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In recent years, the continuous development of innovative nanopharmaceuticals is expanding their biomedical and clinical applications. Nanomedicines are being revolutionized to circumvent the limitations of unbound therapeutic agents as well as overcome barriers posed by biological interfaces at the cellular, organ, system, and microenvironment levels. In many ways, the use of nanoconfigured delivery systems has eased challenges associated with patient differences, and in our opinion, this forms the foundation for their potential usefulness in developing innovative medicines and diagnostics for special patient populations. Here, we present a comprehensive review of nanomedicines specifically designed and evaluated for disease management in the pediatric population. Typically, the pediatric population has distinguishing needs relative to those of adults majorly because of their constantly growing bodies and age-related physiological changes, which often need specialized drug formulation interventions to provide desirable therapeutic effects and outcomes. Besides, child-centric drug carriers have unique delivery routes, dosing flexibility, organoleptic properties (e.g., taste, flavor), and caregiver requirements that are often not met by traditional formulations and can impact adherence to therapy. Engineering pediatric medicines as nanoconfigured structures can potentially resolve these limitations stemming from traditional drug carriers because of their unique capabilities. Consequently, researchers from different specialties relentlessly and creatively investigate the usefulness of nanomedicines for pediatric disease management as extensively captured in this compilation. Some examples of nanomedicines covered include nanoparticles, liposomes, and nanomicelles for cancer; solid lipid and lipid-based nanostructured carriers for hypertension; self-nanoemulsifying lipid-based systems and niosomes for infections; and nanocapsules for asthma pharmacotherapy.

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The paucity of suitable drug formulations for pediatric patients generates a need for customized, compounded medications. This research study was set out to comprehensively analyze the physical properties of the new, proprietary anhydrous oral vehicle SuspendIt® Anhydrous, which was designed for compounding pediatric oral liquids. A wide range of tests was used, including sedimentation volume, viscosity, droplet size after dispersion in simulated gastric fluid, microscopic examination and content uniformity measurements to evaluate the properties of the anhydrous vehicle. The results showed that the vehicle exhibited consistent physical properties under varying conditions and maintained stability over time. This can be attributed to the unique blend of excipients in its formulation, which not only maintain its viscosity but also confer thixotropic behavior. The unique combination of viscous, thixotropic and self-emulsifying properties allows for rapid redispersibility, sedimentation stability, accurate dosing, potential drug solubility, dispersion and promotion of enhanced gastrointestinal distribution and absorption. Furthermore, the vehicle demonstrated long-term sedimentation stability and content uniformity for a list of 13 anhydrous suspensions. These results suggest that the anhydrous oral vehicle could serve as a versatile base for pediatric formulation, potentially filling an important gap in pediatric drug delivery. Future studies can further investigate its compatibility, stability and performance with other drugs and in different clinical scenarios.

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Apnea of prematurity can be treated with a body-weight-adjusted dosage of caffeine. Semi-solid extrusion (SSE) 3D printing represents an interesting approach to finely tailor personalized doses of active ingredients. To improve compliance and ensure the right dose in infants, drug delivery systems such as oral solid forms (orodispersible film, dispersive form, and mucoadhesive form) can be considered. The aim of this work was to obtain a flexible-dose system of caffeine by SSE 3D printing by testing different excipients and printing parameters. Gelling agents (sodium alginate (SA) and hydroxypropylmethyl cellulose (HPMC)) were used to obtain a drug-loaded hydrogel matrix. Disintegrants (sodium croscarmellose (SC) and crospovidone (CP)) were tested for get rapid release of caffeine. The 3D models were patterned by computer-aided design with variable thickness, diameter, infill densities, and infill patterns. The oral forms produced from the formulation containing 35% caffeine, 8.2% SA, 4.8% HPMC, and 52% SC (w/w) were found to have good printability, achieving doses approaching to those used in neonatology (between 3 and 10 mg of caffeine for infants weighing approximately between 1 and 4 kg). However, disintegrants, especially SC, acted more as binder/filler, showing interesting properties to maintain the shape after extrusion and enhance printability without a significant effect on caffeine release.

