Antimicrobial compositions, methods of preparation thereof, and uses thereof

• US 8,642,086 B2
• Filed: 03/31/2011
• Issued: 02/04/2014
• Est. Priority Date: 03/31/2011
• Status: Expired due to Fees

• 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 Joseph, Fukushima, Kazuki, Hedrick, James Lupton, Yang, Yi Yan
• Primary Examiner(s): Tran, Susan
• Assistant Examiner(s): WORSHAM, JESSICA N
• Application Number:
  US13/077,005
• Publication Number:
  US 20120251607A1
• Time in Patent Office: 1,041 Days
• Field of Search: None
• US Class Current: 424/486
• CPC Class Codes: A01N 2300/00 Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
• CPC Class Codes: A01N 25/10 Macromolecular compounds
• CPC Class Codes: A01N 33/12 Quaternary ammonium compounds
• CPC Class Codes: A61K 31/77 of oxiranes
• CPC Class Codes: A61K 31/78 of acrylic acid or derivatives thereof
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61L 15/26 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof A61L15/225 takes precedence
• CPC Class Codes: A61L 15/28 Polysaccharides or their derivatives A61L15/225 takes precedence
• CPC Class Codes: A61L 15/46 Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
• CPC Class Codes: A61L 17/10 containing macromolecular materials
• CPC Class Codes: A61L 17/12 Homopolymers or copolymers of glycolic acid or lactic acid
• CPC Class Codes: A61L 2300/40 characterised by a specific therapeutic activity or mode of action
• CPC Class Codes: A61L 29/043 Polysaccharides
• CPC Class Codes: A61L 29/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A composition of matter comprises a cationic polymer comprising a polycarbonate chain fragment, the polycarbonate chain fragment comprising a repeat unit comprising a side chain moiety containing a quaternary amine group; and a non-charged polymer comprising a polyester chain segment and a poly(alkylene oxide) chain segment; wherein i) the cationic polymer and the non-charged polymer are amphiphilic and biocompatible, ii) the cationic polymer and the non-charged polymer form a mixed complex by non-covalent interactions in water, and iii) the mixed complex is a more effective antimicrobial agent against at least a Gram-negative microbe compared to the cationic polymer and the non-charged polymer alone when tested using otherwise identical conditions.

Claims

1. A composition of matter, comprising:

a cationic triblock copolymer having an ABA block structure, wherein a block A is a hydrophobic peripheral block comprising a first polyester chain segment, and a block B is a hydrophilic cationic core block comprising a polycarbonate chain segment, the polycarbonate comprising a repeat unit comprising a cationic side chain moiety, the cationic side chain moiety comprising a quaternary amine group; and

a non-charged triblock copolymer having a FEF block structure, wherein block E is a hydrophilic non-charged core block comprising a poly(alkylene oxide) chain segment, and block F is a peripheral hydrophobic block comprising a second polyester chain segment;

wherein i) the non-charged triblock copolymer and the cationic triblock copolymer are amphiphilic and biocompatible, ii) the non-charged triblock copolymer and the cationic triblock copolymer form a mixed complex by non-covalent interactions in water, and iii) the mixed complex is a more effective antimicrobial agent against at least a Gram-negative microbe compared to the cationic triblock copolymer alone and the non-charged triblock copolymer alone when tested using otherwise identical conditions.

2. The composition of claim 1, wherein the cationic triblock copolymer and the non-charged triblock copolymer are present in the composition in a weight ratio of about 0.25:

10 w/w to about 3;

2 w/w.

3. The composition of claim 1, wherein block A, block B, block F, and optionally block E are enzymatically biodegradable.

4. The composition of claim 1, wherein the composition comprises water and the composition is a hydrogel.

5. The composition of claim 1, wherein block A comprises a first stereospecific repeat unit, and the block F comprises a second stereospecific repeat unit.

6. The composition of claim 5, wherein the first stereospecific repeat unit is a non-superposable mirror image of the second stereospecific repeat unit.

7. The composition of claim 1, wherein block A comprises a poly(D-lactide) chain segment and the block F comprises a poly(L-lactide) chain segment.

8. The composition of claim 1, wherein the block A comprises a poly(L-lactide) chain segment and the block F comprises a poly(D-lactide) chain segment.

9. The composition of claim 1, wherein the poly(alkylene oxide) chain segment is a poly(ethylene oxide) chain segment.

10. The composition of claim 1, wherein the composition is toxic to a Gram-negative microbe and to a Gram-positive microbe selected from the group consisting of bacteria, fungi, yeasts, and combinations thereof.

11. The composition of claim 1, wherein the cationic triblock copolymer alone and the non-charged triblock copolymer alone are individually not effective antimicrobial agents against the Gram-negative microbe.

12. The composition of claim 1, wherein the Gram-negative microbe is Escherichia coli.

13. A loaded complex comprising i) the composition of claim 1 and ii) a drug and/or a gene.

14. A method, comprising contacting a microbe with the composition of claim 1, thereby killing the microbe.

15. A method, comprising:

forming an aqueous mixture of the composition of claim 1, the aqueous mixture being an effective antimicrobial agent against at least a Gram-negative microbe.

16. The method of claim 15, wherein at a temperature of 18°

C. to 28°

C. and a pH of 4.5 to 8.0, the aqueous mixture is a liquid micelle solution.

17. The method of claim 15, wherein at a temperature of 18°

C. to 28°

C. and a pH of 4.5 to 8.0, the aqueous mixture is a hydrogel.

18. The method of claim 15, further comprising heating the aqueous mixture to a temperature of 32°

C. to 40°

C., the aqueous mixture having a pH of 4.5 to 8.0, thereby forming a hydrogel.

