Why is 3D printing good for paediatric tablets?

Paediatric patients span a wide range of sizes and metabolic capacities – from pre-term babies to adolescents – and require a wide range of doses to meet their needs. Often the available tablets are too bulky for young children to swallow and the doses are too large. Pharmacists often have to compound medicines for children, for example, by preparing tailor-made oral solutions, but this is a labour- and time-intensive process. “3D printing could be especially suitable for paediatric doses because it can produce the correct dose for paediatric patients without the extra labour that is needed when compounding, for instance, an oral solution”, says Ms Lafeber.

At the GERPAC congress in 2023 she presented the results of a study entitled “The determination of bio-equivalence of 3D printed doses for paediatric use”. This described how 3D-printed tablets containing sildenafil had been prepared and then tested not only against manufacturing standards (product uniformity, drug content etc) but also for bio-availability (i.e. the extent and rate at which the drug reaches the bloodstream).

How semi-solid extrusion technology works in 3D tablet printing

Semi-solid extrusion (SSE) technology for tablets involves printing from a syringe filled with a gel or paste.

In this case, the material (‘ink’) used to make the tablets was a lipid semi-solid – polyethylene glycol monostearate.  “It melts at about 45-50° C ….. however, if you stay below that temperature it softens but it doesn’t quite melt and that is the temperature at which we operate”, explains Ms Lafeber. Keeping the formulation at 43° C, just below the melting point means that it becomes pliable and can be moulded or ‘printed’ in layers.

Sildenafil was chosen for this study because it is used in low dosages for the treatment of pulmonary arterial hypertension in young children but it is difficult to provide accurate doses using the available products. Although the 3D-printed tablets look and feel different from compressed tablets, volunteers in this study did not perceive them as being particularly different. When asked about the experience, they said ‘it was just swallowing a tablet’.

Can 3D tablet printing be translated into practice?

Ms Lafeber conducted a randomised, cross-over study which demonstrated bioequivalence of the 3D-printed sildenafil tablets with one commercial formulation.

In future, pharmacies might be able to print tablets on demand but for this to happen two key hurdles will need to be overcome. First, measures to check the quality of the printed tablets are required and second, stock mixtures of pharmaceutical ink (ideally prepared by the pharmaceutical industry) will be needed.

At present, 3D printing of tablets is a rapidly developing field.  Ms Lafeber says, “I think this is a wonderful technique that can be of benefit for a lot of patients so I really hope to see this being implemented very soon – and very safely”.

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Bioequivalence study

In order to test for bioequivalence a randomised, open-label, crossover, single-dose study was conducted. Healthy adult volunteers (12) received either commercially-available 20 mg sildenafil tablets (Revatio) or two tablets of 3D-printed sildenafil 10mg. After a seven-day washout period they received the other medication. After each dose blood samples were collected for 12 hours. There was no difference between the concentration-time profiles for the two formulations – indicating bioequivalence.

Results such as these raise the possibility of pharmacy departments keeping 3D printers for medicines and being able to print personalised doses for individual patients when required. “I think it’s very much feasible to keep a 3D printer in the pharmacy ……. because they’re not really that big ……. so they are really bench-top, so to say, in size.  If you can keep stock mixtures then you can easily produce …… 3D-printed tablets”, says Ms Lafeber.  In fact, this might be possible in both hospital and community pharmacies. The main hurdle at present is the question of quality control. “While we have the possibility to check our tablets before they go to the patients most pharmacies will not have that opportunity”, she explains. This is the subject of ongoing work.

Another important step would be the preparation of stock mixtures of pharmaceutical ink (drug solutions) ready to use for printing. “We would like to see that the stock mixtures can be produced by the pharmaceutical industry so that we don’t have to do that [labour-intensive] work ourselves at the pharmacy with all the implications for the operators”, she says.

Ms Lafeber is cautious about the next steps as 3D printing of tablets is a rapidly developing field at present. “We need to be absolutely sure that these 3D printed tablets are of good quality be go before they go to the patients” she says, noting that of anything goes wrong at this stage it could seriously set back the introduction of 3D printing for medicines.  “I think this is a wonderful technique that can be of benefit for a lot of patients so I really hope to see this being implemented very soon – and very safely”, she concludes.

