Application of biorelevant in vitro assays for the assessment and optimization of ASD-based formulations for pediatric patients

In recent years, innovative formulation strategies have been developed to enable the oral administration of complex and challenging drug molecules. Enabling formulation concepts such as lipid-based formulations or an amorphous solid dispersions (ASD) enable the oral delivery of even extremely poorly water-soluble drugs [1], [2], [3]. However, the design of these formulations mostly focuses on serving the needs of the broad population of adults while the particular needs of special populations such as children are often not considered [4].

Developing ASD-based pediatric formulations presents various biopharmaceutical challenges. For ASDs the complex interplay between dissolution, supersaturation, precipitation, redissolution and absorption must be considered [5]. In this context, disintegration can be a critical bioavailability attribute as a formulation that disintegrates too quickly may dissolve faster. This could lead to a higher degree of supersaturation, which could drive extensive and early precipitation in the small intestine. This mechanism may even be more relevant in case of weakly basic drugs. On the other hand, a too slow disintegration as it is often seen for high drug-load ASD-based tablets may limit oral drug bioavailability [6], [7]. Thus, a sweet spot in terms of drug release exists which depends on kinetic parameters such as gastric emptying, precipitation and absorption. Ideally, the formulation disintegrates and releases the drug steadily over a defined period of time so that moderately supersaturated solutions are emptied into the intestinal compartment.

While from a patient centered perspective, pediatric formulation platforms like orodispersible tablets or film formulations are highly desirable [8], from a biopharmaceutical point of view their fast disintegration may not be ideal in case of ASDs for the reasons mentioned above. In this work, mini-tablets were chosen as an alternative platform for pediatric formulations. They represent a common approach for pediatric formulations [9] and in terms of ASDs, they exhibit highly desirable features all of the above-stated aspects. The following four main advantages supported the decision for mini-tablets. First, due to the larger specific surface area of the mini-tablets as compared to conventionally sized tablets, a faster disintegration can be expected, potentially increasing the robustness of the dosage form towards varying physiological conditions. As IR mini-tablets initially have to undergo disintegration to enable drug release, the disintegration and supersaturation mechanisms can be actively controlled by using a formulation tailored for the desired disintegration and release kinetics within the GI tract, while minimizing precipitation in the small intestine. Second, mini-tablets are easy to administer and have repeatedly proven high acceptability in children over a wide age range [10], [11], [12]. Moreover, they also enable a flexible dosing regimen. Third, drugs like ritonavir can be extremely bitter and thus, the different opportunities for taste masking were also considered for the final decision [13]. Forth, drug combinations are feasible by administering mini-tablets from different products and exhibiting various properties. While the abovementioned dosage forms partially or completely dissolve in the oral cavity inducing a bitter taste perception, mini-tablets remain largely intact. Furthermore, they can be easily coated with a non-functional coating for taste masking [14].

The rational and targeted design of pediatric formulations can be supported by powerful in vitro and in silico tools [9]. For the early assessment of formulations as well as their optimization, biorelevant in vitro testing can be particularly valuable and provide useful insights into the effects of physiological parameters such as luminal pH, luminal fluid volume kinetics or hydrodynamics. It has been demonstrated in several review articles that children represent a patient group with high physiological variability [15]. In this respect, biorelevant in vitro testing can provide valuable insights into the potential in vivo drug product performance. By applying tools such as the two-stage method, the transfer model or the tiny-TIM, the varying physiological conditions and their impact on the drug release of different formulations can be simulated [16]. The results of such investigations can give the scientific rationale for the selection of a suitable pediatric formulation.

It was the primary aim of this research project to establish and apply a structured protocol for biorelevant dissolution testing to systemically support the development of oral ASD-based formulations for children. Ritonavir was selected as a BCS class IV model compound with poor aqueous solubility and poor permeability [17]. This drug is formulated as an ASD-based tablet formulation for adults and as an oral powder for pediatric patients [13], [18]. In this work, the powder was compressed into a mini-tablet and a conventional tablet. Through the systematic application of different biorelevant assays, it was studied how the drug release kinetics can affect the potential in vivo performance of the different formulations in pediatric patients.