Additive manufacturing approaches towards personalised and patient group specific pharmaceutical formulations

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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.