# US 11,999,822 B2 · Polyoxazoline copolymer comprising calcium binding groups

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- Number: US 11,999,822 B2
- Document ID: US11999822B2
- Status: Granted
- Kind: B2
- Application number: 17/586,428
- Filed: 2022-01-27
- Published: 2022-05-19
- Granted: 2024-06-04
- Earliest claimed: 2019-07-30
- Assignees: Cilag GmbH International
- Applicants: Gatt Technologies B.V.
- Inventors: Sander Cornelis Gerardus Leeuwenburgh; Jan Cornelis Maria Van Hest; María José Sánchez-Fernández; Rosa Pilar Felix Lanao; Joost Opsteen; Johannes Caspar Mathias Elizabeth Bender
- Web page: https://patentgrep.com/patent/US11999822B2

## CPC

- C08G 73/0233: {Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups}
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

The present disclosure provides polyoxazoline (POx) copolymers which exhibit very high affinity for calcium ions, are capable of forming hydrogels and are bioresorbable. The polyoxazoline copolymers comprise at least 20 oxazoline units, including at least 4 non-terminal oxazoline units that contain a calcium binding group. Methods of making such polyoxazoline copolymers and using them in biomedical applications are also provided.

## Claims

### Claim 1

A polyoxazoline (POx) copolymer comprising at least 20 oxazoline units, including at least 4 non-terminal oxazoline units that contain a calcium binding group selected from bisphosphonate, citrate, ethylenediaminetetraacetic acid (EDTA) and combinations thereof,
wherein the copolymer comprises:
(a) repeating units A of formula —[N(Ra)CH2CH2]—;
(b) repeating units B of formula —[N(Rb)CH2CH2]—;
(c) optionally repeating units C of formula —[N(Rc)CH2CH2]—;
(d) optionally repeating units D of formula —[N(Rd)CH2CH2]—; and
(e) optionally repeating units E of formula —[N(Re)CH2CH2]—;
wherein:
Ra is CO—(CHR1)t—H;
Rb is CO—(CHR1)t—CONH—R2—X—CO—(CHR3)u—CONR4—CO-ccr;
R1 represents H or optionally substituted C1-5 alkyl;
R2 represents an optionally substituted C1-5 alkylene;
R3 represents H or optionally substituted C1-5 alkyl;
R4 represents H or CH3;
X represents O, NR11, S or +NR11(R12);
R11 and R12 represent H, methyl or ethyl;
t represents 1, 2 or 3;
u represents 1, 2 or 3; and
ccr represents a calcium binding group.

### Claim 2 (depends on 1)

The copolymer according to claim 1, wherein the oxazoline units containing a calcium binding group represent 3-50% of the monomeric units contained in the POx copolymer.

### Claim 3 (depends on 1)

The copolymer according to claim 1, wherein the copolymer comprises:
repeating units C of formula —[N(Rc)CH2CH2]—;
wherein:
Rc is CO—(CHR1)t—CONH—R2—X—CO—R5-cbx;
R5 represents an optionally substituted C1-5 alkylene; and
cbx represents a carboxylate containing group.

### Claim 4 (depends on 3)

The copolymer according to claim 3, wherein cbx represents COOH or COO−M+, wherein M represents a monovalent metal cation or NH4+.

### Claim 5 (depends on 1)

The copolymer according to claim 1, wherein the copolymer comprises:
repeating units D of formula —[N(Rd)CH2CH2]—;
wherein:
Rd is CO—(CHR1)t—CONH—R2—X—R6; and
R6 represents H, methyl or ethyl.

### Claim 6 (depends on 1)

The copolymer according to claim 1, wherein the copolymer comprises:
repeating units E of formula —[N(Re)CH2CH2]—;
wherein:
Re is CO—(CHR1)t—CONH—R2—X—CO—R5—CO-nhs; and
nhs represents a N-hydroxysuccinimidyl group.

### Claim 7 (depends on 1)

The copolymer according to claim 1, wherein the copolymer comprises:
repeating units E of formula —[NHCH2CH2]—.

### Claim 8 (depends on 1)

The copolymer according to claim 1, wherein the calcium binding group is bisphosphonate.

### Claim 9 (depends on 1)

The copolymer according to claim 1, wherein R1 represents H.

### Claim 10 (depends on 1)

The copolymer according to claim 1, wherein X represents O.

### Claim 11 (depends on 1)

The copolymer according to claim 1, wherein the total number of repeating units A, B, C, D and E in the copolymer is in the range of 60 to 200.

### Claim 12 (depends on 1)

A biocompatible medical product comprising a copolymer according to claim 1.

### Claim 13 (depends on 1)

A process of preparing a copolymer according to claim 1, said process comprising:
(a) cationic ring opening polymerizing a mixture comprising the following 2-oxazoline monomers A and B:
wherein R1 and t are defined as in claim 1, and wherein R11 represents an optionally substituted C1-5 alkyl;
(b) subjecting at least some of the alkylcarboxy groups of the intermediate polyoxazoline copolymer to amidation by reacting the groups with an amine represented by the following formula: H2N—R2−X—H, wherein R2 and X are as defined in claim 1;
(c) optionally functionalizing at least some of the amidated groups by reacting the groups with succinic anhydride;
(d) optionally activating at least some of the functionalized groups by reacting the groups with N-hydroxysuccinimide to introduce repeating units E of formula —[N(Re)CH2CH2]—; wherein Re is CO—(CHR1)t—CONH—R2—X—CO—R5—CO-nhs; and nhs represents a N-hydroxysuccinimidyl group;
(e) introducing calcium scavenging functionality by reacting at least some of the activated groups with a reactant comprising a calcium binding group selected from bisphosphonate, citrate, ethylenediaminetetraacetic acid (EDTA) and combinations thereof.