Chronic Oral Administration of Mineral Oil Compared With Corn Oil: Effects on Gut Permeability and Plasma Inflammatory and Lipid Biomarkers.

We investigated the effects of chronic oral administration of mineral oil, versus corn oil as control, on intestinal permeability, inflammatory markers, and plasma lipids in APOE*3-Leiden.CETP mice. Mice received mineral oil or corn oil 15 or 30 µL/mouse/day for 16 weeks (15 mice/group). Intestinal permeability was increased with mineral versus corn oil 30 µL/day, shown by increased mean plasma FITC-dextran concentrations 2 h post-administration (11 weeks: 1.5 versus 1.1 µg/ml, p = 0.02; 15 weeks: 1.7 versus 1.3 µg/ml, p = 0.08). Mean plasma lipopolysaccharide-binding protein levels were raised with mineral versus corn oil 30 µL/day (12 weeks: 5.8 versus 4.4 µg/ml, p = 0.03; 16 weeks: 5.8 versus 4.5 µg/ml, p = 0.09), indicating increased intestinal bacterial endotoxin absorption and potential pro-inflammatory effects. Plasma cholesterol and triglyceride concentrations were decreased with mineral oil, without affecting liver lipids among treated groups. Fecal neutral sterol measurements indicated increased fecal cholesterol excretion with mineral oil 30 µL/day (+16%; p = 0.04). Chronic oral administration of mineral oil in APOE*3-Leiden.CETP mice increased intestinal permeability, with potential pro-inflammatory effects, and decreased plasma cholesterol and triglyceride levels. Our findings may raise concerns about the use of mineral oil as a placebo in clinical studies.

Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs.

We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy ß-oxidized atorvastatin. Atorvastatin and M1 pharmacokinetics and inflammatory markers were assessed in C57BL6/J mice given atorvastatin 5 mg/kg/day or 10 mg/kg/day, as a single dose or for 21 days, with or without 10 µL or 30 µL mineral oil. No consistent differences in plasma exposure of atorvastatin or M1 were observed in mice after single or repeat dosing of atorvastatin with or without mineral oil. However, mice administered atorvastatin 10 mg/kg with 30 µL mineral oil for 21 days had significantly increased plasma levels of serum amyloid A (mean 9.6 µg/mL vs 7.9 µg/mL without mineral oil; p < 0.01) and significantly increased proportions of C62Lhigh B cells (mean 18% vs 12% without mineral oil; p = 0.04). There were no statistically significant differences for other inflammatory markers assessed. In dogs, pharmacokinetics of atorvastatin, its two hydroxy metabolites and pravastatin (a hydrophilic statin) were evaluated after single administration of atorvastatin 10 mg plus pravastatin 40 mg with or without 2 g mineral oil. Pharmacokinetics of atorvastatin, hydroxylated atorvastatin metabolites or pravastatin were not significantly different after single dosing with or without mineral oil in dogs. Collectively, the results in mice and dogs indicate that mineral oil does not affect atorvastatin or pravastatin pharmacokinetics, but could cause low-grade inflammation with chronic oral administration, which warrants further investigation.

Effect of the manufacturing conditions on the structure and permeability of polymer films intended for coating undergoing phase separation.

The major aim of this work was to study the effect of two process parameters, temperature and coating flow, on permeability to water and structure of free films sprayed from mixtures of ethyl cellulose (EC), hydroxypropyl cellulose (HPC), and ethanol. The films were sprayed in a new spraying setup that was developed to mimic the film coating process in a fluid bed and to provide well controlled conditions. EC and HPC phase separated during the film drying process, and EC- and HPC-rich domains were formed. The process parameters had a great impact on the structure and the permeability to water of the films. The longer the time before the film structure was locked by a high film viscosity, that is, the lower the temperature and the higher the coating flow, the larger the domains and the lower the film permeability. The effective diffusion coefficient of water in the films varied by about six times within the range of the process parameters studied. Structures of sprayed films and water effective diffusion coefficients in sprayed films were compared to those of cast films. For the cast films, the domains were bigger, and the permeability to water was significantly lower compared to those of the sprayed films. The results indicate that the process parameters can be used as a mean to regulate structure and permeability of coating films undergoing phase separation.

Polymer leaching from film coating: effects on the coating transport properties.

The release mechanism of metoprolol succinate pellets coated with a blend of a water-insoluble polymer, ethyl cellulose (EC), and a water-soluble polymer, hydroxypropyl cellulose (HPC), is mechanistically explained. The kinetics of drug release and HPC leaching were followed for drug doses. The coating was initially not permeable to the drug, and release started only after a critical amount of the HPC had been leached out. Drug release occurred mainly through pores created in the coating by the HPC dissolution. Single-pellet release experiments were also performed. The coating thickness and size of each pellet were measured. In order to quantitatively characterize the transport properties of the coating of the individual pellets, and to determine the effective diffusion coefficient (D(e)) of the drug in the coating, a mechanistic model was used to fit the single-pellet release data. It was found that D(e) increased with time due to an increase in the amount of HPC leached. It was also found that D(e) was dependent on the coating thickness, and increased more slowly with a thicker coating. This agreed well with the finding that the HPC leaching rate decreased with increasing film thickness.