Abstract
Icariin (ICA) is a major flavonoid that contains the active compound Epimedii Folium. However, ICA’s pharmacokinetic characteristics remain unsatisfactory due to its low bioavailability, and hence limited drugability. In order to improve its pharmacokinetics and achieve prolonged blood circulation time, a novel polymeric micelle, made of the self-assembled micelle between poly (ethylene glycol)-poly (L-lactic acid) (PEG-PLLA) and poly (D-lactic acid)-poly(N-isopropylacrylamide) (PDLA-PNIPAM), was designed to encapsulate ICA. Our experimental results showed that this polymeric micelle formulation of ICA exhibited uniform nano-size distribution and high stability within 48 h. The new formulation also allowed sustained ICA release in an in vitro drug release study. Furthermore, in vivo experiments revealed that ICA bioavailability in the PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation was significantly higher compared to ICA alone, or ICA in the traditional Pluronic F127 micelle formulation. Finally, we show that metabolite analysis confirmed that ICA within the PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation provided better drug protection, reduced drug metabolites production, and decreased undesired first-pass effects. Overall, these data show that ICA within PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation exhibit advantages, in terms of improved physicochemical properties, sustained release of ICA in vitro, and improved bioavailability of ICA in vivo, which represent a feasible approach for improving the drugability of pharmaceutical small molecules with low bioavailability or poor stability.
Highlights
Epimedii Folium is the dry aerial part of various plants of the genus Epimedium brevicornu Maxim of Berberidaceae
The core is formed by hydrophobic segments (i.e., saturated fat chains, poly(lactic acid), and poly(caprolactone)), while the shell is formed by hydrophilic segments (i.e., chitosan, poly(ethylene glycol) or PEG, and hyaluronic acid), or temperature-sensitive material (poly(N-isopropyl acrylamide) or PNIPAM)
In PEG-PLLA/PDLA-PNIPAM polymeric material, PNIPAM is a temperature-sensitive segment with the lowest critical solution temperature (LCST), while the shell chain consisted of random-coil structures below the critical solution temperature
Summary
The core is formed by hydrophobic segments (i.e., saturated fat chains, poly(lactic acid), and poly(caprolactone)), while the shell is formed by hydrophilic segments (i.e., chitosan, poly(ethylene glycol) or PEG, and hyaluronic acid), or temperature-sensitive material (poly(N-isopropyl acrylamide) or PNIPAM). This unique structure would allow loading the core with hydrophobic drugs, thereby reducing the drug’s toxicity or other side effects. In PEG-PLLA/PDLA-PNIPAM polymeric material, PNIPAM is a temperature-sensitive segment with the lowest critical solution temperature (LCST), while the shell chain consisted of random-coil structures (hydrophilic state) below the critical solution temperature. To investigate whether PEG-PLLA/PDLA-PNIPAM polymeric nanomicelle formulation could have significant improvements on the pharmacokinetic properties of ICA, we compared the physical, chemical, and in vivo pharmacokinetic properties of PEG-PLLA/PDLA-PNIPAM and traditional F127 micelles
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