Development of Medicines for Rare Pediatric Diseases

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (17 February 2023) | Viewed by 33163

Special Issue Editors


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Guest Editor
Department of Pharmacy, Università degli Studi di Genova, Genoa, Italy
Interests: retinoids; drug delivery systems; polymeric micelles; liposomes; passive targeting; active targeting; poorly soluble drugs; formulation strategies; cancer; neuroblastoma; melanoma; tumor mouse models; oncology, apoptosis
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Stem Cell Laboratory and Cell Therapy Center, IRCCS Istituto Giannina Gaslini, via G. Gaslini 5, 16147 Genova, Italy
Interests: cell biology; extracellular vesicles; tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is estimated that up to 7000 rare diseases exist, affecting between 6% and 8% of the global population and >30 million people in the European Union. Symptoms often occur early at birth or during childhood and may progressively increase, becoming chronic or relapsing, leading to life-threatening conditions. In fact, 75% of rare diseases are known to affect children, and about 3 out of 10 of these children die before reaching 5 years of age. Therefore, incentivizing medicine development is crucial for this subset of the population, who is disproportionately affected by rare diseases. Furthermore, only 5% of rare diseases have effective treatment options, which leaves 95% of rare diseases without any approved medicines. Since both the Orphan Regulation, first, and the Paediatric Regulation, later, came into force, the development of medicinal products suitable for pediatrics has consistently increased, but much more needs to be done. To date, the medical and scientific knowledge on rare diseases remains limited, and the absence of approved treatment options has led physicians and pharmacists to the harmful off-label use of medicines. This Special Issue is addressed to all researchers and partners involved in the development of pediatric medicines, with the aim of collecting opinions from industry, regulators, academia, and hospitals, thus contributing to providing solutions to unmet pediatric needs.

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

  • Pediatric formulations;
  • Drug-delivery design in pediatrics;
  • Orphan drugs;
  • Rare-disease treatment;
  • The pharmacology and toxicology of drugs and excipients in pediatrics;
  • Translational research in pediatrics;
  • Pediatric drug targeting;
  • Extemporaneous pediatric preparations compounded in hospital pharmacies.

Dr. Guendalina Zuccari
Dr. Danilo Marimpietri
Guest Editors

Manuscript Submission Information

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Keywords

  • pediatric formulations
  • drug-delivery design in pediatrics
  • orphan drugs
  • rare-disease treatment
  • the pharmacology and toxicology of drugs and excipients in pediatrics
  • translational research in pediatrics
  • pediatric drug targeting
  • extemporaneous pediatric preparations compounded in hospital pharmacies

Published Papers (13 papers)

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Editorial

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4 pages, 199 KiB  
Editorial
Development of Medicines for Rare Pediatric Diseases
by Danilo Marimpietri and Guendalina Zuccari
Pharmaceuticals 2023, 16(4), 513; https://doi.org/10.3390/ph16040513 - 30 Mar 2023
Viewed by 1049
Abstract
To date, approximately 7000 rare diseases exist, affecting between 6% and 8% of the global population and >30 million people in the European Union [...] Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)

