# US 2013/0280306 A1 · Block copolymers for stable micelles

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- Number: US 2013/0280306 A1
- Document ID: US20130280306A1
- Status: Published application
- Kind: A1
- Application number: 13/840,133
- Filed: 2013-03-15
- Published: 2013-10-24
- Earliest claimed: 2012-04-11
- Assignees: Intezyne Technologies, Inc.
- Applicants: Intezyne Technologies, Inc.
- Inventors: Kevin Sill; Tomas Vojkovsky; Adam Carie
- Web page: https://patentgrep.com/patent/US20130280306A1

## CPC

- C08G 69/40: Polyamides containing oxygen in the form of ether groups (C08G69/12, C08G69/32 take precedence)
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C08F 283/06: on to polyethers, polyoxymethylenes or polyacetals {(C08F283/004 takes precedence)}
- C08G 69/10: Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- 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
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.

## Claims

### Claim 1

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is SN-38.

### Claim 2 (depends on 1)

The micelle according to claim 1, wherein the triblock copolymer of formula VII is:

### Claim 3

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is aminopterin.

### Claim 4 (depends on 3)

The micelle according to claim 3, wherein the triblock copolymer of formula VII is:

### Claim 5

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is epothilone D.

### Claim 6 (depends on 5)

The micelle according to claim 5, wherein the triblock copolymer of formula VII is:

### Claim 7

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is daunorubicin.

### Claim 8 (depends on 7)

The micelle according to claim 7, wherein the triblock copolymer of formula VII is:

### Claim 9

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is berberine.

### Claim 10 (depends on 9)

The micelle according to claim 9, wherein the triblock copolymer is formula VII is:

### Claim 11

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is cabazitaxel.

### Claim 12 (depends on 11)

The micelle according to claim 11, wherein the triblock copolymer is formula VII is:

### Claim 13

A micelle comprising a triblock copolymer, wherein said micelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell, wherein the triblock copolymer is of formula VII:
wherein:
n is 20-500;
m is 1 or 2;
x1 is 1-20;
x2 is 0-20;
y is 5 to 100;
Ry is selected from one or more natural or unnatural amino acid side chain groups such that the overall block is hydrophobic;
M is a metal ion;
RT is —Z(CH2CH2Y)p(CH2)tR3, wherein:
Z is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
p is 0-10;
t is 0-10;
each R3 is independently selected from —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
the drug is docetaxel.

### Claim 14 (depends on 13)

The micelle according to claim 13, wherein the triblock copolymer of formula VII is: