WATER SOLUBLE POLYCARBONATES FOR MEDICAL APPLICATIONS

• US 20160095933A1
• Filed: 10/06/2014
• Published: 04/07/2016
• Est. Priority Date: 10/06/2014
• Status: Active Grant

• Current Assignee: Agency For Science Technology and Research, International Business Machines Corporation
• Original Assignee: Agency For Science Technology and Research, International Business Machines Corporation
• Inventors: Coady, Daniel J., Engler, Amanda C., Hedrick, James L., Ke, Xiyu, Yang, Yi Yan
• Granted Patent: US 9,469,726 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: C08G 64/0233 containing halogens
• CPC Class Codes: C08G 64/0241 containing nitrogen
• CPC Class Codes: C08G 64/18 Block or graft polymers
• CPC Class Codes: C08G 64/30 using carbonates
• CPC Class Codes: C08G 64/42 Chemical after-treatment

Abstract

Water soluble biodegradable polymers were prepared by an organoacid catalyzed ring opening polymerization (ROP) of a cyclic carbonate monomer bearing an active ester side chain. The initial polymer comprising an active ester side chain was treated with an amino-alcohol, which transformed the active ester groups to N-substituted amide groups bearing mono-hydroxy alkyl groups and/or dihydroxy alkyl groups, thereby forming the water soluble polymers. The water-soluble polymers are non-toxic and exhibit stealth properties in buffered serum solution.

Claims

1. A polymer comprising a carbonate repeat unit of formula (1):

2. The polymer of claim 1, wherein R′

is selected from the group consisting of

3. The polymer of claim 1, wherein the polymer has a number average molecular weight (Mn) of about 1500 or more.

4. The polymer of claim 1, wherein the polymer has a mouse intravenous LD50 value of greater than 500 mg/kg.

5. The polymer of claim 1, wherein the polymer is biodegradable in accordance with ASTM D6400.

6. The polymer of claim 1, wherein the polymer comprises one polymer branch linked by a terminal repeat unit to a polymer end group having the structure I′

—

O—

*, the polymer branch is homopolymer of the carbonate repeat unit, and I′

comprises 1-20 carbons.

7. The polymer of claim 6, wherein the polymer has a structure according to formula (1a):

8. The polymer of claim 1, wherein the polymer comprises one polymer branch linked by a terminal repeat unit to a polymer end group having the structure I′

—

O—

*, the polymer branch is a random copolymer of the carbonate repeat unit and a non-charged hydrophobic second repeat unit, and I′

comprises 1-20 carbons.

9. The polymer of claim 8, wherein the polymer is a random copolymer having a structure according to formula (2):

10. The polymer of claim 1, wherein the polymer comprises one polymer branch linked by a terminal repeat unit to a polymer end group having a structure I′

—

O—

*, the polymer branch is a diblock copolymer comprising a first block linked to a second block, the first block comprises the carbonate repeat unit, and the second block comprises a non-charged hydrophobic second repeat unit.

11. The polymer of claim 10, wherein the polymer is a diblock copolymer having a structure according to formula (3):

12. The polymer of claim 1, wherein the polymer comprises two polymer branches, the two polymer branches are linked by respective terminal repeat units to a divalent linking group having a structure *—

O—

I″

—

O—

*, I″

comprises 2-20 carbons, and each of the two polymer branches comprises the carbonate repeat unit.

13. The polymer of claim 12, wherein the polymer has a structure according to formula (4):

14. The polymer of claim 1, wherein R″

is methyl.

15. The polymer of claim 1, wherein the carbonate repeat unit is stereospecific.

16. A composition comprising:

the polymer of claim 1; and

a therapeutic agent for a medical treatment, the therapeutic agent selected from the group consisting of genes, proteins, peptides, drugs, and combinations thereof;

wherein

the polymer and the therapeutic agent are bound by non-covalent interactions,

the composition is dispersible in water as a particle having an average circular diameter of about 10 nm to about 500 nm, and

an aqueous mixture of the composition is suitable for intravenous injection.

17. The composition of claim 16, wherein the polymer has a structure according to formula (4):

18. The composition of claim 17, wherein m has an average value of about 20 to about 50.

19. The composition of claim 16, wherein the polymer has a number average molecular weight (Mn) of about 5000 to about 10000.

20. The composition of claim 16, wherein the polymer is a diblock copolymer having a structure according to formula (3):

21. A method, comprising:

forming a first mixture comprising water and a non-charged polymer comprising a carbonate first repeat unit of formula (1);

22. The method of claim 21, wherein R′

is

23. The method of claim 21, wherein the polymer has a structure according to formula (4):

24. The method of claim 21, wherein the polymer is a diblock polymer having a structure according to formula (3):