Drinkable Hydrogels Bridge the Gap Between Pills and Liquid Therapies

Some 50% of children and more than 37% of adults cannot swallow standard-sized pills or capsules. To facilitate oral drug administration, researchers have developed a drinkable formulation called LIFT (liquid in situ–forming tough) hydrogels that transitions from liquid to solid upon mixing in the stomach.

Gary W. Liu, PhD, a fellow at the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Giovanni Traverso, MD, PhD, MBBCH, an investigator there and in the Division of Gastroenterology, Hepatology and Endoscopy at Brigham and Women’s Hospital; and colleagues show in Nature Materials how LIFT hydrogels could expand access to advanced therapeutics for people who have trouble swallowing.


Given the relatively short residence of liquids in the stomach (<30 minutes) and the complexity of gastric fluid, the researchers chose materials they believed could rapidly form two interpenetrating polymer networks. All materials are FDA-approved or have “generally recognized as safe” status.

The final system calls for:

  • Ingestion of a 200-mL crosslinker solution containing calcium chloride plus either dimercaptosuccinic acid (DMSA) or poly(ethylene glycol) (PEG)-dithiol
  • Subsequent ingestion of a 20- to 40-mL polymer solution containing alginate and four-arm PEG-maleimide


In vitro, LIFT hydrogels formed rapidly even in gastric fluid, were mechanically tough, and were biocompatible. Both DMSA and PEG–dithiol could crosslink with the alginate and PEG-maleimide solution.

In pigs, which have a human-sized gastrointestinal tract, LIFT hydrogels and their components did not affect blood chemistry, were safely cleared, and did not cause obstruction or lack of appetite.

Small-Molecule Release

Lumefantrine, a small-molecule drug poorly soluble in water, was administered to pigs in a solution containing alginate and PEG-maleimide. Other pigs received the same lumefantrine dose within gelatin pills as a free drug control.

The area under the receiver operator characteristic curve (AUC) was similar with the two approaches, but the maximum observed drug concentration was significantly higher with free drug than with LIFT hydrogels.

The ability of LIFT hydrogels to deliver comparable doses of drug at lower plasma concentrations may reduce drug toxicity. This has important implications for drugs whose efficacy is driven by AUC and not plasma concentration, such as tetracyclines.

Protection of Therapeutic Enzymes and Bacteria

In additional experiments, LIFT hydrogels protected therapeutic enzyme activity both in vitro and in rats (lactase was the enzyme studied in both models). The hydrogels are also protected against a protease (trypsin).

In pigs, LIFT hydrogels supported the viability of Lactococcus lactis, a bacterium being investigated for oral delivery of synthetic biologic drugs.

Clinical Outlook

LIFT hydrogels may have wide applications in gastric drug modulation and delivery, weight loss, and protection of encapsulated biologics. They may be able to:

  • Control water-soluble drug release
  • Prolong transit time
  • Reduce surface area-to-volume ratios, which could further control drug release
  • Facilitate programmed drug release within specific tissues if protease- or pH-sensitive linkers are included
  • Prolong the drug residence and activity of engineered bacteria and enzyme therapies

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