Administration of serine protease inhibitors to the stomach
Inventors
Schmid-Schonbein, Geert W. • Lee, Yung-Tsai (Andrew) • Wei, Jeng
Assignees
University of California San Diego UCSD • Leading Biosciences Inc
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Publication Number
US-10137100-B2
Publication Date
2018-11-27
Expiration Date
Abstract
The inventors have unexpectedly discovered that shock and/or potential multi-organ failure due to shock can be effectively treated by administration of liquid high-dose protease inhibitor formulations to a location upstream of where pancreatic proteases are introduced into the gastrointestinal tract. Most preferably, administration is directly to the stomach, for example, via nasogastric tube under a protocol effective to treat shock by such administration without the need of providing significant quantities of the protease inhibitor to the jejunum and/or ileum.
Core Innovation
The invention relates to treating shock in a mammal by administering an aqueous pharmaceutical composition that includes a protease inhibitor, polyethylene glycol-3350, and electrolytes. The approach targets shock and shock-related multi-organ failure by delivering protease inhibition through a gastrointestinal route upstream of pancreatic protease release.
The protease inhibitor is described as a protease inhibitor formulation for controlling protease activity associated with shock, including proteases such as amylase activity, lipase activity, trypsin, chymotrypsin, kallikrein, and elastase. Examples and described candidates include serine protease inhibitors and specific inhibitors such as gabexate mesilate (FOY) and related listed agents.
The invention further describes treatment across different shock subtypes, including traumatic, septic, cardiogenic, and hypovolemic shock, and their relationship to multiple organ failure. The partial content includes a human case study shifting from intravenous to enteral stomach-delivered gabexate mesilate (FOY) with reported stabilization and improved clinical/laboratory outcomes.
Claims Coverage
The independent claim provides a method of treating shock in a mammal using a specific aqueous composition that contains three components: a protease inhibitor, polyethylene glycol-3350, and electrolytes, administered in a therapeutically effective amount. Dependent claims further define shock subtypes and refine the protease inhibitor selection and administration route/device.
Therapeutic oral protease-inhibitor aqueous composition for shock
A method of treating shock in a mammal comprising orally administering a therapeutically effective amount of an aqueous pharmaceutical composition comprising a protease inhibitor, polyethylene glycol-3350, and electrolytes.
Protease inhibitor selection for the aqueous shock composition
The method wherein the protease inhibitor is selected from serine, cysteine, threonine, aspartate, glutamate protease inhibitors, matrix metalloprotease inhibitors, or combinations thereof.
Protease inhibitor composition list for the aqueous shock composition
The method wherein the protease inhibitor is selected from serpin, alpha-1 antitrypsin, alpha-2 macroglobulin, and small-molecule inhibitors including gabexate monomethanesulfonate, diisopropylfluorophosphate, p-(amidinophenyl)methanesulfonyl fluoride, tranexamic acid, 4-(2-aminoethyl)benzenesulfonyl fluoride, and camostate.
Protease inhibitor amount range in the aqueous shock composition
The method practiced with a composition that contains about 2 grams to about 20 grams of a protease inhibitor.
Nasogastric tube oral administration
The method includes orally administering the composition via a nasogastric tube.
Overall, the claim coverage centers on treating shock via oral delivery of an aqueous composition combining a protease inhibitor, polyethylene glycol-3350, and electrolytes, with dependent refinements specifying protease-inhibitor categories and examples, numeric protease-inhibitor mass range, and administration via a nasogastric tube.
Stated Advantages
Effective treatment of shock is achieved without significant delivery to the jejunum/ileum.
A human case study reports stabilization and improved clinical/laboratory outcomes after shifting from intravenous to enteral stomach-delivered gabexate mesilate (FOY).
Documented Applications
Treating shock in a mammal using oral administration of an aqueous pharmaceutical composition comprising a protease inhibitor, polyethylene glycol-3350, and electrolytes.
Treatment of traumatic shock, septic shock, cardiogenic shock, and hypovolemic shock.
Enteral delivery of gabexate mesilate (FOY) to the stomach via nasogastric tube in a human case study with reported stabilization and improved clinical/laboratory outcomes.
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