# US 10,765,638 B2 · Particle formulation with polycation complex

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- Number: US 10,765,638 B2
- Document ID: US10765638B2
- Status: Granted
- Kind: B2
- Application number: 16/179,605
- Filed: 2018-11-02
- Published: 2019-05-09
- Granted: 2020-09-08
- Earliest claimed: 2017-11-03
- Assignees: Yale University
- Applicants: Yale University
- Inventors: W. Mark Saltzman; Joseph Contessa; Amanda King
- Web page: https://patentgrep.com/patent/US10765638B2

## CPC

- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 35/00: Antineoplastic agents
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compositions and methods for efficient delivery of therapeutic agents in vivo are provided. Typically, the compositions are in the form of polymeric particles formed from one or more therapeutic agent complexed with a polycationic polymer which is further encapsulated in one or more amphiphilic polymers, preferably diblock copolymer of a polyalkylene oxide and a polyester such as poly(D,L-lactide)-poly(ethylene glycol) (PLA-PEG). In the preferred embodiments, the chemotherapeutic agent reduces, or inhibits N-glycosylation of one or more receptor tyrosine kinases of cancer cells. Methods of using the particles to treat cancer are also provided.

## Claims

### Claim 1

Particles for delivery of one or more small molecule, non-polymeric therapeutic, prophylactic or diagnostic agents comprising
a) a core comprising a complex formed by the ionic association of the one or more small molecule, non-polymeric therapeutic, prophylactic, or diagnostic agents and one or more polycationic polymers, and
b) an outer layer comprising one or more amphiphilic block copolymers non-covalently associated on the outside of the complex.

### Claim 2 (depends on 1)

The particles of claim 1, wherein the complex forms nanoparticles having an average diameter of between 5 and 500 nm, inclusive.

### Claim 3 (depends on 2)

The particles of claim 2, wherein the nanoparticles have a diameter of between 20 nm and about 500 nm, between about 25 nm and about 250 nm, between about 25 nm and about 150 nm, between about 50 nm and about 150 nm, or between about 50 nm and about 100 nm.

### Claim 4 (depends on 1)

The particles of claim 1, wherein at least one of the one or more amphiphilic block copolymers is a polyester-polyalkylene oxide block polymer.

### Claim 5 (depends on 4)

The particles of claim 4, wherein the polyester-polyalkylene oxide block polymer is a poly(D,L-lactide)-poly(ethylene glycol) diblock polymer.

### Claim 6 (depends on 1)

The particles of claim 1, wherein at least one of the one or more polycationic polymers is polyethyleneimine.

### Claim 7 (depends on 1)

The particles of claim 1, wherein at least one of the one or more polycationic polymers has a molecular weight between about 5,000 Daltons and about 50,000 Daltons.

### Claim 8 (depends on 1)

The particles of claim 1, wherein the one or more small molecule, non-polymeric therapeutic agents are selected from the group consisting of chemotherapeutic agents, anti-angiogenesis agents, immunomodulators, and antiinfectives.

### Claim 9 (depends on 1)

The particles of claim 1, wherein at least one of the one or more small molecule, non-polymeric therapeutic agents directly or indirectly reduces or inhibits N-glycosylation of one or more receptor tyrosine kinases, by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than 90%.

### Claim 10 (depends on 9)

The particles of claim 9, wherein at least one of the one or more receptor tyrosine kinases is one or more EGFR family members, FGFR family members, or combinations thereof.

### Claim 11 (depends on 1)

The particles of claim 1, wherein at least one of the one or more small molecule, non-polymeric therapeutic agents is an inhibitor of oligosaccharyltransferase.

