Pharmaceutics

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12 pages, 5047 KiB

Open AccessArticle

Medicines Acceptability in Hospitalized Children: An Ongoing Need for Age-Appropriate Formulations

by Thibault Vallet, Omar Elhamdaoui, Amina Berraho, Lalla Ouafae Cherkaoui, Yamna Kriouile, Chafiq Mahraoui, Nezha Mouane, Anne-Marie Pense-Lheritier, Fabrice Ruiz and Yahya Bensouda

Pharmaceutics 2020, 12(8), 766; https://doi.org/10.3390/pharmaceutics12080766 - 13 Aug 2020

Cited by 26 | Viewed by 3863

Abstract

Although knowledge on medicine acceptability remains fragmented, this multi-faceted concept has emerged as a key factor for compliance in pediatrics. In order to investigate the acceptability of medicines used in the University Medical Centre Ibn Sina (CHIS) of Rabat, Morocco, an observational study [...] Read more.

Although knowledge on medicine acceptability remains fragmented, this multi-faceted concept has emerged as a key factor for compliance in pediatrics. In order to investigate the acceptability of medicines used in the University Medical Centre Ibn Sina (CHIS) of Rabat, Morocco, an observational study was conducted. Using a multivariate approach integrating the many aspects of acceptability, standardized observer reports were collected for 570 medicine intakes in patients up to the age of 16, then analyzed on a reference framework. Tablets appeared to be well accepted in children greater than 6 years old, but were crushed/dissolved for 90% of the 40 children aged from 3 to 5, and 100% of the 38 patients younger than 3. Moreover, the prescribed dose was fully taken for only 52% and 16% of these younger children, respectively. Despite this, tablets represented 24% of evaluations in children from 3 to 5 and 20% in infants and toddlers. Oral liquid preparations appeared to be better accepted than tablets in preschoolers, but not for those under 3. Overall, these findings highlight the lack of suitable alternatives for the younger children, especially for formulations of antiepileptics, antithrombotic, and psycholeptic agents in the local context. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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15 pages, 3600 KiB

Open AccessArticle

Effects of Formulation Excipients on Skin Barrier Function in Creams Used in Pediatric Care

by Anita Kovács, Dóra Péter-Héderi, Katalin Perei, Mária Budai-Szűcs, Attila Léber, Attila Gácsi, Erzsébet Csányi and Szilvia Berkó

Pharmaceutics 2020, 12(8), 729; https://doi.org/10.3390/pharmaceutics12080729 - 4 Aug 2020

Cited by 11 | Viewed by 6814

Abstract

Semisolid dosage forms are recommended for the dermal care of babies and children. If we look at the ingredients of these preparations, there are still many cases in which there are substances (occlusive agents, preservatives) that no longer meet certain requirements of the [...] Read more.

Semisolid dosage forms are recommended for the dermal care of babies and children. If we look at the ingredients of these preparations, there are still many cases in which there are substances (occlusive agents, preservatives) that no longer meet certain requirements of the modern age, so it is timely to replace them with other substances. The aim of this work was to formulate a science-based formulation with new components that keep or improve its moisturizing properties, rheological parameters, and microbiological stability. Occlusive oils, like white petrolatum and liquid paraffin and the preservative parabens are traditional ingredients in oil in water creams, were replaced with white beeswax, sunflower oil, and phenoxyethanol, respectively. Cocoa butter, urea, and glycerol were added to improve long-lasting hydration and support the barrier function of the reformulated creams. The rheological properties of the formulations were determined. The effects of the preparations on skin hydration and on the barrier function of the skin were tested. Furthermore, microbiological stability was investigated. The result of the reformulation was an o/w cream that provided a good longer-lasting hydration effect; supported the barrier function of the baby skin without occlusion; and had adequate consistency, easy spreading, a pleasant skin feeling, proper pH, and good microbiological stability. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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18 pages, 331 KiB

Open AccessArticle

Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs

by John N. Van den Anker, Susan McCune, Pieter Annaert, Gerri R. Baer, Yeruk Mulugeta, Ramy Abdelrahman, Kunyi Wu, Kevin M. Krudys, Jeffrey Fisher, William Slikker, Connie Chen, Gilbert J. Burckart and Karel Allegaert

Pharmaceutics 2020, 12(7), 685; https://doi.org/10.3390/pharmaceutics12070685 - 20 Jul 2020

Cited by 21 | Viewed by 4012

Abstract

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be [...] Read more.

