Pediatric trazodone compositions and methods of treatment thereof
A technology of trazodone and composition, applied in directions such as drug combination, drug delivery, and pharmaceutical formulation
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Embodiment 1
[0078] Two formulations were developed as oral drop solutions containing two different concentrations of trazodone hydrochloride as the active ingredient:
[0079] ·Trazodone hydrochloride 15mg / ml (1.5%w / V)
[0080] ·Trazodone Hydrochloride 30mg / ml (3%w / V)
[0081] It can be used to treat the pediatric population between the ages of 2-6 years and 6-17 years, respectively.
[0082]Formulations have been developed according to the requirements of the EMA guidelines for drug development of medicines for pediatric use.
[0083] The drops are especially ample for dosage flexibility and can be mixed with fruit juice or sugar water to improve patient compliance.
[0084] Table 4 below reports the two drop formulations.
[0085] Table 4. Pediatric drop compositions (no preservatives)
[0086]
[0087] According to this embodiment, the preferred drop composition with a concentration of trazodone of 1-3% w / V also comprises the following excipients: Propylene Glycol 20-40% w / V, pr...
Embodiment 2
[0105] A number of syrup formulations were developed with the same concentration of trazodone hydrochloride (0.26% w / V) and are reported in Table 7 below, numbered 4, 5 and 6.
[0106] Table 7. Exemplary Syrup Formulations
[0107]
[0108] Other syrup formulations were developed and tested, as described in the table below:
[0109] Table 8. Alternative Exemplary Syrup Compositions
[0110]
[0111] Notably, the pH of all formulations was about 4.5.
[0112] Formulations F and G were evaluated as palatable even without added flavoring. However, as a test, berry flavor was also added to Formulations F and G at 0.15% w / V to improve palatability. The stability of these flavored formulations under the same test conditions was confirmed.
[0113] As reported in the table above, two different formulations ("F" and "G"), both containing 0.2% API, were considered the best products matching all initial requirements of the product in terms of solubility and stability.
[0114...
Embodiment 3
[0119] The method used to estimate the appropriate starting dose of trazodone to support clinical trials in children is physiology-based pharmacokinetic (PBPK) modeling.
[0120] The Simcyp Population-Based Simulator (Version 14 release 1) (Simcyp Population-Based Simulator (Version 14 release 1)) was used for all simulations (Simcyp Ltd, Sheffield, United Kingdom). The Simcyp Caucasian Healthy Volunteer population model was used for adult simulations, while the Simcyp Pediatric population model was used for simulations of children aged 2–6, >6–12, and >12–17 years. A PBPK model of trazodone was developed based on available physicochemical parameters, data from in vitro experiments, clinical PK parameters and predictive parameters. The export of key parameters is described below. The final parameters used in the model are shown in Table 9.
[0121] Table 9. Input parameter values used to simulate trazodone kinetics
[0122]
[0123] B / P, blood to plasma; CLint, intrins...
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