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Special Issue "Paediatric Formulation: Design and Development"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 30 June 2020.

Special Issue Editors

Prof. Dr. Nunzio Denora
Website
Guest Editor
Department of Pharmacy–Pharmaceutical Sciences, University of Bari “Aldo Moro”, I-70125 Bari, Italy
Interests: targeted drug delivery; micro- and nano-incapsulation; age-related formulation
Special Issues and Collections in MDPI journals
Dr. Antonio Lopalco
Website1 Website2
Guest Editor
Department of Pharmacy–Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Interests: drug delivery; nanotechology; drug stability; paediatric formulation

Special Issue Information

Dear Colleagues,

The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. A medicine designed for use in paediatric patients must consider the following aspects: patient population variability; the need for dose flexibility; route of administration; patient compliance; excipient tolerability. For example, the toxicity of excipients may differ in children compared to adults and children have different taste preferences.

Globally, about 75% of drugs do not carry regulatory approval for use in children; worldwide, many medications prescribed for the treatment of paediatric diseases are used off label, and less than 20% of package inserts have sufficient information for treating children.

The aim of this Special Issue is to provide an update on both state-of-the-art methodology and operational challenges in paediatric formulation design and development. It aims at re-evaluating what is needed for more progress in the design and development of age-appropriate treatments for paediatric diseases.

We welcome original research, review, opinion papers, editorials, or short communications on the following topics:

  • paediatric formulation development;
  • drug delivery design in paediatrics;
  • orphan drugs;
  • pharmacology and toxicology of drugs and excipients in paediatrics.

Prof. Dr. Nunzio Denora
Dr. Antonio Lopalco
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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Open AccessArticle
Development and Palatability Assessment of Norvir® (Ritonavir) 100 mg Powder for Pediatric Population
Int. J. Mol. Sci. 2019, 20(7), 1718; https://doi.org/10.3390/ijms20071718 - 06 Apr 2019
Abstract
Norvir® (ritonavir) is a Biopharmaceutical Classification System Class IV compound with poor solubility in water (~5 µg/mL) and limited oral bioavailability. Early stage development efforts were focused on an oral solution (OS) which provided reasonable bioavailability but exhibited taste-masking challenges and required [...] Read more.
Norvir® (ritonavir) is a Biopharmaceutical Classification System Class IV compound with poor solubility in water (~5 µg/mL) and limited oral bioavailability. Early stage development efforts were focused on an oral solution (OS) which provided reasonable bioavailability but exhibited taste-masking challenges and required the use of solvents with potential pediatric toxicity. Norvir® oral powder, 100 mg (NOP) was developed to replace OS. The objective of this study is to provide an overview of the development of NOP and palatability assessment strategy. Palatability of NOP was assessed using the flavor profile method: (1) As an aqueous suspension dose/response and (2) evaluation with foods. The dose/response sensory analysis indicated that NOP has strong intensity bitterness and burnt aromatics (3 on the 0–3 flavor profile scale) at the clinical dose (100 mg/10 mL) and the recognition threshold was determined to be 0.3 mg/10 mL. To improve palatability, 100 mg/10 mL NOP aqueous suspension was evaluated with foods. Consuming foods high in fat and/or sugar content after NOP administration successfully reduced bitterness to a 1.5 intensity. In summary, NOP provides dose flexibility, enhanced stability, eliminated solvents, and maintains consistent bioavailability, with reduced bitterness and improved palatability via administration with common food products. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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Open AccessArticle
Combining Mechanochemistry and Spray Congealing for New Praziquantel Pediatric Formulations in Schistosomiasis Treatment
Int. J. Mol. Sci. 2019, 20(5), 1233; https://doi.org/10.3390/ijms20051233 - 12 Mar 2019
Cited by 2
Abstract
Praziquantel (PZQ) is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children. In this study, the association of mechanochemical activation (MA) and the spray congealing (SC) technology was evaluated [...] Read more.
Praziquantel (PZQ) is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children. In this study, the association of mechanochemical activation (MA) and the spray congealing (SC) technology was evaluated for developing a child-friendly PZQ dosage form, with better product handling and biopharmaceutical properties, compared to MA materials. A 1:1 by wt PZQ—Povidone coground—was prepared in a vibrational mill under cryogenic conditions, for favoring amorphization. PZQ was neat ground to obtain its polymorphic form (Form B), which has an improved solubility and bioactivity. Then, activated PZQ powders were loaded into microparticles (MPs) by the SC technology, using the self-emulsifying agent Gelucire® 50/13 as a carrier. Both, the activated powders and the corresponding loaded MPs were characterized for morphology, wettability, solubility, dissolution behavior, drug content, and drug solid state (Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction Studies (PXRD), and FT-IR). Samples were also in vitro tested for a comparison with PZQ against Schistosoma mansoni newly transformed schistosomula (NTS) and adults. MPs containing both MA systems showed a further increase of biopharmaceutical properties, compared to the milled powders, while maintaining PZQ bioactivity. MPs containing PZQ Form B represented the most promising product for designing a new PZQ formulation. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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Open AccessArticle
Tridimensional Retinoblastoma Cultures as Vitreous Seeds Models for Live-Cell Imaging of Chemotherapy Penetration
Int. J. Mol. Sci. 2019, 20(5), 1077; https://doi.org/10.3390/ijms20051077 - 02 Mar 2019
Cited by 4
Abstract
A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell [...] Read more.
A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core (p < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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Open AccessArticle
Dasatinib/HP-β-CD Inclusion Complex Based Aqueous Formulation as a Promising Tool for the Treatment of Paediatric Neuromuscular Disorders
Int. J. Mol. Sci. 2019, 20(3), 591; https://doi.org/10.3390/ijms20030591 - 30 Jan 2019
Cited by 3
Abstract
New scientific findings have recently shown that dasatinib (DAS), the first-choice oral drug in the treatment of chronic myeloid leukemia (CML) for adult patients who are resistant or intolerant to imatinib, is also potentially useful in the paediatric age. Moreover, recent preclinical evidences [...] Read more.
New scientific findings have recently shown that dasatinib (DAS), the first-choice oral drug in the treatment of chronic myeloid leukemia (CML) for adult patients who are resistant or intolerant to imatinib, is also potentially useful in the paediatric age. Moreover, recent preclinical evidences suggest that this drug could be useful for the treatment of Duchenne muscular dystrophy, since it targets cSrc tyrosin kinase. Based on these considerations, the purpose of this work was to use the strategy of complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) in order to obtain an aqueous preparation of DAS, which is characterized by a low water solubility (6.49 × 10−4 mg/mL). Complexation studies demonstrated that HP-β-CD is able to form a stable host-guest inclusion complex with DAS with a 1:1 apparent formation constant of 922.13 M−1, as also demonstrated by the Job’s plot, with an increase in DAS aqueous solubility of about 21 times in the presence of 6% w/v of HP-β-CD (0.014 mg/mL). The inclusion complex has been prepared in the solid state by lyophilization and characterized by Fourier Transform Infrared (FT-IR), Nuclear Magnetic Resonance (NMR), Differential Scanning Calorimetry (DSC) techniques, and its dissolution profile was studied at different pH values. Moreover, in view of potential use of DAS for Duchenne muscular dystrophy, the cytotoxic effect of the inclusion complex has been assessed on C2C12 cells, a murine muscle satellite cell line. In parallel, a one-week oral treatment was performed in wild type C57Bl/6J mice to test both palatability and the exposure levels of the new oral formulation of the compound. In conclusion, this new inclusion complex could allow the development of a liquid and solvent free formulation to be administered both orally and parenterally, especially in the case of an administration in paediatric age. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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Review