Research

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13 pages, 2091 KiB  
Article
Model-Informed Target Morning 17α-Hydroxyprogesterone Concentrations in Dried Blood Spots for Pediatric Congenital Adrenal Hyperplasia Patients
by Viktoria Stachanow, Uta Neumann, Oliver Blankenstein, Nele Alder-Baerens, Davide Bindellini, Peter Hindmarsh, Richard J. Ross, Martin J. Whitaker, Johanna Melin, Wilhelm Huisinga, Robin Michelet and Charlotte Kloft
Pharmaceuticals 2023, 16(3), 464; https://doi.org/10.3390/ph16030464 - 21 Mar 2023
Cited by 1 | Viewed by 1556
Abstract
Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous [...] Read more.
Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous alternative to traditional plasma sampling, especially in pediatric patients. However, target concentrations for important disease biomarkers such as 17α-hydroxyprogesterone (17-OHP) are unknown using DBS. Therefore, a modeling and simulation framework, including a pharmacokinetic/pharmacodynamic model linking plasma cortisol concentrations to DBS 17-OHP concentrations, was used to derive a target morning DBS 17-OHP concentration range of 2–8 nmol/L in pediatric CAH patients. Since either capillary or venous DBS sampling is becoming more common in the clinics, the clinical applicability of this work was shown by demonstrating the comparability of capillary and venous cortisol and 17-OHP concentrations collected by DBS sampling, using a Bland-Altman and Passing-Bablok analysis. The derived target morning DBS 17-OHP concentration range is a first step towards providing improved therapy monitoring using DBS sampling and adjusting hydrocortisone (synthetic cortisol) dosing in children with CAH. In the future, this framework can be used to assess further research questions, e.g., target replacement ranges for the entire day. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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12 pages, 882 KiB  
Article
Individual Treatment Trials—Do Experts Know and Use This Option to Improve the Treatability of Mucopolysaccharidosis?
by Anna-Maria Wiesinger, Hannah Strobl and Florian B. Lagler
Pharmaceuticals 2023, 16(3), 416; https://doi.org/10.3390/ph16030416 - 09 Mar 2023
Cited by 2 | Viewed by 1581
Abstract
Mucopolysaccharidoses (MPS) are a group of rare, heterogeneous, lysosomal storage disorders. Patients show a broad spectrum of clinical features with a substantial unmet medical need. Individual treatment trials (ITTs) might be a valid, time- and cost-efficient way to facilitate personalized medicine in the [...] Read more.
Mucopolysaccharidoses (MPS) are a group of rare, heterogeneous, lysosomal storage disorders. Patients show a broad spectrum of clinical features with a substantial unmet medical need. Individual treatment trials (ITTs) might be a valid, time- and cost-efficient way to facilitate personalized medicine in the sense of drug repurposing in MPS. However, this treatment option has so far hardly been used—at least hardly been reported or published. Therefore, we aimed to investigate the awareness and utilization of ITTs among MPS clinicians, as well as the potential challenges and innovative approaches to overcome key hurdles, by using an international expert survey on ITTs, namely, ESITT. Although 74% (20/27) were familiar with the concept of ITTs, only 37% (10/27) ever used it, and subsequently only 15% (2/16) published their results. The indicated hurdles of ITTs in MPS were mainly the lack of time and know-how. An evidence-based tool, which provides resources and expertise needed for high-quality ITTs, was highly appreciated by the vast majority (89%; 23/26). The ESITT highlights a serious deficiency of ITT implementation in MPS—a promising option to improve its treatability. Furthermore, we discuss the challenges and innovative approaches to overcome key barriers to ITTs in MPS. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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22 pages, 2150 KiB  
Article
Pyrazole-Enriched Cationic Nanoparticles Induced Early- and Late-Stage Apoptosis in Neuroblastoma Cells at Sub-Micromolar Concentrations
by Guendalina Zuccari, Alessia Zorzoli, Danilo Marimpietri, Chiara Brullo and Silvana Alfei
Pharmaceuticals 2023, 16(3), 393; https://doi.org/10.3390/ph16030393 - 05 Mar 2023
Cited by 3 | Viewed by 1808
Abstract
Neuroblastoma (NB) is a severe form of tumor occurring mainly in young children and originating from nerve cells found in the abdomen or next to the spine. NB needs more effective and safer treatments, as the chance of survival against the aggressive form [...] Read more.
Neuroblastoma (NB) is a severe form of tumor occurring mainly in young children and originating from nerve cells found in the abdomen or next to the spine. NB needs more effective and safer treatments, as the chance of survival against the aggressive form of this disease are very small. Moreover, when current treatments are successful, they are often responsible for unpleasant health problems which compromise the future and life of surviving children. As reported, cationic macromolecules have previously been found to be active against bacteria as membrane disruptors by interacting with the negative constituents of the surface of cancer cells, analogously inducing depolarization and permeabilization, provoking lethal damage to the cytoplasmic membrane, and cause loss of cytoplasmic content and consequently, cell death. Here, aiming to develop new curative options for counteracting NB cells, pyrazole-loaded cationic nanoparticles (NPs) (BBB4-G4K and CB1H-P7 NPs), recently reported as antibacterial agents, were assayed against IMR 32 and SHSY 5Y NB cell lines. Particularly, while BBB4-G4K NPs demonstrated low cytotoxicity against both NB cell lines, CB1H-P7 NPs were remarkably cytotoxic against both IMR 32 and SHSY 5Y cells (IC50 = 0.43–0.54 µM), causing both early-stage (66–85%) and late-stage apoptosis (52–65%). Interestingly, in the nano-formulation of CB1H using P7 NPs, the anticancer effects of CB1H and P7 were increased by 54–57 and 2.5–4-times, respectively against IMR 32 cells, and by 53–61 and 1.3–2 times against SHSY 5Y cells. Additionally, based on the IC50 values, CB1H-P7 was also 1-12-fold more potent than fenretinide, an experimental retinoid derivative in a phase III clinical trial, with remarkable antineoplastic and chemopreventive properties. Collectively, due to these results and their good selectivity for cancer cells (selectivity indices = 2.8–3.3), CB1H-P7 NPs represent an excellent template material for developing new treatment options against NB. