Development of a new pediatric formulation of hydrophilic suppositories of pentobarbital and comparison with lipophilic formulations

Background and Objectives
Our hospital pharmacy prepares lipophilic suppositories containing sodium pentobarbital (P) in Witepsol^® (W) used for pediatric sedation during radiological exams. However, this formulation presents difficulties in preparation, specifically homogenization difficulties due to the insolubility of P in W. As a result, it falls short of complying with the requirements of the European Pharmacopoeia (EP) Uniformity of Dosage Units (U) test. The objective of this study was to develop a new hydrophilic suppository (HS) formulation based on gelatin and polyethylene glycol 4000 (PEG), which would be easier to prepare and control.

Materials and methods
After determining the solubility of P in water through overloading and centrifugation, we prepared three batches of 60 units each of four different HS formulations at 60 mg of P: F1 (25% gelatin), F2 (20% gelatin), F3 (25% gelatin and 4% PEG), and F4 (20% gelatin and 4% PEG). The U of the batches, prepared by two operators with no prior suppository preparation experience, was calculated using acceptance values (AV) as per EP monograph 2.9.40 (target AV < 15%). Additionally, we measured hardness (H) and softening time (ST). Dissolution tests were conducted using a continuous flow cell system with 500 mL phosphate buffer at pH 6.8 and a flow rate of 20 mL/min, following the EP monograph 2.9.3. Dissolution samples (up to 120 min) were collected and quantified using a validated UV spectroscopy method at 240 nm. Results were compared with two lipophilic formulations, F5 containing W and F6 containing W and oleic acid (1). All analyses were performed in triplicate and the results are presented as mean ± standard deviation.

Results
The solubility of P in water was found at 450 mg/ml. The U test was compliant for all HS formulations (AV: 5.7 ± 0.4%, 6.5 ± 1.0%, 6.4 ± 1.2%, and 7.9 ± 3.9% for F1, F2, F3, and F4, respectively) and for F6 (6.2 ± 1.4%), but not for F5 (28 ± 22.0%). ST were less than 2 minutes for all HS formulations, compared to 8 minutes for F5 and 3 minutes for F6. H measurements revealed a crush weight of 1.7 ± 0.1 kg for F1 and F3, 1.2 ± 0.0 kg for F2, and 0.9 ± 0.1 kg for F4, whereas F5 had a crush weight of 3.4 ± 0.2 kg and F6 had 0.9 ± 0.1 kg. The amount of P released during dissolution tests exceeded 80% of the nominal amount at 10 minutes for F1 and F4, and at 5 minutes for F2 and F3. For F5 and F6, this threshold was only reached after 90 minutes.

Discussion - Conclusion
The results demonstrate the superiority of HS formulations in terms of compliance rate and galenic properties, except for those containing less gelatin due to poor crush resistance. Softening times and release kinetics suggest a faster release compared to lipophilic suppositories, implying a potential reduction in sedation time. Pending formulation validation in collaboration with clinicians, a stability study will be conducted.

Reference
1. Lebrat M et al. Pharmaceutics. 2023, 15(3), 755