# US 12,109,252 B2 · Systems, methods and products for minimizing tissue reactions and tissue injury at an infusion site

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- Number: US 12,109,252 B2
- Document ID: US12109252B2
- Status: Granted
- Kind: B2
- Application number: 18/145,471
- Filed: 2022-12-22
- Published: 2023-08-31
- Granted: 2024-10-08
- Earliest claimed: 2016-04-12
- Assignees: Cell and Molecular Tissue Engineering, LLC
- Applicants: Cell and Molecular Tissue Engineering, LLC
- Inventors: Ulrike W. Klueh; Donald L Kreutzer
- Web page: https://patentgrep.com/patent/US12109252B2

## CPC

- A61K 38/28: Insulins
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/12: Ketones
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 38/18: Growth factors; Growth regulators
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/40: Cyclodextrins; Derivatives thereof
- A61M 5/1582: {Multi-lumen needles}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07K 14/62: Insulins
- 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)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- 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)

## Abstract

Products, systems and methods are disclosed for lowering the concentrations of at least one of preservatives and fibrils in a liquid insulin composition. One method comprises replacing at least a portion of at least one of phenol and m-cresol with at least one of cyclodextrins, cyclodextrin polymers, cyclodextrin beads, and an ion exchange resin.

## Claims

### Claim 1

A method of lowering the concentrations of preservatives in a liquid insulin composition delivered through a transdermal insulin pump system, the preservatives including at least one of phenol and m-cresol, the method comprising filtering the liquid insulin composition by incorporating into the insulin pump system a filter comprising a cyclodextrin configured to remove phenol and m-cresol without removing insulin.

### Claim 2 (depends on 1)

The method of claim 1, wherein the insulin pump system includes an insulin infusion set including an insulin delivery line, and the cyclodextrin is incorporated into at least one of the insulin infusion set delivery line, a cannula, and a housing that can be disposed between the insulin delivery line and the cannula.

### Claim 3 (depends on 2)

The method of claim 2, further comprising coating at least one of a cannula and a collar for a cannula in the insulin infusion set with at least one of an extracellular matrix, a gel, an oil and a biological lubricant.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cyclodextrin is configured to remove additional anti-microbial agents from the liquid insulin composition.

### Claim 5 (depends on 1)

The method of claim 1, further comprising incorporating an agent that suppresses inflammation into an infusion site for the insulin pump system, the agent comprising at least one member selected from the group consisting of corticosteroids, acetylsalicylic acid, and 3-chloro-N-tert-butyl-β-keto-α-methylphenethylamine (buproprion).

### Claim 6 (depends on 2)

The method of claim 2, wherein the cyclodextrin is located in inline tubing, in an infusion cap, or in a cannula of the insulin infusion set.

### Claim 7 (depends on 1)

The method of claim 1, further comprising including an anti-protease component in the liquid insulin composition, the anti-protease component comprising at least one of aprotinin, alpha-1-antitrypsin (AAT), SP16 serine protease inhibitor, and pepstatin.

### Claim 8 (depends on 1)

The method of claim 1, wherein the cyclodextrin comprises a polymer.

### Claim 9 (depends on 1)

The method of claim 1, further comprising incorporating [(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid into an infusion site for the insulin pump system.

### Claim 10 (depends on 1)

The method of claim 1, further comprising incorporating into an infusion site for the insulin pump system an agent that suppresses insulin degradation, the agent comprising at least one member selected from the group consisting of alpha-2-macroglobulin, alpha-1-antitrypsin, aprotinin and pepstatin.

### Claim 11 (depends on 1)

The method of claim 1, further comprising incorporating into an infusion site for the insulin pump system at least one member selected from the group consisting of VEGFa, VEGFc and VEGFd.

### Claim 12 (depends on 1)

The method of claim 1, further comprising incorporating into an infusion site for the insulin pump system a chemokine inhibitor comprising at least one member selected from the group consisting of 3,7-dimethyl-1-(5-oxohexyl)purine-2,6-dione, (2R)-2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropanamide, (2S)-2-[[(2R)-2-[[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-acetamido-5-(diaminomethylideneamino) pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-sulfanylpropanoyl]amino]-5-(diaminomethylideneamino)pentanamide, and 2-[(1-benzylindazol-3-yl)methoxy]-2-methylpropanoic acid.

### Claim 13 (depends on 1)

The method of claim 1, further comprising removing fibrils by incorporating a fibril filtration system into the insulin pump system in order to remove at least one of proteins and protein complexes having a molecular weight between 36 thousand and 50 thousand.

### Claim 14 (depends on 1)

The method of claim 1, wherein the insulin pump system comprises a syringe.

### Claim 15 (depends on 14)

The method of claim 14, wherein the syringe includes a syringe chamber and the filter is incorporated into the syringe chamber.

### Claim 16 (depends on 1)

The method of claim 1, wherein the insulin pump system comprises a needle and a plunger system and the filter is associated with the plunger system.