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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22 pages, 5490 KiB  
Article
Preparation and Characterization of Amorphous Solid Dispersions for the Solubilization of Fenretinide
by Guendalina Zuccari, Eleonora Russo, Carla Villa, Alessia Zorzoli, Danilo Marimpietri, Leonardo Marchitto and Silvana Alfei
Pharmaceuticals 2023, 16(3), 388; https://doi.org/10.3390/ph16030388 - 02 Mar 2023
Cited by 6 | Viewed by 1607
Abstract
Fenretinide (4-HPR), a retinoid derivative, has shown high antitumor activity, a low toxicological profile, and no induction of resistance. Despite these favorable features, the variability in oral absorption due to its low solubility combined with the high hepatic first pass effect strongly reduce [...] Read more.
Fenretinide (4-HPR), a retinoid derivative, has shown high antitumor activity, a low toxicological profile, and no induction of resistance. Despite these favorable features, the variability in oral absorption due to its low solubility combined with the high hepatic first pass effect strongly reduce clinical outcomes. To overcome the solubility and dissolution challenges of poorly water-soluble 4-HPR, we prepared a solid dispersion of the drug (4-HPR-P5) using a hydrophilic copolymer (P5) previously synthesized by our team as the solubilizing agent. The molecularly dispersed drug was obtained by antisolvent co-precipitation, an easy and up-scalable technique. A higher drug apparent solubility (1134-fold increase) and a markedly faster dissolution were obtained. In water, the colloidal dispersion showed a mean hydrodynamic diameter of 249 nm and positive zeta potential (+41.3 mV), confirming the suitability of the formulation for intravenous administration. The solid nanoparticles were also characterized by a high drug payload (37%), as was also evidenced by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR) investigation. The 4-HPR-P5 exhibited antiproliferative activity, with IC50 values of 1.25 and 1.93 µM on IMR-32 and SH-SY5Y neuroblastoma cells, respectively. Our data confirmed that the 4-HPR-P5 formulation developed herein was able to increase drug apparent aqueous solubility and provide an extended release over time, thus suggesting that it represents an efficient approach to improve 4-HPR bioavailability. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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10 pages, 259 KiB  
Article
Antithymocyte Globulin Plus Post-Transplant Cyclophosphamide Combination as an Effective Strategy for Graft-versus-Host Disease Prevention in Haploidentical Peripheral Blood Stem Cell Transplantation for Children with High-Risk Malignancies
by Kang-Hsi Wu, Te-Fu Weng, Ju-Pi Li and Yu-Hua Chao
Pharmaceuticals 2022, 15(11), 1423; https://doi.org/10.3390/ph15111423 - 17 Nov 2022
Cited by 1 | Viewed by 1594
Abstract
Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this [...] Read more.
Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this setting. The addition of antithymocyte globulin (ATG) in PTCy-based regimens for GVHD reduction in haploidentical hematopoietic stem cell transplantation is rational and was reported in adult series. However, its feasibility is unknown in pediatric patients. Here, we firstly describe our experience of 15 consecutive children with high-risk malignancies receiving haploidentical peripheral blood stem cell transplantation using ATG plus PTCy for GVHD prophylaxis. Only three patients developed grade 1–2 acute GVHD, limited to skin. No grade 3–4 acute GVHD and chronic GVHD were observed. Viral reactivations were frequently seen but manageable. Six patients relapsed, as the main cause of death in our series. None died from events related to GVHD. Our data suggest that ATG plus PTCy is an effective strategy for GVHD prevention in haploidentical peripheral blood stem cell transplantation and is feasible in children with high-risk malignancies. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
14 pages, 1218 KiB  
Article
Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug
by John Dike N. Ogbonna, Edite Cunha, Anthony A. Attama, Kenneth C. Ofokansi, Helena Ferreira, Susana Pinto, Joana Gomes, Ítala M. G. Marx, António M. Peres, José Manuel Sousa Lobo and Isabel F. Almeida
Pharmaceuticals 2022, 15(11), 1331; https://doi.org/10.3390/ph15111331 - 27 Oct 2022
Cited by 7 | Viewed by 1817
Abstract
Designing oral formulations for children is very challenging, especially considering their peculiarities and preferences. The choice of excipients, dosing volume and palatability are key issues of pediatric oral liquid medicines. The purpose of the present study is to develop an oral pediatric solution [...] Read more.
