The pH–induced crystallization of weakly basic drugs in the small intestine limits oral bioavailability. In this study, we investigated the solubilization and inhibitory effects on nintedanib in the presence of enteric polymers (HPMCAS LG, HPMCAS MG, Eudragit L100 55, and Eudragit L100). These polymers provided maintenance of supersaturation by increasing the solubility of nintedanib in PBS 6.8 in a concentration–dependent manner, and the improved ranking was as follows: Eudragit L100 > Eudragit L100 55 > HPMCAS MG > HPMCAS LG. After being formulated into amorphous solid dispersions (ASDs) by a solvent evaporation method, the drug exhibited an amorphous state. The pH shift dissolution results of polymer–ASDs demonstrated that four polymers could effectively maintain the drug supersaturation even at the lowest ratio of nintedanib and polymer (1:1, w/w). Eudragit L100–ASD could provide both acid resistance and the favorable mitigation of crystallization in GIF. In comparison to the coarse drug, the relative bioavailability of Eudragit L100–ASD was 245% after oral administration in rats, and Tmax was markedly delayed from 2.8 ± 0.4 h to 5.3 ± 2.7 h. Our findings indicate that enteric ASDs are an effective strategy to increase the intestinal absorption of nintedanib by improving physiologically generated supersaturation and subsequent crystallization.
Increasing
evidence has shown that nanocarriers have effects on
several efflux drug transporters. To date, little is known about whether
influx transporters are also modulated. Herein, we investigated the
impact of amphiphilic polymer micelles on the uptake function of organic
cation transporters (OCTs) and the influence on the pharmacokinetics
and pharmacodynamics of metformin, a well-characterized substrate
of OCTs. Five types of polymeric micelles (mPEG2k-PCL2k, mPEG2k-PCL3.5k, mPEG2k-PCL5k, mPEG2k-PCL7.5k, and mPEG2k-PCL10k) were prepared to evaluate the inhibition
of hOCT1-3-overexpressing Madin–Darby canine kidney cells.
The mPEG2k-PCL
x
micelles played
an inhibitory role above the critical micelle concentration. The inhibitory
potency could be ranked as mPEG2k-PCL2k >
mPEG2k-PCL3.5k > mPEG2k-PCL5k >
mPEG2k-PCL7.5k > mPEG2k-PCL10k, which negatively declined with the increase of molecular
weight
of the hydrophobic segment. The inhibitory effects of polymeric micelles
on the hOCT1 isoform were the most pronounced, with the lowest IC50 values ranging from 0.106 to 0.280 mg/mL. The mPEG2k-PCL2k micelles distinctly increased the plasma concentration
of metformin and significantly decreased V
ss by 35.6% (p < 0.05) after seven consecutive
treatments in rats, which was interrelated with the restrained metformin
distribution in the liver and kidney. The uptake inhibition of micelles
on hepatic and renal rOcts also diminished the glucose-lowering effect
of metformin and fasting insulin levels in the oral glucose tolerance
test. Consistent with the inhibitory effects, the mRNA and protein
levels of rOct1 and rOct2 were decreased in the liver, kidney, and
small intestine. The present study demonstrated that mPEG2k-PCL
x
micelles could inhibit the transport
function of OCTs, indicating a potential risk of drug–drug
interactions during concomitant medication of nanomedicine with organic
cationic drugs.
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