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

13 pages, 421 KiB

Open AccessArticle

Y-Site Physical Compatibility of Numeta G13E with Drugs Frequently Used at Neonatal Intensive Care

by Katerina Nezvalova-Henriksen, Niklas Nilsson, Camilla Tomine Østerberg, Vigdis Staven Berge and Ingunn Tho

Pharmaceutics 2020, 12(7), 677; https://doi.org/10.3390/pharmaceutics12070677 - 18 Jul 2020

Cited by 10 | Viewed by 3930

Abstract

Preterm neonates require parenteral nutrition (PN) in addition to intravenous drug therapy. Due to limited venous access, drugs are often co-administered with PN via the same lumen. If incompatible, precipitation and emulsion destabilization may occur with the consequent risk of embolism and hyper-immune [...] Read more.

Preterm neonates require parenteral nutrition (PN) in addition to intravenous drug therapy. Due to limited venous access, drugs are often co-administered with PN via the same lumen. If incompatible, precipitation and emulsion destabilization may occur with the consequent risk of embolism and hyper-immune reactions. Information on intravenous compatibility is scarce. Our aim was to analyse the compatibility of Numeta G13E with paracetamol, vancomycin and fentanyl because of the frequency of their use. A panel of methods was chosen to assess precipitation (sub-visual particle counting, turbidity measurement, Tyndall beam effect and pH measurement) and emulsion destabilization (mean droplet diameter measurement and sub-visual counting of oil droplets, followed by estimation of PFAT5 (percentage of fat residing in globules larger than 5 µm) and pH measurement). Samples in clinically relevant mixing ratios were tested immediately and after 4 h. All samples of drugs mixed with Numeta G13E were compared to unmixed controls. None of the tested drugs precipitated in contact with Numeta G13E, and we did not see any sign of emulsion destabilization when clinically relevant mixing ratios were applied. These results are reassuring. However, when contact time exceeds the established norm, caution in the form of filter utilisation and close inspection is advised. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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10 pages, 1157 KiB

Open AccessArticle

How Do Orodispersible Tablets Behave in an In Vitro Oral Cavity Model: A Pilot Study

by Neel Desai, Andrew Redfearn, Graeme MacLeod, Catherine Tuleu, Ben Hanson and Mine Orlu

Pharmaceutics 2020, 12(7), 651; https://doi.org/10.3390/pharmaceutics12070651 - 9 Jul 2020

Cited by 10 | Viewed by 4835

Abstract

Orodispersible tablets (ODTs) offer rapid disintegration of the dosage form when placed on the tongue, which leads to fast release of the active pharmaceutical ingredient. Despite increased use in diverse patient populations, there have been numerous challenges associated with ODTs. One such concern [...] Read more.

Orodispersible tablets (ODTs) offer rapid disintegration of the dosage form when placed on the tongue, which leads to fast release of the active pharmaceutical ingredient. Despite increased use in diverse patient populations, there have been numerous challenges associated with ODTs. One such concern is the lack of standardised assessment of disintegration behaviour. In the European Pharmacopoeia, ‘orodispersibles’ are defined as such if disintegration time is faster than 3 min. Common in vitro measurement methods only provide single time point data and have limited physiological accuracy. To determine more bio-predictive disintegration kinetics, a bench-top in vitro oral cavity model (OCM) was modified and piloted to assess disintegration of three ODTs of differing hardness. All ODTs disintegrated similarly within the OCM—surface breakdown/swelling, initial ‘wash away’ and final ‘wash away’. The distinct advantage presented within this pilot study using the OCM is the opportunity to ascertain disintegration behaviour profiles of ODTs by evaluating changes in the observable area during simulated oral processing. The model could be implemented as a decision-support tool during the early stages of the drug design process to improve acceptability and further understand ODT disintegration behaviour. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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16 pages, 1143 KiB

Open AccessArticle

Manipulation of Medicinal Products for Oral Administration to Paediatric Patients at a German University Hospital: An Observational Study

by Julia Zahn, André Hoerning, Regina Trollmann, Wolfgang Rascher and Antje Neubert

Pharmaceutics 2020, 12(6), 583; https://doi.org/10.3390/pharmaceutics12060583 - 23 Jun 2020

Cited by 32 | Viewed by 4544

Abstract

Pharmacotherapy in children requires medicinal products in age-appropriate dosage forms and flexible dose strengths. Healthcare professionals often encounter a lack of licensed and commercially available formulations, which results in the need for manipulation. This study aimed to investigate the nature, frequency and preventability [...] Read more.

