# US 10,500,256 B2 · Polymers for delivery of therapeutic proteins

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- Number: US 10,500,256 B2
- Document ID: US10500256B2
- Status: Granted
- Kind: B2
- Application number: 14/870,807
- Filed: 2015-09-30
- Published: 2016-04-21
- Granted: 2019-12-10
- Earliest claimed: 2014-09-30
- Assignees: Board of Regents, The University of Texas System
- Applicants: Board of Regents, the University of Texas System
- Inventors: Michael Koetting; Nicholas Peppas
- Web page: https://patentgrep.com/patent/US10500256B2

## CPC

- A61K 38/482: {Serine endopeptidases (3.4.21)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 38/23: Calcitonins
- C07K 16/2887: {against CD20}
- C12Y 304/21073: u-Plasminogen activator (3.4.21.73), i.e. urokinase
- 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)
- 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)
- C12Y: ENZYMES

## Abstract

In some aspects, improved hydrogel copolymers (e.g., comprising itaconic acid and N-vinylpyrrolidone) are provided and may be used, e.g., for oral delivery of a therapeutic protein. In some embodiments, improved methods for loading a therapeutic protein (e.g., a high isoelectric point protein) into a hydrogel copolymer are provided, and may comprise incubating the therapeutic protein and the hydrogel in a reduced ionic strength loading solution. In some embodiments, use of the reduced ionic strength loading solution can result in hydrogel copolymer-therapeutic protein compositions that display improved pharmacokinetic attributes, e.g., improved loading and/or release of a therapeutic protein.

## Claims

### Claim 1

A polymer comprising:
a) a copolymer comprising itaconic acid, methacrylic acid, and/or N-vinylpyrrolidone; wherein the copolymer is at least partially crosslinked; and
b) a therapeutic protein wherein the therapeutic protein has been loaded into the copolymer using a solution having an ionic strength of less than about 100 mM PBS at about pH 7.4.

### Claim 2 (depends on 1)

The polymer of claim 1, wherein the therapeutic protein is a high isoelectric point protein having an isoelectric point of greater than 7.

### Claim 3 (depends on 2)

The polymer of claim 2, wherein the therapeutic protein has an isoelectric point of greater than 7.4.

### Claim 4 (depends on 2)

The polymer of claim 2, wherein the therapeutic protein has an isoelectric point of from 7.6 to 9.2.

### Claim 5 (depends on 2)

The polymer of claim 2, wherein the therapeutic protein has an isoelectric point of from 8.2 -9.2.

### Claim 6 (depends on 3)

The polymer of claim 3, wherein the therapeutic protein has an isoelectric point of greater than 8.

### Claim 7 (depends on 2)

The polymer of claim 2, wherein the therapeutic protein is calcitonin, an antibody, a fusion protein, a peptide, or an enzyme.

### Claim 8 (depends on 7)

The polymer of claim 7, wherein the therapeutic protein is an antibody, wherein the antibody is adalimumab, infliximab, rituximab, bevacizumab, trastuzumab, ranibizumab, cetuximab, palivizumab, alemtuzumab, ibritumomab tiuxetan, arcitumomab, muromonab, basiliximab, daclizumab or tositumomab.

### Claim 9 (depends on 7)

The polymer of claim 7, wherein the therapeutic protein is calcitonin.

### Claim 10 (depends on 1)

The polymer of claim 1, wherein the solution has an ionic strength of from about 15 mM PBS to 100 mM PBS at about pH 7.4.

### Claim 11 (depends on 1)

The polymer of claim 1, wherein the solution has an ionic strength of less than about 15 mM PBS at about pH 7.4.

### Claim 12 (depends on 1)

The polymer of claim 1, wherein one component of said copolymer is itaconic acid.

### Claim 13 (depends on 1)

The polymer of claim 1, wherein one component of said copolymer is N-vinylpyrrolidone.

### Claim 14 (depends on 1)

The polymer of claim 1, wherein the copolymer further comprises poly(ethylene glycol).

### Claim 15 (depends on 1)

The polymer of claim 1, wherein at least about 75% of the copolymer comprises itaconic acid and/or N-vinylpyrrolidone.

### Claim 16 (depends on 15)

The polymer of claim 15, wherein at least about 90% of the copolymer comprises itaconic acid and/or N-vinylpyrrolidone.

### Claim 17 (depends on 16)

The polymer of claim 16, wherein at least about 95% of the copolymer comprises itaconic acid and/or N-vinylpyrrolidone.

### Claim 18 (depends on 17)

The polymer of claim 17, wherein at least about 99% of the copolymer comprises itaconic acid and/or N-vinylpyrrolidone.

### Claim 19 (depends on 1)

The polymer of claim 1, wherein the copolymer is poly(itaconic acid-co-N-vinylpyrrolidone), poly(itaconic acid-co-N-vinylpyrrolidone-co-methacrylic acid), poly(itaconic acid-g-poly(ethylene glycol)), poly(methacrylic acid-g-poly(ethylene glycol)), poly(methacrylic acid-co-N-vinylpyrrolidone), or poly(itaconic acid-co-N-vinylpyrrolidone-co-methyl methacrylate).

### Claim 20 (depends on 19)

The polymer of claim 19, wherein the copolymer is poly(itaconic acid-co-N-vinylpyrrolidone).

### Claim 21 (depends on 20)

The polymer of claim 20, wherein the ratio of itaconic acid:N-vinylpyrrolidone is from about 1:1 to about 1:9.

### Claim 22 (depends on 20)

The polymer of claim 20, wherein the ratio of itaconic acid:N-vinylpyrrolidone is from about 1:1 to about 1:4.

### Claim 23 (depends on 21)

The polymer of claim 21, wherein the ratio of itaconic acid:N-vinylpyrrolidone is about 1:2.

### Claim 24 (depends on 1)

The polymer of claim 1, wherein the polymer is further defined as a hydrogel, wherein the hydrogel at least partially swells at a pH above about 5.

### Claim 25 (depends on 1)

The polymer of claim 1, wherein the copolymer is from about 1 to about 10% crosslinked.

### Claim 26 (depends on 25)

The polymer of claim 25, wherein the copolymer is crosslinked using tetra(ethylene glycol) dimethacrylate (TEGDMA), poly(ethylene glycol) dimethacrylate (PEGDMA), a peptide, or ethylene glycol dimethacrylate.

### Claim 27 (depends on 1)

A method of producing a copolymer comprising a therapeutic protein, comprising:
(a) admixing the copolymer and the therapeutic protein in a solution with an ionic strength of less than 100 mM PBS at about pH 7.4; and
(b) allowing the copolymer and the therapeutic protein to remain in the solution for a period of time sufficient to allow for incorporation or diffusion of the therapeutic protein into the copolymer;
wherein the copolymer comprises itaconic acid, methacrylic acid, and/or N-vinylpyrrolidone; and wherein the copolymer is at least partially crosslinked;
thereby producing the polymer of claim 1.

### Claim 28 (depends on 11)

The polymer of claim 11, solution having an ionic strength of less than 2 mM PBS at pH 7.4.

### Claim 29 (depends on 1)

The polymer of claim 1 wherein the solution has an ionic strength of less than 60 mM PBS at about pH 7.4.

### Claim 30 (depends on 29)

The polymer of claim 29, wherein the solution has an ionic strength of less than 40 mM PBS at about pH 7.4.

### Claim 31 (depends on 30)

The polymer of claim 30, wherein the solution has an ionic strength of less than 30 mM PBS at about pH 7.4.

### Claim 32 (depends on 31)

The polymer of claim 31, wherein the solution has an ionic strength of less than 20 mM PBS at about pH 7.4.