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New Developments in Pediatric Drug Formulations

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 34037

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Special Issue Editors

Dr. Lidwien Marieke Hanff

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Guest Editor

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Interests: drug formulations; pediatrics; pediatric oncology; extemporaneous preparation; drug administration

Dr. Nikoletta Fotaki

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Guest Editor

1. Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK
2. Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK
Interests: physiologically based pharmacokinetic (PBPK) modeling; in vitro-in vivo correlations (IVIVC); drug absorption; biopharmaceutics; precision medicines; in vitro dissolution-biorelevant/ compendial methods; dissolution imaging; biowaivers; pharmacometrics; animal models; formulation development; poor solubility
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Dear Colleagues,

A well-designed pediatric drug formulation is a vital part of drug treatment. The compliance of (young) children depends heavily on the acceptability of the (oral) formulation, which will in turn be determined by factors such as taste and the texture of the dosage form. Drug safety is also an important issue in pharmacotherapy, and dosage errors can be easily made when a drug formulation is not well adjusted to the patient. In daily practice, extemporaneously prepared drug formulations or manipulation by caregivers are still common practice, and quality issues have to be described.

All these aspects have shifted the focus to the development of new drug formulations that are suitable for use in pediatrics, such as 3D printing, minitablets, and oromucosal films. In this issue, new developments are described.

Dr. Lidwien Marieke Hanff
Dr. Nikoletta Fotaki
Guest Editors

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Keywords

pediatrics
drug formulation
3D printing
minitablet
oromucosal film

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Published Papers (9 papers)

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Research

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17 pages, 4391 KiB

Open AccessArticle

Pharmaceutical Development of Film-Coated Mini-Tablets with Losartan Potassium for Epidermolysis Bullosa

by Valentinë Elezaj, Ard Lura, Luis Canha and Jörg Breitkreutz

Pharmaceutics 2022, 14(3), 570; https://doi.org/10.3390/pharmaceutics14030570 - 5 Mar 2022

Cited by 6 | Viewed by 4180

Abstract

Epidermolysis bullosa is a genetically heterogenous skin fragility disorder with multiorgan involvement appearing already in newborn children. Severe progressive fibrosis follows skin blistering, mucosa lesions, and wound healing, favouring development of highly aggressive squamous cell carcinomas. Losartan potassium (LP) has been described to show positive effects; therefore, it was of clinical interest to develop 2 mm mini-tablets with LP for treatment of the affected children. Several challenges emerged during development: limited flowability and sticking to punches were observed in the first tableting experiments due to a high drug load, and a bitter taste of the LP was reported. Sticking to punches was reduced by using SMCC 50 and a combination of different lubricants; however, direct compression trials on a Korsch XM 12 rotary press were not successful due to compaction phenomena in the hopper. Thus, an intermediate dry granulation was successfully introduced. Two final formulations of the mini-tablets complied with the requirements of the European Pharmacopoeia regarding disintegration times (<15 min) and friability (<1.0%); mean tensile strengths amounted to about 1 MPa as a compromise between manufacturability and sufficient mechanical strength for further coating studies. The subsequent coating step succeeded delaying the initial drug release for more than 2 min. An acceptance value ≤15 was matched for the coated mini-tablets, and stability studies showed a promising shelf life. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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16 pages, 278 KiB

Open AccessArticle

Assessing the Appropriateness of Formulations on the WHO Model List of Essential Medicines for Children: Development of a Paediatric Quality Target Product Profile Tool

by Jennifer Walsh, Tiziana Masini, Benedikt D. Huttner, Lorenzo Moja, Martina Penazzato and Bernadette Cappello

Pharmaceutics 2022, 14(3), 473; https://doi.org/10.3390/pharmaceutics14030473 - 22 Feb 2022