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In an effort to combine a child-friendly dosage form for medication administration in hospitalized pediatric patients and a user-friendly automated process for its preparation by health-care providers, the current study proposes a method for drug administration with breakfast using semi-solid extrusion 3D printing. Cereal was used as the platform carrier of the hydrophobic ibuprofen and the hydrophilic paracetamol to develop the drug loaded cereal ink. Rheological analysis was performed to identify the cereal ink with optimum viscosity for extrusion printing. Drug distribution and crystallinity within the printed cereal were assessed with confocal Raman microscopy and thermal and X-ray diffraction analysis, respectively, indicating molecular dispersion of both drugs within the cereal. High cereal porosity was associated with a higher milk absorption capacity and a decrease in their flexural force upon immersion in milk. Dissolution studies were performed in biorelevant media under fasted and fed state conditions and in the presence of full-fat and low-fat milk showing dissolution enhancement of the poorly soluble ibuprofen in the presence of the higher fat content milk. Concealing drug administration under the auspice of this essential daily eating habit is expected to facilitate overcoming adherence barriers to medication intake by pediatric patients within a hospital setting.

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INTRODUCTION: Child appropriate dosage forms are indispensable in modern medicine and are a prerequisite for successful pediatric drug therapy. For years, experts have called for a paradigm shift, from liquid dosage forms to novel oral solid dosage forms. This review aims to shed light on recent developments in Orodispersible tablets (ODTs) and mini-tablets (ODMTs). AREAS COVERED: This review focuses on the presentation and critical discussion of current challenges as well as recent advances in ODTs for pediatric drug delivery. Highlighted aspects are the evidence for acceptability by children, e.g. in comparison to other dosage forms, and limitations given by tablet size at different ages, as well as advances in special ODT formulations (taste masking, modified release, enabling formulations). EXPERT OPINION: It is the authors' belief that OD(M)Ts have significant potential as dosage forms in pediatric therapy that has not yet been fully exploited. The reasons for this are, first, that the number of direct acceptance studies is extremely low and the resulting knowledge is therefore rather anecdotal. Despite the high relevance, there seems to be reluctance both in the therapeutic use and conduction of respective studies in children. However, if one combines the knowledge from the few existing studies, surveys, and from approved products, it becomes apparent that so far there is no evidence on limitations of the use of ODTs in pediatric patients.

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3D printed pharmaceuticals offers the potential to manufacture personalized medicines for patients. Such technology is of particular benefit to pediatric populations from the offer of increased patient compliance and dose flexibility. With a bench-to-patient approach, this study established and optimized the critical parameters of the semi-solid micro-extrusion 3D printing process to guarantee the quality attributes of the final dosage form. Pediatrics orodispersible printlets of hydrochlorothiazide were manufactured through the modification of printing parameters, as well as printing surfaces materials. The printlets were characterized and the dimensions were measured using a digital caliper and computer vision algorithm. This study identified that the printing surface material and the first printing layer are critical parameters for high-resolution printlets. Following the optimization of 3D printing parameters, high quality orodispersible printlets loaded with hydrochlorothiazide - specifically tailored for pediatric patient's dosage forms - were obtained (4.62 mm × 1.90 mm). Mass and content uniformity assays demonstrated that the printlets satisfied the requirements for orodispersible printlets set by the European Pharmacopoeia. As such, in order to transition from laboratory research towards the treatment of patients, distinguishing accurate 3D printing parameters is necessary for the manufacture of medicines with key quality attributes that follow Pharmacopoeia requirements.