Pharmacotherapy in children requires medicinal products in age-appropriate dosage forms and flexible dose strengths. Healthcare professionals often encounter a lack of licensed and commercially available formulations, which results in the need for manipulation. This study aimed to investigate the nature, frequency and preventability of the manipulation of medicinal products before oral drug administration to paediatric inpatients in Germany. A prospective, direct observational approach was used. Two thousand and three medication preparation processes (MPP) in 193 patients were included in the analysis. Medicines were manipulated in 37% of oral administrations, affecting 57% of the patients. The percentage of manipulations was highest in infants/toddlers (42%) and lowest in adolescents (31%). Antiepileptics were most frequently manipulated (27%), followed by vitamins (20%) and drugs for acid-related disorders (13%). Fifty-six per cent of all manipulations were off-label. In 71% of these, no alternative appropriate medicinal product was commercially available. These results demonstrate that the manipulation of medicinal products before oral administration is common in paediatric wards in Germany. About half of the manipulations were off-label, indicating that no suitable formulation was available. Evidence-based guidelines for manipulations are required, with the overall aim of improving the safety of paediatric drug therapy. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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13 pages, 460 KiB

Open AccessArticle

Comparing Two Methods of Tablet Manipulation to Adjust the Warfarin Dose in Paediatric Care

by Jørgen Brustugun, Elisabeth Birkedal Aas, Ingunn Tho and Kathrin Bjerknes

Pharmaceutics 2020, 12(4), 375; https://doi.org/10.3390/pharmaceutics12040375 - 18 Apr 2020

Cited by 2 | Viewed by 3300

Abstract

Tablets containing prescribed doses are not always available, and this is of particular importance in paediatric care where suitable age-appropriate formulations are generally lacking. To obtain a child-adjusted dose, tablets are manipulated in several ways; e.g., they may be dispersed in water before [...] Read more.

Tablets containing prescribed doses are not always available, and this is of particular importance in paediatric care where suitable age-appropriate formulations are generally lacking. To obtain a child-adjusted dose, tablets are manipulated in several ways; e.g., they may be dispersed in water before a fraction is extracted, or they may be split before the resulting fragment is dispersed. In this study, the accuracy attained through these manipulation methods was investigated for two generic tablets containing the anticoagulant warfarin. Tablets were dispersed in water (10 mL) before a fraction (10%) was withdrawn, alternatively tablets were split in half or quarter fragments before the fragments were dispersed in water. To investigate the contribution of variability from the different steps in the manipulation processes, the amount of warfarin recovered from the various dispersions was determined, as was the accuracy of the splitting. A validated UHPLC-method was used for quantitative determination of warfarin. Splitting of the tablets could result in deviation >30% from the ideal, theoretical weight. The amount of drug substance extracted as a fraction from the dispersed tablets deviated no more than 10% from the intended amount. To obtain the most accurate child-adjusted fraction dose of warfarin, the tablets investigated in this study should be dispersed and the desired proportion extracted. Practices that involve splitting tablets are likely to increase the variation, and should be avoided. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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20 pages, 2790 KiB

Open AccessArticle

Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms

by Alison V. Keating, Jessica Soto, Claire Forbes, Min Zhao, Duncan Q. M. Craig and Catherine Tuleu

Pharmaceutics 2020, 12(4), 369; https://doi.org/10.3390/pharmaceutics12040369 - 17 Apr 2020

Cited by 17 | Viewed by 4028

Abstract

The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two [...] Read more.

The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two in vivo (a human taste panel and a rat brief-access taste aversion (BATA) model) and one in vitro (sensor) method. The response of the Insent TS-5000Z electronic tongue was compared to the in vivo drug concentration found to elicit and suppress half the maximum taste response (EC₅₀ in human and IC₅₀ in rats). Using dose-relevant concentrations, an overarching rank order of bitterness was derived (rifampicin > ethambutol > pyrazinamid~isoniazid). In vitro, only ethambutol exhibited a linear response for all sensors/concentrations. Based on the EC₅₀/IC₅₀ generated, a ‘taste index’ was proposed to allow for anticipation of the likelihood of taste issues in practice, taking in account the saturability in the saliva and therapeutic doses; ethambutol and isoniazid were found to be the worst tasting using this measure. The study presents the first quantitative taste analysis of these life-saving drugs and has allowed for a comparison of three methods of obtaining such data. Such information allows the operator to identify and prioritise the drugs requiring taste masking to produce palatable formulations. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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12 pages, 1319 KiB

