Granted Patent B2

US 12,599,578 · App. 17/689,271 · Granted Apr 14, 2026

Inventor: Lynn Kirkpatrick (La Jolla, CA)

Assignee: Ensysce Biosciences Inc.

A61K31/155A61K9/1623A61K9/1635A61K9/1652A61K38/07A61K47/32A61K47/38A61K47/64A61K47/65

Abstract

Claims (65)

1 . A composition comprising:

an active agent prodrug selected from the group consisting of:

1) a compound of formula KC-(IIIa):

wherein:

X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)-NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ;

R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;

each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;

each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;

or R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;

n is an integer from 2 to 4;

R 3 is hydrogen or (1-4C) alkyl;

R 4 is

each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each W is independently —NR 8 —, —O— or —S—;

each R 8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

p is an integer from one to 100; and

R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

or a salt, hydrate or solvate;

2) a compound of formula PC-(I)

X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )  (PC-(I))

or a pharmaceutically acceptable salt thereof, wherein:

X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );

R 1 represents a (1-4C) alkyl group;

R 2 and R 3 each independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3;

R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and

R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide; and

3) a compound of formula AM-(I):

wherein

R 1 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and

R 2 is an acyl, substituted acyl, or an N-acyl derivative of a peptide;

or a salt, hydrate or solvate thereof; and

an oral composition comprising nafamostat or a pharmaceutically acceptable salt thereof, wherein the composition comprises:

an immediate release composition comprising nafamostat or a pharmaceutically acceptable salt thereof; and

a plurality of controlled release beads, each bead comprising:

a core;

an active agent layer comprising nafamostat or a pharmaceutically acceptable salt thereof; and

a controlled release layer comprising one or more polymers.

2 . The composition of claim 1 , wherein the core comprises a cellulose polymer, or silicon dioxide, or a sugar selected from the group consisting of glucose, sucrose, lactose, mannitol, xylitol, and sorbitol.

3 . The composition of claim 1 , wherein the active agent layer further comprises a binder.

4 . The composition of claim 1 , wherein the controlled release layer comprises a combination of:

acrylate copolymer A comprising poly (ethylacrylate, methyl-methacrylate and chlorotrimethyl-ammonioethyl methacrylate) comprising about 50 mEq of quaternary ammonium groups per 100 g of polymer; and

acrylate copolymer B comprising poly (ethylacrylate, methyl-methacrylate and chlorotrimethyl-ammonioethyl methacrylate) comprising about 25 mEq of quaternary ammonium groups per 100 g of polymer.

5 . The composition of claim 4 , wherein the controlled release layer comprises:

acrylate copolymer comprises: 95% by weight acrylate copolymer B and 5% by weight acrylate copolymer A;

acrylate copolymer comprises: 93% by weight acrylate copolymer B and 7% by weight acrylate copolymer A;

acrylate copolymer comprises: 92% by weight acrylate copolymer B and 8% by weight acrylate copolymer A;

acrylate copolymer comprises: 90% by weight acrylate copolymer B and 10% by weight acrylate copolymer A;

acrylate copolymer comprises 87% by weight acrylate copolymer B and 13% by weight acrylate copolymer A;

acrylate copolymer comprises: 80% by weight acrylate copolymer B and 20% by weight acrylate copolymer A; or

acrylate copolymer comprises: 70% by weight acrylate copolymer B and 30% by weight acrylate copolymer A.

6 . The composition of claim 1 , wherein the controlled release layer comprises from 5% and 30% by weight of each of the plurality of beads.

7 . The composition of claim 1 , wherein the active agent layer or the controlled release layer further comprise a plasticizer.

8 . The composition of claim 1 , wherein each of the plurality of beads comprises from 5% and 20% by weight of the nafamostat or a pharmaceutically acceptable salt thereof.

9 . The composition of claim 1 , wherein the composition comprises a plurality of controlled release beads, each bead comprising:

a microcrystalline cellulose core;

an active agent layer comprising nafamostat or a pharmaceutically acceptable salt thereof and a water soluble methylcellulose polymer; and

a controlled release layer comprising:

a first polymer comprising poly (ethylacrylate, methyl-methacrylate and chlorotrimethyl-ammonioethyl methacrylate) containing about 50 mEq of quaternary ammonium groups per 100 g of polymer;

a second polymer comprising poly (ethylacrylate, methyl-methacrylate and chlorotrimethyl-ammonioethyl methacrylate) containing about 25 mEq of quaternary ammonium groups per 100 g of polymer;

triethyl citrate; and

a glidant selected from micronized talc and syloid,

wherein the controlled release layer is formulated to provide for controlled release of the nafamostat or pharmaceutically acceptable salt thereof.

10 . The composition of claim 9 , wherein the controlled release layer is formulated to provide for release of 60% or more of the nafamostat or pharmaceutically acceptable salt thereof within 6 hours after administration.

11 . The composition of claim 9 , wherein the controlled release layer is formulated to provide for release of nafamostat or pharmaceutically acceptable salt thereof at a first rate for a first predetermined period of time followed by release of the nafamostat or pharmaceutically acceptable salt thereof at a second rate for a second predetermined period of time.

12 . A method comprising administering to a subject in need thereof a composition of claim 1 .

Assignments (3)

Continuity (2)

References Cited (166)