PurposeTo 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.MethodsMixed 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.ResultsMixed 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.ConclusionsMixed 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-016-1954-9) contains supplementary material, which is available to authorized users.

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Background Venous thromboembolism is a potentially fatal complication of hospitalisation, affecting approximately 3% of non-surgical patients. Administration of low molecular weight heparins to the appropriate patients adequately decreases venous thromboembolism incidence, but guideline adherence is notoriously low. Objective To determine the effect of a multifaceted intervention on thromboprophylaxis guideline adherence. The secondary objective was to study the effect on guideline adherence specifically in patients with a high venous thromboembolism risk. As an exploratory objective, we determined how many venous thromboembolisms may be prevented. Setting A Dutch general teaching hospital. Method A prospective study with a pre- and post-intervention measurement was conducted. A multifaceted intervention, consisting of Clinical Decision Support software, a mobile phone application, monitoring of duplicate anticoagulants and training, was implemented. Guideline adherence was assessed by calculating the Padua prediction and Improve bleeding score for each patient. The number of preventable venous thromboembolisms was calculated using the incidences of venous thromboembolism in patients with and without adequate thromboprophylaxis and extrapolated to the annual number of admitted patients. Main outcome measure Adherence to thromboprophylaxis guidelines in pre- and post-intervention measurements. Results 170 patients were included: 85 in both control and intervention group. The intervention significantly increased guideline adherence from 49.4 to 82.4% (OR 4.78; 95%CI 2.37–9.63). Guideline adherence in the patient group with a high venous thromboembolism risk also increased significantly from 54.5 to 84.3% (OR 2.46; 95%CI 1.31–4.62), resulting in the potential prevention of ± 261 venous thromboembolisms per year. Conclusions Our multifaceted intervention significantly increased thromboprophylaxis guideline adherence.

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