Incorporation of simvastatin into lipid membranes: Why deliver a statin in form of inclusion complex with hydrophilic cyclodextrin.

In this work, the effects of simvastatin (SIM), (2-hydroxypropyl)-β-cyclodextrin (HPβCD) and their complex (SIM:HPβCD) on the structure and properties of lipid membranes were investigated for the first time by Langmuir technique combined with PM-IRRAS spectroscopy. An improved understanding of the differences of the interactions between free SIM, and SIM in the form of an inclusion complex with HPβCD with the lipid membrane will improve the development of preparation methods for in vivo applications. Monolayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), cholesterol (Chol) and their mixture DMPC:Chol (7:3) served as simple models of one leaflet of the cell membrane. The penetration of well-organized lipid layers by simvastatin lead to their fluidization but the extent of this unwanted effect was smaller when the drug was delivered in the form of the SIM:HPβCD complex. Surface pressure vs. time dependencies showed that the drug encapsulated with cyclodextrin dissociated from the complex upon contact with the lipid layer and the weak interactions between the exterior polar part of the HPβCD and the polar headgroups of the lipid layer facilitated smooth incorporation of the released lipophilic drug into the membrane. At a longer time-scale, the HPβCD ligand released from the complex removed some cholesterol, but not DMPC, from the lipid layer, hence, similarly to the enzyme inhibiting action of statins - it lead to the decrease of the amount of cholesterol in the membrane. Delivery of simvastatin in the form of an inclusion complex with HPβCD is proposed as an approach improving its bioavailability in the cholesterol-lowering therapies.