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Multiple considerations are essential to address the main challenges of dose flexibility and patient adherence in pediatric drug development, particularly for oncology. Mini-tablets, 2 mm in diameter, were manufactured using a rotary tablet press at a set weight and compression force level. The physical characteristics were consistent for mini-tablets throughout multiple batches. Polymeric amorphous solid dispersion (ASD) was used as a solubility enhancing technique to increase solubility and exposure of lapatinib. The effects of the polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellulose E3 (HPMCE3) formulation provided a higher percentage of drug release compared to hydroxypropyl methylcellulose phthalate (HPMCP). The intermolecular interaction within the ASD system plays a role in the level of apparent solubility, physical stability, and concentration of free drug available in an aqueous environment. Juvenile porcine models at two different weight groups (10 and 20 kg) were used to obtain the pharmacokinetic parameters of lapatinib. While the dose-normalized exposure of drug was found to be lower in the pig study, the dose flexibility of mini-tablets enabled a constant dose level to be administered to achieve equivalent plasma concentration-time profiles between the two groups. This linear scaling in the amount of drug in pediatric and adult population has also been observed in human clinical studies.

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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.

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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.

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Child-appropriate dosage forms are critical in promoting adherence and effective pharmacotherapy in pediatric patients, especially those undergoing long-term treatment in low-resource settings. The present study aimed to develop orodispersible films (ODFs) for isoniazid administration to children exposed to tuberculosis. The ODFs were produced from the aqueous solutions of natural and semi-synthetic polymer blends using electrospinning. The spinning solutions and the resulting fibers were physicochemically characterized, and the disintegration time and isoniazid release from the ODFs were assessed in simulated salivary fluid. The ODFs comprised of nanofibers with adequate thermal stability and possible drug amorphization. Film disintegration occurred instantly upon contact with simulated salivary fluid within less than 15 s, and isoniazid release from the ODFs in the same medium followed after the disintegration profiles, achieving rapid and total drug release within less than 60 s. The ease of administration and favorable drug loading and release properties of the ODFs may provide a dosage form able to facilitate proper adherence to treatment within the pediatric patient population.

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Tuberculosis (TB) is a major cause of childhood death. Despite the startling statistics, it is neglected globally as evidenced by treatment and clinical care schemes, mostly extrapolated from studies in adults. The objective of this study was to formulate and evaluate a reconstitutable dry suspension (RDS) containing isoniazid, a first-line anti-tubercular agent used in the treatment and prevention of TB infection in both children and adults. The RDS formulation was prepared by direct dispersion emulsification of an aqueous-lipid particulate interphase coupled with lyophilization and dry milling. The RDS appeared as a cream-white free-flowing powder with a semi-crystalline and microparticulate nature. Isoniazid release was characterized with an initial burst up to 5 minutes followed by a cumulative release of 67.88% ± 1.88% (pH 1.2), 60.18% ± 3.33% (pH 6.8), and 49.36% ± 2.83% (pH 7.4) over 2 hours. An extended release at pH 7.4 and 100% drug liberation was achieved within 300 minutes. The generated release profile best fitted the zero order kinetics (R2 = 0.976). RDS was re-dispersible and remained stable in the dried and reconstituted states over 4 months and 11 days, respectively, under common storage conditions.

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The aim of the current study was the development of pediatric-friendly 3D printed chocolate-based oral dosage forms. Corn syrup was used to both facilitate the incorporation of a lipophilic, namely ibuprofen or a hydrophilic, namely paracetamol, active compound that were used as model drugs and to enable 3D printing of the chocolate-based dosage forms. Physicochemical (differential scanning calorimetry, X-Ray diffraction, Fourier-Transform infrared spectroscopy, particle size distribution) and rheological studies were applied for the characterization of the prepared chocolate-based formulations. Texture profile analysis and in vitro digestion studies were performed in order to further analyze the texture attributes and to evaluate drug dissolution of the final dosage forms, respectively. In the present study, we reported on a facile method for the preparation of a 3D printed chewable chocolate-based dosage form with rapid and high release of both hydrophobic and hydrophilic drugs in simulated salivary fluid. The application of 3D printing technology enables accuracy in dose adjustment, while at the same time introducing the potential of patient's active involvement in customization of the design, textural and organoleptic properties of the final dosage form.

