The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes
The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes
复制标题
DOI：
10.1016/j.ijpharm.2020.120067
复制
发表时间：
2021-01-05
影响因子：
5.8
通讯作者：
Nishida, Kohji
中科院分区：
文献类型：
--
作者：
Baba, Koichi;Hashida, Noriyasu;Nishida, Kohji
氟米龙是一种广泛使用的抗炎眼用制剂，与其他糖皮质激素药物相比，其引起的高眼压反应较低。这有助于减轻类固醇诱导的青光眼的风险。基于改善的角膜渗透性可以增加药物的生物利用度的假设，我们试图获得具有小粒度的悬浮液中的氟甲龙。因此，我们描述了氟甲龙滴眼液的制剂，其平均粒径为201.2 +/-14.1 nm（标准偏差（s.d.））当通过动态光散射测量时。扫描电子显微镜进一步表明，氟甲龙纳米晶体主要是矩形形状。另一方面，具有9.24 ± 4.51 μ m（s.d.）的平均粒度的氟米龙微晶，倾向于具有杆状形态。粉末X-射线衍射显示，氟米龙微晶和氟米龙制剂具有相同的晶体结构，在2 θ = 10.4和15.3度处具有主衍射峰。当在10摄氏度下储存长达6个月时，发现该药物制剂是稳定的、长期的。在体内将氟米龙滴眼液施用到眼表面15-240分钟后，兔眼的房水的高压液相色谱（HPLC）显示该分子已转化为20 α-二氢氟米龙（没有20 β-二氢氟米龙级分的证据），并且渗透性是使用该药物的2-6倍高并且持续时间更长，而不是微晶制剂。在目前的研究中，我们展示了新产生的氟甲龙纳米晶体作为滴眼剂给药时如何进入眼前房并代谢为二氢氟甲龙。
Fluorometholone is a widely used anti-inflammatory ophthalmic formulation, which elicits a lower ocular hypertensive response than other glucocorticoid medications. This serves to mitigate against the risk of steroid-induced glaucoma. Based on the hypothesis that an improved corneal permeability can increase the bioavailability of a drug, we sought to obtain fluommetholone in suspension with a small particle size. Accordingly, we describe the formulation of fluommetholone nanocrystal eye drops, which have a mean particle size of 201.2 +/- 14.1 nm (standard deviation (s.d.)) when measured by dynamic light scattering. Scanning electron microscopy further indicates that fluommetholone nanocrystals are predominantly rectangular in shape. Fluorometholone microcrystals, on the other hand, with a mean particle size of 9.24 +/- 4.51 mu m (s.d.), tend to have a rod-like morphology. Powder x-ray diffraction revealed that fluorometholone microcrystal and nanocrystal formulations have the same crystal structure, with the main diffraction peaks at 2 theta = 10.4 and 15.3 degrees. The nanocrystal formulation was found to be stable, long-term, when stored at 10 degrees C for up to 6-months. High pressure liquid chromatography (HPLC) of the aqueous humor of rabbit eyes 15-240 mins after the in vivo application of fluorometholone eye drops to the ocular surface revealed that the molecule had been converted to 20 alpha-dihydrofluommetholone (with no evidence of a 20 beta-dihydrofluorometholone fraction), and that penetration was 2-6 fold higher and longer lasting with the nanocrystal, rather than the microcrystal, formulation. In current study we show how newly generated fluommetholone nanocrystals when administered as eye drops enter the anterior chamber of the eye and become metabolized to dihydrofluommetholone.