Printing the future of medicine

A combination of personalised medicine and 3D printing is set to change the way drugs are produced and delivered. Sadaf Taheri fills us in… 

It is no secret that that the population is ageing. The concept of being ‘super old’ is no longer a myth, told only in fairy tales and biblical stories. In fact, in 2012 it was reported that close to half a million people over the age of 90 were living in England and Wales¹, corresponding to just under 1% of the population.

This is largely a consequence of advances in modern medicine. Sadly, while the symptoms of old age may be prevented or masked through good quality healthcare, there is ultimately no cure. Spend an hour in your local pharmacy and you will quickly realise that the majority of the patients are over the age of 65. It’s estimated that 40% of people in this age group (65 and over) have at least one limiting longstanding illness². Generally speaking, these patients don’t leave the pharmacy with a neat little paper bag containing one or two items. Many patients in this age group require large bags, full of medicine, to maintain their quality of life for the upcoming months. It is not uncommon for 6 to 10 different tablets to be seen on one person’s prescription. More often than not, the tablets take substantially the same form – around, white tablet. However, each tablet will be accompanied by a different set of rules for the patient to follow. Individuals suffering from multimorbidities are not only dealing with their illnesses, but they are also up against a minefield of confusing and unforgiving dose instructions. Needless to say, this leads to confusion, poor adherence and dosing errors. The need for patient friendly, personalised medicine is apparent.

It is not uncommon for 6 to 10 different tablets to be seen on one person’s prescription

Introducing the poly-pill – essentially more than one drug within the same dosage form. There are currently many poly-pills on the market. These pills are commonly targeted at one disease state that requires a range of medicines to treat, for example diabetes or cardiovascular disease. They can also be described as fixed-dose combination therapies as they are fixed dose, immediate release delivery systems.  The immediate release profile of these formulations is their major drawback, as controlled release is too difficult to achieve, which means that repeat dosing is required. Furthermore, for medicines to be personalised, factors such as enzymatic functions of individuals must be considered. Physicians currently use age, size, race, kidney and liver functions while determining prescribed doses. In 2016, we have enough evidence to be able to confidently say that this is frankly not enough. For the poly-pill to be absolutely personalised, utilisation of new technologies is necessary.

[caption id="attachment_54528" align="alignnone" width="620"] By using a poly-pill, the need to take several different medicines is easily remedied.[/caption]

In August 2015, Spritam (the very first 3D printed drug) was approved by the Food and Drug Administration (FDA). The ground breaking news grabbed the attention of mainstream papers, who reported the development of a “new drug”. Spritam is in fact a very clever way of reintroducing levetricetam, an anti-epileptic drug that has been around since the 1990s. The company responsible for Spritam, Aprecia Pharmaceuticals, has developed a formulation method coined ‘ZipDose Technology’. The technology has facilitated the manufacturing of a highly porous, solid, orodispersible formulation of levetrictam. This formulation disintegrates rapidly (even at very large doses), and the foul taste of the medicine is also masked. The selling point of Spritam is that it’s “surprisingly easy to take”³, but its novelty is that it is 3D printed. So what is 3D printing? The idea is actually relatively simple. In a nutshell, a computer commanded robotic arm is used to deposit layer upon layer of a material to produce three dimensional objects. Making the ‘ink/ filament’ is the difficult bit. The most common method of 3D printing is fused-deposition modelling (FDM), whereby a range of polymer filaments can be used and passed through a heated nozzle which causes the material to melt. The nozzle is capable of moving horizontally as well as vertically. In this manner the first layer of the object is printed. The build plate then lowers to allow for the next layer to be deposited. The printed objects can have any geometric shape and may even be hollow. Furthermore, by blending drug with polymer into a solid dispersion, pre-loaded dosage forms can be printed.

During a study at the University of Lancashire, ellipse shaped prednisolone tablets were 3D printed using FDM?. Prednisolone is a corticosteroid that is very commonly prescribed for the treatment of an array of inflammatory and allergic disorders including – but not limited to – asthma, eczema, inflammatory bowel disease and rheumatic diseases such as arthritis. The dosing regimen for corticosteroids is complex and varies widely from patient to patient, depending on the disorder that needs to be treated. A significant correlation was found between the theoretical volume and the mass of the tablets. This technology could be used in the development of fine-tuned tablets designed specifically for individual patient need. Scientists at UCL School of Pharmacy have been using FDM printers coupled with hot-melt extrusion (HME) to print paracetamol tablets with five different geometric shapes. HME is a processing technique that has been used by the plastic industry since the 1930s. Today HME may also be regarded as an established technique used by pharmaceutical companies for development of drug delivery systems. Simply put, the process involves feeding the materials through a stationary, heated barrel containing a rotating screw which mixes the materials.

[caption id="attachment_54536" align="alignnone" width="620"] 3D printed polypills have been created but are still not yet commonplace.[/caption]

It can be argued that by using HME to prepare filaments a higher percentage of drug can be incorporated into the dosage forms. The dissolution testing results of the printed tablets shows that the geometry had a significant effect on the release profile of the drug. They found that paracetamol release was dependent on the ratio between surface area and volume and not just surface area?, giving the sphere and cube shaped tablets the fastest release rate. To move things forward the group has gone on to print caplets of the commonly available paracetamol and caffeine combination. Once more FDM was coupled with HME to impregnate a polymer with both active ingredients to create the filament. Although the possibility of printing caplets containing more than two active ingredients using this method is proposed, it has not yet been executed. It was found that printing the two ingredients in a layer by layer fashion allowed for immediate release of both drugs at a similar rate. Printing one active in the core of another however, created a lag time before the ingredient in the core was released. This result was achieved in both cases of paracetamol being the external layer and the core?.

