“For a long time the personalised pill was a mere conceptual term, because its realisation was too complex or too expensive. This new production process of tablets will fundamentally change that”, says assistant professor and project leader Soh Siow Ling [Paywall] of Singapore’s National University. He and his phD student Sun Yajuan have developed a simple and cost-effective process with which it is possible to produce tablets containing several active agents. The active ingredients can be dispensed within the human body at different times at different doses.
At what time should how much agent be where?
After a medication is administered, the release of the active ingredient from its encapsulation body is the first and the rate-limiting step. However, the matter as to when and how much agent is released from the encapsulation body depends on the therapeutic objective involved. A constant release of active ingredients over a certain period is particularly important if the drug is effective only within a certain concentration range. Should too much agent be released, undesirable effects increase; at too low amounts, the medicating agent has no effect.
Some substances such as hormones, on the other hand, should be dispensed in the body with periodicity. In doing so the aim is to imitate biological cycles. Dosage forms that release an ever increasing amount of medication over time are for instance desirable with drugs to which the patient develops a tolerance. Some medications in contrast require a high loading dose and a somewhat lower maintenance dose. One example of this occurs in the treatment of arthritis. With oral dosage forms release and uptake in the body can be altered through special membrane (for eg. enteric capsules) or galenic adjuvants (eg. polymers).
Pills from the 3D printer on the market already
The idea of a pill especially tailored to the patient and produced using 3D printing technology is nothing new. Already in mid-2015 the Food and Drug Administration (FDA) gave the green light for the antiepileptic Spritam®. It is produced through ZipDose® technology. Here a 3D printer applies powder layers which contain the active ingredient one after another in sequence and using an aqueous solution bonds each layer to the next. This results in porous tablets with patient-specific dosage which can easily dissolve in water.
In order to achieve constant plasma levels, and specifically with antiepileptics for instance, sustained release tablets would be more functional. With the help of 3D printing further release profiles have been realised, as earlier studies [Paywall] have already shown. To achieve this, however, complex mathematical models and/or iterative algorithms are necessary. Moreover, the production of the layer-on-layer structure is complex, and mechanical durability is often poor. Timed-controlled active agent release can also be achieved as part of systems which do not involve oral application. An example of this is the microchip. A disadvantage of this method however is that the chips must be implanted in the human body – a procedure which is not suitable for every patient.
The new all-in-one pill derived by the scientists from Singapore will now solve all these problems: it can be easily and inexpensively produced and is fully adaptable. The tablet may in fact be adapted at will to suit the patient’s needs. The form required for the release of the selected active agent is intuitive, and the manufacturing process inexpensive and simple.
The tablet consists of three components
The medication or the mixture of different medications is located in the innermost layer, the shape of which depends on the desired release profile. It consists of a polymer blend, the surface of which slowly dissolves upon contact with an aqueous medium. It is surrounded by another layer of the same material which however contains no active agent. The sheath forms an impervious yet biodegradable material which surrounds the tablet over all sides except for one.
If this pill is placed in an aqueous medium, the polymer blend (with or without agent) gradually degrades from the side where it is not surrounded by the impermeable protective film. How much agent is released depends on how large the area of the innermost layer is which has been exposed.
The scientists used an ordinary 3D printer for production because it is inexpensive and easy to use. The digital pill model with special design is created by computer – based on the desired release profile, which is then printed out by the 3D printer. The template possesses the same form that the agent-polymer mixture should have later. According to publication, the scientists in the next step added a non-toxic, liquid polymer to the template. After curing, they removed the template and filled the depression with the degradable polymer blend including the medication.
The scientists used an orange dye for their studies instead of an active ingredient. After setting, this second polymer blend including dye was taken from the mould, placed in the impermeable casing and the intermediate space filled with polymer blend without dye.
For pills that are intended to release two medications at different times, the scientists instead of one drug-polymer mixture put two into the shell. The two together as in this case were made as thick as that of the tablet with only one agent. The scientists had printed out the shell in a separate step. Subsequent tests confirmed the expected active agent release. The release rate of the dye was able to be influenced by the scientists by altering the concentration of individual polymers in the polymer blend.
Multinational enterprise showing interest
The scientists are already negotiating with a multinational company. If things go as the researchers wish, this approach should in the future be available to both clinics and pharmacies. Physicians and pharmacists could then determine the ideal dosage for the patient, taking into account age, gender or renal function, and create the tailored pill on site.
Since the all-in-one pill does not come out of the printer complete, but rather various manufacturing steps are necessary, for which time and different equipment are needed, it remains to be seen how the use of the process progresses. Another possibility could be that pharmaceutical companies pre-produce the special pills in large quantities. A few years may yet come to pass before the all-in-one pill comes onto the market, Currently, Soh Siow Ling and colleagues are investigating how the composition of polymer blend has affects on active agent release. The aim is to be able to better customise the tablet to the needs of the individual.