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Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary vascular remodeling, in which pulmonary arterial hypertension (PAH) requires long-term combination drug therapy. In this study, we developed bosentan (BST) and sildenafil citrate (SIL) combination tablets to address the complexity of clinical combination drug regimens and poor patient compliance. An HPLC method for the determination of the content at pH 1.2, 4.5 and 6.8 was established through pre-prescription studies, which confirmed that the solubility of BST increased with the increase of pH, while the opposite was true for SIL. The prescription was optimized using wet granulation process with dissolution and content uniformity as the core indexes, and the optimal composition was determined as 47.8% BST, 31.2% SIL, 8%-18% maize starch-pre-gelatinized starch (2∶1), 2%-8% sodium carboxymethyl starch, 3% behenic acid glycerol ester and 1% magnesium stearate. Quality evaluation showed that the tablets complied with pharmacopoeial standards and had good stability. Pharmacokinetic studies in SD rats showed that the tmax of BST and SIL in the compounded tablets were 3.76 and 0.94 h, respectively, which were comparable to those of the commercially available preparations and the half-life was extended by 3-fold and 2-fold, respectively. This compound preparation significantly improves patient compliance by simplifying the dosing regimen (43 mg BST+28 mg SIL, 3 times daily). The two drugs can reach blood drug concentration at the same time, creating favorable pharmacokinetic conditions for achieving synergistic effects at the pharmacological level. This characteristic makes the compound preparation a potential new strategy for the treatment of PAH. The study was approved by the Animal Ethics Committee of China Pharmaceutical University, and all experiments complied with ethical regulations (Approval number: YSL-202505069).
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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