Production Of Medicines Using Stereolithography (SLA) 3D Printing

Pharmaceutical researchers are becoming more interested in the use of three-dimensional printing (3DP) to manufacture medicines. Since 3DP is a highly flexible technique to manufacture personalised objects, 3DP can potentially become a new method to fabricate patient-tailored printlets (3D printed tablets).

Different 3DP systems have been explored for their use in Pharmaceutics, including fused deposition modelling (FDM), selective laser sintering (SLS), powder liquid and recently stereolithography (SLA). SLA has some advantages over other types of 3DP, mainly its remarkable resolution and the avoidance of thermal processes which can be detrimental for certain drug molecules.

What is stereolithography?

Stereolithography (SLA) 3D printing is an additive manufacturing process where a photocurable liquid resin is solidified in a highly accurate, controlled and rapid way.

Schematic representation of an SLA 3D printer

In SLA 3D printing the solidification of the building material occurs in a layer by layer manner by means of a photopolymerisation process. During photopolymerisation, 3-dimensional crosslinked networks are formed upon exposure to an appropriate source of light which allows the possibility of fabricating hydrogels.

mage of a Form 1+ SLA 3D printer (Formlabs Inc.)

Why hydrogels are important

Hydrogels are three-dimensional hydrophilic polymeric networks, which are able to absorb large amounts of water or other liquid agents hence having gel behaviour. This property makes hydrogels great candidates for their use for biomedical purposes, for instance in tissue engineering and in drug delivery systems. The use of hydrogels as medicines allows the possibility of having a controlled release of drugs over time from these polymeric matrices which is desirable to enhance efficacy and safety.

SLA 3D printed hydrogels

Researchers at the UCL School of Pharmacy fabricated for the first time ibuprofen-containing hydrogel printlets using a highly biocompatible photoinitiator (which is a molecule capable of initiating a light-triggered polymerisation process) and a commercial desktop SLA 3D printer. The hydrogels had different contents of initial water in the liquid formulation to modify the speed at which the drug is released from the printlets which can be useful to tailor drug release profiles to the individual needs of patients.

Images of hydrogels printlets containing ibuprofen fabricated using SLA printing

How is the drug contained in the printlets and how is it released?

During 3D printing the drug becomes entrapped in between the polymer crosslinked network. When the printlets are placed in water, they swell as the network loosens. When this happens, the drug molecules are released in a controlled manner. Depending on multiple factors including how tight the polymer networks are, the drug release can be modified, in this research since the hydrogels retain the water added prior to printing, this acts as a pre-swelling agent that increases the drug release rate.

Drug dissolution profiles from the hydrogel printlets. The drug released was determined in a dynamic dissolution system to mimic the conditions in the gastrointestinal tract; the red line shows the pH values of the media.

The Potential of SLA 3DP in the Pharmaceutical area

SLA can become a new method for fabricating drug-loaded hydrogels with tunable mechanical and physical properties and drug release profiles. SLA avoids the risk of thermal degradation and additionally offers a way to fabricate highly complex structures with a great resolution, which can be useful to modify the way in which the drug is released.

The use of 3-dimensional printing (3DP) in the healthcare industry is becoming an increasingly popular trend. 3DP allows the manufacturing of personalized-dose medicines to be tailored to the individual combining different drugs. The replacement of conventional drug manufacture and distribution could provide patients with personalized polypills fabricated at the point of care, thus reducing cost and enhancing therapy adherence. The FDA approval, in August 2015, of the first 3D printed medicine (Spritam®) proved that 3DP technology works and the race is now on to push forward its development in the pharmaceutical field.

3D printing technologies

In recent years different 3DP technologies have been used to produce these new medicines e.g. stereolithography (SLA) or fused deposition modeling (FDM), which has been the most employed 3DP technology to date, due to it being inexpensive and easy to use.

Printlets, 3D printed tablets

Researchers from FabRx Ltd. and UCL – School of Pharmacy have recently reported in the International Journal of Pharmaceutics the use, for the first time, of selective laser sintering (SLS) to produce personalised 3D printed tablets (Printlets™).

What about selective laser sintering (SLS)?

Selective laser sintering is currently used for industrial manufacturing of plastic, metallic and ceramic objects but, to date, there have been no reports on the use of SLS to fabricate oral drug loaded products.

Schematic representation of the SLS printer (Fabrizio Fina)

SLS uses a laser to bind together the powder particles from a powder bed. During the printing process, the laser is directed to draw a specific pattern onto the surface of the powder bed. Once the first layer is completed, a roller distributes a new layer of powder on top of the previous one. The object is built layer-by-layer, which is then recovered from underneath the powder bed. Advantages of SLS technology include the fact that it is a solvent-free process and offers faster production and resolution compared to other methods.

Is it an industrial process?

In this first study paracetamol (acetaminophen) was selected as a model drug, mixed with pharmaceutical excipients and incorporated in the powder bed of a commercial desktop SLS 3D printer, Sintratec kit. Sintratec printer is the first desktop printer in the market which makes SLS accessible to consumer customers.

Image of a Sintratec kit desktop SLS 3Dprinter

Sintratec SLS technology has enabled printing of personalized-dose printlets of different shapes, with high resolution and no drug degradation. The SLS technology offers a platform technology to formulate and manufacture 3D printed medicines with almost any drug compound in a range of shapes, sizes, colours, textures and flavours to make them more attractive to various patient groups, particularly the young or the elderly, facilitating compliance of the treatment. The manufacturing process allows precision of dose strength and is suitable for both low and high drug concentrations.

