Mustafa Wesam W, Khoder Mouhamad, Abdelkader Hamdy, Singer Richard, Alany Raid G
Department of Pharmacy, Al-Mustafa University College, Baghdad, Iraq.
Drug Discovery, Delivery and Patient Care Theme, Department of Pharmacy, Kingston University, London, UK.
Curr Drug Deliv. 2024;21(1):126-139. doi: 10.2174/1567201820666230320164210.
Poor solubility and dissolution rate of drugs are largely responsible for erratic drug absorption and limited oral bioavailability. Etodolac (ETO) is a non-steroidal anti-inflammatory drug (NSAID) that is classified as BCS class II (dissolution rate-dependent absorption). ETO has high safety and efficacy in pain relief and control of inflammation. ETO is commercially available as (400- 600 mg) tablets; poor solubility and dissolution rate of ETO could result in variable oral absorption and inconsistent analgesic responses. The aim of this study was to improve solubility and dissolution rates of ETO by complexation with cyclodextrins (CDs).
Four different CDs namely β-, γ-, HP β-CDs, and HP γ-CDs were prepared using three different methods; solvent evaporation (CO), freeze-drying (FD), and physical mixing (PM). The prepared drug: excipient mixtures were investigated for aqueous solubility, as well as via DSC, XRD, FTIR, SEM, dissolution, and docking.
The results revealed a solubility phase diagram of the AL type, indicating a 1:1 complexation of ETO: CD. These results agreed with our molecular docking calculations. DSC, FTIR, XRD, and SEM results confirmed the formation of an inclusion complex. The complexation efficiency, solubility, and dissolution enhancement were in the order of HPγ-CD > γ -CD > HPβ-CD > β-CD. FD method was superior to both CO and PM.
Superior dissolution enhancements of ETO were recorded for the FD mixture (up to 90% dissolved in less than 10 min). In conclusion, γ- and hydroxypropyl γ-derivative of cyclodextrins can be considered a promising excipient for enhancement of dissolution rates concerned for ETO.
药物的低溶解度和溶出速率在很大程度上导致了药物吸收不稳定和口服生物利用度有限。依托度酸（ETO）是一种非甾体抗炎药（NSAID），属于BCS II类（溶出速率依赖型吸收）。ETO在缓解疼痛和控制炎症方面具有高安全性和有效性。ETO有市售的（400 - 600毫克）片剂；ETO的低溶解度和溶出速率可能导致口服吸收可变和镇痛反应不一致。本研究的目的是通过与环糊精（CDs）络合来提高ETO的溶解度和溶出速率。
使用三种不同方法制备了四种不同的CDs，即β -、γ -、羟丙基β - CDs和羟丙基γ - CDs；溶剂蒸发法（CO）、冷冻干燥法（FD）和物理混合法（PM）。对制备的药物：辅料混合物进行了水溶性研究，以及通过差示扫描量热法（DSC）、X射线衍射法（XRD）、傅里叶变换红外光谱法（FTIR）、扫描电子显微镜法（SEM）、溶出度和分子对接研究。
结果显示为AL型溶解度相图，表明ETO与CD形成了1:1络合物。这些结果与我们的分子对接计算结果一致。DSC、FTIR、XRD和SEM结果证实了包合物的形成。络合效率、溶解度和溶出度增强顺序为羟丙基γ - CD > γ - CD > 羟丙基β - CD > β - CD。冷冻干燥法优于溶剂蒸发法和物理混合法。
冷冻干燥混合物的ETO溶出度增强效果显著（在不到10分钟内高达90%溶解）。总之，环糊精的γ - 和羟丙基γ - 衍生物可被认为是提高ETO溶出速率的有前景的辅料。