### Claim 12 (depends on 1)

The particles of claim 1, wherein at least one of the one or more small molecule, non-polymeric therapeutic agents is a compound of Formula I:
wherein,
A is unsubstituted aryl, substituted aryl, unsubstituted polyaryl, substituted polyaryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted C3-C20 cycloalkyl, unsubstituted C3-C20 cycloalkyl, substituted C3-C20 heterocyclyl, unsubstituted C3-C20 heterocyclyl, substituted C3-C20 cycloalkenyl, unsubstituted C3-C20 cycloalkenyl, substituted C3-C20 cycloalkynyl, or unsubstituted C3-C20 cycloalkynyl;
L1 and L3 are independently, —SO2—, —NHC(O)—, —NRa′C(O)—, —C(O)NH—, —C(O)NRa′—, —C(O)O—, —OC(O)—, —C(O)—, —C(O)OCH2—, —SO2NRa′—, —CH2Ra′—, —O—, —NRa′H—, —NRa′—, —OCONH—, —NHCOO—, —OCONRa′—, —NRa′COO—, —NHCONH—, —NRa′CONH—, —NHCONRa′—, —NRa′CON Ra″—, —CHOH—, —C Ra′OH—, unsubstituted alkyl, substituted alkyl, substituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl;
L2 is absent, —SO2—, —NHC(O)—, —NRa′C(O)—, —C(O)NH—, —C(O)NRa′—, —C(O)O—, —OC(O)—, —C(O)—, —C(O)OCH2—, —SO2NRa′—, —CH2Ra′—, —O—, —NRa′H—, —NRa′—, —OCONH—, —NHCOO—, —OCONRa′—, —NRa′COO—, —NHCONH—, —NRa′CONH—, —NHCONRa′—, —NRa′CON Ra″—, —CHOH—, —C Ra′OH—, unsubstituted alkyl, substituted alkyl, substituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl;
Ra′ and Ra″ are hydrogen, halogen, hydroxyl, unsubstituted alkyl, substituted alkyl, substituted alkylene, unsubstituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl, an aryl group, or a heterocyclic group;
R1 is unsubstituted dialkylamine, substituted dialkylamine, substituted C3-C20 heterocyclyl, unsubstituted C3-C20 heterocyclyl, substituted N-aryl-N-alkylamine, unsubstituted N-aryl-N-alkylamine, substituted aralkylamine, or unsubstituted aralkylamine;
R2 is hydrogen, substituted C3-C20 heterocyclyl, unsubstituted C3-C20 heterocyclyl, substituted C3-C20 cycloalkyl, unsubstituted C3-C20 cycloalkyl, substituted dialkylamine, or unsubstituted dialkylamine; and
R3 is substituted heteroaryl, unsubstituted heteroaryl, substituted aryl, unsubstituted aryl, unsubstituted polyaryl, substituted polyaryl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted C3-C20 cycloalkyl, unsubstituted C3-C20 cycloalkyl, substituted C3-C20 heterocyclyl, or unsubstituted C3-C20 heterocyclyl.

### Claim 13 (depends on 1)

The particles of claim 1, wherein at least one of the one or more small molecule, non-polymeric therapeutic agents is 5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-(pyrrolidin-1-yl)benzamide.

### Claim 14 (depends on 1)

A method of delivering one or more small molecule, non-polymeric therapeutic, prophylactic or diagnostic agents to a subject comprising administering a pharmaceutical composition comprising the particles of claim 1 to the subject.