Open AccessArticle

Extended Pharmacopeial Characterization of Surfactant Aerosols Generated by a Customized eFlow Neos Nebulizer Delivered through Neonatal Nasal Prongs

by Federico Bianco, Elena Pasini, Marcello Nutini, Xabier Murgia, Carolin Stoeckl, Martin Schlun, Uwe Hetzer, Sauro Bonelli, Marta Lombardini, Ilaria Milesi, Marisa Pertile, Stephan Minocchieri, Fabrizio Salomone and Albert Bucholski

Pharmaceutics 2020, 12(4), 319; https://doi.org/10.3390/pharmaceutics12040319 - 2 Apr 2020

Cited by 16 | Viewed by 3496

Abstract

The delivery of nebulized medications to preterm infants during Non-Invasive Ventilation (NIV) remains an unmet clinical need. In this regard, the effective delivery of nebulized surfactant has been particularly investigated in preclinical and clinical studies. In this work, we investigated the feasibility of [...] Read more.

The delivery of nebulized medications to preterm infants during Non-Invasive Ventilation (NIV) remains an unmet clinical need. In this regard, the effective delivery of nebulized surfactant has been particularly investigated in preclinical and clinical studies. In this work, we investigated the feasibility of delivering nebulized surfactant through various commercially available nasal prong types. We first performed a compendial characterization of surfactant aerosols generated by the eFlow Neos nebulizer, customized to be used in neonates, determining the amount of surfactant delivered by the device as well as the aerodynamic characteristics of surfactant aerosols. Additionally, we extended the compendial characterization by testing the effect of different nasal prong types on the estimated lung dose using a realistic Continuous Positive Airway Pressure (CPAP) circuit that included a cast of the upper airways of a preterm neonate. The compendial characterization of surfactant aerosols delivered through different nasal prongs achieved relatively high delivered surfactant doses (in the range 63–74% of the nominal dose), with aerodynamic characteristics displaying mass median aerodynamic diameters ranging between 2.52 and 2.81 µm. Nevertheless, when using a representative in vitro setup mimicking NIV in a clinical setting, significant differences were observed in terms of the estimated lung dose accounting for up to two-fold differences (from 10% to 20% estimated lung deposition of the nominal dose) depending on the chosen nasal prong type. Considering that surfactant lung deposition rates are correlated with therapeutic efficacy, this study points out the relevance of choosing the appropriate NIV interface to maximize the lung dose of nebulized medications. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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12 pages, 1332 KiB

Open AccessArticle

In Vitro Performance of an Investigational Vibrating-Membrane Nebulizer with Surfactant under Simulated, Non-Invasive Neonatal Ventilation Conditions: Influence of Continuous Positive Airway Pressure Interface and Nebulizer Positioning on the Lung Dose

by Federico Bianco, Elena Pasini, Marcello Nutini, Xabier Murgia, Carolin Stoeckl, Martin Schlun, Uwe Hetzer, Sauro Bonelli, Marta Lombardini, Ilaria Milesi, Marisa Pertile, Stefan Minocchieri, Fabrizio Salomone and Albert Bucholski

Pharmaceutics 2020, 12(3), 257; https://doi.org/10.3390/pharmaceutics12030257 - 12 Mar 2020

Cited by 11 | Viewed by 4279

Abstract

Non-invasive delivery of nebulized surfactant has been a long-pursued goal in neonatology. Our aim was to evaluate the performance of an investigational vibrating-membrane nebulizer in a realistic non-invasive neonatal ventilation circuit with different configurations. Surfactant (aerosols were generated with a nebulizer in a [...] Read more.

