IP Library › Granted Patent US 9,078,930
Granted Patent B2
US 9,078,930 · App. 13/840,133 · Granted Jul 14, 2015

Block copolymers for stable micelles

Inventors: Kevin Sill (Tampa, FL); Tomas Vojkovsky (Palm Beach Gardens, FL); Adam Carie (Ruskin, FL)
Assignee: Intezyne Technologies, Inc.
A61K47/48315A61K9/1075A61K31/337A61K31/427A61K31/475A61K31/4745A61K31/704A61K47/34A61K47/488A61K47/48215C08F283/06C08G69/10C08G69/40
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Quick Facts
Patent No.
US 9,078,930
App. No.
13/840,133
Granted
Jul 14, 2015
Kind
B2
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 (119)

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10;

each R 3 is independently selected from —N 3 , —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

wherein the drug is 7-ethyl-10-hydroxy-camptothecin.

2. A micelle according to claim 1 , wherein the triblock copolymer is of formula VII:

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10;

each R 3 is independently selected from —N 3 , —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

wherein the drug is aminopterin.

4. A micelle according to claim 3 , wherein the triblock copolymer is of formula VII:

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10;

each R 3 is independently selected from —N 3 , —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

wherein the drug is epothilone D.

6. A micelle according to claim 5 , wherein the triblock copolymer is of formula VII:

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10;

each R 3 is independently selected from —N 3 , —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

wherein the drug is daunorubicin.

8. A micelle according to claim 7 , wherein the triblock copolymer is of formula VII:

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10;

each R 3 is independently selected from —N 3 , —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

wherein the drug is berberine.

10. A micelle according to claim 9 , wherein the triblock copolymer is of formula VII:

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10; and

each R 3 is independently selected from —N 3 , —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

wherein the drug is cabazitaxel.

12. A micelle according to claim 11 , wherein the triblock copolymer is of formula VII:

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;

x 1 is 1-20;

x 2 is 0-20;

y is 5 to 100;

R y 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;

R T is —Z(CH 2 CH 2 Y) p (CH 2 ) t R 3 , wherein:

Z is —O—, —S—, —C≡C—, or —CH 2 —;

each Y is independently —O— or —S—;

p is 0-10;

t is 0-10;

each R 3 is independently selected from —N 3 , —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

wherein the drug is docetaxel.

14. A micelle according to claim 13 , wherein the triblock copolymer is of formula VII:

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 19, 2013
From: SILL, KEVIN; VOJKOVSKY, TOMAS; CARIE, ADAM
To: INTEZYNE TECHNOLOGIES, INC.
Reel/Frame 030043/0622 →
Continuity (3)
Provisional Application 61622755 · Apr 11, 2012
Provisional Application 61659841 · Jun 14, 2012
Related Publication 20130280306A1 · Oct 24, 2013