Images of printlets containing paracetamol (acetaminophen) prepared by SLS printing

How is the drug release?

Drug release tests from the printlets were performed in a Dynamic Dissolution Model that modulates pH over time, precisely simulating gastro intestinal conditions during transit of the medicines. Proper selection of excipients allows FabRx to design printlets possessing any desired drug release profile, ranging from immediate release to sustained and delayed release.

Drug dissolution profiles from printlets. Red line shows the pH values of the media

The Potential of SLS printing in Pharmacy

The new technology provides the means for producing personalized medicines that can be adapted to individual patients’ requirements. The technology offers a simple, fast method to fabricate personalized drug-loaded, high resolution printlets with any drug compound. SLS appears to be a versatile and practical 3D printing technology which can be applied to the pharmaceutical field, thus widening the armamentarium of 3D printing technologies available for the manufacture of modern medicines.

Fused deposition modeling (FDM) 3–Dimensional (3D) printing is becoming an increasingly significant technology in the pharmaceutical sciences, since it allows the manufacture of personalized oral dosage forms by deposition of thin layers of material. FabRx, in collaboration with researchers from University College London – School of Pharmacy, University of Santiago de Compostela and Astellas, have recently published a research paper in the International Journal of Pharmaceutics in which the effect of the internal structure -micropore volume- of drug loaded 3D printed capsule-shape tablets (Printlets™) on drug dissolution behaviour was studied.

Graphical abstract of the article.

A filament extruder was used to obtain filaments of polyvinyl alcohol (PVA) containing paracetamol (acetaminophen) or caffeine appropriate for 3D printing. The filaments were used to manufacture Printlets™ for oral administration using a FDM 3D printer.

The micropore volume of the Printlets™ was primarily determined by the presence of large pores due to gaps in the printed layers/net while printing, and the porosity of the Printlets™ was 10 fold higher than the porosity of the extruded filament.

A scanning electron microscopy image showing the internal structure of a cross-section of a Printlet™ and an image of the cross-section of a low dose paracetamol Printlet™ after porosity analysis.

Dynamic dissolution drug release tests on the Printlets™ in biorelevant bicarbonate media revealed distinctive release profiles, which were dependent on drug solubility and drug loading. Porosity of the Printlets™ bore no relevance in predicting the different drug release profiles.

Response surface for percentage of drug released 270min (D270) as a function of drug content in the formulation and drug solubility.

This study helps to elucidate which factors influence drug release from this type of new dosage form and confirms the potential of 3D printing to fabricate Printlets™.

The use of 3-dimensional printing (3DP) in the healthcare industry is becoming an increasingly popular trend. The FDA approval, in August 2015, of the first 3D printed medicine (Spritam®) proved that 3DP technology works and the race is now on to push forward its development in the pharmaceutical field.

Researchers from the UCL School of Pharmacy and FabRx Ltd., a pharmaceutical biotech specialized in 3D printing, have recently published a paper in the Journal of Controlled Release in which they demonstrate that the combination of 3D printing and 3D scanning has the potential to produce personalised drug loaded devices that can be adapted in shape and size to individual patient requirements.

Graphical abstract of the article.

In the study, 3D scanning technology was used to obtain a 3D model of a nose adapted to the morphology of an individual.

Sense 3D scanner (3DSystems) and templates used as models for printing.

Two different 3D printing technologies, Fused Deposition Modelling (FDM) and stereolithography (SLA), were used to produce flexible, personalised-shape anti-acne drug loaded devices.

Images of a MakerBot Replicator 2X FDM 3Dprinter and a Form 1+ SLA 3D printer.

In Fused-deposition modelling (FDM), an extruded polymer filament is passed through a heated nozzle that softens the polymer. It is then deposited on a build plate, in the x-y dimensions, creating one layer of the object to be printed. The build plate then lowers and the next layer is deposited. In this fashion, an object can be fabricated in three dimensions, and in a matter of minutes.

Stereolithography (SLA) is a type of 3DP technology, based on the solidification of a liquid resin by photopolymerization. A laser is focused, to a specific depth, on a vat of resin, causing localized polymerization (and thus solidification). Solidification is repeated in a layer by layer manner until a solid, 3D object is produced. SLA is superior to other 3DP techniques in terms of resolution.

Salicylic acid, used in the treatment of acne, was selected as a model drug in the study. The drug was incorporated in the filaments used in the FDM printer. The filaments were loaded into a commercial 3D printer, MakerBot Replicator 2X (MakerBot), and used to print the selected shapes. In the case of the SLA printer, the drug was added to the solution of monomers and the resulting photopolymer solution was loaded into the 3D printer, a commercial Form 1+ SLA 3D printer (Formlabs Inc).

Both FDM and SLA technologies enabled printing of nose-shape masks, whereas during the printing process using the FDM printer, part of the drug was degraded due to the high temperatures involved in the process. However, the SLA printer led to 3D printed devices (nose-shaped) with higher resolution and higher drug loading than FDM with no drug degradation. The in vitro results of drug permeation tests showed drug diffusion from all the 3D printed devices.

Image of 3D printed nose-patch loaded with salicylic acid.

According to the authors, the combination of 3D scanning and 3D printing could potentially offer the means to produce personalized drug-loaded devices that can be adapted in shape and size to individual patients’ requirements. These technologies offer a simple, fast method to fabricate personalized drug-loaded devices with high resolution. Compared with FDM 3D printing, SLA printing reduces drug degradation and so offers an alternative route for the production of devices incorporating thermo-sensitive drugs.

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