3D drug printing
Today’s era of advanced technology and personalization, calls for a whole new revolution in the pharmaceutical industry too. This comes in the form of medicine dispensing vending machines, personalized medicines, faster and cheaper diagnostics, and 3D printing technology. 3D printing is already used in the medical industry for designing prosthetics, surgical implants, bone replacements and much more. In the drug development area, 3D printing shows potential to develop drug delivery systems, such as producing capsules, microneedles etc. One field that is of great interest is the possibility of 3D printing drugs themselves, to offer more customized medicines for individuals. Rapidly evolving healthcare industry, has made the one-size-fits-all treatment approach moot. Traditional therapies, that are labor intensive, dose-inflexible and time consuming, show a great percentage of ineffectiveness in treating the targeted conditions. This has led to an urgent need for new, more personalized therapies 1.
3D printing, also known as additive manufacturing, was first proposed in 1980s by Charles Hull. The manufacturing process of 3D printing involves deposition of materials layer by layer to form the final entity. The layers are printed based on a pre-designed 3D digital model. 3D printing is a versatile process, which allows use of local materials for the composition of the additive 2. The last 30 years have seen an exponential growth in the use of 3D printing techniques in biomedical engineering and many other fields. The application of 3D printing in drug delivery is relatively young and has been investigated to great lengths 3.
Benefits of 3D drug printing
In the pharmaceutical industry, drug manufacturing is a time consuming process and the industry is experiencing dormancy in manufacturing advancements. 3D printing can offer some relief and help with revolutionizing, not just drug manufacturing, but also drug development and treatment quality 4. One of the main benefits of 3D drug printing is its use in personalized pharmaceuticals, as it is able to produce small batched that are tailored dosages, shapes, size and release characteristics. Encapsulating drugs can be avoided, which helps improve the taste of the medicines due to use of lesser chemical compounds. 3D printers can be easily installed in local settings such as health centers, hospitals and remote locations. This is particularly useful for drugs that have poor stability and need special storage arrangements. Dispensing such medications in remote and economically backward places will become easier. Pharmaceutical companies benefit too, as it helps reduce cost, wastage, environmental burden and labor intensive work 5.
Unlike conventional tooling methods, 3D printing can combine digitization and mechanization and aids in avoiding constraints in a traditional manufacturing workflow. Due to the nature of manufacturing by layering or additives, 3D printing delivers final products rapidly and with minimal waste. Owing to the digital nature of object design, it is easy to customize, store and transfer. This confers it with the ability ot create complex bespoke products 4.
Methods for 3D drug printing
Inkjet printers used for printing paper work by forming small in droplets on paper. In the same way drug inkjet printers, also, form small liquid droplets and deposit them onto a substrate. A non-powder substrate is used, onto which the inkjet printers spray a combination of binders and medications, at a precise velocity, motion and size. Researchers further improved this technique by spraying ink droplets onto a liquid film. This forms an ink encapsulated liquid particle. This combined with inkjet printers provides an ideal delivery system for small hydrophobic molecules, growth factors, antibodies and microparticles.
Inkjet 3D printing can be accomplished through three methods: (1) droplet formation, (2) droplet impact and spreading and (3) drying or solidification. Thermal actuation requires the use of high vapour or volatile substances, and hence, inkjet printing used piezoelectric approaches in pharmaceutical applications. Many factors such as fluid velocity, density, surface tension and other factors affect droplet formation while printing. This needs to be taken into consideration when picking a method of printing for each pharmaceutical product 6.
Unlike the inkjet printing that uses a non-powder substrate, this method uses a powder-based substrate, as the name suggests. A powder is laid as foundation and the printer sprays ink onto this powder. The ink itself acts as a binder and causes the powder to harden, turning solid, upon spraying. Liquid is continuously sprayed onto the powder to form subsequent layers, finally resulting in a solid form. This is then separated from the rest of the unprinted powder 6.
Fused Deposition Modelling (FDM)
This is one of the most commonest methods used and is very similar to the inkjet printers in its mechanism of action. While the inkjet printer sprays ink, FDM uses beads of heated plastic. The printer head contains the molten materials (such as API and polymer mixtures), which pass through a nozzle and get deposited on a platform in layers, forming a filament. The filaments are ready once they harden. This method is also termed Fused Filament Fabrication (FFF). The final product depends on nozzle diameter, pressure of drop and feed rate. FDM is advantageous over powder-based method, as it can produce multifaceted scaffolds with a more accurate dosing system 7.
Personalized medicines using 3D printing
Personalized drug dosage
Traditional manufacturing process are not suitable for personalized medicines that are tailored according to dosage, release profile and physical state. 3D printing technology offers the ability to produce customized drugs. Personalization of medicines needs to be quick, precise, reliable and easy to handle by health care staff. Since 3D printing in digitally controlled, modifying dosage becomes a possibility. For example, pediatric population may require a very small dosage of the same medicine given to adults. Customizing this becomes easy and efficient with the use of 3D drug printing, as it can be patient specific and dosage can be altered at the site of treatment. Another example is for patients who may have swallowing difficulties and the shape of the tablet can be altered based on the patient, making administration much easier. Thus, 3D drug printing brings manufacturing closer to the patient and provides and great deal of flexibility 8.
