Vitamin functionalized gel-forming block copolymers for biomedical applications

Patent metadata

Field	Value
Publication number	US-9511146-B2
Application number	US-201514697878-A
Country	US
Kind code	B2
Filing date	Apr 28, 2015
Priority date	Apr 9, 2013
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

Gel-forming block copolymers were prepared comprising i) a central hydrophilic block consisting essentially of a divalent poly(ethylene oxide) chain and ii) two peripheral monocarbonate or polycarbonate hydrophobic blocks. The hydrophobic blocks comprise one or more vitamin-bearing subunits. The vitamin-bearing subunits comprise a carbonate backbone portion and a side chain comprising a covalently bound form of a vitamin. The gel-forming block copolymers can be used to prepare various biodegradable and/or biocompatible hydrogel and organogel drug compositions, in particular antimicrobial and/or anti-tumor drug compositions. The hydrogel compositions can be suitable for depot injections. Synergistic enhancement of toxicity to microbes was observed with compositions comprising an antimicrobial cationic polymer and an antimicrobial compound.

First claim

What is claimed is:

1. An aqueous solution for killing a microbe, comprising:
about 0.0001 wt. % to about 10 wt. % of an antimicrobial cationic polycarbonate (first drug); and
about 0.0001 wt. % to about 10 wt. % of an antimicrobial compound (second drug); wherein
weight percent (wt. %) is based on total weight of the aqueous solution,
the first drug and the second drug are associated by noncovalent interactions in the aqueous solution, and
the antimicrobial cationic polycarbonate comprises a vitamin-bearing subunit having a structure in accordance with formula (2):

wherein
the carbonate backbone atoms are numbered 1 to 6,
L d is a single bond or a divalent linking group comprising 1 to about 15 carbons,
V′ is a moiety comprising a covalently bound form of a vitamin,
each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl,
R″ is a monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons,
t is a positive integer having a value of 0 to 2,
t′ is a positive integer having a value of 0 to 2, and
t and t′ cannot both be zero.

2. The aqueous solution of claim 1 , wherein the aqueous solution is suitable for eradicating a microbial biofilm.

3. The aqueous solution of claim 1 ,
wherein the vitamin is selected from the group consisting of vitamin E compounds, and vitamin D compounds.

4. The aqueous solution of claim 1 , wherein the vitamin-bearing subunit has the structure:

5. The aqueous solution of claim 1 , wherein the vitamin-bearing subunit has the structure:

6. The aqueous solution of claim 1 , wherein the antimicrobial cationic polycarbonate comprises a cationic carbonate subunit having a structure in accordance with formula (9):

wherein
L a -Q′(R a ) u′ is a C 6 -C 25 cationic side chain comprising a quaternary ammonium group and/or quaternary phosphonium group, wherein L a is a divalent linking group comprising at least 3 carbons, Q′ is a tetravalent positive-charged nitrogen or phosphorus, u′ has a value of 1 to 3, each R a is an independent radical having a valency of 1 to 3, and each R a comprises at least 1 carbon,
each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl,
R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons,
t is a positive integer having a value of 0 to 2,
t′ is a positive integer having a value of 0 to 2,
t and t′ cannot both be zero, and
X′ is a negative-charged ion.

7. The aqueous solution of claim 1 , wherein the antimicrobial cationic polycarbonate comprises a cationic carbonate subunit having a structure in accordance with formula (10):

wherein
L b -Q′(R a ) u′ is a C 5 -C 24 cationic moiety comprising a quaternary ammonium group and/or quaternary phosphonium group, wherein L b is a divalent linking group comprising at least 2 carbons, Q′ is a tetravalent positive-charged nitrogen or phosphorus, u′ has a value of 1 to 3, each R a is an independent radical having a valency of 1 to 3, and each R a comprises at least 1 carbon,
R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons, and
X′ is a negative-charged ion.

8. The aqueous solution of claim 1 , wherein the antimicrobial cationic polycarbonate comprises a cationic carbonate subunit having a structure in accordance with formula (11):

wherein
L c -Q′(R a ) u′ is a C 5 -C 24 cationic moiety comprising a quaternary ammonium group and/or quaternary phosphonium group, wherein L c is a divalent linking group comprising at least 2 carbons, Q′ is a tetravalent positive-charged nitrogen or phosphorus, u′ has a value of 1 to 3, and each R a is an independent radical having a valency of 1 to 3, wherein each R a comprises at least 1 carbon,
each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl,
R″ is a monovalent radical selected from the group consisting of hydrogen, halogens, and alkyl groups comprising 1 to 6 carbons, and
X′ is a negative-charged ion.

9. The aqueous solution of claim 1 , wherein the second drug is selected from the group consisting of fluconazole, doxycycline, and combinations thereof.

10. The aqueous solution of claim 1 , wherein each oft and t′ of formula (2) is 1.

11. The aqueous solution of claim 1 , wherein each R′ of formula (2) is hydrogen.

12. The aqueous solution of claim 1 , wherein R″ of formula (2) is methyl.

13. The aqueous solution of claim 6 , wherein each oft and t′ of formula (9) is claim 1 .

14. The aqueous solution of claim 6 , wherein each R′ of formula (9) is hydrogen.

15. The aqueous solution of claim 6 , wherein R″ of formula (9) is methyl.

16. The aqueous solution of claim 7 , wherein R″ of formula (10) is methyl.

17. The aqueous solution of claim 8 , wherein each oft and t′ of formula (11) is claim 1 .

18. The aqueous solution of claim 8 , wherein each R′ of formula (11) is hydrogen.

19. The aqueous solution of claim 8 , wherein R″ of formula (11) is methyl.

Assignees

• IBM
• Agency Science Tech & Res

Inventors

• Hedrick James L
• Lee Ashlynn L Z
• Ng Victor W L
• Yang Yi Yan

Classifications

• A61K31/65

  Tetracyclines · CPC title

• C08G2210/00

  Compositions for preparing hydrogels · CPC title

• C08G65/3318

  heterocyclic · CPC title

• A61K47/34 Primary

  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 title

• A61K31/765

  Polymers containing oxygen · CPC title