Amorphous silibinin nanoparticles loaded into porous starch to enhance remarkably its solubility and bioavailability in vivo

https://doi.org/10.1016/j.colsurfb.2020.111474Get rights and content

Highlights

  • Silibinin(SLB) was loaded into porous starch(PS) in the form of nanoparticles (SNPS).

  • The SNPs had better dissolution properties than free SLB and SLB nanoparticles.

  • The SNPs has better oral bioavailability than free SLB and SLB nanoparticles.

Abstract

In the present study, the silibinin (SLB) was loaded into porous starch (PS) in the form of nanoparticles (SNPS) by the liquid antisolvent precipitation (LAP) method, so as to improve its solubility and bioavailability. Firstly, the different experimental parameters on drug loading (DL) of the SLB in the LAP process were optimized through the single-factor experiments. Under the optimum conditions, the DL and the encapsulation efficiency (EE) of the SNPS were 9.49 ± 0.37 % and 89.93 ± 0.64 %, respectively. Compared with free SLB and SLB nanoparticles (SN), the SNPS had a higher solubility, and was about 180.81 ± 5.32 μg/mL in artificial gastric juice (AGJ) and was about 88.91 ± 4.14 μg/mL in artificial intestinal juice (AIJ), respectively. The in vitro release study demonstrated a slow and sustained ± release of SLB from the SNPS with the SN and free SLB as controls. The pharmacokinetic results showed that the Cmax and AUC(0–t) of the SNPS (87.71 ± 7.24 μg/L, 439.55 ± 8.76 μg/L*h) increased when compared with the SN (60.31 ± 8.98 μg/L, 206.51 ± 12.24 μg/L*h) and free SLB (26.08 ± 1.43 μg/L, 102.63 ± 7.15 μg/L*h), showing its ability to improve SLB’s pharmacokinetic properties.

Introduction

Silibinin [SLB, Fig. 1(a)], a flavonolignans compound, is the effective component of silymarin. The SLB is extracted from Silybum marianum seeds [[1], [2], [3]]. This compound is a combination of two diastereomers: silibinin A and silibinin B [4,5]. It has many excellent pharmacological activities and has been widely used in the treatment of acute and chronic liver diseases, such as liver cirrhosis, hepatitis and alcoholic liver diseases [[6], [7], [8], [9]]. In recent years, researchers have found that it also plays important roles in the treatment of various cancer types, including liver cancer, colon cancer, prostate cancer, skin cancer, breast cancer and lung cancer [[10], [11], [12]]. Nevertheless, the SLB has a very poor aqueous solubility. Its bioavailability is also limited by the poor solubility and dissolution rate, which further limits its clinical application and treatment effect.

Starch is a renewable source of abundant resources in the natural world after cellulose, which is an abundant, relatively inexpensive and ecofriendly materials [13]. It has the advantages of good biocompatibility, biodegradability and interaction with living cells [14]. Porous starch (PS), known as microporous starch, is a new type of modified starch with abundant micro-sized pores or hollows from the surface to the center of its granules improving its performance as wall material and increasing the specific surface area [15]. In recent decades, the PS has become an ideal drug delivery system because of their prominent characteristics including relatively large specific surface area and pore volume, excellent pore structure, in vivo degradability and biosafety, and has been applied to many lipophilic drugs [[16], [17], [18]]. For example, Pawar J et al. showed that the oral bioavailability of itraconazole was increased by 3.12 times with PS as carrier [19]; Wu et al. showed that the use of the biodegradable porous starch foam (BPSF) enhanced the release and oral bioavailability of lovastatin in comparison with crude lovastatin and commercial capsules [20]; Meer Tarique Ali et al. reported that the carbamazepine loaed into PS systems showed an improved in vivo performance as compared to Tegretol and neat carbamazepine [21]. In addition, our group has tried to load paclitaxel nanoparticles into porous starch, which could improve the solubility and dissolution rate of paclitaxel more effectively than paclitaxel molecules loaded into porous starch [22]. Therefore, this study attempts to load SLB nanoparticles into porous starch, so as to improve the solubility and bioavailability of the SLB. In addition, our group also prepared SLB nanoparticles by liquid antisolvent precipitation method using Hydroxypropyl-β-cyclodextrin (HP-β-CD) as a cryoprotectant, and the nanoparticles obtained could effectively improve the solubility and bioavailability of the SLB, but they also had the problem of rapid release in vivo [23]. Therefore, we proposed the following hypothesis: whether drug nanoparticles loaded into porous starch can delay their release in vitro and in vivo. However, there is no report on the exploration of the above assumption.

In this study, the SLB was loaded into PS pores in the form of nanoparticles (SNPS) by the LAP method with PS as the carrier. Meanwhile, the SLB nanoparticles (SN) prepared under the same preparation conditions were used as the control. Then they were characterized for various physicochemical properties using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Moreover, the saturation solubility, the dissolution study in vitro and in vivo absorption in rats were also studied and investigated.

Section snippets

Material

Silibinin (SLB, purity = 98 %) was purchased from Baoji Haoxiang Biotechnology Co., Ltd. (Shangxi, China); Insoluble porous starch (corn starch treated with α-amylase and glucoamylase in weak acid)was obtained from Liaoning Lida Bio-technology Co., Ltd. (Liaoning, China); Hydroxy-propyl-methyl-cellulose (HPMC, viscosity∼3 mPa·s) of pharmaceutical grade was purchased from Aladdin (Shanghai, China). Deionized water was obtained by Hitech-K flow water purification system (Hitech Instruments Co.,

Effects of experimental parameters on SLB-loaded PS

The SNPS preparation involved several experiments to select the optimal conditions and obtain the formulation composition and production conditions. Several main factors influencing the DL, including SLB concentration, HPMC concentration, antisolvent/solvent volume ratio, temperature, stirring speed and stirring time were investigated. As shown in Fig. 2A, the DL clearly increased with increasing SLB concentration. The result indicated that the opportunities for PS to contact SLB increased as

Conclusion

In summary, we reported the SLB was loaded into the PS in the form of nanoparticles (SNPS) by the liquid antisolvent precipitation (LAP) method, thus the solubility and bioavailability of SLB were significantly improved. Several main factors that had the effects on the DL and the EE of the SLB had been evaluated by the single-factor experiments, and the DL and the EE of the SNPS were 9.49 ± 0.37 % and 89.93 ± 0.64 % under the optimum conditions, respectively. The solubility of the SNPS obtained

CRediT authorship contribution statement

Weiwei Wu: Conceptualization, Data curation, Writing - original draft, Visualization, Funding acquisition. Lingling Wang: Software, Formal analysis. Siying Wang: Methodology, Investigation.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgement

The authors would also like to acknowledge the financial support from the Science and Technology Project of Guangdong Province (No.2018A050506019) and the National Natural Science Foundation of China (no. 31870943).

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