Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics

Gary W Liu; Matthew J Pickett; Johannes L P Kuosmanen; Keiko Ishida; Wiam A M Madani; Georgia N White; Joshua Jenkins; Sanghyun Park; Vivian R Feig; Miguel Jimenez; Christina Karavasili; Nikhil B Lal; Matt Murphy; Aaron Lopes; Joshua Morimoto; Nina Fitzgerald; Jaime H Cheah; Christian K Soule; Niora Fabian; Alison Hayward; Robert Langer; Giovanni Traverso

doi:10.1038/s41563-024-01811-5

Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics

Nat Mater. 2024 Sep;23(9):1292-1299. doi: 10.1038/s41563-024-01811-5. Epub 2024 Feb 27.

Authors

Gary W Liu¹, Matthew J Pickett^{1

2}, Johannes L P Kuosmanen³, Keiko Ishida^{1

4

5}, Wiam A M Madani^{1

6}, Georgia N White¹, Joshua Jenkins^{3

7}, Sanghyun Park^{1

3

4}, Vivian R Feig^{1

4

8}, Miguel Jimenez^{1

3

4

9}, Christina Karavasili^{1

4}, Nikhil B Lal^{3

4

10}, Matt Murphy^{3

4}, Aaron Lopes^{1

4}, Joshua Morimoto¹, Nina Fitzgerald^{1

11}, Jaime H Cheah^{1

12}, Christian K Soule^{1

12}, Niora Fabian^{1

3

13}, Alison Hayward^{1

4

13}, Robert Langer¹, Giovanni Traverso^{14

15

16}

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Chemistry, Yale University, New Haven, CT, USA.
³ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Fractyl Health, Inc., Lexington, MA, USA.
⁶ Weill Cornell Medical College, New York City, NY, USA.
⁷ Ross University School of Veterinary Medicine, Basseterre, St. Kitts and Nevis.
⁸ Stanford University, Stanford, CA, USA.
⁹ Boston University, Boston, MA, USA.
¹⁰ MIT Media Lab, Cambridge, MA, USA.
¹¹ Tufts University, Medford, MA, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
¹⁵ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
¹⁶ Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cgt20@mit.edu.

Abstract

Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.

MeSH terms

Alginates / chemistry
Animals
Hydrogels* / chemistry
Polyethylene Glycols / chemistry
Rats
Swine

Substances

Hydrogels
Polyethylene Glycols
Alginates

Grants and funding

INV-009529/GATES/Bill & Melinda Gates Foundation/United States