**4. Conclusions**

Development of medicines is challenging per se, and this is even more relevant in the development of medicines for children, let alone preterm babies and neonates. When those children have such rapidly changing physiology and biopharmaceutical characteristics accompanied by critical clinical conditions and requirements, such as is the case for neonates (and in particular preterm neonates), then product development is very challenging. Neonates are still 'therapeutic orphans' in terms of access to appropriate drugs and formulations that have been studied and approved by regulators. To design an appropriate formulation for neonates, it is important to understand their physiological status, development and care environment as well as methods of drug administration and the limitations these factors place on formulation development. Given that neonates will usually form a very small fraction of the population that might benefit from a drug, there may be other constraints that limit the ability to provide unique neonatal formulations. A good understanding of the various constraints will allow the formulator to provide for neonates whilst having due regard for the needs of the older population. If the neonate is considered early in the formulation design process, some delays in clinical trials in this population may be avoided.

In recent years, grea<sup>t</sup> strides have been made in understanding physiological development in paediatrics in general and neonates in particular. Nonetheless, it is clear that as ye<sup>t</sup> some fundamental information is not available to inform the pharmaceutical development process. For example, further research is needed on the safety of excipients in this population, the development of the CNS and in particular the e ffect of API and excipients on the maturation of the BBB, the robustness of the skin barrier. The maturation of drug elimination processes and the e ffect of a rapidly changing fat/lean ratio on drug distribution. Guidance is also needed on compatibility studies that are required and/or desirable in the light of the polypharmacy that is common in the treatment of neonates. Finally, the place of oral therapy with minitablets needs clarification. Further research in these areas will help inform even better product development for this patient group.

Nevertheless, this review has provided information, advice and guidance on factors for the product developer and, in particular, the formulator when seeking to meet the requirements of this highly vulnerable patient group. In general, guidance is given for what is required for treatment in ICU settings but where possible, we have set that in the context of paediatric product development as a whole.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
