Editorial

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Open AccessEditorial

Paediatric Formulation: Design and Development

by

Antonio Lopalco

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Nunzio Denora

Int. J. Mol. Sci. 2020, 21(19), 7118; https://doi.org/10.3390/ijms21197118 - 27 Sep 2020

Cited by 4 | Viewed by 2174

Abstract

The development of medicines designed for children can be challenging since this distinct patient population requires specific needs. A formulation designed for paediatric patients must consider the following aspects: patient population variability; dose flexibility; route of administration; patient compliance; drug and excipient tolerability. [...] Read more.

The development of medicines designed for children can be challenging since this distinct patient population requires specific needs. A formulation designed for paediatric patients must consider the following aspects: patient population variability; dose flexibility; route of administration; patient compliance; drug and excipient tolerability. The purpose of this Special Issue entitled “Paediatric Formulation: Design and Development” is to provide an update on both state-of-the-art methodology and operational challenges in the design and development of paediatric formulations. It aims at re-evaluating what is needed for more progress in the design and development of age-appropriate treatments for paediatric diseases, focusing on: formulation development; drug delivery design; efficacy, safety, and tolerability of drugs and excipients. This editorial, briefly, summarizes the objects of nine original research and review papers published in this Special Issue. Full article

(This article belongs to the Special Issue Paediatric Formulation: Design and Development)

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Open AccessArticle

Optimal Design, Characterization and Preliminary Safety Evaluation of an Edible Orodispersible Formulation for Pediatric Tuberculosis Pharmacotherapy

by

Nyaradzo Matawo

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Oluwatoyin A. Adeleke

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James Wesley-Smith

Int. J. Mol. Sci. 2020, 21(16), 5714; https://doi.org/10.3390/ijms21165714 - 10 Aug 2020

Cited by 8 | Viewed by 2510

Abstract

The severity of tuberculosis (TB) in children is considered a global crisis compounded by the scarcity of pharmaceutical formulations suitable for pediatric use. The purpose of this study was to optimally develop and evaluate a pyrazinamide containing edible orodispersible film formulation potentially suitable [...] Read more.

The severity of tuberculosis (TB) in children is considered a global crisis compounded by the scarcity of pharmaceutical formulations suitable for pediatric use. The purpose of this study was to optimally develop and evaluate a pyrazinamide containing edible orodispersible film formulation potentially suitable for use in pediatrics actively infected with TB. The formulation was prepared employing aqueous-particulate blending and solvent casting methods facilitated by a high performance Box Behnken experimental design template. The optimized orodispersible formulation was mechanically robust, flexible, easy to handle, exhibited rapid disintegration with initial matrix collapse occurring under 60 s (0.58 ± 0.05 min ≡ 34.98 ± 3.00 s) and pyrazinamide release was controlled by anomalous diffusion coupled with matrix disintegration and erosion mechanisms. It was microporous in nature, light weight (57.5 ± 0.5 mg) with an average diameter of 10.5 mm and uniformly distributed pyrazinamide load of 101.13 ± 2.03 %^w/_w. The formulation was physicochemically stable with no evidence of destructive drug–excipient interactions founded on outcomes of characterization and environmental stability investigations. Preliminary inquiries revealed that the orodispersible formulation was cytobiocompatible, palatable and remained intact under specific storage conditions. Summarily, an edible pyrazinamide containing orodispersible film formulation was optimally designed to potentially improve TB pharmacotherapy in children, particularly the under 5 year olds. Full article

(This article belongs to the Special Issue Paediatric Formulation: Design and Development)

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Open AccessArticle

Development and Palatability Assessment of Norvir^® (Ritonavir) 100 mg Powder for Pediatric Population

by

John B. Morris

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David A. Tisi

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David Cheng Thiam Tan

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Jeffrey H. Worthington

Int. J. Mol. Sci. 2019, 20(7), 1718; https://doi.org/10.3390/ijms20071718 - 06 Apr 2019

Cited by 10 | Viewed by 3674

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

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Int. J. Mol. Sci. 2019, 20(5), 1233; https://doi.org/10.3390/ijms20051233 - 12 Mar 2019

Cited by 10 | Viewed by 3929

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

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Int. J. Mol. Sci. 2019, 20(5), 1077; https://doi.org/10.3390/ijms20051077 - 02 Mar 2019

Cited by 18 | Viewed by 2864

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

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Int. J. Mol. Sci. 2019, 20(3), 591; https://doi.org/10.3390/ijms20030591 - 30 Jan 2019

Cited by 16 | Viewed by 3870

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

Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML

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Int. J. Mol. Sci. 2020, 21(12), 4469; https://doi.org/10.3390/ijms21124469 - 23 Jun 2020

Cited by 19 | Viewed by 4018

Abstract

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options [...] Read more.

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy. Full article

(This article belongs to the Special Issue Paediatric Formulation: Design and Development)

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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

by

Monika Trofimiuk

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Katarzyna Wasilewska

and

Katarzyna Winnicka

Int. J. Mol. Sci. 2019, 20(13), 3200; https://doi.org/10.3390/ijms20133200 - 29 Jun 2019

Cited by 26 | Viewed by 7155

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

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Int. J. Mol. Sci. 2019, 20(11), 2688; https://doi.org/10.3390/ijms20112688 - 31 May 2019

Cited by 28 | Viewed by 8302

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

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Int. J. Mol. Sci. 2019, 20(8), 1898; https://doi.org/10.3390/ijms20081898 - 17 Apr 2019

Cited by 52 | Viewed by 5851

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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