# US 9,040,034 B2 · Vitamin functionalized gel-forming block copolymers for biomedical applications

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- Number: US 9,040,034 B2
- Document ID: US9040034B2
- Status: Granted
- Kind: B2
- Application number: 13/859,062
- Filed: 2013-04-09
- Published: 2014-10-09
- Granted: 2015-05-26
- Earliest claimed: 2013-04-09
- Assignees: International Business Machines Corporation; Agency for Science, Technology and Research
- Applicants: International Business Machines Corporation; Agency for Science, Technology and Research
- Inventors: James L. Hedrick; Ashlynn L. Z. Lee; Victor W. L. Ng; Yi Yan Yang
- Web page: https://patentgrep.com/patent/US9040034B2

## CPC

- 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)
- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/355: Tocopherols, e.g. vitamin E
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/592: 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
- A61K 31/593: 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
- A61K 31/65: Tetracyclines
- A61K 31/765: Polymers containing oxygen
- A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 35/00: Antineoplastic agents
- C07K 16/32: against translation products of oncogenes
- C08G 64/183: {containing polyether sequences}
- C08G 65/3318: {heterocyclic}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/90: characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C08G 2210/00: Compositions for preparing hydrogels
- 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
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A drug composition, comprising:
about 4 wt.% to about 10 wt.% of a gel-forming block copolymer;
a solvent; and
about 0.0001 wt.% to about 10 wt.% of a drug;
wherein
the gel-forming block copolymer has a structure in accordance with formula (1):
wherein
d′ is a positive number having a value of about 100 to about 600,
each K′ is an independent divalent linking group selected from the group consisting of 0, NH, S, and combinations thereof,
each Pa is an independent monocarbonate or polycarbonate chain comprising 1 to about 10 vitamin-bearing subunits, wherein each of the vitamin-bearing subunits comprises a carbonate backbone portion and a side chain linked to the carbonate backbone portion, the side chain comprising a covalently bound form of a vitamin,
Za is a first end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons, and Zb is a second end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons;
and wherein
weight percent (wt.%) is based on total weight of the drug composition,
the drug composition is a gel formed by noncovalent interactions of polymer chains of the block copolymer in the solvent, and
the drug is contained in the gel.

### Claim 2 (depends on 1)

The drug composition of claim 1, wherein each Pa consists essentially of 1 to about 8 vitamin-bearing subunits.

### Claim 3 (depends on 1)

The drug composition of claim 1, wherein the vitamin is selected from the group consisting of vitamin E compounds, vitamin D compounds, and combinations thereof.

### Claim 4 (depends on 1)

The drug composition of claim 1, wherein each of the vitamin-bearing subunits comprises an alpha-tocopheryl moiety.

### Claim 5 (depends on 1)

The drug composition of claim 1, wherein each of the vitamin-bearing subunits comprises an ergocalcipheryl moiety.

### Claim 6 (depends on 1)

The drug composition of claim 1, wherein Za is hydrogen and Zb is hydrogen.

### Claim 7 (depends on 1)

The drug composition of claim 1, wherein the vitamin-bearing subunits of have a structure in accordance with formula (2):
wherein
the carbonate backbone atoms are numbered 1 to 6,
Ld 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.

### Claim 8 (depends on 1)

The drug composition of claim 1, wherein the vitamin-bearing subunits of the gel-forming block copolymer have the structure:

### Claim 9 (depends on 1)

The drug composition of claim 1, wherein each of the vitamin-bearing subunits of the gel-forming block copolymer has the structure:

### Claim 10 (depends on 1)

The drug composition of claim 1, wherein the drug is an anti-tumor agent and the drug composition is suitable for treating a cancer.

### Claim 11 (depends on 10)

The drug composition of claim 10, wherein the anti-tumor agent is a mono-clonal antibody.

### Claim 12 (depends on 11)

The drug composition of claim 11, wherein the mono-clonal antibody is herceptin.

### Claim 13 (depends on 10)

The drug composition of claim 10, wherein the solvent is water, the composition is a hydrogel, and the composition inhibits growth of cancer cells in vivo when administered by a depot injection.

### Claim 14 (depends on 10)

A method of treating a cancer, comprising performing an in vivo depot injection of the drug composition of claim 10 near or in contact with a cancerous tumor.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is a breast cancer.

### Claim 16

An antimicrobial drug composition, comprising:
about 4 wt.% to about 10 wt.% of a gel-forming block copolymer;
a solvent; and
about 0.0001 wt.% to about 10 wt.% of an antimicrobial cationic polycarbonate (first drug);
wherein
the gel-forming block copolymer has a structure in accordance with formula (1):
wherein
d′ is a positive number having a value of about 100 to about 600, each K′ is an independent divalent linking group selected from the group consisting of 0, NH, S, and combinations thereof,
each Pa is an independent monocarbonate or polycarbonate chain comprising 1 to about 10 vitamin-bearing subunits, wherein each of the vitamin-bearing subunits comprises a carbonate backbone portion and a side chain linked to the carbonate backbone portion, the side chain comprising a covalently bound form of a vitamin,
Za is a first end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons, and
Zb is a second end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons;
and wherein
weight percent (wt.%) is based on total weight of the antimicrobial drug composition,
the antimicrobial drug composition is a gel formed by noncovalent interactions of polymer chains of the gel-forming block copolymer in the solvent,
the antimicrobial cationic polycarbonate is contained in the gel.

