A safety, tolerability, and pharmacokinetic study of a novel simvastatin silica-lipid hybrid formulation in healthy male
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ORIGINAL ARTICLE
A safety, tolerability, and pharmacokinetic study of a novel simvastatin silica-lipid hybrid formulation in healthy male participants Tahlia R. Meola 1,2 & Ahmad Y. Abuhelwa 1,3 & Paul Joyce 1,2 & Peter Clifton 1 & Clive A. Prestidge 1,2 Accepted: 7 September 2020 # Controlled Release Society 2020
Abstract Simvastatin (SIM) is a commonly used cholesterol-lowering drug that can reduce the risk of major cardiovascular events. However, due to its poor intrinsic water solubility, the drug is poorly absorbed from the gastrointestinal tract and exhibits a low oral bioavailability of approximately 5%. The aim of this study was to fabricate and optimize SIM encapsulated silica-lipid hybrids (SLH) as a solid-state lipid-based formulation to enhance absorption and bioavailability during a human in vivo pharmacokinetic study. SLH formulations were formulated by spray drying a submicron emulsion with either Aerosil® 300 fumed silica nanoparticles (SLH-A) or Syloid® 244 amorphous micronized silica (SLH-B). A cross-over, double-blinded study design was implemented to evaluate the performance of SLH formulations compared with a commercially available formulation in 12 healthy male participants after oral administration under fasting conditions. SLH formulations enhanced the bioavailability of SIM up to 1.6-fold and more importantly the active simvastatin acid (SIMA), 3.5-fold when compared with an equivalent dose of commercial formulation. The results demonstrate that the porous nanostructure of SLH impact systemic SIM and SIMA concentrations and may serve as a novel approach to enhance the bioavailability of specifically the parent or metabolite. No significant difference was observed in exposure when SLH formulations were administered at 10 mg in comparison with 20 mg of the commercial formulation, suggesting the potential for dose reduction. The study indicated that SLH formulations were safe and well-tolerated when administered to healthy males, confirming the commercial potential of SLH to enhance the bioavailability of poorly water-soluble drugs.
Keywords Simvastatin . Clinical trial . Oral delivery . Bioavailability . Lipid formulation . Silica Abbreviations AUC Area under the curve Cmax Maximum concentration DSC Differential scanning calorimetry HbsAg Hepatitis B surface antigen HCV Hepatitis C virus
* Clive A. Prestidge [email protected] 1
UniSA Clinical & Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia
2
ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, University of South Australia, Adelaide, South Australia 5000, Australia
3
Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
HMG-CoA HPLC ke LBFs LCMS SIM SIMA SLH SSF T1/2 Tmax
3-hydroxy-3-methyl-glutaryl-coenzyme A High-performance liquid chromatography Apparent terminal elimination rate constant Lipid-based formulations Liquid chromatography-mass spectrometry Simvastatin Simvas
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