Designing oral formulations for children is very challenging, especially considering their peculiarities and preferences. The choice of excipients, dosing volume and palatability are key issues of pediatric oral liquid medicines. The purpose of the present study is to develop an oral pediatric solution of a model bitter drug (ranitidine) following a patient centric design process which includes the definition of a target product profile (TPP). To conclude on the matching of the developed solution to TPP, its chemical and microbiological stability was analyzed over 30 days (stored at 4 °C and room temperature). Simulation of use was accomplished by removing a sample with a syringe every day. Taste masking was assessed by an electronic tongue. The developed formulation relied on a simple taste masking strategy consisting in a mixture of sweeteners (sodium saccharine and aspartame) and 0.1% sodium chloride, which allowed a higher bitterness masking effectiveness in comparison with simple syrup. The ranitidine solution was stable for 30 days stored at 4 °C. However, differences were noted between the stability protocols (unopened recipient and in-use stability) showing the contribution of the simulation of use to the formation of degradation products. Stock solution was subjected to acid and alkali hydrolysis, chemical oxidation, heat degradation and a photo degradation stability assessment. The developed pediatric solution matched the TPP in all dimensions, namely composition suitable for children, preparation and handling adapted to hospital pharmaceutical compounding and adequate stability and quality. According to the results, in-use stability protocols should be preferred in the stability evaluation of pediatric formulations. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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17 pages, 3778 KiB  
Article
Surfactant-Free Chitosan/Cellulose Acetate Phthalate Nanoparticles: An Attempt to Solve the Needs of Captopril Administration in Paediatrics
by Noelia Nieto González, Guido Cerri, Jesús Molpeceres, Massimo Cossu, Giovanna Rassu, Paolo Giunchedi and Elisabetta Gavini
Pharmaceuticals 2022, 15(6), 662; https://doi.org/10.3390/ph15060662 - 25 May 2022
Cited by 7 | Viewed by 2147
Abstract
The Paediatric Committee of the European Medicines Agency encourages research into medicinal products for children, in particular, the development of an age-appropriate formulation of captopril is required in the cardiovascular therapeutic area. The aim of this study was the development of a liquid [...] Read more.
The Paediatric Committee of the European Medicines Agency encourages research into medicinal products for children, in particular, the development of an age-appropriate formulation of captopril is required in the cardiovascular therapeutic area. The aim of this study was the development of a liquid formulation using nanoparticles based only on chitosan and cellulose acetate phthalate containing captopril for the treatment of hypertension, heart failure and diabetic nephropathy in paediatric patients. Nanoparticles were prepared by a nanoprecipitation method/dropping technique without using surfactants, whose use can be associated with toxicity. A range of different cellulose to chitosan weight ratios were tested. A good encapsulation efficiency (61.0 ± 6.5%) was obtained when a high chitosan concentration was used (1:3 ratio); these nanoparticles (named NP-C) were spherical with a mean diameter of 427.1 ± 32.7 nm, 0.17 ± 0.09 PDI and +53.30 ± 0.95 mV zeta potential. NP-C dispersion remained stable for 28 days in terms of size and drug content and no captopril degradation was observed. NP-C dispersion released 70% of captopril after 2 h in pH 7.4 phosphate buffer and NP-C dispersion did not have a cytotoxicity effect on neonatal human fibroblasts except at the highest dose tested after 48 h. As a result, chitosan/cellulose nanoparticles could be considered a suitable platform for captopril delivery in paediatrics for preparing solid/liquid dosage forms. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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15 pages, 1924 KiB  
Article
P2X7 Receptor Antagonist Reduces Fibrosis and Inflammation in a Mouse Model of Alpha-Sarcoglycan Muscular Dystrophy
by Lizzia Raffaghello, Elisa Principi, Serena Baratto, Chiara Panicucci, Sara Pintus, Francesca Antonini, Genny Del Zotto, Andrea Benzi, Santina Bruzzone, Paolo Scudieri, Carlo Minetti, Elisabetta Gazzerro and Claudio Bruno
Pharmaceuticals 2022, 15(1), 89; https://doi.org/10.3390/ph15010089 - 13 Jan 2022
Cited by 11 | Viewed by 2310
Abstract
Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim [...] Read more.
Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim of this study was to evaluate the therapeutic effectiveness of a selective P2X7 purinoreceptor antagonist, A438079. Sgca knockout mice were treated with A438079 every two days at 3 mg/Kg for 24 weeks. The P2X7 antagonist improved clinical parameters by ameliorating mice motor function and decreasing serum creatine kinase levels. Histological analysis of muscle morphology indicated a significant reduction of the percentage of central nuclei, of fiber size variability and of the extent of local fibrosis and inflammation. A cytometric characterization of the muscle inflammatory infiltrates showed that A438079 significantly decreased innate immune cells and upregulated the immunosuppressive regulatory T cell subpopulation. In α-sarcoglycan null mice, the selective P2X7 antagonist A438079 has been shown to be effective to counteract the progression of the dystrophic phenotype and to reduce the inflammatory response. P2X7 antagonism via selective inhibitors could be included in the immunosuppressant strategies aimed to dampen the basal immune-mediated damage and to favor a better engraftment of gene-cell therapies. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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Review

