Additive manufacturing approaches towards personalised and patient group specific pharmaceutical formulations

自2006年欧洲联盟（欧盟）关于儿童药品的立法出台以来，以儿科为中心的药品有所增加。然而，在儿科配方方面，一些疾病状态，如罕见病，仍然被忽视。成人上市剂型仍然通过粉碎/稀释/分裂或在药房临时配制来调整。因此，增材制造或三维（3D）打印在提高儿科配方的生物利用度、安全性和个性化方面发挥着重要作用。在儿科配方供应方面被忽视的疾病的一个例子是特纳综合症，这是一种罕见的染色体疾病，大约每2500名女性中就有1人患病。其表现为第二条X染色体部分或完全缺失，于1938年由亨利·特纳首次作为临床综合征报道。最常见的症状包括身材矮小，通常在5岁时就可以识别出来，但其他症状，如卵巢功能的早期丧失，只有在晚些时候才会出现，从而阻止了青春期，并导致不孕。许多其他表现包括先天性心脏缺陷、网状颈、骨骼异常、胃肠道疾病、淋巴水肿、高血压和II型糖尿病的高发病率以及其他各种疾病。目前，特纳综合征的临床治疗有两种选择，口服片剂和透皮贴剂。雌二醇贴片有不同的剂量（14 - 100微克），并以可控的方式释放激素。它们是一种受欢迎的给药平台，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，贴片改善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，并且缺乏适合少女的低剂量，仅需要3-7微克/天作为起始剂量，这意味着必须削减商业贴片以给予正确的剂量。本博士的第一个项目，将专注于喷墨打印，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。喷墨打印是一个总称，它以连续喷墨打印（CIJ）或按需喷墨打印（DoD）的形式将小体积滴液沉积到表面上。两者的不同之处在于液滴的产生过程，CIJ是从喷嘴中连续流出的液体流，而DoD仅在需要液滴以响应触发时才涉及液体喷射。因此，这项工作的主要目标将是确定关键疾病状态，如前面提到的特纳综合征，并利用喷墨打印来克服儿科治疗中的配方和剂型限制。该项目将首先关注特纳综合征作为第一种感兴趣的疾病，首先将重点放在开发适合喷墨打印的油墨配方上，包括分析密度、表面张力和粘度等关键成分。在墨水生产成功后，将打印不同剂量的雌二醇以获得所需的个性化剂量，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.