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七（2,6-二-O-甲基）-β-环糊精对奥美沙坦酯的主客体络合作用：与辅料的相容性研究

Host-Guest Complexation of Olmesartan Medoxomil by Heptakis(2,6-di-O-methyl)-β-cyclodextrin: Compatibility Study with Excipients.

作者信息

Man Dana Emilia, Nițu Ema-Teodora, Temereancă Claudia, Sbârcea Laura, Ledeți Adriana, Ivan Denisa, Ridichie Amalia, Andor Minodora, Jîjie Alex-Robert, Barvinschi Paul, Rusu Gerlinde, Văruţ Renata-Maria, Ledeți Ionuț

机构信息

Faculty of Medicine, "Victor Babeş" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.

Faculty of Pharmacy, "Victor Babeş" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.

出版信息

Pharmaceutics. 2024 Dec 4;16(12):1557. doi: 10.3390/pharmaceutics16121557.

DOI:10.3390/pharmaceutics16121557
PMID:39771536
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11677897/
Abstract

Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve the solubility of OLM, a host-guest inclusion complex (IC) between heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMβCD) and the drug substance was obtained. Along with active substances, excipients play a crucial role in the quality, safety, and efficacy of pharmaceutical formulations. Therefore, the compatibility of OLM/DMβCD IC with several pharmaceutical excipients was evaluated. IC was characterized in both solid and liquid states, employing thermoanalytical techniques, universal-attenuated total reflectance Fourier-transform infrared spectroscopy, powder X-ray diffractometry, UV spectroscopy, and saturation solubility studies. Compatibility studies were carried out using thermal and spectroscopic methods to assess potential physical and chemical interactions. The 1:1 OLM:DMβCD stoichiometry ratio and the value of the apparent stability constant were determined by means of the phase solubility method that revealed an -type diagram. The binary system showed different physicochemical characteristics from those of the parent entities, supporting IC formation. The geometry of the IC was thoroughly investigated using molecular modeling. Compatibility studies revealed a lack of interaction between the IC and all studied excipients at ambient conditions and the thermally induced incompatibility of IC with magnesium stearate and α-lactose monohydrate. The results of this study emphasize that OLM/DMβCD IC stands out as a valuable candidate for future research in the development of new pharmaceutical formulations, in which precautions should be considered in choosing magnesium stearate and α-lactose monohydrate as excipients if the manufacture stage requires temperatures above 100 °C.

摘要

奥美沙坦酯（OLM）是奥美沙坦的前体药物，奥美沙坦是一种血管紧张素II 1型受体阻滞剂，具有抗高血压、抗氧化活性及肾脏保护特性。它的水溶性较低，导致生物利用度差，限制了其临床应用潜力。为提高OLM的溶解度，制备了七（2,6-二-O-甲基）-β-环糊精（DMβCD）与该药物的主客体包合物（IC）。辅料与活性物质一样，在药物制剂的质量、安全性和有效性方面起着关键作用。因此，评估了OLM/DMβCD IC与几种药物辅料之间的相容性。采用热分析技术、通用衰减全反射傅里叶变换红外光谱法、粉末X射线衍射法、紫外光谱法和饱和溶解度研究等方法对IC在固态和液态下进行了表征。使用热分析和光谱方法进行相容性研究，以评估潜在的物理和化学相互作用。通过相溶解度法确定了OLM与DMβCD为1:1化学计量比及表观稳定常数的值，并得到了一个 - 型相图。该二元体系表现出与母体不同的物理化学特性，证明了IC的形成。利用分子模型对IC的几何结构进行了深入研究。相容性研究表明，在环境条件下IC与所有研究的辅料之间不存在相互作用，但IC与硬脂酸镁和一水合α-乳糖在热诱导下不相容。本研究结果强调，OLM/DMβCD IC作为新型药物制剂开发未来研究的一个有价值候选物脱颖而出，如果制造阶段需要高于100°C的温度，则在选择硬脂酸镁和一水合α-乳糖作为辅料时应予以考虑。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/10c79e01ffca/pharmaceutics-16-01557-g010a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/accc54f5314b/pharmaceutics-16-01557-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/06bb7aa8d3e1/pharmaceutics-16-01557-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/5b702203270a/pharmaceutics-16-01557-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/04b51534c659/pharmaceutics-16-01557-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/10c79e01ffca/pharmaceutics-16-01557-g010a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/accc54f5314b/pharmaceutics-16-01557-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/7bb2811a4325/pharmaceutics-16-01557-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/d01550760d4e/pharmaceutics-16-01557-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/3dce29fed399/pharmaceutics-16-01557-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/5d21b7d5fc48/pharmaceutics-16-01557-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/2ac29158e4dc/pharmaceutics-16-01557-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/06bb7aa8d3e1/pharmaceutics-16-01557-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/5b702203270a/pharmaceutics-16-01557-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/04b51534c659/pharmaceutics-16-01557-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bd3/11677897/10c79e01ffca/pharmaceutics-16-01557-g010a.jpg

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