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13 pages, 1186 KiB  
Review
The Role of Pharmaceutical Compounding in Promoting Medication Adherence
by Maria Carvalho and Isabel F. Almeida
Pharmaceuticals 2022, 15(9), 1091; https://doi.org/10.3390/ph15091091 - 31 Aug 2022
Cited by 16 | Viewed by 4784
Abstract
Pharmaceutical compounding is an important component of pharmacy practice despite its low prevalence. Several therapeutic needs can be met by a compounded medicine such as dosing adjusted for pediatric patients, special drug combinations, medicines for patients allergic to a given excipient, and medicines [...] Read more.
Pharmaceutical compounding is an important component of pharmacy practice despite its low prevalence. Several therapeutic needs can be met by a compounded medicine such as dosing adjusted for pediatric patients, special drug combinations, medicines for patients allergic to a given excipient, and medicines for orphan drugs not provided by the pharmaceutical industry. Examples of such applications are provided in this review. Adherence to medication is a critical public health issue as nonadherence to pharmacotherapy has been associated with adverse outcomes and higher costs of patient care. Adherence to therapy represents a key factor in the reduction in morbidity and mortality and optimization of the use of financial resources. The role of pharmaceutical compounding in promoting medication adherence is underexploited. The customization might represent a positive reinforcement of the initiation of the treatment, while implementation and persistence might also be favored in a pharmacy setting. However, studies addressing the influence of compounding in adherence promotion are lacking in the literature. The results of such studies could support health policies including proper regulatory framework, pharmacist training, and information to health care practitioners. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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20 pages, 4840 KiB  
Review
Nanotechnology for Pediatric Retinoblastoma Therapy
by Eleonora Russo, Andrea Spallarossa, Bruno Tasso, Carla Villa and Chiara Brullo
Pharmaceuticals 2022, 15(9), 1087; https://doi.org/10.3390/ph15091087 - 31 Aug 2022
Cited by 13 | Viewed by 2829
Abstract
Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic [...] Read more.
Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic protocols are applied. In more advanced forms of the disease, surgical removal of the entire globe and its intraocular contents (enucleation) is, unfortunately, necessary, whereas in other cases, conventional chemotherapy is normally used. To overcome the side-effects and reduced efficacy of traditional chemotherapic drugs, nanodelivery systems that ensure a sustained drug release and manage to reach the target site have more recently been developed. This review takes into account the current use and advances of nanomedicine in the treatment of retinoblastoma and discusses nanoparticulate formulations that contain conventional drugs and natural products. In addition, future developments in retinoblastoma treatment are discussed. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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36 pages, 3104 KiB  
Review
Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics
by Guendalina Zuccari, Silvana Alfei, Danilo Marimpietri, Valentina Iurilli, Paola Barabino and Leonardo Marchitto
Pharmaceuticals 2022, 15(1), 108; https://doi.org/10.3390/ph15010108 - 17 Jan 2022
Cited by 19 | Viewed by 7015
Abstract
In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. [...] Read more.
In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. Despite considerable efforts by regulatory agencies, the pediatric population is still exposed to questionable and potentially harmful practices. When designing medicines for children, the ability to fine-tune the dosage while ensuring the safety of the ingredients is of paramount importance. For these purposes solid formulations may represent a valid alternative to liquid formulations for their simpler formula and more stability, and, to overcome the problem of swelling ability, mini-tablets could be a practicable option. This review deals with the different approaches that may be applied to develop mini-tablets intended for pediatrics with a focus on the safety of excipients. Alongside the conventional method of compression, 3D printing appeared particularly appealing, as it allows to reduce the number of ingredients and to avoid both the mixing of powders and intermediate steps such as granulation. Therefore, this technique could be well adaptable to the daily galenic preparations of a hospital pharmacy, thus leading to a reduction of the common practice of off-label preparations. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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Other

