Polymer hydrogels for in vivo applications and methods for using and preparing same

Patent metadata

Field	Value
Publication number	US-10039831-B2
Application number	US-201214005320-A
Country	US
Kind code	B2
Filing date	Mar 19, 2012
Priority date	Mar 17, 2011
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

Compositions and methods are described for a polymer hydrogel created by a cycloaddition reaction between an azide and an alkyne that proceeds rapidly without catalyst to produce the polymer hydrogel in less than ninety seconds. The polymer hydrogel can be used in in vivo applications for the localized delivery of therapeutic agent in aqueous solutions. An example of therapeutic delivery of a protein in a mouse model is demonstrated.

First claim

The invention claimed is:

1. A composition comprising a polymer hydrogel, the polymer hydrogel comprising:
a polyacrylate backbone comprising a structure according to Formula II

wherein
R 1 and R 2 are each independently hydrogen or a C 1 to C 6 hydrocarbon;
R 3 is hydrogen or methyl;
X is —O—, —S—, or —NR—;
Z is —OR 6 , —SR 6 , or NR 5 R 6 ;
m is greater than or equal to 1;
x is an integer greater than zero and z is zero or an integer greater than zero;
R 5 is hydrogen or C 1 to C 6 hydrocarbon; and
R 6 is hydrogen, C 1 to C 6 hydrocarbon or a polyglycol chain of two to ten glycol units;

a crosslinking member comprising a structure according to the Formula III

wherein
each R 10 , R 11 , R 12 , R 13 , R 10′ , R 11′ , R 12′ , and R 13′ is independently hydrogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, nitro, fluoro, chloro, or bromo;
Y 1 and Y 2 is each independently —O—, —S—, or —NR 4 —;
wherein R 4 is hydrogen or a C 1 to C 6 hydrocarbon; and
L comprises a polyglycol;

wherein the polyacrylate backbone and the crosslinking member are spontaneously polymerized to link the polyacrylate backbone and crosslinking member at the triazole ring to form the polymer hydro gel; and
a therapeutic agent not chemically bonded to the polymer hydrogel.

2. The composition of claim 1 , wherein Y 1 is —NH— and Y 2 is —O—.

3. The composition of claim 1 wherein L comprises 10-100 ethylene glycol units.

4. The composition of claim 3 , wherein L further comprises one or more ester, amide, carbonate, carbamate, or urea groups, or a mixture thereof.

5. The composition of claim 1 wherein R 10 , R 11 , R 12 , R 13 , R 10′ , R 11′ , R 12′ , and R 13′ are each independently hydrogen or fluoride.

6. The composition of claim 1 , wherein when z is greater than zero, the ratio of x to z is between about 5:1 to about 2:1.

7. The composition of claim 1 , wherein m is from 2 to about 6.

8. The composition of claim 1 , wherein the polyacrylate backbone and the crosslinking member are connected through the triazole ring.

9. The composition of claim 1 , wherein the polymer hydrogel has a structure of Formula IX:

wherein
R 1 and R 2 are each independently hydrogen or a C 1 to C 6 hydrocarbon;
x is an integer greater than zero, z is zero or an integer greater than zero;
X is —O—or —NR 5 —;
Y 1 is —NH— and Y 2 is —O—;
Z is —OR 6 or NHR 6 , wherein R 6 is hydrogen, C 1 to C 6 hydrocarbon or a polyethylene glycol chain of two to ten ethylene glycol units;
m is greater than or equal to 2, and
L comprises a polyethylene glycol.

10. The composition of claim 1 , wherein the therapeutic agent is a protein of between about 15 and about 35 kDa.

11. The composition of claim 1 , wherein the therapeutic agent is a recombinant protein that inhibits BMP.

12. The composition of claim 1 , wherein the polymer hydrogel is at a concentration of about 1.5% to about 15% weight to volume of water.

13. The composition of claim 1 , wherein said spontaneous polymerization of said polymer hydrogel is complete in less than three minutes.

14. The composition of claim 1 , wherein said polymer hydrogel achieves gelation within ninety seconds.

Assignees

• Murthy Niren
• Hermann Christopher
• Wilson David Scott
• Ning Xinghai
• Boyan Barbara D
• Schwartz Zvi
• Guldberg Robert
• Diab Tamim
• Georgia Tech Res Inst
• Childrens Healthcare Atlanta Inc

Inventors

• Murthy Niren
• Hermann Christopher
• Wilson David Scott
• Ning Xinghai
• Boyan Barbara D
• Schwartz Zvi
• Guldberg Robert
• Diab Tamim

Classifications

• A61L2400/06

  Flowable or injectable implant compositions · CPC title

• A61L27/54

  Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} · CPC title

• A61K47/32 Primary

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K38/1709

  from mammals · CPC title

• C07K14/51

  Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor · CPC title