Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France; University Félix Houphouet-Boigny, School of Pharmacy, Abidjan, Côte d'Ivoire.
Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
Eur J Pharm Sci. 2018 Feb 15;113:185-192. doi: 10.1016/j.ejps.2017.09.013. Epub 2017 Sep 7.
We have optimized a formulation of a prodrug of dexamethasone (DXM), dexamethasone palmitate (DXP) for pulmonary delivery as a dry powder. Formulations were prepared by spray drying DXP with 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Hyaluronic Acid (HA) as excipients. Large porous particles around 13 μm were produced with a tap density of 0.05g/cm and a Fine particle fraction around 40%. The palmitate moiety favors DXP insertion into DPPC bilayers therefore limiting its in vitro release as shown by differential scanning calorimetry. After administering DXP powder intratracheally to rats by insufflation, bronchoalveolar lavage fluid (BALF) and blood samples were collected up to 24h and DXP and DXM concentrations were determined by HPLC analysis after extraction. PK parameters were evaluated according to a non-compartmental model. We observe that DXP remains for up to 6h in the epithelial lining fluid (ELF) of the lungs at very high concentration. In addition, DXP concentration decreases according to two characteristic times. Consequently, DXM can be detected at rather important concentration in ELF up to 24h. The passage of DXP from the lungs to the bloodstream is very poor whereas DXM seems to be absorbed in the blood more easily. These results suggest that once administered DXP undergoes two different processes: hydrolysis into DXM due to the presence of esterases in the lungs and distribution in the lung tissue. This formulation appears promising to reduce systemic exposure and prolong the effect of the drug locally.
我们优化了一种地塞米松（DXM）前药棕榈酸地塞米松（DXP）的配方，以干粉形式用于肺部给药。通过喷雾干燥 DXP 与 1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱（DPPC）和透明质酸（HA）作为赋形剂制备了配方。通过喷雾干燥产生了大约 13μm 的大孔颗粒，堆密度为 0.05g/cm3，细颗粒分数约为 40%。棕榈酸部分有利于 DXP 插入 DPPC 双层膜，因此如差示扫描量热法所示，限制了其体外释放。通过气管内吹入将 DXP 粉末施用于大鼠后，在 24 小时内收集支气管肺泡灌洗液（BALF）和血液样本，并通过 HPLC 分析在提取后测定 DXP 和 DXM 的浓度。根据非房室模型评估 PK 参数。我们观察到 DXP 在肺部的上皮衬里液（ELF）中以非常高的浓度保持长达 6 小时。此外，DXP 浓度根据两个特征时间减少。因此，在 ELF 中可以在长达 24 小时的时间内检测到相当重要浓度的 DXM。DXP 从肺部向血液的传递非常差，而 DXM 似乎更容易在血液中被吸收。这些结果表明，一旦给予 DXP，它就会经历两个不同的过程：由于肺部中存在酯酶，DXP 水解为 DXM，以及在肺部组织中的分布。这种配方有望减少全身暴露并延长药物的局部作用。