Non-invasive delivery of nebulized surfactant has been a long-pursued goal in neonatology. Our aim was to evaluate the performance of an investigational vibrating-membrane nebulizer in a realistic non-invasive neonatal ventilation circuit with different configurations. Surfactant (aerosols were generated with a nebulizer in a set-up composed of a continuous positive airway pressure (CPAP) generator with a humidifier, a cast of the upper airway of a preterm infant (PrINT), and a breath simulator with a neonatal breathing pattern. The lung dose (LD), defined as the amount of surfactant collected in a filter placed at the distal end of the PrINT cast, was determined after placing the nebulizer at different locations of the circuit and using either infant nasal mask or nasal prongs as CPAP interfaces. The LD after delivering a range of nominal surfactant doses (100–600 mg/kg) was also investigated. Surfactant aerosol particle size distribution was determined by laser diffraction. Irrespective of the CPAP interface used, about 14% of the nominal dose (200 mg/kg) reached the LD filter. However, placing the nebulizer between the Y-piece and the CPAP interface significantly increased the LD compared with placing it 7 cm before the Y-piece, in the inspiratory limb. (14% ± 2.8 vs. 2.3% ± 0.8, nominal dose of 200 mg/kg). The customized eFlow Neos showed a constant aerosol generation rate and a mass median diameter of 2.7 μm after delivering high surfactant doses (600 mg/kg). The customized eFlow Neos nebulizer showed a constant performance even after nebulizing high doses of undiluted surfactant. Placing the nebulizer between the Y-piece and the CPAP interface achieves the highest LD under non-invasive ventilation conditions. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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15 pages, 4814 KiB

Open AccessArticle

Technology of Orodispersible Polymer Films with Micronized Loratadine—Influence of Different Drug Loadings on Film Properties

by Katarzyna Centkowska, Elżbieta Ławrecka and Malgorzata Sznitowska

Pharmaceutics 2020, 12(3), 250; https://doi.org/10.3390/pharmaceutics12030250 - 10 Mar 2020

Cited by 36 | Viewed by 4036

Abstract

The production of orodispersible films (ODFs) with suspended insoluble drug substances is still a challenge, mainly due to the difficulty associated with achieving a proper homogeneity and mechanical properties of the films. Hypromellose (HPMC) and a mixture of polyvinyl alcohol (AP) and povidone [...] Read more.

The production of orodispersible films (ODFs) with suspended insoluble drug substances is still a challenge, mainly due to the difficulty associated with achieving a proper homogeneity and mechanical properties of the films. Hypromellose (HPMC) and a mixture of polyvinyl alcohol (AP) and povidone (PVP) were compared in terms of their suitability for ODFs incorporating suspended micronized loratadine (LO) in a concentration range of 10%–40%. In a planetary mixer (Thinky), a uniform dispersion of LO in an aqueous viscous casting solution was obtained. The suspended LO particles caused dose-dependent changes in the viscosity of the casting mass and affected the mechanical quality of ODFs. Drug concentrations higher than 30% reduced the film flexibility and tear resistance, depending on the polymer type. LO films with a thickness of 100 µm disintegrated within 60-100 s, with no significant influence of the LO content in the range 10%–30%. HPMC films, regardless of the drug concentration, met the pharmacopoeial requirements regarding the uniformity of the drug content. AP/PVP films were too elastic, and the drug content uniformity was not achieved. The conclusion is that, using an HPMC matrix, it is possible to obtain a high load of a poorly water-soluble drug (30% of dry film mass corresponds to a dose of 5 mg per 1.5 cm²) in ODFs characterized by proper physical characteristics. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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11 pages, 1055 KiB

Open AccessArticle

Benefits and Prerequisites Associated with the Adoption of Oral 3D-Printed Medicines for Pediatric Patients: A Focus Group Study among Healthcare Professionals

by Maria Rautamo, Kirsi Kvarnström, Mia Sivén, Marja Airaksinen, Pekka Lahdenne and Niklas Sandler

Pharmaceutics 2020, 12(3), 229; https://doi.org/10.3390/pharmaceutics12030229 - 5 Mar 2020

Cited by 37 | Viewed by 5123

Abstract

The utilization of three-dimensional (3D) printing technologies as innovative manufacturing methods for drug products has recently gained growing interest. From a technological viewpoint, proof-of-concept on the performance of different printing methods already exist, followed by visions about future applications in hospital or community [...] Read more.

The utilization of three-dimensional (3D) printing technologies as innovative manufacturing methods for drug products has recently gained growing interest. From a technological viewpoint, proof-of-concept on the performance of different printing methods already exist, followed by visions about future applications in hospital or community pharmacies. The main objective of this study was to investigate the perceptions of healthcare professionals in a tertiary university hospital about oral 3D-printed medicines for pediatric patients by means of focus group discussions. In general, the healthcare professionals considered many positive aspects and opportunities in 3D printing of pharmaceuticals. A precise dose as well as personalized doses and dosage forms were some of the advantages mentioned by the participants. Especially in cases of polypharmacy, incorporating several drug substances into one product to produce a polypill, personalized regarding both the combination of drug substances and the doses, would benefit drug treatments of several medical conditions and would improve adherence to medications. In addition to the positive aspects, concerns and prerequisites for the adoption of 3D printing technologies at hospital settings were also expressed. These perspectives are suggested by the authors to be focus points for future research on personalized 3D-printed drug products. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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11 pages, 2303 KiB

