# US 12,599,578 B2 · Compositions comprising enzyme-cleavable prodrugs and controlled release nafamostat and methods of use thereof

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- Number: US 12,599,578 B2
- Document ID: US12599578B2
- Status: Granted
- Kind: B2
- Application number: 17/689,271
- Filed: 2022-03-08
- Published: 2022-09-15
- Granted: 2026-04-14
- Earliest claimed: 2021-03-09
- Assignees: Ensysce Biosciences Inc.
- Applicants: Ensysce Biosciences Inc.
- Inventors: Lynn Kirkpatrick
- Web page: https://patentgrep.com/patent/US12599578B2

## CPC

- A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5078: {with drug-free core}
- A61K 31/245: Amino benzoic acid types, e.g. procaine, novocaine (salicylic acid esters A61K31/60)
- A61K 38/07: Tetrapeptides
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61K 47/38: Cellulose; Derivatives thereof
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Aspects of the present disclosure include pharmaceutical compositions, and their methods of use, where the pharmaceutical compositions include an active agent prodrug that provides enzymatically-controlled release of an active agent, and controlled release nafamostat or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 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)-NR5—(C(R1)(R2))n—NR3R4;
R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R1 and R2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R2 or R3 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;
R3 is hydrogen or (1-4C) alkyl;
R4 is
each R6 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, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each W is independently —NR8—, —O— or —S—;
each R8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R6 and R8 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
R7 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)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) (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)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5);
R1 represents a (1-4C) alkyl group;
R2 and R3 each independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3;
R4 represents —CH2CH2CH2NH(C═NH)NH2 or —CH2CH2CH2CH2NH2, the configuration of the carbon atom to which R4 is attached corresponding with that in an L-amino acid; and
R5 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
R1 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and
R2 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 4)

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.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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.

### Claim 11 (depends on 9)

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.

### Claim 12 (depends on 1)

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