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Lack of age-appropriate commercially drug products availability is a common problem in pediatric therapeutics; this population needs improved and safer drug delivery. In addition, biopharmaceutic aspects, dosage requirements, and swallowing abilities demand pediatric forms different to adult formulations. The objective of this study was to evaluate the authorization availability from United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) of oral essential medicines for children and analyze its age-appropriateness for oral administration in children. All oral drugs from 7th List of Essential Medicines for Children by World Health Organization (WHO) were selected. Availability of commercial drug products was collected from OrangeBook, Spanish drug product catalogue, British electronic Medicines Compendium, and the International Vademecum. Tablets, effervescent tablets, and capsules were considered as not age-appropriate forms. Liquid forms, powder for oral suspension, mini tablets, granules, and soluble films were considered as age-appropriate forms due to their flexibility. More than 80% of the studied drugs possess a commercial authorization in oral forms in both EMA and FDA. Nevertheless, around 50% of these formulations are not age-appropriate for most pediatric groups. This study shows the lack of age-appropriate medicines for children. More efforts are needed to improve development and approval of pediatric medicines.

AimsUnavailability and lack of appropriate, effective and safe formulations are common problems in paediatric therapeutics. Key factors such as swallowing abilities, organoleptic preferences and dosage requirements determine the need for optimization of formulations. The provisional Biopharmaceutics Classification System (BCS) can be used in paediatric formulation design as a risk analysis and optimization tool. The objective of this study was to classify six neglected tropical disease drugs following a provisional paediatric BCS (pBCS) classification adapted to three paediatric subpopulations (neonates, infants and children). MethodsAlbendazole, benznidazole, ivermectin, nifurtimox, praziquantel and proguanil were selected from the 5th edition of the Model List of Essential Medicines for Children from the World Health Organization. Paediatric drug solubility classification was based on dose number calculation. Provisional permeability classification was based on logP comparison versus metoprolol logP value, assuming passive diffusion absorption mechanisms and no changes in passive membrane permeability between paediatric patients and adults. pBCS classes were estimated for each drug, according to different doses and volumes adapted for each age stage and were compared to the adult classification. ResultsAll six drugs were classified into provisional pBCS in the three paediatric subpopulations. Three drugs maintained the same classification as for adults, ivermectin and benznidazole changed solubility class from low to high in neonates and proguanil changed from low to high solubility in all age stages. ConclusionProvisional pBCS classification of these six drugs shows potential changes in the limiting factors in oral absorption in paediatrics, depending on age stage, compared to the adult population. This valuable information will aid the optimization of paediatric dosing and formulations and can identify bioinequivalence risks when comparing different formulations and paediatric populations.

beta-Lapachone is a naphthoquinone with high and diverse biological activity. It is useful to treat several pathologies, in particular cancer due to its ability to induce selective apoptosis in tumoral cells. Despite its advantages, beta-lapachone's clinical applications are limited by its low solubility in biological fluids and its low specific distribution pattern. In the last decade various formulation strategies have been designed and developed in order to overcome these limitations and to make feasible its wide therapeutic use. The most relevant strategies for oral administration have been focused on the improvement of its solubility in order to increase beta-lapachone oral bioavailability. The use of cyclodextrins or the inclusion of the active substance in micelles and microparticles has demonstrated to be successful approaches. For topical and local application temperature-sensitive hydrogels have been developed to achieve high target concentrations. Polymeric micelles administrated subcutaneously have proved to be a long-lasting circulating system and to increase accumulation in tumor tissue making them an interesting formulation strategy.

Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan.