Additive manufacturing approaches towards personalised and patient group specific pharmaceutical formulations

自2006年欧洲联盟（欧盟）出台儿童药品立法以来，以儿科为中心的药品有所增加。然而，在儿科制剂方面，仍忽略了几种疾病状态，如罕见病。成人上市剂型仍通过粉碎/稀释/拆分进行调整或在药房临时制备。因此，增材制造或三维（3D）打印在提高儿科制剂的生物利用度、安全性和个性化方面发挥着重要作用。在儿科制剂可用性方面被忽视的疾病的一个例子是特纳综合征，这是一种罕见的染色体疾病，影响约1/2500的女性。它以第二条X染色体的部分或完全缺失为代表，亨利特纳于1938年首次报道为临床综合征。最常见的症状包括身材矮小，通常在5岁时就可以识别，但其他症状，如卵巢功能的早期丧失，只能在以后看到，阻止青春期，并导致不孕。许多其他的表现包括先天性心脏缺陷、蹼颈、骨骼异常、胃肠道疾病、水肿、高血压和II型糖尿病的高发病率，以及各种其他。目前，临床上有两种治疗特纳综合征的方法，口服片剂和透皮贴剂。雌二醇贴片有不同的剂量（14 - 100微克），并以受控的方式释放激素。它们是一种受欢迎的药物输送平台，因为它们是非侵入性的，易于管理，并且不影响日常生活。研究还表明，与口服途径相比，贴剂提高了雌二醇的生物利用度。然而，目前的剂量仅适用于成年女性，并且缺乏针对少女的低剂量，仅需要3-7 ug/天作为起始剂量，这意味着必须削减商业贴片以管理正确的剂量。对于本博士的第一个项目，喷墨打印的重点将旨在为患有特纳综合征的少女制定个性化的透皮雌二醇贴片。喷墨印刷是用于以连续喷墨印刷（CIJ）或按需滴墨（DoD）的形式将小体积液滴沉积到表面上的总称。两者的不同之处在于液滴生成过程，CIJ是来自喷嘴的连续液体流，而DoD仅涉及当液滴响应于触发而需要时的液体喷射。因此，这项工作的主要目标将是确定关键的疾病状态，如特纳综合征之前提到的，并利用喷墨打印，以克服在儿科治疗的配方和剂型的限制。随着特纳综合征作为第一个关注的疾病的重点，该项目将首先专注于开发适用于喷墨打印的油墨配方，包括密度，表面张力和粘度等关键成分的分析。成功生产墨水后，将打印不同剂量的雌二醇以获得所需的剂量个性化，同时进行药物释放研究以评估打印配方的可行性。

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.