Article Dans Une Revue International journal of pharmaceutics Année : 2024

Bosentan monohydrate and sildenafil base as two companions in enabling formulations

Résumé

Hypothesis: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs. Experiments: The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs. Findings: It was shown that binary formulations in which bosentan was molecularly dispersed in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS.
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hal-04689965 , version 1 (06-09-2024)

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Dominik Strojewski, Sebastian Lalik, Florence Danede, Natalia Górska, Aleksandra Deptuch, et al.. Bosentan monohydrate and sildenafil base as two companions in enabling formulations. International journal of pharmaceutics , 2024, International journal of pharmaceutics, 661, pp.124312. ⟨10.1016/j.ijpharm.2024.124312⟩. ⟨hal-04689965⟩
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