Search Results (42)

Background/Aims: This preference study aimed to identify the maximum number of mini-tablets of two different sizes that children and adolescents would be willing to take, and parents, nurses, and pediatricians would be willing to administer to children and adolescents. Methods: A total of 336 participants (24 per cohort) were stratified into 14 cohorts: Acutely and chronically sick children/adolescents aged 6–<12 years (y) and 12–<18 y, parents of acutely and chronically sick children/adolescents aged 0–<2 y, 2–<6 y, 6–<12 y, and 12–<18 y, nurses, and pediatricians. After participants were shown seven different numbers of 2 and 3 mm mini-tablets, they were asked to assess the maximum number acceptable for short-, middle-, and long-term treatment using cohort-specific questionnaires. Results: Within all groups and treatment durations, the specified maximum accepted number of 2 mm mini-tablets was higher than the number of 3 mm mini-tablets. The maximum number of mini-tablets acceptable to the participants increased with increasing age of the children and ranged from 40–500 (30–400) for the 2 mm (3 mm) mini-tablets. With increasing duration of treatment, a lower maximum number of mini-tablets was considered tolerable. Chronically sick children were willing to take higher numbers of mini-tablets than acutely sick children. The maximum accepted numbers of mini-tablets specified by pediatric patients, parents, and healthcare professionals were similar for each age group; however, pediatricians consistently specified slightly higher numbers of mini-tablets than parents and nurses. Conclusions: The study demonstrated that even a high number of mini-tablets would be well-accepted by children during middle- or long-term treatment. Full article

Background/Objectives: Mini-tablets are a novel pediatric dosage form designed to mask drug taste and facilitate easier administration. This study aimed to assess the feasibility and acceptability of uncoated acetylsalicylic acid (ASA) mini-tablets in Japanese children with Kawasaki disease (KD) aged 1 to 4 years. Methods: A retrospective case series study of three pediatric patients with KD treated with ASA mini-tablets (3 mm diameter, 10 mg) was conducted at Showa University Hospital. ASA mini-tablets were administered for up to 68 days. Caregivers recorded daily medication intake and any issues in medication logbooks. Results: All three patients successfully took 100% of the prescribed doses. No adverse events related to mini-tablet ingestion were reported. Patients could take the mini-tablets for extended periods (63–68 days) as part of their KD treatment. Conclusions: ASA mini-tablets showed potential acceptability in this small cohort of pediatric patients with KD. This study represents the first investigation into the acceptability of mini-tablets containing active ingredients in Japanese pediatric patients. Larger studies are needed to confirm these findings and evaluate long-term safety and efficacy. Full article

Background: Angiotensin-converting enzyme inhibitors, such as enalapril, are foundational in treating pediatric heart failure. However, they are often administered off-label to young children using extemporaneous formulations. This study, conducted as part of the EU-funded Labeling of Enalapril from Neonates up to Adolescents (LENA) project, aimed to evaluate the acceptability and palatability of an age-appropriate enalapril orodispersible minitablet (ODMT). These factors are critical for ensuring adherence, efficacy, and safety in pediatric patients. Methods: An 8-week trial was conducted in children with heart failure caused by dilated cardiomyopathy or congenital heart disease. Enalapril ODMTs (0.25 mg or 1.0 mg) were dose-titrated and administered to 38 children aged 0–6 months and 22 children aged 6 months to 6 years. This study aimed to assess its acceptability and palatability, key factors contributing to adherence, and therefore, efficacy and safety. Results: Across all 169 assessments in 38 children aged 0–6 months and 22 aged 6 months to 6 years, complete or partial swallowability was observed, and the acceptability rate was 100%. There were no cases of choking, inhalation/coughing, or spitting out. A favorable or neutral rating was observed in 96% of palatability assessments based on observations of facial expressions. Acceptability and palatability were higher in subjects aged 6 months–6 years than 0–6 months, with no significant influence from repeated administration. Conclusions: Enalapril ODMTs are widely accepted and well-tolerated among young children, including neonates, with heart failure. These findings suggest that ODMTs are a suitable and effective method for administering pediatric medicinal products. Full article