11 pages, 868 KiB  
Brief Report
Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies
by Domenico Umberto De Rose, Iliana Bersani, Maria Paola Ronchetti, Fiammetta Piersigilli, Sara Cairoli, Andrea Dotta, Amit Desai, Laura Lynn Kovanda, Bianca Maria Goffredo and Cinzia Auriti
Pharmaceuticals 2023, 16(3), 472; https://doi.org/10.3390/ph16030472 - 22 Mar 2023
Cited by 1 | Viewed by 1516
Abstract
Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To [...] Read more.
Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To assess the pharmacokinetics of increased doses (8 to 15 mg/kg/day) of micafungin in preterm and term neonates with invasive candidiasis and to complete previously presented results, we analyzed the pharmacokinetic data on a total of 53 newborns treated with micafungin, whereby 3 of them had Candida meningitis and hydrocephalus. Methods: Fifty-three neonates with systemic candidiasis, three of them with meningitis, were treated for at least 14 days with intravenous micafungin (Mycamine®) at a dosage ranging from 8 to 15 mg/kg/day. Plasma and cerebrospinal fluid (CSF) concentrations of micafungin were measured before the drug administration and at 1, 2, and 8 h after the end of the infusion using high-performance liquid chromatography (HPLC). Systemic exposure was assessed according to AUC0–24, plasma clearance (CL), and half-life measured in 52/53 patients, divided by chronological age. Results and conclusions: The mean micafungin clearance is higher in neonates than in older infants (0.036 L/h/kg before 28 days of life versus 0.028 L/h/kg after 120 days). The drug half-life is shorter in neonates than in older patients (13.5 h before 28 days of life versus 14.4 h after 120 days). With doses ranging between 8 and 15 mg/kg/day, micafungin crosses the blood–brain barrier reaching therapeutic levels in CSF. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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