### Claim 15 (depends on 14)

The method of claim 14, wherein at least one of the one or more small molecule, non-polymeric therapeutic agents is a compound of Formula I:
wherein,
A is unsubstituted aryl, substituted aryl, unsubstituted polyaryl, substituted polyaryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted C3-C20 cycloalkyl, unsubstituted C3-C20 cycloalkyl, substituted C3-C20 heterocyclyl, unsubstituted C3-C20 heterocyclyl, substituted C3-C20 cycloalkenyl, unsubstituted C3-C20 cycloalkenyl, substituted C3-C20 cycloalkynyl, or unsubstituted C3-C20 cycloalkynyl;
L1 and L3 are independently, —SO2—, —NHC(O)—, —NRa′C(O)—, —C(O)NH—, —C(O)NRa′—, —C(O)O—, —OC(O)—, —C(O)—, —C(O)OCH2—, —SO2NRa′—, —CH2Ra′—, —O—, —NRa′H—, —NRa′—, —OCONH—, —NHCOO—, —OCONRa′—, —NRa′COO—, —NHCONH—, —NRa′CONH—, —NHCONRa′—, —NRa′CON Ra″—, —CHOH—, —C Ra′OH—, unsubstituted alkyl, substituted alkyl, substituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl;
L2 is absent, —SO2—, —NHC(O)—, —NRa′C(O)—, —C(O)NH—, —C(O)NRa′—, —C(O)O—, —OC(O)—, —C(O)—, —C(O)OCH2—, —SO2NRa′—, —CH2Ra′—, —O—, —NRa′H—, —NRa′—, —OCONH—, —NHCOO—, —OCONRa′—, —NRa′COO—, —NHCONH—, —NRa′CONH—, —NHCONRa′—, —NRa′CON Ra″—, —CHOH—, —C Ra′OH—, unsubstituted alkyl, substituted alkyl, substituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl; Ra′ and Ra″ are hydrogen, halogen, hydroxyl, unsubstituted alkyl, substituted alkyl, substituted alkylene, unsubstituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl, an aryl group, or a heterocyclic group;
wherein Ra′ and Ra″ are hydrogen, halogen, hydroxyl, unsubstituted alkyl, substituted alkyl, substituted alkylene, unsubstituted alkylene, substituted alkenyl, unsubstituted alkenyl, substituted alkylamino, unsubstituted alkylamino, substituted carbonyl, or unsubstituted carbonyl, an aryl group, or a heterocyclic group;
R1 is unsubstituted dialkylamine, substituted dialkylamine, substituted C3-C20 heterocyclyl, unsubstituted C3-C20 heterocyclyl, substituted N-aryl-N-alkylamine, unsubstituted N-aryl-N-alkylamine, substituted aralkylamine, or unsubstituted aralkylamine;
R2 is hydrogen, substituted C3-C20 heterocyclyl, unsubstituted C3-C20 heterocyclyl, substituted C3-C20 cycloalkyl, unsubstituted C3-C20 cycloalkyl, substituted dialkylamine, or unsubstituted dialkylamine; and
R3 is substituted heteroaryl, unsubstituted heteroaryl, substituted aryl, unsubstituted aryl, unsubstituted polyaryl, substituted polyaryl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted C3-C20 cycloalkyl, unsubstituted C3-C20 cycloalkyl, substituted C3-C20 heterocyclyl, or unsubstituted C3-C20 heterocyclyl.

### Claim 16 (depends on 15)

The method of claim 15, wherein the subject has cancer.

### Claim 17 (depends on 16)

The method of claim 16, where in the cancer is non-small-cell lung cancer or glioma.

### Claim 18 (depends on 17)

The method of claim 17, wherein the pharmaceutical composition is administered in combination with a chemotherapeutic agent, radiotherapy, or a combination thereof.

### Claim 19 (depends on 18)

The method of claim 18, where in the cancer is associated with one or more mutations in one or more receptor tyrosine kinases.

### Claim 20

Particles for delivery of one or more therapeutic agents comprising
a) a core comprising a complex formed by the ionic association of the one or more therapeutic agents and one or more polycationic polymers, and
b) an outer layer comprising one or more amphiphilic block copolymers non-covalently associated on the outside of the complex,
wherein the one or more therapeutic agents reduce or inhibit N-glycosylation.

### Claim 21 (depends on 20)

The particles of claim 20, wherein the one or more therapeutic agents are selected from the group consisting of proteins, peptides, sugars, lipids, nucleic acids, or small molecules.

### Claim 22

Particles for delivery of one or more therapeutic agents comprising
a) a core comprising a complex formed by the ionic association of the one or more therapeutic agents and one or more polycationic polymers, and
b) an outer layer comprising one or more amphiphilic block copolymers non-covalently associated on the outside of the complex,
wherein the one or more therapeutic agents are selected from the group consisting of proteins, peptides, sugars, lipids, nucleic acids, or small molecules, and
wherein the one or more therapeutic agents reduce N-glycosylation of one or more receptor tyrosine kinases by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than 90%.