Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug
Abstract
:1. Introduction
2. Results
2.1. Taste Masking Effectiveness vs. Standard Vehicle
- i.
- syrup, with and without Ra-HCl, and water with Ra-HCl (Figure 1A), using a classification discriminant model with two DFs, explaining 100% of the data variability, based on the potential signals (in Volts) of two sensors: DF1 = −1066 × S2:11 + 963 × S2:12; DF2 = −56 × S2:11 − 68 × S2:12;
- ii.
- oral formulation, with or without Ra-HCl, and water with Ra-HCl (Figure 1B), using a classification discriminant model with two DFs, explaining 100% of the data variability, based on the potential signals (in Volts) of two sensors: DF1 = 3235 × S2:9 − 904 × S2:13; DF2 = −170 × S2:9 + 235 × S2:13; and,
- iii.
- the five oral solutions, using a classification discriminant model which two first DFs explained ~100% of the data variability, and were based on the potential signals (in Volts) of two sensors: DF1 = −1745 × S1:11 − 684 × S2:5 + 2511 × S2:11; DF2 = −292 × S1:11 + 226 × S2:5 + 333 × S2:11.
2.2. Chemical and Microbiological Stability
3. Discussion
Limitations
4. Materials and Methods
4.1. Chemicals and Materials
4.2. Composition of the Oral Pediatric Solution
4.3. Evaluation of Taste Masking Effectiveness vs. Standard Vehicle (Simple Syrup) Using E-Tongue
4.3.1. E-Tongue Apparatus and Potentiometric Analysis of Ra-HCl Solutions
4.3.2. Statistical Analysis
4.4. Study of the Stability of the Developed Oral Solution
4.4.1. Sample Preparation
4.4.2. Microbiological Stability
4.4.3. Chemical Stability Evaluation
pH Determination
Ranitidine Assay
Chromatographic Conditions
Method Validation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Time | Temperature | pH | Appearance | Color | Odor |
---|---|---|---|---|---|
0 days | 4 °C | 5.10 ± 0.03 | clear | Colorless | Characteristic of bubble gum |
Room Temperature | 5.12 ± 0.02 | clear | Colorless | ||
7 days | 4 °C | 5.10 ± 0.02 | clear | Colorless | |
Room Temperature | 5.11 ± 0.02 | clear | Colorless | ||
15 days | 4 °C | 5.09 ± 0.03 | clear | Colorless | |
Room Temperature | 5.15 ± 0.02 | clear | Colorless | ||
30 days | 4 °C | 5.21 ± 0.01 | clear | Colorless | |
Room Temperature | 5.22 ± 0.01 | clear | Slightly yellow | ||
30 days | Unopened 4 °C | 5.20 ± 0.01 | clear | Colorless | |
30 days | Unopened Room Temperature | 5.29 ± 0.01 | clear | Slightly yellow |
% of Initial Ranitidine Content | |||
---|---|---|---|
Day | In-Use Stability (4 °C) | In-Use Stability (RT) | Unopened Recipient (4 °C) |
0 | 100.0 | 100.0 | 100.0 |
7 | 99.8 ± 0.5 | 99.3 ± 0.4 | |
15 | 99.7 ± 0.2 | 99.0 ± 0.3 | |
30 | 99.5 ± 0.1 | 98.4 ± 0.7 | 99.7 ± 0.2 |
Characteristic | Target | Comment |
---|---|---|
Concentration | 25 mg/mL | Allows a low volume administration |
pH | 4.5–5.5 | pH of maximum stability of Ra-HCl |
Chemical and microbiological stability | At least 30 days | Comparison between solution in closed recipient and solution with once daily sample removal (in-use stability) [13] |
Flavor | Bubble gum | One of the preferred flavors for children |
Taste masking strategy | Sweeteners and sodium chloride | Synergistic effect of aspartame and sodium saccharine [17] and sorbitol Sodium chloride affords bitterness masking [18,19,20] |
Viscosity | Very fluid | Appropriated for administration with a syringe |
Excluded excipients | Sugar-free, alcohol-free and paraben free | Parabens and alcohol are not recommended for pediatric formulations [21]. Sugar-free formulation is non-cariogenic and suitable for children with diabetes and hereditary fructose intolerance [13] |
Preparation | Simple, with low energy consumption | Feasible in a hospital pharmacy setting |
Sodium Saccharin | Sorbic Acid | Potassium Sorbate | Sorbitol 70% | Citric Acid | Aspartame | Sodium Chloride | Sodium Citrate |
---|---|---|---|---|---|---|---|
0.6 | 0.1 | 0.1 | 5 | 0.1 | 0.3 | 0.1 | 0.5 |
Calibration Equation | Determination Coefficient (R2) | LOD (mg/mL) | LOQ (mg/mL) | Repeatability (% RSD), n = 6 | Intermediate Precision (% RSD), n = 6 |
---|---|---|---|---|---|
y = 367.33x + 11.9 | 0.996 | 0.0075 | 0.0249 | 1.8 | 2.7 |
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Ogbonna, J.D.N.; Cunha, E.; Attama, A.A.; Ofokansi, K.C.; Ferreira, H.; Pinto, S.; Gomes, J.; Marx, Í.M.G.; Peres, A.M.; Lobo, J.M.S.; et al. Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug. Pharmaceuticals 2022, 15, 1331. https://doi.org/10.3390/ph15111331
Ogbonna JDN, Cunha E, Attama AA, Ofokansi KC, Ferreira H, Pinto S, Gomes J, Marx ÍMG, Peres AM, Lobo JMS, et al. Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug. Pharmaceuticals. 2022; 15(11):1331. https://doi.org/10.3390/ph15111331
Chicago/Turabian StyleOgbonna, John Dike N., Edite Cunha, Anthony A. Attama, Kenneth C. Ofokansi, Helena Ferreira, Susana Pinto, Joana Gomes, Ítala M. G. Marx, António M. Peres, José Manuel Sousa Lobo, and et al. 2022. "Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug" Pharmaceuticals 15, no. 11: 1331. https://doi.org/10.3390/ph15111331