Deliver the goods3 December 2021
Pharmaceuticals have come a long way throughout history. These days, therapeutic agents can even be delivered at a controlled dosage after being embedded within implants. Abi Millar speaks to Paris Fouladian, a PhD scholar at the University of South Australia who is currently conducting research into delivering anti-cancer drugs via implant, about how 3D printing is changing the field of drug delivery.
Innovations in the world of 3D printing have already led to medicine becoming more personalised, with devices moving away from a one-size-fits-all model to a more custom approach. Examples like custom-made prosthetics for amputees or patient-specific anatomical models used within surgical training help to illuminate the change. Conventional methods of production here would be costly, labour-intensive and not especially viable. By contrast, 3D printing (also known as additive manufacturing) can cut costs, save time and open up a host of new applications for devices. Increasingly, the same applies within drug delivery. While 3D-printed pharmaceuticals are still a relatively new idea, many different research groups are exploring different applications for the technology. The promise is clear: freed from the constraints of traditional manufacturing, one might be able to create dosage forms or formulations tailored to individual patients.
“Over the last decade, 3D printing has gained considerable attention in pharmaceutical formulations and drug delivery systems as an effective strategy to overcome the challenges of conventional manufacturing approaches,” says Paris Fouladian, a PhD scholar at the University of South Australia, who is exploring 3D printing within drug delivery systems. “Beyond rapid prototyping, 3D printing provides significant advantages, including the manufacture of personalised pharmacotherapy products based on the patient’s needs.”
At the moment, pharmaceutical formulations are typically designed for a generic, everyman patient (read: a white adult male). This means they fail to capture the diversity of the actual patient population. Smaller patients may end up taking a higher dose of medication than they actually need, while larger patients may not take enough to feel the effects.
Through 3D printing, researchers hope to improve that dosing accuracy – and to reduce the waste and cost associated with personalised dosage forms. Pharmacists would be able to look at a patient’s profile to determine their optimal dose before 3D printing and dispensing it using an automated system.
3D printing might also help manufacturers improve a drug’s solubility, control the speed of absorption or incorporate it into a range of drug-eluting implants.
“It opens up the possibility of designing and fabricating customised and complex geometries to achieve different drug release kinetics,” says Fouladian. “It also gives you the ability to control the spatial distribution of the therapeutic agent within the body, and allows for the deposition of very small amounts of therapeutic agents.”
Dose on demand
To give a quick primer on how 3D printing works: 3D objects are fabricated from a digital file, which can be easily changed or adapted according to need. Unlike traditional manufacturing processes, in which a raw material is shaped into its final form via carving or injection moulding, 3D printing builds up different materials, layer upon layer. This intricate process allows for the creation of complex, customised objects.
Within drug delivery specifically, the most popular technique is called fused deposition modelling (FDM), in which filaments are loaded with medicine. Other common techniques include direct powder extrusion (suitable for delayed or sustained release dosing), stereolithography, inkjet printing and selective laser sintering. In most cases, these methods are based around polymers.
“Polymers, as the most versatile class of materials, play a crucial role in drug delivery systems,” explains Fouladian. “To identify possible polymers for the desired application, several criteria need to be considered, including chemical inertness, biocompatibility, ease of fabrication, sterilisation and compatibility with drugs.”
The world’s first 3D-printed drug, Spritam, was approved for the treatment of epilepsy by the FDA in 2015. Normally, a large dose of medication means a large pill, which can stick in the throat, causing problems for elderly patients. By 3D printing the tablets, the manufacturer, Aprecia, was able to improve their porosity and make them easier to swallow.
Since then, a UK start-up called FabRx has used 3D printing to create personalised medicine for children with a rare metabolic disorder that causes a harmful buildup of amino acids in the blood and urine. The pharma giant Merck has also announced plans to produce 3D-printed tablets for clinical trials, in partnership with additive manufacturing company AMCM.
More recently, Chinese company Triastek has received investigational new drug (IND) approval from the FDA for its own 3D printed drug product, T19. The drug in question – which is likely to become the second 3D-printed pharmaceutical on the market – is designed to treat rheumatoid arthritis. According to the manufacturer, its internal geometry allows the mode of drug delivery to be closely controlled and adjusted.
Another line of research lies with ‘polypills’ – multiple drugs combined into a single pill. These would be suitable for patients suffering multiple conditions who want to simplify their treatment regimen. Because 3D printing enables manufacturers to build up different layers with different geometries, the drugs would be physically separated from each other and could be given different release profiles, meaning they didn’t interact. In 2019, a research team successfully 3D-printed polypills containing six different drugs (paracetamol, naproxen, caffeine, prednisolone, aspirin and chloramphenicol) in spatially separated compartments.