Cited by 12 | Viewed by 4062

Abstract

The World Health Organization’s Model List of Essential Medicines for Children (EMLc) presents a list of the most efficacious, safe, and cost-effective medicines for priority conditions, intended for use in children up to 12 years of age. However, gaps in global availability and use of age-appropriate formulations of medicines for children still exist. To address these shortcomings, a comprehensive analysis of the appropriateness of formulations of essential medicines for children is being undertaken through the Global Accelerator for Paediatric Formulations (GAP-f) network, a WHO network launched in 2020 to respond to the paediatric treatment gap. This article describes the development and application of a paediatric Quality Target Product Profile (pQTPP) tool by WHO, to retrospectively evaluate the paediatric age-appropriateness of formulations on the EMLc and identify potential formulation gaps, to inform the review of the EMLc in 2023. A combination of paediatric-centric and global health-focused attributes and targets were defined, taking into consideration regulatory agency paediatric development guidelines and literature sources, and a qualitative scoring system was developed and tested. Example evaluations of paracetamol and clofazimine are provided, illustrating the tool’s use. The assessment of EMLc formulations is ongoing and shortcomings and gaps in EMLc formulations have already been identified. The pQTTP tool may also be applied to national lists and prospectively when designing new paediatric formulations. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

15 pages, 1384 KiB

Open AccessArticle

Evaluating the Taste Masking Ability of Two Novel Dispersible Tablet Platforms Containing Zinc Sulfate and Paracetamol Reconstituted in a Breast Milk Substitute

by Samuel Orubu, Richard A. Kendall, Yucheng Sheng and Catherine Tuleu

Pharmaceutics 2022, 14(2), 420; https://doi.org/10.3390/pharmaceutics14020420 - 15 Feb 2022

Cited by 3 | Viewed by 2868

Abstract

Milk is often used as a dispersion medium for medicines administration in young children but its taste-masking ability is unknown. A human taste panel was conducted to assess the potential of infant formula milk (Aptamil^® 1) to mask the taste of two model WHO priority medicines, zinc sulfate and paracetamol, manufactured as dispersible tablets. Simultaneously, the palatability of powder blends of the tablet platforms was assessed. Twenty healthy adult volunteers performed a swirl-and-spit assessment of placebos and API-containing blends in either a lactose-based or a mannitol-based dispersible tablet platform, reconstituted in 10 mL of either water or Aptamil^® 1. Eighteen samples were rated for aversion using a 100-mm Visual Analogue Scale, grittiness using a 5-point Likert scale, and “acceptability-as-a-medicine” evaluated as: “Would you find this sample acceptable to swallow as a medicine?” with binary answers of Yes/No. The API-containing formulations were more aversive than the placebos; the paracetamol-containing samples being more aversive than zinc sulfate samples. The platforms themselves were not aversive. Non-gritty samples had four-fold greater odds of being acceptable as a medicine. Aptamil^® 1 masked the taste of zinc sulfate in the mannitol-based formulation but did not mask the taste of paracetamol in either platform, suggesting a limited taste-masking ability, which may be API and formulation dependent. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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20 pages, 3794 KiB

Open AccessArticle

Understanding the Impact of Age-Related Changes in Pediatric GI Solubility by Multivariate Data Analysis

by Mariana Guimarães, Anil Maharaj, Andrea Edginton, Maria Vertzoni and Nikoletta Fotaki

Pharmaceutics 2022, 14(2), 356; https://doi.org/10.3390/pharmaceutics14020356 - 4 Feb 2022

Cited by 1 | Viewed by 2124

Abstract

The aim of this study was to understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in newborns and young infants in comparison to adults. Multivariate statistical analysis was used to understand drug solubilization as a function of drug’s physicochemical properties and the composition of gastrointestinal fluids. The solubility of seven poorly soluble compounds was assessed in adult and age-specific fasted and fed state biorelevant media. Partial least squares regression (PLS-R) was used to assess the influence of (i) drug physicochemical properties and (ii) age-related changes in simulated GI fluids, as well as (iii) their interactions, on the pediatrics-to-adult solubility ratio (Sp/Sa (%)). For five out of seven of the compounds investigated, Sp/Sa (%) values fell outside of the 80–125% limits in at least one of the pediatric media. Lipophilicity was responsible for driving drug solubility differences between adults and children in all the biorelevant media investigated, while drug ionization was most relevant in the fed gastric media, and the fasted/fed intestinal media. The concentration of bile salts and lecithin in the fasted and fed intestinal media was critical in influencing drug solubility, while food composition (i.e., cow’s milk formula vs. soy formula) was a critical parameter in the fed gastric state. Changes in GI fluid composition between younger pediatric patients and adults can significantly alter drug luminal solubility. The use of pediatric biorelevant media can be helpful to identify the risk of altered drug solubilization in younger patients during drug development. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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11 pages, 745 KiB