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Open AccessReview
How to Modify Drug Release in Paediatric Dosage Forms? Novel Technologies and Modern Approaches with Regard to Children’s Population
Int. J. Mol. Sci. 2019, 20(13), 3200; https://doi.org/10.3390/ijms20133200 - 29 Jun 2019
Cited by 2
Abstract
In the pharmaceutical technology, paediatric population still presents the greatest challenge in terms of developing flexible and appropriate drug dosage forms. As for many medicines, there is a lack of paediatric dosage forms adequate for a child’s age; it is a prevailing practice [...] Read more.
In the pharmaceutical technology, paediatric population still presents the greatest challenge in terms of developing flexible and appropriate drug dosage forms. As for many medicines, there is a lack of paediatric dosage forms adequate for a child’s age; it is a prevailing practice to use off label formulations. Children need balanced and personalized treatment, patient-friendly preparations, as well as therapy that facilitates dosing and thus eliminates frequent drug administration, which can be ensured by modified release (MR) forms. MR formulations are commonly used in adult therapy, while rarely available for children. The aim of this article is to elucidate how to modify drug release in paediatric oral dosage forms, discuss the already accessible technologies and to introduce novel approaches of manufacturing with regard to paediatric population. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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Open AccessReview
Making Medicines Baby Size: The Challenges in Bridging the Formulation Gap in Neonatal Medicine
Int. J. Mol. Sci. 2019, 20(11), 2688; https://doi.org/10.3390/ijms20112688 - 31 May 2019
Cited by 2
Abstract
The development of age-appropriate formulations should focus on dosage forms that can deliver variable yet accurate doses that are safe and acceptable to the child, are matched to his/her development and ability, and avoid medication errors. However, in the past decade, the medication [...] Read more.
The development of age-appropriate formulations should focus on dosage forms that can deliver variable yet accurate doses that are safe and acceptable to the child, are matched to his/her development and ability, and avoid medication errors. However, in the past decade, the medication needs of neonates have largely been neglected. The aim of this review is to expand on what differentiates the needs of preterm and term neonates from those of the older paediatric subsets, in terms of environment of care, ability to measure and administer the dose (from the perspective of the patient and carer, the routes of administration, the device and the product), neonatal biopharmaceutics and regulatory challenges. This review offers insight into those challenges posed by the formulation of medicinal products for neonatal patients in order to support the development of clinically relevant products. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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Open AccessReview
Unveiling the Efficacy, Safety, and Tolerability of Anti-Interleukin-1 Treatment in Monogenic and Multifactorial Autoinflammatory Diseases
Int. J. Mol. Sci. 2019, 20(8), 1898; https://doi.org/10.3390/ijms20081898 - 17 Apr 2019
Cited by 9
Abstract
Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of interleukin-1(IL-1)β that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood [...] Read more.
Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of interleukin-1(IL-1)β that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients’ quality of life. IL-1β blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1β antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting. Full article
(This article belongs to the Special Issue Paediatric Formulation: Design and Development)
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