Pharmaceutical nanotechnology
Amorphous isradipine nanosuspension by the sonoprecipitation method

https://doi.org/10.1016/j.ijpharm.2014.08.017Get rights and content

Abstract

The aims of this study are to increase and explain the mechanism of dissolution enhancement of isradipine using the sonoprecipitation method for stable nanosuspensions. There have been still few of published researches on formulation of isradipine using nanoparticle engineering. Nanosuspension systems were prepared upon various factors including amplitude and the time length of ultrasonication. The dissolution test was performed according to the USP paddle method in intestinal fluid (pH 6.8). The crystalline structure of drug, the molecular interaction, morphology and size of nanosuspension were also investigated to determine the mechanism of dissolution enhancement. The sonoprecipitation method with use of HPMC 6 showed its potential in enhancement of the drug release rate. Stable nanosuspension was significantly depended on amplitude and time of ultrasonication since these factors affected on the size of nanoparticles. The synergistic effects of reduction of drug crystallinity and particle size could increase the dissolution rate of isradipine by providing a stable nanosuspension. This work may contribute to a new strategy for improvement dissolution rate of isradipine.

Introduction

Currently, more than 40% of drugs are poorly water-soluble, leading to the poor bioavailability (Müller et al., 2006, Patel and Agrawal, 2011). Therefore, one of the major current challenges of the pharmaceutical industry is related to strategies that improve the water solubility of drugs. A number of studies have been conducted with the aim to enhance solubility and dissolution rate of poorly water-soluble drugs. Sonoprecipitation method is one of the promising approaches for formulation of poorly water-soluble drug compounds (Dalvi and Dave, 2009, Dalvi and Dave, 2010, Dhumal et al., 2008, Liu et al., 2012, Miao et al., 2011, Moorthi and Kathiresan, 2013, Zheng et al., 2010) because ultrasound has been proved to be an effective method for breaking down particles into nanoparticles (Kim et al., 2013). Factors such as amplitude level and ultrasonication time can be controlled to produce highly stable nanosuspension and high drug dissolution rate.

Isradipine (IS), is a dihydropyridine calcium channel blocker, was chosen as the model drug in this research. It is virtually insoluble in water but freely soluble in acetone (Chrysant and Cohen, 1997, Leroueil-Le Verger et al., 1998) and may be degraded under the light. An IS formulation with improvement of dissolution and photo-instability hence should be investigated. In previous studies, we have successfully enhanced the dissolution rate and controlled release rate of IS using solid dispersion techniques (Tran and Tran, 2013, Tran et al., 2010). Recently, Park et al. has developed the inclusion complex of IS and β-cyclodextrin for improvement of photo-instability and dissolution profile (Park et al., 2013). However, there have been few of such studies on nano-sized formulation of IS apart from the research of Verger et al. (Leroueil-Le Verger et al., 1998). The aim of those nanoparticles was to prolong the antihypertensive effect of the drug.

Herein, this study was aimed to develop nanoparticulate systems for improving bioavailability of IS through an improved drug dissolution. Various polymers and ultrasonication conditions were used to investigate the improvement of dissolution rate and nanosuspention stablity. The structural behaviors of drug were characterized by powder X-ray diffraction (PXRD). Morphology and particle size analyses were also conducted through transmission electron microscope (TEM) and scanning electron microscope (SEM). The potential molecular interaction between drug and polymer was also investigated by Fourier transform infrared spectroscopy (FTIR).

Section snippets

Materials

Polyethylene oxide N-60K (PEO), hydroxypropyl methylcellulose 6 cps (HPMC 6) and hydroxypropyl methylcellulose 4000 cps were provided by from Dow Chemical Company (Midland, Michigan, USA). Acetone was purchased from Xilong Chemical Co., Ltd., (Shantou, Guangdong, China). The solvents (methanol and acetonitrile) for high performance liquid chromatography (HPLC) were purchased from Fisher Scientific (Pittsburgh, Pennsylvania, USA). All other chemicals were of analytical grade and were used without

Effect of polymer types and polymer concentrations on dissolution rate of IS

In order to find out the possibility of the varied release rate of drug by polymers, three types of polymers (HPMC 6, HPMC 4000 and PEO) were used to prepare the nanosuspension under the same ultrasonication conditions (Fig. 1). All of the polymers significantly increased the dissolution rate of IS as compared to the dissolution rate of pure drug. Thus, the sonoprecipitation method was effective in enhancing the drug release rate. However, drug release from the nanosuspension of PEO formulation

Conclusion

The sonoprecipitation method showed that it was an effective method for preparation of stable nanosuspension of IS. HPMC 6 significantly increased the dissolution rate of IS. The reduction of drug particle size and the change of crystalline form to amorphous form may attribute the main mechanism to the dissolution enhancement. The stability and size of nanosuspension were significantly affected by ultrasonication conditions such as amplitude level and time. F6 (amplitude level 5 in 5 min) was an

Acknowledgement

This research is funded by the International University, VNU-HCM under grant number SV-06-2012/HĐ-ĐHQT-QHQT&QLKH.

References (23)

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