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Drug delivery to the neonatal and premature pediatric populations is very challenging. This research assessed the potential of delivering midazolam by transdermal iontophoresis as an alternative strategy in pediatric therapy. In vitro experiments used intact and tape-stripped porcine skin as models for the skin barrier function of full-term and premature newborns, respectively. Midazolam transdermal transport was significantly enhanced by applying higher currents, increasing the formulation pH, and optimizing the drug's mole fraction in the vehicle. When the skin barrier was decreased to half of its baseline competence, the passive permeation of midazolam increased by approximately 60-fold; and complete stratum corneum removal led to an additional 20-fold enhancement in permeation. Iontophoresis retained control of the drug transport trough partially compromised skin. However, a very high passive contribution undermined the iontophoretic control when the barrier was fully compromised. Overall, midazolam delivery could be rate-controlled by iontophoresis in most circumstances, and therapeutically useful fluxes could be achieved.

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The feasibility of a colorimetric technique was investigated in CIELAB color space as an analytical quality control method for content uniformity of printed orodispersible pediatric delivery systems. Inkjet printing was utilized to fabricate orodispersibe film formulations containing propranolol hydrochloride in a colored ink base using three different edible substrates. A thin sweetener coating layer of saccharin was successfully included in the final dosage forms for palatability purposes using a casting knife. Optical microscopy, scanning electron microscopy and scanning white light interferometry analyses were conducted to study the effect of printing on the surface morphology and topography of the substrates. Differential scanning calorimetry and attenuated total reflectance infrared spectroscopy were used to study the solid state properties and possible interactions between the drug and the excipients. The inkjet printing technique deposited precise and uniform escalating doses (0.08-3.16mg) of the active pharmaceutical ingredient onto the substrates (R(2)≥0.9934). A disintegration test with clear end-point detection confirmed that all the substrates meet the requirements of the Ph. Eur. to disintegrate within 180s. The colorimetric technique proved to be a reliable method to distinguish the small color differences between formulations containing an escalating dose of propranolol hydrochloride.

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INTRODUCTION: Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. AREAS COVERED: The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems. EXPERT OPINION: Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery.

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BACKGROUND: The human respiratory airway undergoes dramatic growth during infancy and childhood, which induces substantial variability in air flow pattern and particle deposition. However, deposition studies have typically focused on adult subjects, the results of which cannot be readily extrapolated to children. We developed models to quantify the growth of human nasal-laryngeal airways at early ages, and to evaluate the impact of that growth on breathing resistance and aerosol deposition. METHODS: Four image-based nasal-laryngeal models were developed from 4 children, ages 10 days, 7 months, 3 years, and 5 years, and were compared to a nasal-laryngeal model of a 53-year-old adult. The airway dimensions were quantified in terms of different parameters (volume, cross-section area, and hydraulic diameter) and of different anatomies (nose, pharynx, and larynx). Breathing resistance and aerosol deposition were computed using a high-fidelity fluid-particle transport model, and were validated against the measurements made with the 3-dimensional models fabricated from the same airway computed tomography images. RESULTS: Significant differences in nasal morphology were observed among the 5 subjects, in both morphology and dimension. The turbinate region appeared to experience the most noticeable growth during the first 5 years of life. The nasal airway volume ratios of the 10-day, 7-month, 3-year, and 5-year-old subjects were 6.4%, 18.8%, 24.2%, and 40.3% that of the adult, respectively. Remarkable inter-group variability was observed in air flow, pressure drop, deposition fraction, and particle accumulation. The computational fluid dynamics predicted pressure drops and deposition fractions were in close agreement with in vitro measurements. CONCLUSIONS: Age effects are significant in both breathing resistance and micrometer particle deposition. The image/computational-fluid-dynamics coupled method provides an efficient and effective approach in understanding patient-specific air flows and particle deposition, which have important implications in pediatric inhalation drug delivery and respiratory disorder diagnosis.

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