HPMC improves protective effects of naringenin and isonicotinamide co-crystals against abdominal aortic aneurysm,Cardiovascular Drugs and Therapy

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HPMC improves protective effects of naringenin and isonicotinamide co-crystals against abdominal aortic aneurysm
Cardiovascular Drugs and Therapy ( IF 3.1 ) Pub Date : 2021-09-07 , DOI: 10.1007/s10557-021-07206-x
Xing Zhang _{1,

2,

3,

4,

5,

6} , Anyi Wang _{1,

2,

3,

4,

5} , Xiaotong Yang ₇ , Yunxia Wang _{1,

2,

3,

4,

5} , Qinyu Wang _{1,

2,

3,

4,

5} , Rui Hu _{1,

2,

3,

4,

5,

6} , Gulinigaer Anwaier _{1,

2,

3,

4,

5,

6} , Chang Di _{1,

2,

3,

4,

5} , Rong Qi _{1,

2,

3,

4,

5,

6} , Yanbin Huang ₇

Affiliation

Purpose

Abdominal aortic aneurysm (AAA) rupture is one of the most common causes of mortality in cardiovascular diseases, but currently there is no approved drug for AAA treatment or prevention in the clinic. Naringenin (NGN) has been reported to have anti-AAA effects. However, water solubility and in vivo absorption of NGN are not satisfactory, which leads to its low bioavailability, thus affecting its pharmacological effects. In this project, the improving effects of isonicotinamide (INT) co-crystal and hydroxy propyl methyl cellulose (HPMC) or polyvinyl pyrrolidone (PVP) on the solubility, in vivo absorption, and anti-AAA effects of NGN were evaluated.

Methods

In the current study, co-crystals of naringenin-isonicotinamide (NGN-INT) were prepared, and effects of PVP or HPMC on precipitation rate, supersaturation, and bioavailability of NGN were explored. In addition, with or without HPMC supply, the effects of NGN-INT co-crystal on anti-AAA efficacy of NGN were investigated on an elastase-induced AAA mouse model, and the results were compared with the efficacy of the NGN crude drug.

Results

Our results demonstrate that NGN-INT formulation, compared to the NGN crude drug, enhanced the dissolution rate of NGN and significantly increased C_max and AUC_(0–∞) of NGN by 18 times and 1.97 times, respectively. Addition of PVP or HPMC in NGN-INT co-crystal further increased bioavailability of NGN in NGN-INT. The in vivo pharmacodynamic study showed that NGN-INT with HPMC significantly improved the inhibitory effects of NGN against AAA.

Conclusion

NGN-INT significantly improved the absorption and aortic protective effects of NGN. The supersaturation-prolonging effect of HPMC further enhanced bioavailability and anti-AAA effects of NGN-INT.

Graphical abstract

中文翻译：

HPMC提高柚皮素和异烟酰胺共晶对腹主动脉瘤的保护作用

目的

腹主动脉瘤(abdominal aortic aneurysm, AAA)破裂是心血管疾病中最常见的死亡原因之一，但目前临床上尚无批准用于AAA治疗或预防的药物。据报道，柚皮素 (NGN) 具有抗 AAA 作用。但NGN的水溶性和体内吸收不尽如人意，导致其生物利用度低，从而影响其药理作用。在该项目中，评估了异烟酰胺 (INT) 共晶和羟丙基甲基纤维素 (HPMC) 或聚乙烯吡咯烷酮 (PVP) 对 NGN 的溶解度、体内吸收和抗 AAA 作用的改善作用。

方法

在目前的研究中，制备了柚皮素-异烟酰胺 (NGN-INT) 的共晶，并探讨了 PVP 或 HPMC 对 NGN 的沉淀速率、过饱和度和生物利用度的影响。此外，在弹性蛋白酶诱导的 AAA 小鼠模型上，研究了 NGN-INT 共晶在供应或不供应 HPMC 的情况下对 NGN 抗 AAA 功效的影响，并将结果与 NGN 原料药的功效进行比较。

结果

我们的结果表明，与 NGN 原料药相比，NGN-INT 制剂提高了 NGN 的溶出度，并显着增加了 NGN 的 C _max和 AUC _(0–∞)，分别为 18 倍和 1.97 倍。在 NGN-INT 共晶中添加 PVP 或 HPMC 进一步提高了 NGN-INT 中 NGN 的生物利用度。体内药效学研究表明，NGN-INT 与 HPMC 显着提高了 NGN 对 AAA 的抑制作用。