Development of novel mesoporous nanomatrix-supported lipid bilayers for oral sustained delivery of the water-insoluble drug, lovastatin.
The purpose of this study was to investigate the effect of a core/shell structured nanocomposite, mesoporous nanomatrix-supported lipid bilayer (MN-SLB), as an oral drug nanocarrier, on the dissolution behavior and in vivo absorption of a water-insoluble drug, lovastatin (LOV). The formulation strategy was based on the use of drug-loaded mesoporous silica as the core for the fusion of liposomes. Field emission scanning electron microscopy (FESEM), cryogenic transmission electron microscopy (Cryo-TEM) and nitrogen adsorption were used to systematically characterize the drug carrier and drug-loaded MN-SLB formulation, confirming the successful inclusion of LOV into the nano-pores of MN-SLB. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) confirmed that the incorporated drug in the carrier was in an amorphous state. An in vitro dissolution study showed that LOV-loaded MN-SLB exhibited a sustained drug release behavior. Compared with the LOV-loaded mesoporous silica particles, LOV-loaded MN-SLB markedly suppressed the burst release. Furthermore, the pharmacokinetics and relative bioavailability of the LOV-loaded MN-SLB formulation was studied in beagle dogs after oral administration and using a commercially available immediate release formulation (Sandoz Lovastatin®) as a reference. It was found that the relative bioavailability of LOV and LOV β-hydroxy acid (LOVA) for the LOV-loaded MN-SLB formulation was 207.2% and 192.1%, respectively. In addition, MN-SLB exhibited negligible toxicity against Caco-2 and HT-29 cells in cytotoxicity assays. The results of this study indicate that the MN-SLB nanocomposite is a promising candidate as a novel oral drug delivery nanovehicle for controlling the dissolution rate and improving the oral absorption of water-insoluble drugs.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou 221004, China. Electronic address: yanzhuozhang@126.com.
Yanzhuo
Y
Zhang
Centre for Pharmaceutical Preparations Technology & Research, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
Heran
H
Zhang
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Erxi
E
Che
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou 221004, China.
Lihua
L
Zhang
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou 221004, China.
Jin
J
Han
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou 221004, China.
Yihua
Y
Yang
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Siling
S
Wang
Pharmaceutical Division, Jiangsu Hengrui Medicine Co. Ltd., Lianyungang 222047, China.
Miao
M
Zhang
Pharmaceutical Division, Jiangsu Hengrui Medicine Co. Ltd., Lianyungang 222047, China.
Cunqiang
C
Gao
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations; D004285:Dogs; D004339:Drug Compounding; D065546:Drug Liberation; D019073:HT29 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry* / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology; D008148:Lovastatin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D065568:Oral Mucosal Absorption; D012822:Silicon Dioxide / Q000737:chemistry*
D000924:Anticholesteremic Agents; D003692:Delayed-Action Preparations; D008051:Lipid Bilayers; D008081:Liposomes; D012822:Silicon Dioxide; D008148:Lovastatin
Amorphous state; Cytotoxicity; Drug delivery; Oral absorption; Sustained release