Formulation and Characterisation of Carbamazepine Orodispersible 3D-Printed Mini-Tablets for Paediatric Use

Flexible dosing is one of the main challenges in developing medicinal products suitable for the target age group(s) of interest, also known as “age-appropriate” from the Guideline on Pharmaceutical Development of Medicines for Paediatric Use established by the European Medicines Agency (EMA) [1]. In order to boost the development of child-appropriate medicines, drugs can be authorised in the EU with a new dosage form or route of administration designed for paediatric patients and apply for a paediatric-use marketing authorisation (PUMA) with market protection extension [2]. Additionally, the EMA has established the Paediatric Investigation Plan (PIP) to ensure that adequate clinical data collected to show potential acceptability in children are required for paediatric medicine authorisation [3]. While such regulatory frameworks have encouraged studies in paediatric formulation design, including designing medicinal forms and manufacturing processes for dosing personalisation, detailed guidance for developing novel dosage forms still needs to be established and standardised [4].

A new dosage form, mini-tablets, has provoked a specific interest in paediatric formulation design. Some literature characterised mini-tablets as tablets with a diameter under 5 mm [5,6]. Other literature also defined mini-tablets more precisely, with their height and diameter less than 3 mm [7]. This dosage form is introduced into the latest EMA guidelines for being child-appropriate [1]. It is suggested that by dividing the initial dose into tablets with decreased size, this formulation approach can realise a flexible dosing rationale with improved acceptability of children patients. Instead of replacing inaccurate tablet-splitting, the dose adjustment can be achieved by modifying the counting of tablets in a single dosing unit [8].

In addition to the use of mini-tablets, developing and optimising orodispersible formulations can be another strategy with great potential in paediatric medicine acceptability. The term “orodispersible” is used in the European Pharmacopeia to define uncoated formulations that disperse in 3 min upon mixture with the saliva in the oral cavity before the medicine is swallowed [9]. In the United States Pharmacopeia, such dosage forms are named orally disintegrating formulations, and the time for disintegration may range from seconds to about one minute [10]. Orodispersible formulations can be particularly beneficial in treating patients without the capability of proper swallowing, such as children or the elderly. It is noteworthy that several critical attributes need to be characterised specifically for this type of formulation, such as disintegrating time and palatability. The latter is defined in the EMA guideline as an overall appreciation of an oral formulation, considering its smell, taste, aftertaste and mouthfeel [1]. Unpleasant mouthfeel and bitter taste from the active pharmaceutical ingredient (API) or other excipients may impact patients’, and especially, children’s acceptability of the medicine, impairing their compliance to the treatment. Taste masking strategies have been applied to shelter any unpleasant taste generated by APIs and improve the palatability of medicines.

The combination of the above two strategies, results in orodispersible mini-tablets (ODMTs); these were first reported in 2011 [8]. By adapting it to hydrochlorothiazide (a diuretic drug), this novel formulation design was deemed to enable flexible dosing for children, along with improved stability and less risk of dosing errors compared with suspension products. By far, ODMT is still a novel concept in paediatric drug delivery, with limited reports and no commercially available products. In comparison with current age-appropriate formulations, ODMTs have the potential to provide precise, accurate and flexible dosing regimens to different age groups. Additionally, it applies to multiple delivery methods, including taken directly or dispersed in liquid or semi-solid for oral or nasogastric administration. Following the first report in 2011, a risperidone ODMT formulation was developed in 2015 as a needle-free alternative that is more suitable for children [11].

However, no specific discussion of taste assessment or masking was discussed, which should be regarded as a critical quality attribute considering orodispersible medicines usually expose drug particulates to taste buds. Another study reported a lorazepam ODMT, explicitly focusing on establishing a fabrication method via direct compression [12]. The formulation reported included flavouring agents to shield the bitter taste of lorazepam, yet no assessment of the masking effect was performed. In a more recent study, an electronic tongue (E-tongue) was used for taste masking assessment in an ODMT formulation [13]. An E-tongue is a device with multiple sensors which can detect different signals reflecting different taste qualities. Lipid sensors are used in E-tongue systems to transduce chemical reactions between the sensor and taste substances into electrical signals [14]. Potentiometric measurement principles are applied, and sensor responses are recorded as potential electrode values. This technology can be used in paediatric medicine development to reduce children’s participation in trials while providing reliable evidence of taste masking. The technology can reflect interactions between taste substances and is thus capable of evaluating the natural bitterness masking effect of flavouring agents or sweeteners [15].

This study aims at developing a novel ODMT formulation suitable for paediatric use. This formulation will be tested with the model drug, carbamazepine (CBZ). CBZ is an anti-epileptic drug approved with a significant clinical application in treating generalised tonic-clonic and partial seizures in epilepsy and neuropathic pain [16]. With its low solubility and its narrow therapeutic window, CBZ is often observed with variable plasma concentration in paediatric patients [17,18,19]. Currently, CBZ is authorised with a target population among all age groups, although solid dosage forms such as tablets are not recommended for children below five. This study will investigate the feasibility of adapting ODMT formulation to CBZ, along with fabricating, characterising and assessing the quality attributes of produced CBZ ODMTs. This study will specifically look at producing ODMTs with semi-solid extrusion (SSE). SSE is one of the 3D printing techniques applicable for tablet production by accumulating pastes or gels, which will form into solid dosage forms after the semi-solid preparation hardens [20]. The process of SSE for printing tablets is illustrated in Figure 1.

SSE has been applied in developing orodispersible formulation, with its simple process of preparation and fabrication [21]. The variability in printed product also makes SSE suitable for dosage personalisation, and thus it is used in this study to produce ODMTs [22].

This study also aimed at developing a new formulation for CBZ using the quality by Design (QbD) approach. QbD is a statistical approach to investigate the impact of different parameters, including material, formulation and process parameters on critical quality attributes (CQAs) [23]. The QbD paradigm can associate the quality of the product with its (clinical) performance and its capability of meeting patients’ needs, making it especially suitable for developing child-appropriate dosage forms. Meanwhile, physical charcterisation and other quality attributes, including drug loading, dissolution profiles and taste masking effects, of the optimized CBZ ODMTs will also be assessed in this study.