Open AccessArticle

Preparations of Rectal Suppositories Containing Artesunate

by Suzanne Persaud, Sandra Eid, Natalia Swiderski, Ioannis Serris and Hyunah Cho

Pharmaceutics 2020, 12(3), 222; https://doi.org/10.3390/pharmaceutics12030222 - 2 Mar 2020

Cited by 32 | Viewed by 7484

Abstract

Rectal artesunate suppositories are a useful option for pre-referral treatment of severe malaria, specifically in children under 6 years of age in remote malaria-endemic areas. The main challenges are to improve the solubility of drugs in the rectal fluids and prevent the product [...] Read more.

Rectal artesunate suppositories are a useful option for pre-referral treatment of severe malaria, specifically in children under 6 years of age in remote malaria-endemic areas. The main challenges are to improve the solubility of drugs in the rectal fluids and prevent the product from turning rancid or melting in a tropical climate. In this short proof-of-concept study, three types of rectal suppositories of artesunate were prepared: (i) polyethylene glycol (PEG)-based suppositories carrying free artesunate (non-modified artesunate), (ii) PEG-based suppositories carrying artesunate-loaded micelles and (iii) 3D-printed suppositories carrying a PEG/artesunate mixture. Physical parameters of suppositories, release profiles of artesunate (the fastest to the slowest: ii≥i>iii) and thermostability (the most stable to the least stable: iii>ii>i) of suppositories at increased temperature were assessed to determine the advantages and disadvantages of each formulation. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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13 pages, 1928 KiB

Open AccessArticle

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics

by Ana Santoveña-Estévez, Javier Suárez-González, Amor R. Cáceres-Pérez, Zuleima Ruiz-Noda, Sara Machado-Rodríguez, Magdalena Echezarreta, Mabel Soriano and José B. Fariña

Pharmaceutics 2020, 12(2), 195; https://doi.org/10.3390/pharmaceutics12020195 - 24 Feb 2020

Cited by 13 | Viewed by 4962

Abstract

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) [...] Read more.

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-β-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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10 pages, 338 KiB

Open AccessArticle

A Pediatrics Utilization Study in The Netherlands to Identify Active Pharmaceutical Ingredients Suitable for Inkjet Printing on Orodispersible Films

by J. Carolina Visser, Lisa Wibier, Olga Kiefer, Mine Orlu, Jörg Breitkreutz, Herman J. Woerdenbag and Katja Taxis

Pharmaceutics 2020, 12(2), 164; https://doi.org/10.3390/pharmaceutics12020164 - 17 Feb 2020

Cited by 15 | Viewed by 4244

Abstract

Background: The use of medication in pediatrics, children aged 0–5 years, was explored so as to identify active pharmaceutical ingredients (APIs) suitable for inkjet printing on a plain orodispersible film (ODF) formulation in a pharmacy. Methods: The database IADB.nl, containing pharmacy dispensing data [...] Read more.

Background: The use of medication in pediatrics, children aged 0–5 years, was explored so as to identify active pharmaceutical ingredients (APIs) suitable for inkjet printing on a plain orodispersible film (ODF) formulation in a pharmacy. Methods: The database IADB.nl, containing pharmacy dispensing data from community pharmacies in the Netherlands, was used to explore medication use in the age group of 0–5 years old, based on the Anatomical Therapeutic Chemical classification code (ATC code). Subsequently, a stepwise approach with four exclusion steps was used to identify the drug candidates for ODF formulation development. Results: there were 612 Active Pharmaceutical Ingredients (APIs) that were dispensed to the target group, mostly antibiotics. Of the APIs, 221 were not registered for pediatrics, but were used off-label. After the exclusion steps, 34 APIs were examined regarding their suitability for inkjet printing. Almost all of the APIs were sparingly water soluble to practically insoluble. Conclusion: Pharmaceutical inkjet printing is a suitable new technique for ODF manufacturing for pediatric application, however the maximal printed dose as found in the literature remained low. From the selected candidates, only montelukast shows a sufficiently high water-solubility to prepare a water-based solution. To achieve higher drug loads per ODF is ambitious, but is theoretically possible by printing multiple layers, using highly water-soluble APIs or highly loaded suspensions. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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13 pages, 545 KiB

