Alkylene-dicarboxylate-containing biodegradable poly(ester-amides) and methods of use
View Patent ↗The invention provides new aliphatic diester-di-acid-containing PEA polymer compositions with significant improvement in hydrolytic degradation rates as compared to aliphatic di-acid-containing PEA polymers. The di-acids used in the invention PEA compositions include non-toxic fatty aliphatic homologs. These molecules inherently contain two-ester groups, which easily can be cleaved by biotic (enzymatic) and abiotic hydrolysis. Additional di-acid-type compounds useful for active polycondensation are α,ω-alkylene dicarboxylates composed of short aliphatic non toxic diols and di-acids. In addition, the invention PEA polymer compositions optionally can include a second monomer, such as a C-protected L-lysine-based monomer, to introduce additional chain flexibility into the polymer. The invention PEA polymer compositions are useful for delivery of bioactive agents when administered internally.
1. A biodegradable polymer composition comprising at least one
(PEA) polymer have a structure according to formula (IV):
wherein
n ranges from about 5 to about 150,
m ranges about 0.1 to 0.9;
p ranges from about 0.9 to 0.1;
R 1 is independently selected from residues of α,ω-alkylene dicarboxylates of structural formula (III)
optionally in combination with (C 2 -C 20 ) alkylene;
R 5 and R 6 in Formula (III) are independently selected from (C 2 -C 12 ) alkylene or (C 2 -C 12 ) alkenylene;
each R 2 is independently hydrogen, (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl or a protecting group;
the R 3 s in individual m monomers are independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, and —(CH 2 ) 2 S(CH 3 );
R 4 is independently selected from (C 2 -C 20 )alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 )alkyloxy, (C 2 -C 20 )alkylene, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II)
and residues of saturated or unsaturated therapeutic diols and combinations thereof; and
R 7 is independently selected from (C 2 -C 20 ) alkyl or (C 2 -C 20 ) alkenyl.
2. The composition of claim 1 , wherein at least one of the R 1 s in an n or m unit is independently selected from residues of αω-alkylene dicarboxylates of formula (III), wherein R 5 and R 6 in Formula (III) are independently selected from (C 2 -C 12 )alkylene and (C 2 -C 12 ) alkenylene, and wherein at least one of the R 1 s in the n or m unit is (C 2 -C 20 ) alkylene.
3. The composition of claim 1 , wherein R5 in Formula (III) is (CH═CH); and R6 is (CH2)3, (CH2)4, (CH2)6, or (CH2)8.
4. The composition of claim 1 , wherein at least one R1 is 1,4-hydroxybutyl disuccinate, 1,3-hydroxypropyl dimalonate or 1,6-hydroxyhexyl diglutarate.
5. The composition of claim 1 , wherein at least one R1 is a saturated or unsaturated residue of a therapeutic di-acid.
6. The composition of claim 1 , wherein the R3 s in an n or m monomer are independently selected from hydrogen, CH2-CH(CH3)2, CH3, CH(CH3)2, CH(CH3)-CH2-CH3, CH2-C6H5, or (CH2)2SCH3.
7. The composition of claim 1 , wherein from about 0.1 part to about 0.9 part of R4 is 1,4:3,6-dianhydrohexitol.
8. The composition of claim 1 , wherein the polymer has a molecular weight in the range from about 15,000 Da to about 600,000 Da.
9. The composition of claim 1 , wherein the composition further comprises an effective amount of at least one bioactive agent dispersed in the polymer.
10. The composition of claim 9 , wherein the composition includes from about 5 to about 150 molecules of the bioactive agent per polymer molecule chain.
11. The composition of claim 9 wherein the at least one bioactive agent is covalently bonded to the polymer.
12. The composition of claim 9 , wherein there are at least two bioactive agents dispersed in the composition.
13. The composition of claim 1 , wherein formula (III):
R 5 is selected from (CH 2 ) 2 , (CH 2 ) 3 , and CH═CH; and R 6 is selected from(CH 2 ) 3 , (CH 2 ) 4 , (CH 2 ) 6 , and (CH 2 ) 8 .