Although the possibility of printing caplets containing more than two active ingredients using FDM and HME is proposed, it has not yet been executed

Work carried out by The University of Nottingham has moved us one step closer to the tailor made 3D printed poly-pill. In the first of such studies, a 3D extrusion system was operated at room temperature to produce tablets containing 3 different active ingredients (captopril, nifedipine and glipizide). The pills demonstrated two different delivery systems. By using a wide range of polymers in a calculated blend, an osmotic pump section was printed for the captopril, while a controlled porosity membrane was printed for nifedipine and glipizide. Furthermore, all three drugs sat in their own compartments, preventing the possibility of any reactions between them?. Launched in the 1980s, captopril was the first Angiotensin-Converting-Enzyme (ACE) inhibitor on the market. Although described as a great advance in cardiovascular medicine, captopril is now regarded as old fashioned and is very rarely used. This is largely due to its major shortfall compared to its offspring. Captopril has a short half-life (2 hours), whereas newer ACE inhibitors are used once daily.

The work does not stop there; more recently poly-pills containing 5 different active ingredients have been printed by the same group. The tablets conveyed two defined release mechanisms – Aspirin and Hydrochlorothiazide were released immediately, while Atenolol, Ramipril and Pravastatin were held within the so-called extended release compartment of the tablets?. Patients with cardiovascular disease often require a form of this cocktail of anti-platelet, diuretic, beta blocker, ACE inhibitor and lipid regulating drug to maintain their level of health. Alterations in release profiles are of great importance. The diuretic which must be taken in the morning is released immediately while the pravastatin that has to be taken at night is retained. With development of gene sequencing techniques such as Sanger sequencing and Nextgen sequencing, personalisation of medicine is no longer a dream. Many pharmaceutical scientists have singled out 3D printing of delivery systems as the future of modern medicine. The ability to manufacture flexible delivery systems would benefit patients in a huge variety of ways. The technology offers the means of accurately altering the dose depending on the exact amount the patient requires. Imagine the dilemma consultants confront as they try to choose between risking overdosing the patient with poor kidney or liver function versus an unlicensed method of prescribing the right dose. This is why liquid drug delivery systems are often preferably used in geriatrics and paediatrics.

Patients with cardiovascular disease often require a form of this cocktail of anti-platelet, diuretic, beta blocker, ACE inhibitor and lipid regulating drug to maintain their level of health

Unfortunately, not every medicine is available in this format and liquid preparations are generally more expensive, more unstable or require a nurse to inject them. Visualise the struggle of the elderly patient with rheumatoid arthritis, who has to try and quarter the already tiny tablet in order to provide them with a lower dose. Picture the nervous young mother, worrying about the dose her child gets as they won’t swallow the lot of the nasty tasting medicine. 3D printing has a possible solution for that too. Complete freedom in geometry means that children could have whatever shaped delivery system they desired, for example a favourite animal or fictional character. As discussed, 3D printing provides a viable method for the personalisation of medicines and greatly facilitates the development of sophisticated multi-drug delivery systems.

The elephant in the room however is the FDA and other regulatory bodies. Will they approve it? Technically, presenting old drugs in new formulations requires time consuming clinical studies to occur before approval. However, there is no need to sweep multi-drug delivery systems or 3D printed medicine under the rug. Spritam has after all been approved. Entresto has also been approved by both the FDA and the European Commission. Although not developed through 3D printing, Entresto is a combination of sacubitril (neprilysin inhibitor) and valsartan (angiotensin II receptor blocker), indicated for heart failure. What Norvatis has achieved with Entresto is unique in a completely different way; a duel-acting pharmaceutical built as a supramolecular complex9, the first of its kind. As the computer scientist Alan Kay famously said: “The best way to predict the future...is to invent it”. Such studies truly do give us new insights into old drugs. The research must continue.

Author 

Sadaf Taheri is a PhD student at the Department of Pharmacy, University of Huddersfield. Her project is focused on engineering crystalline multi-component pharmaceutical materials to improve their physiochemical properties. She is a Pharmacy graduate from the School of Pharmacy, University College London.

Sadaf Was shortlisted for the United Kingdom and Ireland Controlled Release Society (UKICRS) essay copmpetition. The Society has a membership of scientists, predominantly based in the UK and from both academia and industry that are interested in Drug Delivery

www.ukicrs.org

References 

1. Points K. Statistical Bulletin Estimates of the Very Old ( including and Wales. 2013;(October 2013):2002-2012. 2. Age UK. Later life in the United Kingdom. 2014;(May):1-34. http://www.ageuk.org.uk/Documents/EN-GB/Factsheets/Later_Life_UK_factsheet.pdf?dtrk=true. 3. Spritam. Aprecia Pharmaceutical Company. 4. Skowyra J, Pietrzak K, Alhnan MA. Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. Eur J Pharm Sci. 2015;68:11-17. doi:10.1016/j.ejps.2014.11.009. 5. Goyanes A, Robles Martinez P, Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm. 2015;494(2):657-663. doi:10.1016/j.ijpharm.2015.04.069. 6. Goyanes A, Wang J, Buanz A, et al. 3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics. Mol Pharm. 2015;12(11):4077-4084. doi:10.1021/acs.molpharmaceut.5b00510. 7. Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of tablets containing multiple drugs with defined release profiles. Int J Pharm. 2015;494(2):643-650. doi:10.1016/j.ijpharm.2015.07.067. 8. Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. J Control Release. 2015;217:308-314. doi:10.1016/j.jconrel.2015.09.028. 9. Feng L, Karpinski PH, Sutton P, et al. LCZ696: A dual-acting sodium supramolecular complex. Tetrahedron Lett. 2012. doi:10.1016/j.tetlet.2011.11.029.