Open AccessArticle

Dosage Forms Suitability in Pediatrics: Acceptability of Analgesics and Antipyretics in a German Hospital

by Viviane Klingmann, Thibault Vallet, Juliane Münch, Robin Stegemann, Lena Wolters, Hans-Martin Bosse and Fabrice Ruiz

Pharmaceutics 2022, 14(2), 337; https://doi.org/10.3390/pharmaceutics14020337 - 31 Jan 2022

Cited by 11 | Viewed by 3953

Abstract

Although medicine acceptability is likely to have a significant impact on the patient’s adherence in pediatrics and therefore on therapy success, there is still little data even for common therapeutic areas. For analgesics/antipyretics, healthcare professionals face a wide variety of products and need knowledge to select the best adapted product for each patient. We investigated acceptability of those products most used at the University Children’s Hospital Düsseldorf, Germany. Based on 180 real-life observer reports of medicine intake, we used the acceptability reference framework to score acceptability of six distinct medicines. Both ibuprofen and paracetamol tablets, mainly used in adolescents, were positively accepted. This was not the case for the solution for injection of metamizole sodium. Regarding syrups, mainly used in children under 6 years of age, ibuprofen flavored with strawberry and provided with an oral syringe was positively accepted, while paracetamol flavored with orange and provided with a measuring cup was not. Suppository appeared to be an alternative to oral liquids in infants and toddlers with palatability and administration issues. Differences appeared to be driven by dosage forms and formulations. These findings improve knowledge on acceptability drivers and might help formulating and prescribing better medicines for children. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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14 pages, 7775 KiB

Open AccessArticle

Acceptability of Mebendazole Chewable Tablet in Children Aged 2 to 4 Years in Peru

by Fernando Perez, Thibault Vallet, Zarela Bravo, Kristin Callahan and Fabrice Ruiz

Pharmaceutics 2022, 14(1), 27; https://doi.org/10.3390/pharmaceutics14010027 - 23 Dec 2021

Cited by 5 | Viewed by 3911

Abstract

Soil-transmitted helminthiasis (STH) is among the most common of parasitic infections, affecting vulnerable populations in tropical/subtropical areas globally. In endemic countries, children, a high-risk population, require treatment and preventive interventions. Mebendazole, a WHO-recommended medicine, originally formulated as a tablet that was often crushed for administration to young children unable to swallow it, was reformulated as a chewable tablet. Acceptability is a key aspect for treatment effectiveness in pediatrics. Herein, we used a validated data-driven approach to investigate the acceptability of the 500-mg mebendazole chewable tablet in children aged 2 to 4 years in Peru. Observer-reported outcomes were collected for 182 medicine intakes. Acceptability was scored using the acceptability reference framework: a three-dimensional map juxtaposing “positively accepted” and “negatively accepted” profiles. Results found that the 500-mg mebendazole chewable tablet was classified as “positively accepted” in children aged 2 to 4 years. Acceptability increased with age and some acceptability issue remain for the younger children. Nevertheless, this formulation was considerably better accepted than the conventional tablets regardless of treatment in young children. This chewable formulation appears to be an appropriate alternative to the hard tablet of mebendazole for treatment of STH and preventive interventions in children aged 2 to 4 years. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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15 pages, 2513 KiB

Open AccessArticle

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

by Jan Goelen, Benoni Alexander, Haren Eranga Wijesinghe, Emily Evans, Gopal Pawar, Richard D. Horniblow and Hannah K. Batchelor

Pharmaceutics 2021, 13(10), 1729; https://doi.org/10.3390/pharmaceutics13101729 - 19 Oct 2021

