High-Boiled Lozenges of Prednisolone: proof of concept of Novel Paediatric Oral Dosage Form

Introduction

• Paediatric patients require age-appropriate oral dosage forms with flexible dosing and good acceptability.
• Conventional paediatric formulations may require manipulation, potentially affecting dose accuracy and content uniformity.
• Prednisolone (PDL) is widely used in paediatric practice, but low-dose formulations and palatable dosage forms remain limited. Adult oral doses range from 5–60 mg/day, whereas paediatric doses are individualized according to body weight and clinical indication, typically ranging from 0.14–2 mg/kg/day. The 5 mg strength represents the lowest commonly available unit dose, highlighting the need for flexible low-dose formulations.
• High-boiled lozenges (HBLs) represent a promising platform for paediatric drug delivery. Sweet, flavoured format, pleasant mouthfeel, and administration without water may improve acceptability and facilitate administration.
• Aim: To investigate the preparation pathways of isomalt-based, low-dose prednisolone highboiled lozenge as a novel paediatric oral dosage form and to investigate the influence of three drug incorporation strategies on its physicochemical and pharmaceutical.

Materials

Prednisolone (Tokyo Chemical Industry Co Ltd, Tokyo, Japan) was used as a model drug. Isomalt (galenIQ 720; BENEO Palatinit GmbH, Obrigheim/Pfalz, Germany) and citric acid (Merck KGaA, Darmstadt, Germany) were used as lozenge excipients.

Table 1. Content uniformity of prednisolone HBLs according to Ph. Eur. 2.9.40. Acceptance value (AV) calculated as M=98.5 and for assuming as M=X.

Methods

• HBL preparation: prednisolone was incorporated into molten isomalt according to three strategies (Fig. 1): Scenario 1 (dry powder), Scenario 2 (aqueous suspension) and Scenario 3 (ethanolic solution).

Figure 1. Scenario 1: PDL incorporated as a dry powder into the molten isomalt. Scenario 2: PDL dispersed in purified water prior to addition of isomalt. Scenario 3: PDL dissolved in ethanol (96%) before incorporation into the molten isomalt.

• Optical microscopy: to characterise prednisolone substance and HBLs.
• Particle size distribution test: determined by laser diffraction using a Mastersizer 3000
• Statistical analysis: differences between scenarios were evaluated by ANOVA, with calculations performed using Microsoft Excel (Microsoft 365; Redmond, Washington, DC, USA; Supplementary Materials).
• Impurity profile: chromatographic profiles of the three scenarios were compared with thermally processed placebo HBLs and a non-heated prednisolone reference to identify additional peaks potentially originated from the excipients or from the analytical procedure itself.
• Content Uniformity test: individual lozenges were dissolved in PBS pH 6.8/methanol (100/20 mL) and prednisolone quantification was subsequently performed by HPLC using a PBS/acetonitrile (70:30, v/v) mobile phase. Results were expressed as % of label claim (LC%) and evaluated according to Ph. Eur. 2.9.40 using the following equation:

  AV=|M−XX̄|+ksc

• Disintegration test: was determined in 1000 mL purified water using an Erweka ZT 732 apparatus.
• Dissolution test: was performed in the USP-2 apparatus (paddle) at 50 rpm in PBS 6.8 pH solution (37°C) at a given volume of 500 mL. The prednisolone concentration was determined UV-spectrophotometrically at a λmax of 249 nm (C = 22.905 × Abs – 0.486, R² = 0.9994).
• Moisture content: determined in triplicate using a moisture analyser at 105 °C after crushing of the HBLs.

Results

• Prednisolone substance showed a particle size distribution between 1 and 150 μm, with D10, D50, and D90 of 5.5 μm, 56.5 μm and 89 μm, respectively (Fig. 2B).
• HBLs prepared in accordance with Scenario 2 (Fig. 3C) and 3 (Fig. 3D), showed a relatively homogenous distribution of prednisolone crystals in the glassy isomalt. While in the Scenario 1 formulation samples were observed not only single crystals (Fig. 3B) but also agglomerates of prednisolone crystals (Fig. 3A).
• Two additional HPLC peaks were detected in all three scenarios but were absent in placebo and nonthermal reference samples (Fig. 5). Recent work reported no chemical degradation of prednisolone after processing at 190–220℃, supporting its thermal stability under controlled processing conditions.
• According to Ph. Eur. 2.9.40. (M=98.5), Scenario 3 showed the highest mean drug recovery (88.37%), lowest RSD (2.96%), and lowest Acceptance Value (16.41), compared with S2 (78.56%, 3.32%, AV =26.20) and S1 (79.03%, 6.30%, AV = 31.43). Assuming M = X, the AV decreased from S3 to S2 and to S1, meeting the Ph. Eur. acceptance criterion for S2 and S3 (Table 1, Fig. 4 ).
• Scenario 2 showed the shortest disintegration time (Fig. 6), with no statistically significant differences between scenarios, but a positive correlation with unit weight was observed (R = 0.728).
• All three formulations exhibited a biphasic dissolution behavior, with an initial release phase (20 min) followed by a markedly slower release phase. Scenario 3 showed the highest and most reproducible drug release, whereas Scenario 1 showed the greatest variability (Fig. 7).

Conclusion

• HBLs represent a promising patient-friendly platform for low-dose prednisolone delivery.
• The pre-dispersion of prednisolone in a solvent influenced the distribution of the drug in the glassy isomalt. Drug incorporation in Scenarios 2 and 3 resulted in a more homogeneous distribution, as evidenced by content uniformity, drug release, and optical microscopy results.
• Scenario 3 (pre-dispersion in ethanol) yielded more favorable outcomes compared to pre-treatment in water (Scenario 2) or incorporation as dry powder (Scenario 1).
• No visible precipitation occurred after 2 months; however, minor impurity peaks require further drug investigation.
• This proof-of-concept study laid the groundwork for low-dose prednisolone high-boiled lozenges as a novel paediatric dosage form, focusing primarily on drug incorporation strategies rather than final size and geometry optimization, which will be explored in future studies.

See the full poster on High-Boiled Lozenges of Prednisolone here

(click the picture to download the poster)

Source and Authors: Giada Baccari, Valentina Belfiglio, Kirils Kukuls, Zoltán Márk Horváth, Līga Pētersone, Antonio Di Stefano, Valentyn Mohylyuk, poster: High-Boiled Lozenges of Prednisolone: proof of concept of Novel Paediatric Oral Dosage Form, EuPFi, RSU Leading Research Group aenova, MUR, Erasmus+