Pills are printed, not pressed

Additive manufacturing enables the production of three-dimensional objects, and is often used to quickly produce prototypes or spare parts on site. This technique, known as 3D printing, has however also arrived in pharmaceutical production and is supposed to further personalise medicine.

Using 3D printing, drugs can be produced that are tailored exactly to match the clinical pattern of the patient. A research group has now developed a new method in this field. In the project HME 3D, scientists from the Cologne University and the Heinrich-Heine University in Düsseldorf (HHU) have developed a new printing method that allows more active substances and carrier materials to be printed.

3D printing technology usually utilises so-called filaments – plastics that have been melted and shaped into long threads. The 3D printer melts these again and then uses them to shape the finished product. “If pharmaceutical polymers are used in such a process and heated twice, this damages the medically active substances contained within. Filaments from pharmaceutical polymers also are often too soft or too brittle, and cannot be printed reliably. Therefore we developed a process that directly prints plastics without first producing a filament,” says Ines Haase from the Institute of Product Development and Engineering Design at the University of Applied Sciences of Cologne, the TH Köln.

Especially concerning children, the dosage of drugs should really be adjusted in small steps that match their quick growth. “If treating doctors calculate the needed dose, we can print the drug exactly as prescribed”, says Prof. Dr. Julian Quodback, former head of the project at the Institute of Pharmaceutics and Biopharmaceutics at HHU, and now professor at the university of Utrecht. The method is also suitable for precision medicine, where the dosage of active medical ingredients exactly matches individual patient needs. Batch sizes between one and several thousand pills are possible.

A team from the laboratory for manufacturing systems at TH Köln has developed a novel printing method for this. It is based on a hot-melt extruder, which melts and mixes polymers and active ingredients. This material is transported into the printing head and shaped into pills. One of the challenges: Hot-melt extrusion is carried out horizontally, but printing happens vertically. Therefore, the molten mass must be redirected. “The pharmaceutical materials that are used are very sensitive. We had to take care that redirection has no negative effect on the quality of the molten mass. Nevertheless, the technology used must be kept simple, as according to the requirements of the ‘Good Manufacturing Practice’ for pharmaceutical production systems, it needs to be easy to dismantle and clean after each extrusion process” says Haase. During the project, a prototype was created which was tested at HHU.

At the same time, the HHU pharmacists have studied the development of the printing materials. “The new technology has enabled us to consider a much broader spectrum of carrier materials and active substances. The reason is, that the gentle processing of the materials allows more sensitive active substances to be used in printing as well. It also becomes possible to use lipids, that is fats, as carrier materials. In this way, we again noticeably broaden the field of possible medically active ingredients, as there are many interesting candidates among these substances that cannot be processed as polymers”, says Arne Schulzen, PhD student at the Institute of Pharmaceutics and Biopharmaceutics at HHU. Other than using polymers and lipids, a next step is to test the printing of waxes in order to gain even more possibilities for manufacturing.

Another additive technology that is applied in manufacturing drugs, is 3D screen printing. US company Laxxon Medical has developed technology that is capable of manufacturing pills with a structured surface. Among other things, this allows a controlled release of pharmaceutically active substances over a prolonged period of time. At the same time, it is possible to combine several ingredients in the same pill. Polymers by Evonik allow for a targeted release of the active substances in these novel pills. The advantage: Controlled release of the active substances reduces side effects and the number of pills that patients need to take. It is also possible to manufacture pills with several layers – for example a combination of active and inactive layers, which allow for the release of several doses of a drug at different times.

Already in 2021, a clinical feasibility trial was started in Heidelberg: The university hospital in Heidelberg cooperated with the start-up DiHeSys Digital Health Systems GmbH to test the digital, two-dimensional printing of drugs on thin wafers of gel, which dissolve in the mouth within seconds. The advantages here are the same, continual adjustment of the dosage over a broad spectrum, and automated manufacture which especially simplifies lowering the dosage of drugs. 2D printing of drugs works in a manner similar to an inkjet printer: The “ink” contains dissolved drugs. A pharmaceutical printer applies it to a wafer not thicker than a postal stamp, which is water soluble and dissolves on its own in the mouth. The start-up provides the university hospital with the necessary technology in the form the 2D drug printer “DiHeSys Flexdose Printer”, which they developed themselves. “The vision of DiHeSys is to supply a complete system for individual, personalised 2D and 3D printing of drugs”, says Prof. Dr. Christian Franken, Executive Manager of DiHeSys. “This not only includes the printer itself, but the entire system consisting of inks containing active pharmaceutical ingredients and the software.”