Discovery & Development Dosage Forms, Drug Delivery, Formulation

Breaking the Mold Layer-by-Layer

How 3D printing could transform solid oral dosage forms

Atul Ashok Kumar Lohade | 11/05/2024 | 6 min read | Technology

3D printing technology was first introduced in the 1980s and has revolutionized manufacturing across various industries by enabling the rapid production of complex objects, from prosthetic limbs to lightweight rocket engine components. The success of 3D printing in other sectors quickly captured the attention of innovators in the pharmaceutical industry. In 2015, the first 3D printed oral suspension tablet was approved by the FDA for the treatment of epilepsy. SPRITAM (developed by Aprecia Pharmaceuticals) is a levetiracetam orally disintegrating tablet for epilepsy treatment produced through a 3D printing manufacturing process that binds layers of powdered medication together with an aqueous (water-based) fluid. This method creates solid yet highly porous tablets, enabling rapid disintegration when taken with a sip of liquid (1).

Since then, the industry has witnessed a surge in R&D projects exploring the potential of 3D printing for solid oral drug development, powered by rising demand for personalized medicine. The technique offers numerous opportunities to customize medicines in terms of size, shape, release profile and dose.

The technique involves the deposition of materials on top of each other, layer-by-layer, according to designs that can be made using a computer. In pharma, a clinical trial is underway for a 3D-printed treatment for gastric retention (2, 3), but in general, there are few trials taking place across the industry. However, further investment in this area could address this and there is certainly an enormous opportunity; the global 3D printed drugs market is predicted to grow at a 16 percent compound annual growth rate between 2023 and 2031, increasing from $98.50 million to potentially $322.91 million (4).

What are the benefits? The technique can be used to develop several dosage formats including tablets, capsules, and films, and offers new levels of flexibility and precision over traditional dosage form manufacturing methods. For instance, tailored drug release profiles can be developed much more easily with 3D printing technology, including immediate- and controlled-release formulations (5, 6).

One of the key benefits of 3D printing is that it allows for the combination of previously incompatible APIs into different compartments within a single pill – known as a polypill.

Here are some examples of the power of 3D printing. Metabolic syndrome, characterized by at least three of the following: insulin resistance, hypertension, dyslipidemia, type 2 diabetes, obesity, inflammation and non-alcoholic fatty liver disease, requires a complex treatment regimen tailored to individual patients’ disease profiles. 3D printing technology could be used to manufacture personalized polypills by enabling advanced customization – incorporating multiple drugs, controlled-release profiles, and offering versatility in formulation design.

In a recent study demonstrating the promise of this approach for metabolic syndrome applications, researchers manufactured a polypill using an innovative 3D printing technology called fused deposition modeling (7). The polypill contained an antihypertensive drug (nifedipine), antihyperlipidemic drug (simvastatin) and antihyperglycemic drug (gliclazide), to address hypertension, dyslipidemia and type 2 diabetes, respectively. The polypill demonstrated a dual-release profile, combining fast release for simvastatin with sustained-release for nifedipine and gliclazide, showcasing the potential for personalized treatment of metabolic syndrome. While the results were promising, the researchers noted that further studies are needed to take this 3D printed polypill from the lab to clinical use, especially in terms of optimizing excipient selection.

In another case study, researchers demonstrated how 3D printing can be leveraged to support the delivery of challenging APIs, including those that are thermo-sensitive, such as the anti-cancer drug 5-fluorouracil (5FU). The researchers created 3D printed oral tablets loaded with 5FU, demonstrating good flow properties, porous texture, and homogenous drug distribution (8). Moreover, the drug dose, release rate, and tablet shape and size could be adjusted by optimizing the composition of the powder bed with pharmaceutical-grade excipients. Benefits could be achieved in poorly soluble, low bioavailability drugs too, such as domperidone – an anti-sickness medicine for nausea and vomiting. One research group also used a fused deposition model to create a 3D printed domperidone tablet with a hollow structure, which allowed the drug to float for a prolonged period of time in the stomach, resulting in increased absorption and bioavailability in an animal model (9).

When considering 3D printed dosage forms, it’s important to consider excipients. Excipients play a fundamental role in the 3D printing of solid oral dosage forms, contributing to the viscosity, rheology, flow properties, structural integrity and overall functionality of the printed drug product. Take HPMC excipients as an example. This biodegradable polymer can bring multiple functions to solid oral drugs developed using different 3D printed drug delivery technologies. Moreover, the properties of HPMC can be modified to suit different 3D printing processes.

For instance, HMPC can be used as a substrate to achieve immediate-release using the printer-based inkjet technique (10, 11). This method consists of the formation and placement of digitally controlled droplets onto a substrate, which can be either a solid or liquid. In one study, HPMC of different viscosity grades was used to create foam-based substrates. Results found that the viscosity of HPMC affected the physical and mechanical properties of the substrate, which impacted the release of the drug. In this case, high viscosity HPMC performed best for creating and retaining a porous structure (10). This highlights how drug developers can tap into the different properties of HPMC to deliver cutting-edge 3D immediate-release dosage forms.

The benefits of HPMC excipients do not stop at immediate-release drugs; they can also support the development of 3D printed drugs with modified-release profiles, particularly controlled-release. Controlled-release was achieved using the printer-based inkjet technique when high viscosity HPMC was used as a controlled-release polymer, combined with low viscosity HPMC as a binding agent to create 3D printed bilayer and polypill tablets (12, 13). In addition, research has demonstrated that 3D printed non-effervescent gastric floating tablets can be produced using the inkjet printing technique with two different viscosity grades of HPMC (14). The combination of these HPMC polymers enabled the creation of a hydrophilic matrix that supported sustained drug release in the stomach, showcasing HPMC's potential in targeted drug delivery systems.

HPMC has also proven effective in nozzle-based deposition systems, another 3D printing system where HPMC has supported both immediate-release and modified-release formulations (15, 16, 17). This technique requires the desired material to be prepared as a filament, which is then heated to produce a melt mass (5). The melt mass is passed through an appropriately sized nozzle and deposited in layers to build a platform according to the design created with the software. The melted material can then fuse to produce the finished product. One study revealed that the viscosity of HPMC could impact the drug release profile in this method – as viscosity increased so did filament strength, while drug release from the printed tablet decreased (18).

While the research on 3D printing for pharmaceutical dosage forms continues to expand, there are several factors to consider:

Regulatory requirements. The regulatory landscape for the 3D printing of pharmaceutical drugs is currently not well-defined in Europe, China or the US. Therefore, drug developers must conduct thorough due diligence to identify any potential regulatory hurdles before implementing a 3D printing process.
Quality control challenges. One of the biggest challenges associated with 3D printing is assuring quality. Manufacturers must implement stringent quality control measures throughout the 3D printing process. This includes sourcing raw materials from reputable suppliers.
Cost considerations. 3D printing currently favors small-scale production and may not be economically viable for mass manufacturing (yet). But when it comes to on-demand manufacturing, 3D printing is a cost-effective solution. While significant upfront costs for printing equipment should be considered, 3D printing also offers unique cost-saving advantages, such as minimal raw material waste and customization without time-consuming manufacturing changes.
Excipient selection. Choosing the most suitable excipient for a given formulation is crucial to achieving the desired functions and overall performance of a printed solid oral dosage form.

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Discovery & Development Dosage Forms, Drug Delivery, Formulation

Aprecia Press Release (2015): FDA Approves The First 3d Printed Drug Product (aprecia.com)
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