### Claim 17 (depends on 16)

The antimicrobial drug composition of claim 16, wherein the antimicrobial cationic polycarbonate has a structure in accordance with formula (8):
Z′—P′—Z″ (8),
wherein
Z′ is a monovalent C1-C15 is first end group, wherein Z′ is linked to a backbone carbonyl group of P′,
Z″ is a monovalent second end group selected from the group consisting of hydrogen and C1-C15 moieties,
P′ is a polymer chain consisting essentially of cationic carbonate subunits, wherein i) P′ has a degree of polymerization (DP) of about 5 to about 45, ii) each of the cationic carbonate subunits comprises a backbone portion and a C6-C25 cationic side chain linked to the backbone portion, and iii) the cationic side chain comprises a positive-charged heteroatom Q′ of a quaternary ammonium group and/or quaternary phosphonium group,
about 25% to about 100% of the cationic carbonate subunits, designated first cationic carbonate subunits, have a cationic side chain comprising 13 to about 25 carbons, and
about 0% to about 75% of the cationic carbonate subunits, designated second cationic carbonate subunits, have a cationic side chain comprising 6 to 12 carbons.

### Claim 18 (depends on 17)

The antimicrobial drug composition of claim 17, wherein each of the cationic carbonate subunits of the antimicrobial cationic polycarbonate has a structure in accordance with formula (9):
wherein
La-Q′(Ra)u, is a C6-C25 cationic side chain comprising a quaternary ammonium group and/or quaternary phosphonium group, wherein La 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 Ra is an independent radical having a valency of 1 to 3, and each Racomprises 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.

### Claim 19 (depends on 17)

The antimicrobial drug composition of claim 17, wherein each of the cationic carbonate subunits of the antimicrobial cationic polycarbonate has a structure in accordance with formula (10):
wherein
Lb-Q′(Ra)u1is a C5-C24 cationic moiety comprising a quaternary ammonium group and/or quaternary phosphonium group, wherein Lb 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 Ra is an independent radical having a valency of 1 to 3,and each Ra 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.

### Claim 20 (depends on 17)

The antimicrobial drug composition of claim 17, wherein each of the cationic carbonate subunits of the antimicrobial cationic polycarbonate has a structure in accordance with formula (11):
wherein
Lc-Q′(Ra)u′ is a C5-C24 cationic moiety comprising a quaternary ammonium group and/or quaternary phosphonium group, wherein Lc 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 Ra is an independent radical having a valency of 1 to 3, wherein each Ra 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.

### Claim 21 (depends on 16)

The antimicrobial drug composition of claim 16, wherein the antimicrobial cationic polycarbonate has a structure in accordance with formula (19):
Zc—Pb—C′—Pb—Zc (19),
wherein
C′ is a C2-C15 divalent linking group joining polymer chains Pb, wherein C′ comprises i) a first heteroatom linked to a first polymer chain Pb, wherein the first heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, and ii) a second heteroatom linked to a second polymer chain Pb, wherein the second heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur,
each Z′ is an independent monovalent end group selected from the group consisting of hydrogen and C1-C15 moieties,
each polymer chain Pb consists essentially of cationic carbonate subunits, wherein i) the cationic polymer comprises a total of 5 to about 45 cationic carbonate subunits, ii) each of the cationic carbonate subunits comprises a backbone portion of the polymer chain and a cationic side chain linked to the backbone portion, and iii) the cationic side chain comprises a positive-charged heteroatom Q′ of a quaternary ammonium group and/or quaternary phosphonium group,
about 25% to 100% of all the cationic carbonate subunits of the cationic polymer, designated first cationic carbonate subunits, have a cationic side chain comprising 10 to about 25 carbons, and
0% to about 75% of the cationic carbonate subunits of the cationic polymer, designated second cationic carbonate subunits, have a cationic side chain comprising 6 to 9 carbons.

### Claim 22 (depends on 21)

The antimicrobial drug composition of claim 21, wherein each of the first cationic carbonate subunits of the antimicrobial cationic polycarbonate has a cationic side chain comprising 13 to about 25 carbons, and each of the second cationic carbonate subunits has a cationic side chain comprising 6 to 12 carbons.

### Claim 23 (depends on 16)

The antimicrobial drug composition of claim 16, further comprising a second drug that is an antimicrobial compound.

### Claim 24 (depends on 23)

The antimicrobial drug composition of claim 23, wherein the antimicrobial compound is selected from the group consisting of fluconazole, doxycycline, and combinations thereof.