Cited by 5 | Viewed by 2771

Abstract

Previous studies have used magnetic resonance imaging (MRI) to quantify the fluid in the stomach and small intestine of children, and the stomach, small intestine and colon of adults. This is the first study to quantify fluid volumes and distribution using MRI in the paediatric colon. MRI datasets from 28 fasted (aged 0–15 years) and 18 fluid-fed (aged 10–16 years) paediatric participants were acquired during routine clinical care. A series of 2D- and 3D-based software protocols were used to measure colonic fluid volume and localisation. The paediatric colon contained a mean volume of 22.5 mL ± 41.3 mL fluid, (range 0–167.5 mL, median volume 0.80 mL) in 15.5 ± 17.5 discreet fluid pockets (median 12). The proportion of the fluid pockets larger than 1 mL was 9.6%, which contributed to 94.5% of the total fluid volume observed. No correlation was detected between all-ages and colonic fluid volume, nor was a difference in colonic fluid volumes observed based on sex, fed state or age group based on ICH-classifications. This study quantified fluid volumes within the paediatric colon, and these data will aid and accelerate the development of biorelevant tools to progress paediatric drug development for colon-targeting formulations. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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Review

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23 pages, 2208 KiB

Open AccessReview

Practical Recommendations for the Manipulation of Kinase Inhibitor Formulations to Age-Appropriate Dosage Forms

by Emma C. Bernsen, Valery J. Hogenes, Bastiaan Nuijen, Lidwien M. Hanff, Alwin D. R. Huitema and Meta H. M. Diekstra

Pharmaceutics 2022, 14(12), 2834; https://doi.org/10.3390/pharmaceutics14122834 - 17 Dec 2022

Cited by 3 | Viewed by 3156

Abstract

Over 75 kinase inhibitors (KIs) have been approved for the treatment of various cancers. KIs are orally administrated but mostly lack pediatric age-appropriate dosage forms or instructions for dose manipulation. This is highly problematic for clinical practice in pediatric oncology, as flexible oral formulations are essential to individually set dosages and to adjust it to a child’s swallowability. Most KIs are poorly soluble, categorized in Biopharmaceutics Classification System (BCS) class II or IV, and improperly manipulating the KI formulation can alter pharmacokinetics and jeopardize KI drug safety and efficacy. Therefore, the goals of this review were to provide practical recommendations for manipulating the formulation of the 15 most frequently used KIs in pediatric oncology (i.e., bosutinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dasatinib, entrectinib, imatinib, larotrectinib, nilotinib, ponatinib, ruxolitinib, selumetinib, sunitinib and trametinib) based on available literature studies and fundamental drug characteristics and to establish a decision tool that supports decisions regarding formulation manipulation of solid oral dosages of KIs that have been or will be licensed (for adult and/or pediatric cancers) but are not included in this review. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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23 pages, 896 KiB

Open AccessEditor’s ChoiceReview

3D Printing of Pediatric Medication: The End of Bad Tasting Oral Liquids?—A Scoping Review

by Iris Lafeber, Elisabeth J. Ruijgrok, Henk-Jan Guchelaar and Kirsten J. M. Schimmel

Pharmaceutics 2022, 14(2), 416; https://doi.org/10.3390/pharmaceutics14020416 - 14 Feb 2022

Cited by 32 | Viewed by 5657

Abstract

3D printing of pediatric-centered drug formulations can provide suitable alternatives to current treatment options, though further research is still warranted for successful clinical implementation of these innovative drug products. Extensive research has been conducted on the compliance of 3D-printed drug products to a pediatric quality target product profile. The 3D-printed tablets were of particular interest in providing superior dosing and release profile similarity compared to conventional drug manipulation and compounding methods, such as oral liquids. In the future, acceptance of 3D-printed tablets in the pediatric patient population might be better than current treatments due to improved palatability. Further research should focus on expanding clinical knowledge, providing regulatory guidance and expansion of the product range, including dosage form possibilities. Moreover, it should enable the use of diverse good manufacturing practice (GMP)-ready 3D printing techniques for the production of various drug products for the pediatric patient population. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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