Background/Objectives: Following tooth extraction, resveratrol (RSV) can support healing by reducing inflammation and microbial risks, though its poor solubility limits its effectiveness. This study aims to develop a solid nanocomposite by embedding RSV in lipid nanoparticles (mLNP) within a hydrophilic matrix, to the scope of improving local delivery and enhancing healing. Hydroxyapatite (HXA), often used as a bone substitute, was added to prevent post-extraction alveolus volume reduction. Methods: The mLNP-RSV dispersion was mixed with seven different polymers in various mLNP/polymer ratios. Following freeze-drying, the powders were redispersed, and the resulting dispersions were tested by DLS experiments. Then, the best two nanocomposites underwent extensive characterization by SEM, XRD, FTIR, Raman spectroscopy, and thermal analysis as well as in vitro partitioning studies aimed at verifying their ability to yield the mLNP-RSV from the hydrophilic matrix to a lipophilic tissue. The characterizations led to identify the best nanocomposite, which was further combined with HXA to obtain hybrid nanocomposites, further evaluated as pharmaceutical powders or in form of mini-tablets. Results: PEG-based nanocomposites emerged as optimal and, following HXA insertion, the resulting powders revealed adequate bulk properties, making them useful as a pharmaceutical intermediate to produce ≈59 mm³ mini-tablets, compliant with the post-extraction socket. Moreover, they were proven ex vivo to be able to promote RSV and GA accumulation into the buccal tissue over time. Conclusions: The here-proposed mini-tablet offers an innovative therapeutic approach for alveolar wound healing promotion as they led to a standardized dose administration, while being handy and stable in terms of physical solid identity as long as it takes to suture the wound. Full article

Background: Trihexyphenidyl (THP) has been widely used for over three decades as pediatric pharmacotherapy in patients affected by segmental and generalized dystonia. In order to achieve effective and safe pharmacotherapy for this population, new formulations are needed. Objective: The aim of this work is the development of trihexyphenidyl orodispersible minitablets (ODMTs) for pediatric use. Methods: Six different excipients were tested as diluents. The properties of powder mixtures were evaluated before direct compression and pharmacotechnical tests were performed on the final formulation. The determination of the API content, uniformity of dosage, and physicochemical stability studies were analyzed by an HPLC-UV method. Results: The developed ODMTs met pharmacopeia specifications for content, hardness, friability, disintegration, and dissolution tests. The physicochemical stability study performed over 18 months shows that API content remains within 90.0–110.0% at least for this period. Conclusions: These ODMTs will allow efficient, safe, and high-quality pharmacotherapy. Full article

Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification by coating or forming matrix systems. The aim of this study was to demonstrate the possibility of the formulation of prolonged-release minitablets with bromhexine hydrochloride (BHX) and bisoprolol fumarate (BFM) dedicated to pediatric patients. Minitablets with 3 mm diameter and 15 mg mass, containing 1 mg of active substance in 1 unit, were prepared by direct compression with hydroxypropyl methylcellulose (HPMC) of different grades, methylcellulose, sodium alginate, or polyvinyl alcohol (PVA) as a sustained-release polymer. Different amounts of polymers and different compression forces were evaluated. Analysis of minitablets included their uniformity, hardness, and dissolution tests. The kinetics of drug substance release were analyzed with dedicated software. The prepared minitablets met the pharmacopeial requirements with respect to the uniformity of mass and content. The compressibility of BFM was significantly better than that of BHX, yet all minitablets had good mechanical properties. Dissolution studies showed a strong relationship between the type of polymer and its amount in the mass of a tablet and the dissolution rate. Prolonged release of up to 8 h was achieved when HPMC of 4000 cP viscosity was used in the amount of 30% to 80%. Sodium alginate in the amount of 50% was also effective in prolonging dissolution, but PVA was much less effective. Studies on the release kinetics showed that dissolution from prolonged-release minitablets with BHX fit the best to Hopfenberg or Hixson–Crowell models, while in the case of BFM, the best fit was found for Hopfenberg or Korsmeyer–Peppas models. Full article

