A Mixed Micelle Formulation for Oral Delivery of Vitamin K

Pharm Res. 2016 Sep;33(9):2168-79. doi: 10.1007/s11095-016-1954-9. Epub 2016 May 31.

Abstract

Purpose: To develop a stable micellar formulation of vitamin K for oral delivery, because the commercial and clinically used formulation of vitamin K (Konakion® MM) destabilizes at gastric pH resulting in low bioavailability of this vitamin in neonates with cholestasis.

Methods: Mixed micelles composed of EPC, DSPE-PEG 2000 and glycocholic acid, with and without vitamin K, were prepared by a film hydration method. The influence of pH on the stability of the micelles was analyzed by dynamic light scattering (DLS). The critical micelle concentration (CMC) was determined by fluorescence spectroscopy using pyrene and the morphology was evaluated by transmission electron microscopy . Caco-2 cells were used to study the cytocompatibilty.

Results: Mixed micelles with mean diameters from 7.1 to 11.0 nm and a narrow size distribution (PDI < 0.2) were obtained after 3 membrane extrusion cycles. Konakion® MM formed aggregated particles at gastric pH, which was avoided through steric stabilization by introducing PEG. TEM showed that mixed micelles had a spherical size (diameter of around 10 nm) with a narrow size distribution in agreement with the DLS results. The loading capacities for vitamin K of mixed micelles with varying molar fractions of DSPE-PEG and EPC (from 0/100 to 50/50 (mol/mol)) were 10.8-5.0 w%, respectively. The mixed micelles showed good cytocompatibility at concentrations of glycocholic acid between 0.12 and 1.20 mM.

Conclusions: Mixed micelles with superior stability to Konakion® MM at low pH were obtained by introducing DSPE-PEG 2000. These are therefore attractive oral formulations for vitamin K.

Keywords: Konakion® MM; Mixed micelles; PEGylation; Vitamin K; pH stability.

MeSH terms

  • Administration, Oral
  • Caco-2 Cells
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • Drug Carriers / chemistry
  • Drug Delivery Systems / methods
  • Glycocholic Acid / chemistry
  • Humans
  • Hydrogen-Ion Concentration
  • Micelles
  • Particle Size
  • Phosphatidylethanolamines / chemistry
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / chemistry
  • Polyethylene Glycols / chemistry
  • Polymers / chemistry
  • Vitamin K / administration & dosage
  • Vitamin K / chemistry*
  • Vitamin K 1 / administration & dosage
  • Vitamin K 1 / chemistry

Substances

  • 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
  • Drug Carriers
  • Micelles
  • Phosphatidylethanolamines
  • Polymers
  • Phosphorylcholine
  • Vitamin K
  • erucylphosphocholine
  • Polyethylene Glycols
  • Vitamin K 1
  • Glycocholic Acid