19. The method of claim 15, wherein the aqueous mixture is a hydrogel, and the hydrogel comprises a rod-like structure comprising the cationic triblock copolymer and the non-charged triblock copolymer.

20. The method of claim 19, wherein the rod-like structure has a diameter of about 100 nm to 500 nm and a length of about 0.5 micrometer to about 50 micrometers.

21. The method of claim 15, further comprising contacting a microbe with the aqueous mixture, thereby killing the microbe.

22. The method of claim 15, further comprising contacting an animal tissue with the aqueous mixture.

23. The method of claim 15, further comprising contacting a surface of an article with the aqueous mixture.

32. An article comprising a medical device in contact with the composition of claim 1.

33. The article of claim 32, wherein the medical device includes at least one of the following:

a swab, a catheter, a suture, a stent, a bedpan, a glove, a facial mask, an absorbent pad, an absorbent garment, an internal absorbant device, and an insertable mechanical device.

24. A method, comprising:

forming an aqueous first mixture of a cationic triblock copolymer having an ABA block structure, wherein a block A is a peripheral hydrophobic block comprising a first polyester chain segment, and a block B is a hydrophilic cationic core block comprising a polycarbonate chain segment, the polycarbonate comprising a repeat unit comprising a cationic side chain moiety, the cationic side chain moiety comprising a quaternary amine group;

forming an aqueous second mixture of a non-charged triblock copolymer having a FEF block structure, wherein a block E is a hydrophilic non-charged core block comprising a poly(alkylene oxide) chain segment, and a block F is a peripheral hydrophobic block, comprising a second polyester chain segment; and

combining the first mixture and the second mixture, thereby forming a third mixture comprising a mixed complex of the cationic triblock copolymer and the non-charged triblock copolymer bound by non-covalent interactions;

wherein i) the non-charged triblock copolymer and the cationic triblock copolymer are amphiphilic and biocompatible, and ii) the mixed complex is a more effective antimicrobial agent against at least a Gram-negative microbe compared to the cationic triblock copolymer alone and the non-charged triblock copolymer alone when tested using otherwise identical conditions.

25. The method of claim 24, wherein the cationic triblock copolymer and the non-charged triblock copolymer are present in the third mixture in a weight ratio of about 0.25:

10 w/w to about 3;

2 w/w.

26. The method of claim 24, wherein the cationic triblock copolymer alone and the non-charged triblock copolymer alone are individually not effective antimicrobial agents against the Gram-negative microbe when tested under otherwise identical conditions.

27. The method of claim 24, wherein heating the third mixture to 32°

C. to 40°

C. produces a hydrogel.

28. The method of claim 24, wherein removing any organic solvent at ambient temperature from the third mixture produces a hydrogel.

29. The method of claim 24, wherein block A comprises a first stereospecific repeat unit, and the block F comprises a second stereospecific repeat unit.

30. The method of claim 24, wherein the cationic triblock copolymer and/or the non-charged triblock copolymer are formed by an organocatalyzed ring opening polymerization of one or more cyclic carbonyl monomers.

31. The method of claim 24, wherein block A, B, F, and optionally E are enzymatically biodegradable.

34. A composition of matter, comprising:

a cationic triblock polymer comprising a polycarbonate chain fragment, the polycarbonate chain fragment comprising a repeat unit comprising a side chain moiety containing a quaternary amine group; and

a non-charged triblock polymer comprising a polyester chain segment and a poly(alkylene oxide) chain segment;

wherein i) the cationic triblock polymer and the non-charged triblock polymer are amphiphilic and biocompatible, ii) the cationic triblock polymer and the non-charged triblock polymer form a mixed complex by non-covalent interactions in water, and iii) the mixed complex is a more effective antimicrobial agent against at least a Gram-negative microbe compared to the cationic triblock polymer and the non-charged triblock polymer alone when tested using otherwise identical conditions.

35. The composition of claim 34, wherein the composition comprises water.

36. The composition of claim 35, wherein the composition is a hydrogel.

37. The composition of claim 34, wherein the cationic triblock polymer comprises a first stereospecific repeat unit, and the non-charged triblock polymer comprises a second stereospecific repeat unit.

38. The composition of claim 34, wherein the cationic triblock polymer and the non-charged triblock polymer alone are individually not effective antimicrobial agents against the Gram-negative microbe when tested under otherwise identical conditions.

39. The composition of claim 34, wherein the cationic triblock polymer is enzymatically biodegradable, and the non-charged triblock polymer is substantially or wholly enzymatically biodegradable.

40. The composition of claim 34, wherein the cationic triblock polymer is a star polymer comprising three or more polymer arms.

41. A method, comprising contacting a microbe with the composition of claim 34, thereby killing the microbe.

42. A loaded complex comprising i) the composition of claim 34 and ii) a drug and/or a gene.

43. A method, comprising:

forming an aqueous mixture of the composition of claim 34 wherein the aqueous mixture is an effective antimicrobial agent against at least a Gram-negative microbe.

44. A method, comprising:

forming an aqueous first mixture containing a cationic triblock polymer comprising a polycarbonate chain fragment, the polycarbonate chain fragment comprising a repeat unit comprising a side chain quaternary amine group;

forming an aqueous second mixture containing a non-charged triblock polymer comprising a polyester chain segment and a poly(alkylene oxide) chain segment; and

combining the first mixture and the second mixture, thereby forming a third mixture comprising a mixed complex of the cationic triblock polymer and the non-charged triblock polymer bound by non-covalent interactions;

wherein i) the cationic triblock polymer and the non-charged triblock polymer are amphiphilic and biocompatible, and ii) the mixed complex is a more effective antimicrobial agent against at least a Gram-negative microbe compared to the cationic triblock polymer alone and the non-charged triblock polymer alone when tested under otherwise identical conditions.