Paediatric formulations : pharmaceutical development and clinical evaluation

Drug development for children has long been a neglected area compared to adult drug development. There are many ‘older’ medicines that have an important place in the treatment of children, but often no suitable dosage form is available. There is a great need for well-studied, child-friendly, oral drugs, which preferably have a large dose flexibility. In collaboration with the Laboratory of Dutch Pharmacists (LNA), we developed two liquid formulations, taking into account the limited amount of excipients that can be safely used, and specific aspects such as taste (acceptance). Amlodipine and lorazepam were chosen as model compounds for water-soluble and non-water-soluble drugs. Subsequently the formulations were studied in adult volunteers and in paediatric patients, in which pharmacokinetics (PK), pharmacodynamics (PD), side effects and acceptance were investigated. In recent years, the importance of suitable dosage forms for children has been increasingly recognized. Pharmacy preparations play an important role here because of the lack of commercial products. Optimization and standardization of these preparations is necessary to guarantee good quality

Oral lorazepam can be substituted for intravenous midazolam when weaning paediatric intensive care patients off sedation

Aim: Intravenous sedatives used in the paediatric intensive care unit (PICU) need to be tapered after prolonged use to prevent ia

Availability of age-appropriate paediatric formulations in the Netherlands: The need in daily clinical practice remains

Objectives: To quantify the availability of authorised, age-appropriate paediatric medicines in clinical practice in the Netherlands and to identify gaps by assessing dispensing practice in a paediatric hospital. Methods: The availability of age-appropriate formulations was assessed by conducting a survey on the use of pharmacy compounded medicines among the paediatric hospitals in the Netherlands, and by analysing dispensing data of oral medication from the inpatient pharmacy of the largest paediatric hospital in the Netherlands. The age-appropriateness of the dispensed formulations was assessed on two aspects: dose-capability and acceptability. Liquid drug products that are unsuitable due to the presence of potentially harmful excipients, were identified based on the dosage in clinical practice. Results: For 129 out of 139 drug substances included in the survey (93%), at least one of the eight respondents stated to use a pharmacy compounded product to meet the needs of their paediatric patients. The age-appropriateness of medicines dispensed from the inpatient pharmacy increased with age, and was higher for non-intensive care unit (ICU) patients than for ICU patients. We identified 15 drug products causing excipient exposure above the European Medicines Agency-recommended values. Conclusions: This study confirms there is still a large need for age-appropriate formu

Manipulation of oral medication for children by parents and nurses occurs frequently and is often not supported by instructions

Aim: Due to a lack of age-appropriate formulations, administration of drugs to children remains a challenge. This study aimed to identify the problems experienced in both the outpatient setting and the clinical setting. Methods: Between June 2017 and January 2018, we performed a cross-sectional, prospective study at the Sophia Children’s Hospital, The Netherlands. The study comprised of a structured interview on drug manipulations with parents visiting the outpatient clinic, and an observational study of drug manipulations by nurses at the wards. Results: A total of 201 questionnaires were collected, accounting for 571 drugs and 169 manipulations (30%). Drug substances that were most often mentioned as manipulated were macrogol (n = 23), esomeprazole (n = 15), paracetamol (n = 8), methylphenidate (n = 7) and melatonin (n = 7). Of all manipulated medicines, 93/169 (55%) were manipulated according to the instructions or recommendations of the Summary of Product Characteristics (SmPC) or patient information leaflet. During the observational study, manipulation was performed by 21/35 of observed nurses (60%), of whom 11 deviated from the hospital protocol for manipulation or SmPC (52%). Conclusion: Manipulation was a widely used method to administer drugs to children. Validated information regarding manipulation of drugs for both parents and nursing staff is needed

Design and stability study of an oral solution of amlodipine besylate for pediatric patients

Introduction: Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10 mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex-tempora and larger scale production. Methods: The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12 months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule. Results: The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12 months at 4 degrees C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18 weeks. Discussion: Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non standardized extemporaneously compounded formulations. (C) 2016 Elsevier B.V. All rights reserved

Bioequivalence study of a newly developed oral solution of amlodipine and commercial tablets after single-dose administration in healthy volunteers

Objective: Amlodipine, a long-acting dihydropyridine calcium channel blocker, is frequently prescribed to pediatric patients. To date, no suitable pediatric formulation has been available. In this study, an amlodipine oral solution was developed and tested for bioequivalence to tablets in healthy adult volunteers. Methods: This study was designed as an open-label, single-dose, two sequence, two-period, crossover trial to assess the bioequivalence of a newly developed amlodipine besylate oral solution 0.5 mg/mL compared to Norvasc 5 mg tablets. 13 adult subjects (mean [standard deviation] age of 23.2 [3.6] years, weight 71.5 [7.7] kg) were included and blood samples were collected for 72 hours. Amlodipine plasma levels were determined using a validated UPLC-MS/MS assay. Non-compartmental pharmacokinetic parameters were compared between the formulations according to European Medicines Agency (EMA) bioequivalence guidelines. Results: The 90% confidence intervals of the test/reference ratios of the geometric means for the primary pharmacokinetic parameters AUC(0-72) (88.24-104.37%) and C-max (99.00-121.40%) were within the acceptance range of 80.00-125.00% for bioequivalence. Mean (SD) AUC(0-72) was 102.7 (26.8) mu gxh/L for the solution and 108.2 (30.6) mu gxh/L for the tablet. Mean (SD) Cmax of the solution was 3.11(1.06) mu g/L with a median (IQR) t(max) of 4.0 (2.6-7.5) hours. Mean (SD) C-max of the tablet was 2.91 (0.84) mu g/L with a median (IQR) t(max) of 6.0 (4.0-14.0) hours. Intrasubject coefficients of variation were 10.2% (AUC(0-72)) and 12.4% (C-max). Conclusions: The formulations are bioequivalent according to EMA guidelines: This warrants further study of our novel amlodipine oral solution in pediatric patients