Pharmaceuticals from the 3D printer

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From additively manufactured orphan drugs to polypills and printed mini pharmaceutical factories: 3D printing opens up new paths in the production of active pharmaceutical ingredients and drugs.

Conventional methods of drug manufacturing are expensive and cost-intensive. Most tablets and capsules are synthesized in large plants and shipped around the world. As mass products with defined dosages and release profiles, most pharmaceuticals are not designed for the needs of individuals. Side effects are one of the results. Many drugs are not even taken and end up in the trash can instead. Special drugs for rare diseases are produced manually in very small quantities in the laboratory and are expensive as a result. In remote regions it is difficult to obtain drugs at all.

New 3D printing processes allow the production of customized drugs exactly where and when they are needed.

The first 3D printed pills are already available

Several printed drugs are on the market. For example, in 2016, the US Food and Drug Administration (FDA) approved the epilepsy drug Spritam from Aprecia Pharmaceuticals, which contains levetiracetam as an active pharmaceutical ingredient (API), as the world’s first tablet from a 3D printer. The ZipDose technology used is based on a printing process that was developed at the Massachusetts Institute of Technology (MIT):

A 3D printer applies the powder containing the API layer by layer. The layers are then stuck together with an aqueous solution. The result is a porous, water-soluble pill. The benefits for patients: The dosage can be chosen individually. The small, easily swallowed pills can also contain very high doses of API up to 1,000 mg. In the future, Aprecia plans to work together with UK-based Cycle Pharmaceuticals and develop orphan drugs for 3D printing. Orphan drugs are special drugs for treating rare diseases, which are commercially unattractive for conventional manufacturing due to the small market.

The European Medicines Agency has given the go-ahead for the 3D-printed HIV drug Prezista containing the API darunavir.

Complete drug factory from the 3D printer

Scientists at the University of Glasgow in Scotland are going one step further. The team, led by Philip J. Kitson and Leroy Cronin, printed a complete miniature drug factory made from plastic, which produces active pharmaceutical ingredients fully automatically. First, software translates the chemical synthesis of the drug into a step-by-step work process and delivers detailed printing instructions for the API factory.

The 3D printer – the Ultimaker 2 model was used – delivers a modular plant, just a few centimeters in size, consisting of several complex shaped reaction chambers. They contain mixing systems, boilers, pressurized vessels and cooling systems, and are equipped with filters, inflows and outflows. In this mini reactor all the necessary chemical reaction steps take place one after the other until, finally, the finished active pharmaceutical ingredient is produced. This process was already used to print the muscle relaxant baclofen, the antiepileptic lamotrigine, and the stomach-protecting API zolimidine. Polypropylene was used as the filament. Glass would be more suited due to its inert properties, but the technical expertise for printing glass is not yet available.

In the future, 3D printers could be used to produce ad hoc laboratory systems that enable flexible production of individualized drugs. For example, hospitals and medical practices would be able to cover their own drug requirements. Instructions on how to produce active pharmaceutical ingredients could be provided as a download. However, there is a drawback: Printing instructions for illegal drug labs would probably soon be available on the Internet.

One for all: the additive polypill

Additive manufacturing of drugs – layer-by-layer production – is especially suitable for manufacturing polypills, which combine several active pharmaceutical ingredients in one pill. US-based Vitae Industries has developed an API printer called Auto Compounder, which, according to the company, can fill polypills three times faster than conventional processes.

The efficiency of pharmaceutical products can be improved considerably if the release profile is controlled. Scientists at the National University of Singapore use 3D printing to produce all-in-one pills that release individual doses to patients at different times. On a computer, the physician enters the medications an individual needs to take, in what dose, and how frequently. This produces a model of a pill template with several prongs in which the active pharmaceutical ingredients are later placed. The pill is printed from polymer, filled with the defined quantities of drugs and then coated with an external layer of polymer. In the patient’s body the external layer dissolves slowly and – depending on the size and shape of the prongs – gradually releases the medication.

An end to bitter pills

When printing drugs, there are virtually no limits to the personalization possibilities. For example, London-based biotech company FabRx manufactures 3D-printed pills that can be adapted to suit the consumer’s needs and preferences in many aspects.

It is not only possible to integrate several drugs with personal doses in one pill and to set whether the active pharmaceutical ingredients should be released in the patient’s body immediately, after a certain time, or continuously over a long period. The size, shape, color, texture, and taste of the pills can also be modified as desired. This will help with the ingestion of drugs – especially children and the elderly. A reduction of side effects could be another bonus with regard to personalized drugs.

Parkinson’s drug from the UV inkjet 3D printer

Scientists at the University of Nottingham in England and at pharmaceutical company GlaxoSmithKline use a combination of inkjet printing and UV hardening to produce drugs. In a study, special inks were used to print ropinirole hydrochloride for treating Parkinson’s disease and restless legs syndrome. The Dimatix Material Printer DMP-2850 was used for this purpose. A glove box was installed to control the oxygen content that is important for controlling photopolymerization. An LED UV lamp was installed beneath the print head. It takes about four minutes to print a 5-mm diameter pill.

DNA synthesis by 3D printer

In the future, 3D printers may also play a role in testing drugs. In many cases, customized genes are needed to test chemicals and drugs. This requires billions of copies of DNA sequences. However, the current process for DNA synthesis is complicated, time consuming, and costly. In addition, toxic chemicals are used in the production process. But this could soon change. The Lawrence Berkeley National Lab in the USA and the Technical University of Darmstadt in Germany are working on DNA synthesis using a 3D printer. The procedure will be faster and more accurate than the conventional method and allow the production of DNA strands that are 10 times longer than at present. What is more, no toxic chemicals are needed.

Bye-bye, drugstore?

It is probably not likely that parents will print dinosaur-shaped antibiotics with strawberry flavor for their children at home when they need them. However, innovative 3D printing methods can give us hope that in the future it will be possible for hospitals, medical practices, and drugstores to use additive manufacturing to make customized drugs in individual doses.

This would enable a rapid response to epidemics and supply drugs to isolated regions. From a technical aspect, this is already possible. But to ensure the quality of drugs from 3D printers, a new legal framework is needed for approval procedures and quality control. Regulators still have to come to terms with the idea of 3D printing as a new method for manufacturing drugs.

3D printing of drugs could be a part of the digital transformation in the health care sector that will change entire supply chains. Additive methods offer numerous opportunities for the pharmaceutical industry. But one thing is clear: It will have to come up with alternative business models. Drug producers could become technology manufacturers, for example.

electronica 2018

You can find out more about 3D printing and digital transformation in medicine and health care at the electronica Medical Electronics Conference.

www.electronica.de

Spritam von Aprecia Pharmaceuticals