pH-Responsive Micelle Sequestrant Polymers Inhibit Fat Absorption

Current antiobesity therapeutics
are associated with side effects
and/or poor long-term patient compliance, necessitating development
of more efficacious and safer alternatives. Herein, we designed and
engineered a new class of orally acting pharmaceutical agents, or
micelle sequestrant polymers (MSPs), that could respond to the pH
change in the gastrointestinal (GI) tract and potentially sequester
lipid micelles; inhibiting lipid absorption through a pH-triggered
flocculation process. These MSPs, derived from poly­(2-(diisopropylamino)­ethyl
methacrylate) and poly­(2-(dibutylamino)­ethyl methacrylate), were soluble
in acidic media, but they transitioned to become insoluble around
pH 7.2 and 6.1, respectively. MSPs showed substantial bile acid and
triglyceride sequestration capacity with fast pH response tested in vitro. In vivo study showed that orally
dosed MSPs significantly enhanced fecal elimination of triglycerides
and bile acids. Several MSPs increased fecal elimination of triglycerides
by 9–10 times compared with that of the control. In contrast,
fecal concentration of bile acids, but not triglycerides, was increased
by cholestyramine or Welchol. Importantly, fecal elimination of bile
acids and triglycerides was unaltered by addition of control dietary
fibers. MSPs may serve as a novel approach to weight loss that inhibits
excess caloric intake by preventing absorption of excess dietary triglycerides.