Background: The angiotensin-converting enzyme inhibitor (ACEI) enalapril is often administered to infants and young children with heart failure (HF) in various dosing regimens and formulations not adapted for their age. Methods: This prospective, two-center, open-label 8-week study evaluated an age-appropriate formulation of orodispersible minitablets (ODMTs) of enalapril (0.25 mg and 1 mg) in children aged 0 to 6 years with HF due to congenital heart disease. An age/weight-based dosing schedule was followed. Measures of echocardiographic parameters, blood pressure, heart rate, modified Ross score, and biochemistry were obtained over the 8-week period. The following two groups were assessed: ACEI-naïve and ACEI-pretreated patients. Results: In total, 53 children (age range of 0.05 to 4.8 years) were enrolled and 29 were ACEI-naïve. The average enalapril dose was 0.098 mg/kg (0.06–0.17 mg/kg) in the naïve group and 0.15 mg/kg (0.07–0.3 mg/kg) in pretreated patients. After 8 weeks, the modified Ross score and left ventricular diastolic dimension (LVD) z-score showed a significant decrease in both groups (p < 0.005). During 8 weeks follow-up, there were no difference in the z-scores for the systolic blood pressure (p = 0.071) or heart rate (p = 0.146). Conclusions: Pediatric patients treated with ODMTs of enalapril for 8 weeks had favorable improvements in LVD and HF symptoms. Full article

The objective of the conducted research was to design 2 mm orodispersible minitablets of pediatric doses of hydrocortisone (0.5 mg; 1.0 mg) with desirable pharmaceutical properties and eliminate the sensation of a bitter taste using preparation of solid dispersion by ball mill. Hydrocortisone was selected as the model substance, as it is widely utilized in the pediatric population. ODMTs were prepared by compression (preceded by granulation) in a traditional single-punch tablet machine and evaluated using pharmacopoeial tests, DSC, and FTIR analysis. The methods used to evaluate the effectiveness of the taste-masking effect included in vivo participation of healthy volunteers, in vitro drug dissolution and utilization of an analytical device—“electronic tongue”. The research employed a preclinical animal model to preliminary investigate the bioequivalence of the designed drug dosage form in comparison to reference products. The study confirmed the possibility of manufacturing good-quality hydrocortisone ODMTs with a taste-masking effect owing to the incorporation of a solid dispersion in the tablet mass. Full article

The aim of this study was to fabricate mini-tablets of polyhedrons containing theophylline using a fused deposition modeling (FDM) 3D printer, and to evaluate the correlation between release kinetics models and their geometric shapes. The filaments containing theophylline, hydroxypropyl cellulose (HPC), and EUDRAGIT RS PO (EU) could be obtained with a consistent thickness through pre-drying before hot melt extrusion (HME). Mini-tablets of polyhedrons ranging from tetrahedron to icosahedron were 3D-printed using the same formulation of the filament, ensuring equal volumes. The release kinetics models derived from dissolution tests of the polyhedrons, along with calculations for various physical parameters (edge, SA: surface area, SA/W: surface area/weight, SA/V: surface area/volume), revealed that the correlation between the Higuchi model and the SA/V was the highest (R² = 0.995). It was confirmed that using 3D- printing for the development of personalized or pediatric drug products allows for the adjustment of drug dosage by modifying the size or shape of the drug while maintaining or controlling the same release profile. Full article

Since the acceptability of a medicine can significantly impact therapeutic outcomes, this study aimed to determine and compare the preferences of children, parents, and healthcare professionals for the most commonly used pediatric oral medicine formulations (syrup, mini-tablets, oblong tablets, round tablets) addressing all pediatric age groups, 0–<18 years (y). This survey study employed sex-, age-, and participant group-adapted questionnaires for eight cohorts of participants, i.e., children 6–<12 y, adolescents 12–<18 y, parents of children in four age groups (0–<2 y, 2–<6 y, 6–<12 y, and 12–<18 y), nurses, and pediatricians. Descriptive statistics were used for data analysis. In the age groups 0–<2 y and 2–<6 y, mini-tablets were preferred over syrup by all participants. In the age group 6–12 y, solid dosage forms were also preferred over syrup by all participants. In the age group 12–<18 y, healthcare professionals preferred solid dosage forms over syrup. Parents preferred higher amounts of mini-tablets and syrup compared to round and oblong tablets, while adolescents’ preferences did not differentiate between these formulations. Based on the study results and in contrast to current practice, it is suggested to consider solid dosage forms for future age-appropriate medicinal products already for younger age groups. Full article

