Abstract
We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines.
Highlights
The treatment of hypertensive subjects decreases the risk factors of cardiovascular diseases, since hypertension is related to the onset of cardiovascular diseases, such as stroke and coronary artery disease, and leads to an increase in mortality [1,2]
We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions using the bead mill method, and we evaluated the intestinal absorption of IRB-NC suspensions
The mean particle size of irbesartan in the IRB powder (IRB-P) suspensions was 4.89 ± 0.49 μm (Figure 1A), which was decreased to approximately 140 nm by bead mill treatment (Figure 1B,C), and the nanoparticles were sphere-shaped (Figure 1D)
Summary
The treatment of hypertensive subjects decreases the risk factors of cardiovascular diseases, since hypertension is related to the onset of cardiovascular diseases, such as stroke and coronary artery disease, and leads to an increase in mortality [1,2]. Nonselective beta blockers, thiazide diuretics, and angiotensin II type 1 (AT1) receptor blockers (ARBs) have been used as a form of therapy for hypertension, and irbesartan. 7.4 [3]; its small molecular active ingredient is a noncompetitive, potent, long-acting ARB and is specific to the AT1 receptor subtype [4,5,6,7]. It is shown in the package insert that the oral administration of irbesartan improves hypertension in stroke-prone spontaneously hypertensive rats (SHR-SP rats) and human patients with hypertension. A high variation of oral BA in irbesartan has been observed among
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