# US 11,896,673 B2 · Glucose responsive insulin delivery compositions and methods

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- Number: US 11,896,673 B2
- Document ID: US11896673B2
- Status: Granted
- Kind: B2
- Application number: 17/188,583
- Filed: 2021-03-01
- Published: 2021-08-26
- Granted: 2024-02-13
- Earliest claimed: 2016-01-14
- Assignees: North Carolina State University
- Applicants: North Carolina State University
- Inventors: Zhen Gu; Chao Wang
- Web page: https://patentgrep.com/patent/US11896673B2

## CPC

- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 9/0021: {Intradermal administration, e.g. through microneedle arrays or needleless injectors}
- A61K 35/18: Erythrocytes (haemoglobin A61K38/42)
- A61K 38/28: Insulins
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07H 13/08: having the esterifying carboxyl radicals directly attached to carbocyclic rings
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Disclosed herein is a glucose-responsive insulin delivery system based on the interaction between the glucose-modified insulin and glucose transporters (GLUTs) on erythrocytes (or red blood cells, RBCs). After being conjugated with glucose, insulin can efficiently bind to RBC membranes. The binding is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of blood glucose (BG) level in vivo. In some embodiments, the delivery vehicle can include: 1) intravenously injectable polymeric nanoparticles (˜100 nm in diameter) coated with RBC membrane and loaded with glucose-modified insulin and/or 2) painless microneedle (MN) patches loaded with the complex of GLUT and glucose-modified insulin.

## Claims

### Claim 1

An insulin delivery system comprising:
a reservoir;
a composition housed in the reservoir, the composition comprising a glucose binding structure and a glucose-modified insulin molecule reversibly bound to the glucose binding structure,
wherein the glucose-modified insulin molecule comprises an insulin moiety conjugated to at least one glucose moiety by at least one linker molecule.

### Claim 2 (depends on 1)

The insulin delivery system of claim 1, wherein the glucose-binding structure releases a portion of the glucose-modified insulin in high glucose conditions.

### Claim 3 (depends on 2)

The insulin delivery system of claim 2, wherein high glucose conditions are glucose concentrations greater than or equal to 200 mg/dL.

### Claim 4 (depends on 2)

The insulin delivery system of claim 2, wherein the glucose-binding structure binds the glucose modified insulin in low glucose conditions, wherein low glucose conditions are glucose concentrations less than 200 mg/dL.

### Claim 5 (depends on 4)

The insulin delivery system of claim 4, wherein the glucose-binding structure is configured to bind the glucose-modified insulin in low glucose conditions for at least 50 days.

### Claim 6 (depends on 1)

The insulin delivery system of claim 1, wherein the glucose-modified insulin molecule comprises two or more glucose moieties, wherein each glucose moiety is conjugated to the insulin moiety by a distinct linker molecule.

### Claim 7 (depends on 1)

The insulin delivery system of claim 1, wherein the linker molecule is synthetic.

### Claim 8 (depends on 7)

The insulin delivery system of claim 7, wherein the linker molecule comprises a maleimide group.

### Claim 9 (depends on 7)

The insulin delivery system of claim 7, wherein the linker molecule comprises a polyethylene glycol (PEG) group.

### Claim 10 (depends on 1)

The insulin delivery system of claim 1, wherein the insulin delivery system comprises a transdermal patch.

### Claim 11 (depends on 1)

The insulin delivery system of claim 1, wherein the insulin delivery system comprises microneedles.

### Claim 12 (depends on 1)

The insulin delivery system of claim 1, wherein the glucose-binding structure comprises a GLUT protein.

### Claim 13

A method of controlling insulin release to a subject using an insulin delivery system, the method comprising:
housing a glucose binding structure and a glucose-modified insulin molecule within a reservoir of the insulin delivery system, the glucose-modified insulin molecule reversibly bound to the glucose binding structure and comprising an insulin moiety conjugated to at least one glucose moiety by at least one linker molecule;
creating a fluidic connection between the reservoir and a blood supply of the subject;
releasing the glucose-modified insulin molecule from the glucose binding structure and into the blood supply as a glucose concentration in the blood supply increases.

### Claim 14 (depends on 13)

The method of claim 13, wherein the glucose-modified insulin molecule is released when the glucose concentration in the blood supply is greater than or equal to 200 mg/dL.

### Claim 15 (depends on 13)

The method of claim 13, further comprising binding the glucose modified insulin molecule to the glucose binding structure for at least 50 days under low glucose conditions.

### Claim 16 (depends on 15)

The method of claim 15, wherein low glucose conditions are glucose concentrations less than 200 mg/dL.

### Claim 17 (depends on 13)

The method of claim 13, wherein the reservoir is part of a transdermal patch.

### Claim 18 (depends on 13)

The method of claim 13, wherein the reservoir is part of a microneedle-array patch.

### Claim 19 (depends on 13)

The method of claim 13, wherein the subject has diabetes.

### Claim 20

A method of controlling glucose levels in a subject, the method comprising;
administering a therapeutically effective amount of a composition to a subject having diabetes, the composition comprising;
a glucose-modified insulin molecule comprising an insulin moiety conjugated to at least one glucose moiety by at least one linker molecule, and
a glucose binding structure,
wherein the glucose-modified insulin molecule is reversibly bound to the glucose binding structure, and
wherein the glucose-binding structure releases a portion of the glucose-modified insulin in high glucose conditions.