Pharmacogenetics and pharmacogenomics has become the cornerstone to personalized medicine. These polymorphisms, including, age gender, race and other profiles can be taken into consideration when manufacturing drugs through 3D printing technology. Optimal dosage of drugs can be provided based on these characteristics. Using 3D printing technology, dosage can even be modified based on patient’s clinical response 8.
Personalized drug release profiles
Apart from dosage personalization, 3D drug printing can also provide freedom in terms of tailoring the drug release characteristics for each medicine. Drug release profiles can be customized based on release rate, profiles and release mechanisms. The below table (Table 1) summarizes some of the release profiles that can be made using 3D printing 7.
Table 1. Drug release profiles personalized through 3D printing
|Drug release type||How it works|
|Immediate Release Tablets||Rapidly dissolve and release medication immediately|
|Pulsatile Drug Release Tablets||Rapid release of entire medicine after a defined lag time|
|Monolithic Sustained Release Tablets||Delivery of medicine at a defined rate over a prolonged period|
|Biphasic Release Tablets||release of medicine at two different time periods at two different rates (e.g. slow/fast or fast/slow)|
|Fast Disintegrating Tablets||meant for people with swallowing difficulties, paediatric, geriatric, stroke victims etc|
|Transdermal drug delivery system||Delivered through the skin. E.g. patches and microneedles|
Developments in the field of 3D drug printing
The one and only 3D printed drug to have received commercial approval by the FDA is Spritam (levetiracetam). Spritam is an anti-epileptic drug and is made using Aprecia Pharmaceuticals’ ZipDose technology. Spritam is an orally dispersible tablet that disintegrates almost instantaneously when in contact with a liquid. Very high doses, as high as 1000 mg can be achieved using 3D printing, which is not possible with conventional methods. The ZipDose printing technology uses a drop-on-solid approach, where liquid binding agent is dropped on a pharmaceutical powder bed. The bed is then lowered and the process is repeated until many layers are added to form a nascent pill 5.
More recently, in April 2020, FabRx launched the first commercial 3D printer for drug manufacturing, called the M3DIMAKER. It is an extrusion based printer that accommodates nozzle change so that dosage requirements can be altered. The unique feature is that along with being able to extrude pharmaceutical material, the M3DIMAKER is also able to use a direct powder extrusion, similar to the ZipDose. This gives it the ability to manufacture multi-drug combinations with different release profiles 5.
Biopharmaceutical companies have only shown a small level of interest in 3D drug printing. Merck KGaA has collaborated with AMCM to develop 3D printed pharmaceuticals that are expected to reach clinical trials in the future. They expect this manufacturing process to be faster and cheaper as it will avoid reformulations. GlaxoSmithKline along with University of Nottingham has used nozzle printing with ultraviolet curing to make ropinirole tablets, used in the treatment of Parkinson’s disease. Most other companies have not announced any developments in the 3D printing front. A lot is still left to explore 5.
Other applications of 3D printing in drug development
Apart from revolutionizing the drug manufacturing process, 3D printing finds various applications in pharmaceuticals and clinical practice. The biggest contribution could be in drug trials. New drugs go through two dimensional cytology, animal testing and clinical trials. 3D printed micro organs on a chip can imitate living organs and can act as animal model for drug testing 2. In cases like bone infections, which needs direct treatment on the site of infection, 3D printing can formulate implantable drug delivery devices 8. A variety of dosage forms, like microcapsules, nano capsules, synthetic matrices etc. can be created.
Limitations of conventional chemotherapy include not being able to achieve enough concentrations of the therapeutic agent at the tumor site. The chemotherapeutic agent tends to accumulate in vital organs such as liver, heart, kidneys, causing serious side effects. Yi et al, in their study, created a 3D printed biodegradable 5-fluorouracil patch, that can be administered at the specific tumor site and the shape can be customized. These flexible patches delivered therapeutic concentrations of the drug at the tumor site, with a controlled and prolonged release profile .
More recently, the concept of a ‘polypill’ has been explored. A polypill is a combination of several drugs and helps patients with adhering to their medication schedule and dosage. This is especially significant in elderly patients and patients requiring multiple drugs. The drugs can be tailored to the individuals drug combinations with various release requirements 8.
3D printing technology is versatile and finds numerous applications across industries. It’s impact on pharmaceuticals and drug manufacturing has been profound. But all developments are restricted to research and have not found much commercial applications in healthcare and clinical practice. Yes, 3D printing is being used in surgical science and other similar fields, but we are still a long way from personalized drug manufacturing at the site of patient treatment. When we reach this thresh hold, we will truly be at the precipice of fully personalized treatments. As discussed in this article, 3D drug printing is a useful tool that can help reduce time, cost and manpower in drug manufacturing process. When used judiciously with good governance in place, this can be one of the biggest steps toward better healthcare.
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