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire^® 44/14 and Precirol^® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages. Full article

Mini-tablets made into hard capsules or administered using special dosing units, as well as pellets in hard capsules or compressed into tablets, offer the advantages of multiparticulate drug delivery systems and are suitable for controlled drug release using polymer coatings. Four different kinds of solid drug preparations were manufactured and investigated concerning drug release. Inert pellets were coated with the model drug sodium benzoate and, in a second step, with the insoluble polymer ethylcellulose. The coated pellets were compressed into mini-tablets and into normal tablets. Another kind of mini-tablet was compressed from a sodium benzoate compression mixture and finally coated with ethylcellulose. The coating of the tablets was performed using fluidized bed technology. The sodium benzoate release plots of the coated pellets show a lag time and retarded release according first-order kinetics. The mini-tablets and normal tablets compressed from pellets release sodium benzoate according to first-order kinetics as well, but without the lag time due to distinct ethylcellulose layer destruction during tableting. The release is retarded with increasing ethylcellulose layer thickness on directly compressed mini-tablets. The different formulations of coated pellets, mini-tablets, and normal tablets offer a broad choice for variable drug release kinetics depending on the biopharmaceutical and pharmacological requirements. Full article

Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were C_max: 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC_0–12: 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid C_max: 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC_0–12: 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy. Full article

Mini-tablets are advantageous over liquid formulations in overcoming challenges related to stability, taste, and dosage. This open-label, single-dose, cross-over study investigated the acceptability and safety of drug-free, film-coated mini-tablets in children aged 1 month–6 years (stratified: 4–6 years, 2–<4 years, 1–<2 years, 6–<12 months, and 1–<6 months), and their preference for swallowing either a high quantity of 2.0 mm or a low quantity of 2.5 mm diameter mini-tablets. The primary endpoint was acceptability derived from swallowability. The secondary endpoints were investigator-observed palatability, acceptability as a composite endpoint derived from both swallowability and palatability, and safety. Of 320 children randomized, 319 completed the study. Across all tablet sizes, quantities and age groups, acceptability rates based on swallowability were high (at least 87%). Palatability was rated as “pleasant/neutral” in 96.6% of children. The acceptability rates as per the composite endpoint were at least 77% and 86% for the 2.0 mm and 2.5 mm film-coated mini-tablets, respectively. No adverse events or deaths were reported. Recruitment in the 1–<6-months group was stopped early due to coughing—evaluated as “choked on” in three children. Both 2.0 mm and 2.5 mm film-coated mini-tablets are suitable formulations for young children. Full article

The availability of age-appropriate oral dosage forms for pediatric patients has remained a challenge. Orodispersible mini-tablets (ODMTs) are a promising delivery system for pediatric patients. The purpose of this work was the development and optimization of sildenafil ODMTs as a new dosage form for the treatment of pulmonary hypertension in children using a design-of-experiment (DoE) approach. A two-factor, three levels (3²) full-factorial design was employed to obtain the optimized formulation. The levels of microcrystalline cellulose (MCC; 10–40% w/w) and partially pre-gelatinized starch (PPGS; 2–10% w/w) were set as independent formulation variables. In addition, mechanical strength, disintegration time (DT), and percent drug release were set as critical quality attributes (CQAs) of sildenafil ODMTs. Further, formulation variables were optimized using the desirability function. ANOVA analysis proved that MCC and PPGS had a significant (p < 0.05) impact on CQAs of sildenafil ODMTs with a pronounced influence of PPGS. The optimized formulation was achieved at low (10% w/w) and high (10% w/w) levels of MCC and PPGS, respectively. The optimized sildenafil ODMTs showed crushing strength of 4.72 ± 0.34 KP, friability of 0.71 ± 0.04%, DT of 39.11 ± 1.03 s, and sildenafil release of 86.21 ± 2.41% after 30 min that achieves the USP acceptance criteria for ODMTs. Validation experiments have shown that the acceptable prediction error (<5%) indicated the robustness of the generated design. In conclusion, sildenafil ODMTs have been developed as a suitable oral formulation for the treatment of pediatric pulmonary hypertension using the fluid bed granulation process and the DoE approach. Full article