Drugs in devices
Other researchers are incorporating drugs into 3D-printed implants, like stents, as well as antitumoural and bone treatment devices. The idea is to administer drugs into the tissue surrounding the implant to avoid the side effects of systemic administration.
In March 2021, a research group outlined a new approach for bone regeneration – 3D-printed bone scaffolds impregnated with antibiotics. This would mitigate the risk of bone infection following an open fracture or surgery, and would eliminate the need for intravenous antibiotics. According to study author Lorenzo Moroni of Maastricht University, “3D-printed polymeric scaffolds possess several unique properties for bone regeneration: their shape can be tailored to fit the specific patient’s anatomy, they are porous to allow cell infiltration, but at the same time mechanically strong, and they can degrade over time to make space for the newly-formed bone.”
He added that incorporating antibiotics into the scaffolds is not straightforward, since the 3D printing process involves high temperatures, and antibiotics are heat-sensitive. However, the team was able to safeguard the antibiotics by covering them with lamellar inorganic protectors. This had the added benefit of ensuring controlled drug release.
Fouladian points out that 3D printing is a valuable tool for the pharmaceutical sector in general, enabling personalised medicine focused on the patients’ needs.
“The FDA approval of the first 3D-printed drug showed pharmaceutical companies the industrial feasibility of this technique, paving the way for the printing of more oral tablets,” she says. “We also hope to see huge progress in 3D-printed localised drug delivery systems, specifically drug-loaded medical devices and implants.”
Fouladian herself has been working on a world-first stent for patients with inoperable oesophageal cancer, which contains chemotherapy drugs within its matrix. As she explains, patients with this form of cancer often struggle with dysphagia (problems swallowing food and drink) because of tumour cells blocking the windpipe. Introducing a stent can relieve symptoms over the short term – and in fact is the most effective palliative treatment for these patients. Unfortunately, the stent itself can end up blocked by cancer cells, compounding the problem.
“Studies have shown that continued stent usage presents complications including tumour ingrowth, recurrence of strictures, reflux disease and perforation, which can limit the long-term success of stents,” she says. “Therefore, several attempts have been made to develop drug-eluting stents as an effective choice for the treatment of occlusion or stenosis of the body’s tubular structures.”
In their in vitro studies, the team loaded a 3D printed, polyurethane stent with a chemotherapy drug, 5-FU. The stent released this drug steadily over a period of 110 days. Should it prove viable in the human body, the device would be able to deliver the drug directly to the tumour site, stopping the cancer from growing while reducing systemic side effects.
More research is needed, starting out with animal studies and eventually moving into clinical trials. Questions remain around the dose of drug required, the mechanical properties of the stent, and whether it needs new folding and deployment mechanisms. However, Fouladian is hopeful about its prospects.
“Our study demonstrated that 3D printing is a powerful tool for manufacturing drug eluting stents, which could easily be customised to provide personalised, patient specific geometries and drug doses in patients with oesophageal cancer,” she says.
On a similar note, a team of researchers from China is working on 3D implants loaded with anticancer drugs for the treatment of osteosarcoma. They designed implants made from poly L-lactic acid, noting that the material was biodegradable with high biocompatibility and biosafety.
Like the oesophageal stent, this drug administration system serves as a form of local chemotherapy, and directly acts on the tumour site. It aims to achieve sustained release of topical drugs, and prolonged duration of drug action.
While most of the work in this field is in its early stages, and does not yet have a clear path to the clinic, momentum is starting to build. 3D printing could prove transformative for drug delivery, with a host of new applications just around the corner. Personalised 3D-printed tablets, along with customised drug-eluting implants, could one day be the norm in medical care.
Implants used to regenerate damaged bone
Each year, around four million people worldwide develop bone infections following an open fracture or surgery. The gold standard treatment consists of a lengthy antibiotic therapy, usually delivered orally or intravenously, and the removal of infected bone tissue, which often leaves behind a hole too large for the body to fi ll via normal bone regeneration. In a study published in April 2021, in the journal Bioactive Materials, a group of researchers from the Netherlands, Italy and Spain, outlined a new treatment approach they have developed – novel antibiotic-releasing and biodegradable 3D printed scaffolds, capable of supporting bone regeneration and delivering antibiotics at the same time.
The study’s multidisciplinary team of scientists found that covering the antibiotics with lamellar inorganic protectors, prior to mixing them with the polymer and placing them in the 3D scaffolds, not only protected the antibacterial agents, it also enabled a more controlled release. This extended the period the antimicrobial was active and helped to keep local antibiotic concentrations under potentially toxic levels. At the same time, the cells in contact with these scaffolds maintained their viability and could perform normal cell functions, including bone formation –the ultimate goal of the implant.
Source: KeAi Communications