The use of inkjet printing to address unmet needs in paediatric populations

Since the introduction of the European Union (EU) legislation on medicines for children in 2006, an increase in paediatric centred medicines has been seen. However, several disease states such as rare diseases are still ignored in terms of paediatric formulations. Adult marketed dosage forms are still adjusted by crushing/diluting/splitting or prepared extemporaneously in a pharmacy. Therefore, additive manufacturing or three-dimensional (3D) printing plays a major role in improving paediatric formulation bioavailability, safety, and personalisation.

An example of a neglected disease in terms of paediatric formulation availability is Turner syndrome, a rare chromosomal disease affecting approximately 1 in 2500 females. It is represented by the partial or complete absence of the second X chromosome, first reported as a clinical syndrome in 1938 by Henry Turner. The most common symptom includes short stature, often recognisable by the age of 5, but other symptoms such as an early loss of ovarian function is only seen later, preventing puberty, and causing infertility. Many additional manifestations include congenital heart defects, web neck, skeletal abnormalities, gastrointestinal disorders, lymphedema, higher incidence of hypertension and type II diabetes, and various others.

Currently, two treatment options are available in the clinic for Turner syndrome, oral tablets, and transdermal patches. Estradiol patches come in varying doses (14 - 100 ug) and release the hormone in a controlled manner. They are a popular platform of drug delivery as they are non-invasive, easy to administer, and do not affect daily life. Studies have also shown that patches have improved bioavailability of estradiol when compared to the oral route. However, current doses exist only for adult females, and there is a lack of low doses for teenage girls that require only 3-7 ug/day as a starting dose, meaning commercial patches must be cut to administer the right dose.

For the first project in this PhD, a focus on inkjet printing will aim to formulate a personalised transdermal estradiol patch for teenage girls suffering with Turner syndrome. Inkjet printing is an umbrella term for the deposition of small volume drops onto a surface, in the form of continuous inkjet printing (CIJ) or drop on demand (DoD). Both differ by the droplet generation process, CIJ being the continuous liquid stream from a nozzle, and DoD involving the liquid ejection only when a droplet is necessary in response to a trigger. Thus, the main objective of this work will be to identify key disease states such as Turner syndrome previously mentioned and utilise inkjet printing to overcome formulation and dosage form limitations in paediatric treatment. With a focus on Turner syndrome as the first disease of interest, the project will first focus on the development of a suitable ink formulation for inkjet printing, involving the analysis of key components such as density, surface tension, and viscosity. After successful ink production, different doses of estradiol will be printed to obtain the desired dose personalisation, alongside drug release studies to assess the feasibility of the printed formulation.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.