Open AccessArticle

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

by Maria Rautamo, Kirsi Kvarnström, Mia Sivén, Marja Airaksinen, Pekka Lahdenne and Niklas Sandler

Pharmaceutics 2020, 12(2), 109; https://doi.org/10.3390/pharmaceutics12020109 - 30 Jan 2020

Cited by 25 | Viewed by 7958

Abstract

Oral drug administration to pediatric patients is characterized by a lack of age-appropriate drug products and the off-label use of medicines. However, drug administration practices at hospital wards is a scarcely studied subject. The aim of this study was to explore the oral [...] Read more.

Oral drug administration to pediatric patients is characterized by a lack of age-appropriate drug products and the off-label use of medicines. However, drug administration practices at hospital wards is a scarcely studied subject. The aim of this study was to explore the oral drug administration practices at pediatric hospital wards, with a focus on experiences and challenges faced, methods used to mitigate existing problems, drug manipulation habits, perceptions about oral dosage forms and future needs of oral dosage forms for children. This was a qualitative study consisting of focus group discussions with physicians, nurses and clinical pharmacists in a tertiary university hospital with the objective of bringing forward a holistic view on this research topic. These healthcare professionals recognized different administration challenges that were classified as either dosage form-related or patient-related ones. A lack of depot formulations developed especially for children as well as oral pediatric dosage forms of drug substances currently available as intravenous dosage forms was recognized. The preferred oral dosage forms were oral liquids and orodispersible tablets. Patient-centered drug administration practices including factors facilitating drug administration both at hospital wards and at home after patient discharge were identified. Among all healthcare professionals, the efficient cooperation in drug prescribing and administration as well as in educating the child’s caregivers in correct administration techniques before discharge and improving the overall discharge process of patients was emphasized. This study complements the prevalent understanding that new dosage forms for children of varying ages and stages of development are still needed. It also brings a holistic view on different aspects of oral drug administration to pediatric patients and overall patient-centered drug administration practices. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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16 pages, 945 KiB

Open AccessArticle

Classification of WHO Essential Oral Medicines for Children Applying a Provisional Pediatric Biopharmaceutics Classification System

by Jose-Manuel delMoral-Sanchez, Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez, Andres Navarro and Marival Bermejo

Pharmaceutics 2019, 11(11), 567; https://doi.org/10.3390/pharmaceutics11110567 - 31 Oct 2019

Cited by 30 | Viewed by 5776

Abstract

The objective was using the Essential Medicines List for children by the World Health Organization (WHO) to create a pediatric biopharmaceutics classification system (pBCS) of the oral drugs included in the Essential Medicines List by the World Health Organization and to compare our [...] Read more.

The objective was using the Essential Medicines List for children by the World Health Organization (WHO) to create a pediatric biopharmaceutics classification system (pBCS) of the oral drugs included in the Essential Medicines List by the World Health Organization and to compare our results with the BCS for adults (aBCS). Several methods to estimate the oral drug dose in different pediatric groups were used to calculate dose number (Do) and solubility (high/low). The estimation of the gastrointestinal water volume was adapted to each pediatric group. Provisional permeability classification was done by comparison of each drug lipophilicity versus metoprolol as the model drug of high permeability. As a result, 24.5% of the included drugs moved from the favorable to unfavorable class (i.e., from high to low solubility). Observed changes point out potential differences in product performance in pediatrics compared to adults, due to changes in the limiting factors for absorption. BCS Class Changes 1 to 2 or 3 to 4 are indicative of drugs that could be more sensitive to the choice of appropriate excipient in the development process. Validating a pBCS for each age group would provide a valuable tool to apply in specific pediatric formulation design by reducing time and costs and avoiding unnecessary pediatric experiments restricted due to ethical reasons. Additionally, pBCS could minimize the associated risks to the use of adult medicines or pharmaceutical compound formulations. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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Review

Jump to: Research, Other

17 pages, 1538 KiB

Open AccessReview

Availability of Authorizations from EMA and FDA for Age-Appropriate Medicines Contained in the WHO Essential Medicines List for Children 2019

by Jose-Manuel delMoral-Sanchez, Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez, Andres Navarro-Ruiz and Marival Bermejo

Pharmaceutics 2020, 12(4), 316; https://doi.org/10.3390/pharmaceutics12040316 - 1 Apr 2020

Cited by 22 | Viewed by 4210

Abstract

Lack of age-appropriate commercially drug products availability is a common problem in pediatric therapeutics; this population needs improved and safer drug delivery. In addition, biopharmaceutic aspects, dosage requirements, and swallowing abilities demand pediatric forms different to adult formulations. The objective of this study [...] Read more.

