations.
	FDA Approval for 3D-Printed Drugs.

Paipa-Jabre-Cantu, S.I.; Rodriguez-Salvador, M.; Castillo-Valdez, P.F. Revealing Three-Dimensional Printing Technology Advances for Oral Drug Delivery: Application to Central-Nervous-System-Related Diseases. Pharmaceutics 2025, 17, 445. https://doi.org/10.3390/pharmaceutics17040445

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Read also our introduction article on Orally Disintegrating Tablets (ODTs) here: