Implantable bio-resorbable polymer charged with fragile macromolecules

Patent metadata

Field	Value
Publication number	US-10064948-B2
Application number	US-201214003528-A
Country	US
Kind code	B2
Filing date	Mar 9, 2012
Priority date	Mar 9, 2011
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

The present invention relates to a macromolecule-loaded bioresorbable crosslinked polymer wherein the polymer is obtainable from the polymerization of: (i) at least one monomer of formula (I) (CH 2 ═CR 1 )CO—K wherein: —K represents O—Z or NH—Z, Z representing (CR 2 R 3 ) m —CH 3 , (CH 2 —CH 2 —O) m —H, (CH 2 —CH 2 —O) m —CH 3 , (CH 2 ) m —NR 4 R 5 with m representing an integer from 1 to 30; —R 1 , R 2 , R 3 , R 4 and R 5 independently represent H or a C1-C6 alkyl; and (ii) at least one bio-resorbable block copolymer cross-linker, and wherein the macromolecule is chosen in the group consisting of proteins and nucleic acids.

First claim

The invention claimed is:

1. A macromolecule-loaded bioresorbable crosslinked polymer wherein the polymer is obtainable from the polymerization of:
(i) at least one monomer of formula (I)
(CH 2 ═CR 1 )CO—K  (I)

wherein:
K represents O—Z or NH—Z, Z representing (CR 2 R 3 ) m —CH 3 , (CH 2 —CH 2 —O) m —H, (CH 2 —CH 2 —O) m —CH 3 , (CH 2 ) m —NR 4 R 5 with m representing an integer from 1 to 30;
R 1 , R 2 , R 3 , R 4 and R 5 independently represent H or a C 1 -C 6 alkyl;

and
(ii) at least one bio-resorbable block copolymer cross-linker, wherein the bio-resorbable block copolymer cross-linker is linear and selected from the group consisting of polyethylene glycol (PEG), poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactic-glycolic acid (PLGA) and poly(caprolactone) (PCL); and is of the following formula (II):
(CH 2 ═CR 7 )CO—(X n ) j —PEG p -Y k —CO—(CR 8 ═CH 2 )  (II)

wherein:
R 7 and R 8 independently represent H or a C 1 -C 6 alkyl;
X and Y independently represent PLA, PGA, PLGA or PCL;
n, p, and k respectively represent the degree of polymerization of X, PEG, and Y, n and k independently being integers from 1 to 150, and p being an integer from 1 to 100;
j represents 0 or 1; and

(iii) at least one chain transfer agent, wherein the at least one chain transfer agent is a cycloaliphatic or an aliphatic thiol having from 2 to 24 carbon atoms,
and wherein the loaded macromolecule is selected from the group consisting of proteins and nucleic acids.

2. The polymer of claim 1 , wherein the bio-resorbable block copolymer cross-linker is of a formula selected from the group consisting of:
(CH 2 ═CR 7 )CO-PLA n -PEG p -PLA k -CO— (CR 8 ═CH 2 ),
(CH 2 ═CR 7 )CO-PGA n -PEG p -PGA k -CO— (CR 8 ═CH 2 ),
(CH 2 ═CR 7 )CO-PLGA n -PEG p -PLGA k -CO— (CR 8 ═CH 2 ),
(CH 2 ═CR 7 )CO-PEG p -PLA k -CO— (CR 8 ═CH 2 ),
(CH 2 ═CR 7 )CO-PEG p -PGA k -CO— (CR 8 ═CH 2 ), and
(CH 2 ═CR 7 )CO-PEG p -PLGA k -CO— (CR 8 ═CH 2 );
wherein R 7 , R 8 , n, p and k are as defined in claim 1 .

3. The polymer of claim 1 , wherein the monomer of formula (I) is selected from the group consisting of sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methylmethacrylate, N-dimethyl-aminoethyl(methyl)acrylate, N,N-dimethylaminopropyl-(meth)acrylate, t-butylaminoethyl (methyl) acrylate, N,N-diethylaminoacrylate, acrylate terminated poly(ethylene oxide), methacrylate terminated poly(ethylene oxide), methoxy poly(ethylene oxide) methacrylate, butoxy poly(ethylene oxide) methacrylate, acrylate terminated poly(ethylene glycol), methacrylate terminated poly(ethylene glycol), methoxy poly(ethylene glycol) methacrylate, butoxy poly(ethylene glycol) methacrylate, and poly(ethylene glycol) methyl ether methacrylate.

4. A macromolecule-loaded bioresorbable crosslinked polymer wherein the polymer is obtainable from the polymerization of:
(i) at least one monomer of formula (I)
(CH 2 ═CR 1 )CO—K  (I)

wherein:
K represents O—Z or NH—Z, Z representing (CR 2 R 3 ) m —CH 3 , (CH 2 —CH 2 —O) m —H, (CH 2 —CH 2 —O) m —CH 3 , (CH 2 ) m —NR 4 R 5 with m representing an integer from 1 to 30;
R 1 , R 2 , R 3 , R 4 and R 5 independently represent H or a C 1 -C 6 alkyl;

(ii) at least one bio-resorbable block copolymer cross-linker, wherein the bio-resorbable block copolymer cross-linker is linear and presents (CH 2 ═(CR 6 ))—groups at both its extremities, wherein R 6 independently represents H or a C 1 -C 6 alkyl;
(iii) at least one chain transfer agent, wherein the at least one chain transfer agent is a cycloaliphatic or an aliphatic thiol having from 2 to 24 carbon atoms, and
(iv) further at least one cyclic monomer having an exo-methylene group of formula (III):

wherein:
R 6 , R 7 , R 8 and R 9 represent independently H or a C 5 -C 7 aryl group or R 7 and R 8 are absent and R 7 and R 8 form
together with the carbon atom on which they are bonded a C 5 -C 7 aryl group;
i and j represent independently an integer from 0 to 2;
and
X represents either O or X is not present and in this latter case, CR 6 R 7 and CR 8 R 9 are linked via a single bond C—C; and

wherein the loaded macromolecule is selected from the group consisting of proteins and nucleic acids.

5. The polymer of claim 4 , wherein the at least cyclic monomer of formula
(III) is selected from the group consisting of 2-methylene-1,3-dioxolane, 2-methylene-1,3-dioxane, 2-methylene-4-phenyl-1,3-dioxolane, 2-methylene-1,3-dioxepane, 5,6-benzo-2-methylene-1,3dioxepane and 2-methylene-1,3,6-trioxocane.

6. A macromolecule-loaded bioresorbable crosslinked polymer wherein the polymer is obtainable from the polymerization of:
(i) at least one monomer of formula (I)
(CH 2 ═CR 1 )CO—K  (I)

wherein:
K represents O—Z or NH—Z, Z representing (CR 2 R 3 ) m —CH 3 , (CH 2 —CH 2 —O) m —H, (CH 2 —CH 2 —O) m —CH 3 , (CH 2 ) m —NR 4 R 5 with m representing an integer from 1 to 30;
R 1 , R 2 , R 3 , R 4 and R 5 independently represent H or a C 1 -C 6 alkyl;

(ii) at least one bio-resorbable block copolymer cross-linker, wherein the bio-resorbable block copolymer cross-linker is linear and presents (CH 2 ═(CR 6 ))—groups at both its extremities, wherein R 6 independently represents H or a C 1 -C 6 alkyl;
(iii) at least one chain transfer agent, wherein the at least one chain transfer agent is a cycloaliphatic or an aliphatic thiol having from 2 to 24 carbon atoms,
optionally at least one cyclic monomer having an exo-methylene group, and at least one further monomer which is a charged, ionisable, hydrophilic, or hydrophobic monomer of the following formula (V):
(CH 2 ═CR 11 )CO-M-F  (V)

wherein:
R 11 represents H or a C 1 -C 6 alkyl;
M represents a single bond or a linker moiety having from 1 to 20 carbon atoms;
F represents a charged, ionisable, hydrophilic, or hydrophobic group having 100 atoms at the most;

wherein the optional at least one cyclic monomer having an exo-methylene group is one of formula (III):

wherein:
R 6 , R 7 , R 8 and R 9 represent independently H or a C 5 -C 7 aryl group or R 6 and R 9 are absent

and R 7 and R 8 form together with the carbon atom on which they are bonded a C 5 -C 7 aryl group;
i and j represent independently an integer from 0 to 2; and X represents either O or X is not present and in this latter case, CR 6 R 7 and CR 8 R 9 are linked via a single bond C—C, and wherein the loaded macromolecule is selected from the group consisting of proteins and nucleic acids.

7. The polymer of claim 6 , wherein F is selected from the group consisting of COOH, COOH, COO − , SO 3 H, SO 3 − , PO 4 H 2 , PO 4 H − , PO 4 2− , NR 9 R 10 , NR 9 R 12 R 10 + , R 9 , R 12 and R 10 independently representing H or a C 1 -C 6 alkyl, a C 1 -C 20 alkyl group, a C 5 -C 20 aryl group, a (5-30-members) heteroaryl group containing an heteroatom selected from the group consisting of O, N or S, a O—C 5 -C 20 aryl group and a O-(5-30-members)heteroaryl group, a crown ether, and a cyclodextrin.

8. The polymer of claim 1 , wherein the loaded macromolecule is selected from the group consisting of enzymes, antibodies, cytokines, growth factor, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNAzymes, aptamers, cationic polymers for nucleic acid loading, anti-inflammatory proteins, bone morphogentic proteins, angiogenic factors, vascular endothelial growth factors, TGF-beta, and inhibitors of angiogenesis.

9. The

Assignees

• Moine Laurence
• Laurent Alexandre
• Wassef Michel
• Bedouet Laurent
• Louguet Stephanie
• Verret Valentin
• Servais Emeline
• Occlugel
• Centre Nat Rech Scient
• Hopitaux Paris Assist Publique
• Univ Paris Diderot—Paris 7

Inventors

• Moine Laurence
• Laurent Alexandre
• Wassef Michel
• Bedouet Laurent
• Louguet Stephanie
• Verret Valentin
• Servais Emeline

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• A61P17/16

  Emollients or protectives, e.g. against radiation · CPC title