Read and watch the full series on our website or on YouTube.

The 3D printed tablets made by Ms Lafeber look different from compressed tablets. “They look different ….. because of the way that they are being produced in a layer-by-layer fashion – so you can really see the layers in the tablet. Furthermore, we use a mixture that has a wax-like feel”, she explains. However, when she asked the healthy volunteers who took the tablets in her study what they thought about the mouth-feel of the tablets and what they were like to swallow “they really looked at me like I was crazy because ‘it was just swallowing a tablet’ – so they didn’t really see the difference [compared] with the normal tablet. So, I think it depends on the patient that has to take the tablet”, she says.  “They do look different but that does not necessarily mean that the patient experiences it differently from a normal tablet”, she adds.

The material (‘ink’) used to make the tablets is a lipid semi-solid – polyethylene glycol monostearate.  “It melts at about 45-50° C ….. however, if you stay below that temperature it softens but it doesn’t quite melt and that is the temperature at which we operate”, explains Ms Lafeber. Keeping the formulation at 43° C, just below the melting point means that it becomes pliable and can be moulded or ‘printed’ in layers. It is important that the ink material should not melt because if it becomes completely liquid there is a risk that the drug substance could settle. Uneven distribution of the drug substance in the gel could then lead to dosing errors. Another useful feature of this system is that it does not rely on the addition of water to make it mouldable. “We also don’t have to use water or any other solution to make it mouldable, which you see with a lot of other semi-solid extrusions. So, we don’t need a drying step and also, we don’t have the chemical stability issues that you would expect when, for instance, water is used”, says Ms Lafeber.

The technique shares some similarities with the process that (in former times) had to be followed for extemporaneous preparation of suppositories. This also involved the dispersal of a drug in a gel or semi-solid. “You would use a mortar and pestle – you would be frantically mixing and pouring the mixture into the moulds, trying to keep the drug from settling”, she notes.

The choice of sildenafil

The objective of the study was to investigate the feasibility of making a 3D-printed tablet formulation that complied with the relevant quality requirements i.e. the European Pharmacopeia standards and the EMA guidelines for bioequivalence. Sildenafil was chosen as the active ingredient for the study. It is a phosphodiesterase-5 (PDE5) enzyme inhibitor used in low dosages for the treatment of pulmonary arterial hypertension in young children. “The tablets that are on the market [contain] …. too high a dose for the paediatric patients and while there’s also an oral suspension on the market, even that suspension has such a high concentration that the small children still cannot be accurately treated with [it]”, says Ms Lafeber.

Read and watch the full series on our website or on YouTube.

Ms Lafeber’s PhD work on 3D printing of pharmaceuticals encompasses drug product development and technical development of the printers but also work on the societal impact and clinical research. At the GERPAC congress in 2023 she presented the results of a study entitled “The determination of bio-equivalence of 3D printed doses for paediatric use”. This described how 3D printed tablets containing sildenafil had been prepared and then tested not only against manufacturing standards (product uniformity, drug content etc) but also for bio-availability (i.e. the extent and rate at which the drug reaches the bloodstream).

The technique of 3D printing has been in use since the 1980s and has been applied in a wide range of fields to make prototypes by building them up in layers, based on a computer-created model. The printing process is digitally controlled which allows for precise adjustment of the dose.  “It’s a manufacturing technique which makes one-of-a-kind products and that’s also something that we would want in the pharmaceutical healthcare”, says Ms Lafeber. No two patients are exactly the same and while the pharmaceutical industry makes good quality products based on a one-size-fits-all principle, some patients benefit more from personalised products or doses, which is what the 3D printer is ideal to produce, she explains.

One field in which 3D printing may be particularly advantageous is paediatrics.  Paediatric patients span a wide range of sizes and metabolic capacities – from pre-term babies to adolescents – and require a wide range of doses to meet their needs. Often the available tablets are too bulky for children to swallow and the doses are too large. Pharmacists often have to compound medicines for children, for example by preparing tailor-made oral solutions, but this is a labour- and time-intensive process. “3D printing could be especially suitable for paediatric doses because it can produce the correct dose for paediatric patients without the extra labour that is needed when compounding, for instance, an oral solution”, says Ms Lafeber.

Read and watch the full series on our website or on YouTube.