Oral Formulation Based on Irbesartan Nanocrystals Improve Drug Solubility, Absorbability, and Efficacy.

Noriaki Nagai,Ayari Ike,Naoki Yamamoto,Fumihiko Ogata,Hanano Osako,Yosuke Nakazawa,Naohito Kawasaki,Yurisa Shimomae

doi:10.3390/pharmaceutics14020387

Noriaki Nagai, Ayari Ike + Show 6 more

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https://doi.org/10.3390/pharmaceutics14020387

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Abstract

We previously reported that the bioavailability (BA) of irbesartan (IRB), a BSC class II drug, was improved by preparing nanocrystalline suspensions. However, nanocrystalline suspensions have chemical and physical instabilities and must be converted into tablets through drying approaches in order to overcome such instabilities. In this study, we attempted to design a molded tablet based on nanocrystalline IRB suspensions (IRB-NP tablet) and investigated the effects of this IRB-NP tablet on blood pressure (BP) in a stroke-prone spontaneously hypertensive (SHR-SP) rat. The IRB-NP tablet (with a hardness of 42.6 N) was developed by combining various additives (methylcellulose, 2-hydroxypropyl-β-cyclodextrin HPβCD, D-mannitol, polyvinylpyrrolidone, and gum arabic) followed by bead-milling and freeze-drying treatments. The mean particle size in the redispersions of the IRB-NP tablet was approximately 118 nm. The solubility and intestinal absorption of IRB in the IRB-NP tablet were significantly enhanced in comparison with the microcrystalline IRB tablet (IRB-MP tablet), and both solubility and clathrin-dependent endocytosis helped improve the low BA of the IRB. In addition, the BP-reducing effect of the IRB-NP tablet was significantly higher than that of the IRB-MP tablet. These results provide useful information for the preservation of nanocrystalline suspensions of BCS class II drugs, such as IRB.

Highlights

Hypertension therapy reduces the risk for the onset of stroke and cardiovascular disease, which often coexist [1,2]
angiotensin II receptor blockers (ARBs) provide a significant blood pressure (BP)-reducing effect without these side effects, since ARBs inhibit the interaction between the angiotensin II type-1 receptor and angiotensin II [4,5]
We reported that the BA of IRB, a nanocrystalline suspensions have chemical and physical instabilities and must be converted class II drug, was improved by preparing nanocrystalline suspensions

Summary

Introduction

Hypertension therapy reduces the risk for the onset of stroke and cardiovascular disease, which often coexist [1,2]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used worldwide to treat hypertension; the antihypertensive effects of ACE inhibitors and ARBs are led by the inhibition of angiotensin. The inhibition of the ACE causes the production of bradykinin and substance P. Angioedema and dry cough were observed as side effects among patients undergoing ACE-inhibitor treatment. ARBs provide a significant blood pressure (BP)-reducing effect without these side effects, since ARBs inhibit the interaction between the angiotensin II type-1 receptor and angiotensin II [4,5].

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