Lack of age-appropriate commercially drug products availability is a common problem in pediatric therapeutics; this population needs improved and safer drug delivery. In addition, biopharmaceutic aspects, dosage requirements, and swallowing abilities demand pediatric forms different to adult formulations. The objective of this study was to evaluate the authorization availability from United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) of oral essential medicines for children and analyze its age-appropriateness for oral administration in children. All oral drugs from 7th List of Essential Medicines for Children by World Health Organization (WHO) were selected. Availability of commercial drug products was collected from OrangeBook, Spanish drug product catalogue, British electronic Medicines Compendium, and the International Vademecum. Tablets, effervescent tablets, and capsules were considered as not age-appropriate forms. Liquid forms, powder for oral suspension, mini tablets, granules, and soluble films were considered as age-appropriate forms due to their flexibility. More than 80% of the studied drugs possess a commercial authorization in oral forms in both EMA and FDA. Nevertheless, around 50% of these formulations are not age-appropriate for most pediatric groups. This study shows the lack of age-appropriate medicines for children. More efforts are needed to improve development and approval of pediatric medicines. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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23 pages, 1152 KiB

Open AccessReview

Patient Centric Pharmaceutical Drug Product Design—The Impact on Medication Adherence

by Enrica Menditto, Valentina Orlando, Giuseppe De Rosa, Paola Minghetti, Umberto Maria Musazzi, Caitriona Cahir, Marta Kurczewska-Michalak, Przemysław Kardas, Elísio Costa, José Manuel Sousa Lobo and Isabel F Almeida

Pharmaceutics 2020, 12(1), 44; https://doi.org/10.3390/pharmaceutics12010044 - 3 Jan 2020

Cited by 82 | Viewed by 11187

Abstract

Medication adherence is a growing concern for public health and poor adherence to therapy has been associated with poor health outcomes and higher costs for patients. Interventions for improving adherence need to consider the characteristics of the individual therapeutic regimens according to the [...] Read more.

Medication adherence is a growing concern for public health and poor adherence to therapy has been associated with poor health outcomes and higher costs for patients. Interventions for improving adherence need to consider the characteristics of the individual therapeutic regimens according to the needs of the patients. In particular, geriatric and paediatric populations as well as dermatological patients have special needs/preferences that should be considered when designing drug products. Patient Centric Drug Product Pharmaceutical Design (PCDPD) offers the opportunity to meet the needs and preferences of patients. Packaging, orodispersible formulations, fixed dose combinations products, multiparticulate formulations, topical formulations and 3D printing are of particular relevance in a PCDPD process. These will be addressed in this review as well as their impact on medication adherence. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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11 pages, 437 KiB

Open AccessReview

Innovations in Pediatric Drug Formulations and Administration Technologies for Low Resource Settings

by Stephen E. Gerrard, Jennifer Walsh, Niya Bowers, Smita Salunke and Susan Hershenson

Pharmaceutics 2019, 11(10), 518; https://doi.org/10.3390/pharmaceutics11100518 - 8 Oct 2019

Cited by 35 | Viewed by 8795

Abstract

Despite advances in regulations and initiatives to increase pediatric medicine development, there is still an unmet need for age-appropriate medicines for children. The availability of pediatric formulations is particularly lacking in resource poor areas, due to, for example, area-specific disease burden and financial [...] Read more.

Despite advances in regulations and initiatives to increase pediatric medicine development, there is still an unmet need for age-appropriate medicines for children. The availability of pediatric formulations is particularly lacking in resource poor areas, due to, for example, area-specific disease burden and financial constraints, as well as disconnected supply chains and fragmented healthcare systems. The paucity of authorized pediatric medicines often results in the manipulation and administration of products intended for adults, with an increased risk of mis-dosing and adverse reactions. This article provides an overview of the some of the key difficulties associated with the development of pediatric medicines in both high and low resource areas, and highlights shared and location specific challenges and opportunities. The utilization of dispersible oral dosage forms and suppositories for low and middle-income countries (LMICs) are described in addition to other platform technologies that may in the future offer opportunities for future pediatric medicine development for low resource settings. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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