RESUMEN
PURPOSE: Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients. METHODS: Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed. RESULTS: Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions. CONCLUSION: Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed.
RESUMEN
More than 10 years after the Paediatric Regulation came into place there is still a strong need for paediatric medicines for off-patent drug substances. Numerous compounds for which a paediatric formulation does not exist can be found on the WHO Model List of Essential Medicines for Children and in the EMA Inventory of the Needs for Paediatric Medicines. Many of these compounds are off patent, which offers the opportunity for obtaining marketing authorisations for paediatric use. The present study focused on the development of paediatric immediate-release mini-tablet formulations for furosemide. Essential formulation criteria included the use of excipients that are regarded as safe for children, the ease of manufacturing, a high dose flexibility, fast disintegration, a robust drug release and a good acceptability. Only excipients regarded as safe for use in children were used in formulation screening. Compressibility, tablet hardness, disintegration and palatability were the main screening parameters. Formulations with a hardness of > 20 N, a disintegration time < 3 min (fast disintegration) and a good palatability were selected for mini-tablet production. Based on this pre-assessment two mini-tablet formulations with a furosemide drug load of 2.5 mg were developed. Both were easy to manufacture, had an appropriate hardness, a short disintegration time and met pharmacopoeial requirements with regard to content uniformity and physical testing. Biorelevant in vitro dissolution experiments mimicking different modes (with water or dosing vehicles) of administering age-appropriate furosemide doses to children of different age groups indicated a fast and robust drug release. Overall, the novel mini-tablet formulations present with an increased dose flexibility, excipient safety, swallowability and palatability and are thus a promising starting point for the development of solid oral dosage forms for drugs with paediatric therapeutic needs.