# US 2022/0193254 A1 · Hydrogel for in-vivo release of medication

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- Number: US 2022/0193254 A1
- Document ID: US20220193254A1
- Status: Published application
- Kind: A1
- Application number: 17/611,659
- Filed: 2020-06-11
- Published: 2022-06-23
- Earliest claimed: 2019-06-11
- Assignees: UMC Utrecht Holding B.V.; SentryX B.V.; Bo-IP B.V.
- Applicants: UMC Utrecht Holding B.V.; SentryX B.V.; Bo-IP B.V.
- Inventors: Susanna Piluso; Jasper Gerard Steverink; Joannes Jacobus Verlaan; Bas Jeroen Oosterman
- Web page: https://patentgrep.com/patent/US20220193254A1

## CPC

- A61K 47/6903: {the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel}
- 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 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61K 47/6915: {the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes}
- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- A61P 19/00: Drugs for skeletal disorders
- A61P 23/02: Local anaesthetics
- 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

## Abstract

A hydrogel for in-vivo release of medication includes at least one medication, where the hydrogel includes (i) a protein-based biopolymer functionalized with a functionalisation agent that is able to form guest-host interactions with oxidized β-cyclodextrin, preferably a primary aminoalkylphenol, more preferably gelatin functionalized with tyramine (GTA) and (ii) oxidized β-cyclodextrin (oβ-CD), where the hydrogel is cross-linked via exposure to visible light in presence of a biocompatible photoinitiator, resulting in a degree of swelling in the range of 2-20 calculated as (swollen weight−dry weight)/dry weight. It further relates to a method for its preparation, as well as to a medication for treatment of musculoskeletal disorders, preferably for treatment of infection, inflammation, malignant processes, growth disorders, degenerative disorders or treatment of pain arising from (surgical treatment of) these disorders.

## Claims

### Claim at position 1

-21. (canceled)

### Claim 22

A hydrogel for in-vivo release of medication comprising at least one medication, wherein the hydrogel comprises
(i) a protein based biopolymer functionalized with a functionalisation agent that has introduced phenolic hydroxyl groups that are able to form guest-host interactions with oxidized β-cyclodextrin, preferably a primary aminoalkylphenol, more preferably gelatin functionalized with tyramine (GTA) and
(ii) oxidized β-cyclodextrin (oβ-CD),
wherein the hydrogel is cross-linked via exposure to visible light in presence of a biocompatible photoinitiator, resulting in a degree of swelling in the range of 2-20 calculated as (swollen weight−dry weight)/dry weight, and wherein the biocompatible photoinitiator is a combination of riboflavin and sodium persulfate.

### Claim 23 (depends on 22)

The hydrogel of claim 22, further comprising a co-solvent, preferably wherein the co-solvent is a plasticizer.

### Claim 24 (depends on 23)

The hydrogel of claim 23, wherein the plasticizer is glycerol.

### Claim 25 (depends on 22)

The hydrogel of claim 22, wherein from 10 to 30%, preferably from 15-25 of the secondary hydroxyl groups within oβ-CD have been converted into aldehyde groups.

### Claim 26 (depends on 22)

The hydrogel of claim 22, wherein the amount of oβ-CD is from 0.1% to 10% by weight of the hydrogel, preferably in the range of 2% to 6% by weight of the hydrogel.

### Claim 27 (depends on 22)

The hydrogel of claim 22, comprising bupivacaine as medication, preferably in crystalline form, in an amount of 0.01-200 mg/mL volume.

### Claim 28 (depends on 22)

The hydrogel of claim 22, wherein the medication is encapsulated in a biopolymer, preferably encapsulated in PLGA, PCL, gelatin, alginate, or liposomes.

### Claim 29 (depends on 22)

The hydrogel of claim 22, comprising bupivacaine as medication and one or more further ingredients, preferably further ingredients selected from co-medication, colorants, and buffers.

### Claim 30 (depends on 22)

The hydrogel of claim 22, comprising crosslinks of the types
(a) phenol-phenol crosslinks in the biopolymer functionalized with the functionalisation agent, preferably with a primary aminoalkylphenol;
(b) Schiff-base crosslinks between amino groups present on the functionalized biopolymer and aldehyde groups of oβ-CD, and
(c) guest-host interactions between the phenol moieties of the primary aminoalkylphenol grafted on the biopolymer and the cavity of oβ-CD.

### Claim 31 (depends on 22)

The hydrogel of claim 22, comprising a modulus of elasticity as measured from the slope of a stress-strain curve obtained by dynamic mechanical analysis in controlled force mode with a force ramp rate of 3 N min−1 up to 18 N at 5-10% strain, that is between 100 and 600 kPa.

### Claim 32 (depends on 22)

The hydrogel of claim 22, covered in part by a coating, preferably a coating of a biodegradable polymer, preferably a coating of PLGA, PCL, gelatin or alginate.

### Claim 33 (depends on 22)

The hydrogel of claim 22, wherein the protein based biopolymer (i) is selected from silk, collagen, fibrin or gelatin, more preferably gelatin.

### Claim 34 (depends on 22)

The hydrogel of claim 22, wherein the functionalisation agent is a primary aminoalkylphenol, preferably tyramine.

### Claim 35 (depends on 22)

The hydrogel of claim 22, wherein the medication is a hydrophobic medication.

### Claim 36 (depends on 35)

The hydrogel of claim 35, wherein the protein based biopolymer functionalized with a functionalisation agent is gelatin functionalized with tyramine (GTA).

### Claim 37 (depends on 22)

A hydrogel according to claim 22, having degree of swelling in the range of approximately 4 and a modulus of elasticity as measured from the slope of a stress-strain curve obtained by dynamic mechanical analysis in controlled force mode with a force ramp rate of 3 N min−1 up to 18 N at 5-10% strain, that is approximately 400 kPa, and that
(a) is provided with a hole for attachment to a bone, or
(b) is shaped as a sleeve to encompass part of a bone, or
(c) Is shaped as a thumbnail and comprises a rigid part for fixation onto a bone.

### Claim 38 (depends on 22)

A hydrogel according to claim 22, having an elongation at break of between 100 and 300%, preferably of between 120 and 250%, as measured from a ring-shaped hydrogel by mounting the sample on a caliper tool, measuring the initial inner diameter (ID) of the ring, and then gradually extending the ring and calculating the elongation as ((ID upon breaking−ID resting state)/ID resting state)*100%.

### Claim 39 (depends on 22)

A method for preparing a hydrogel according to claim 22, the method comprising:
preparing a mixed solution of the protein based biopolymer functionalized with the functionalisation agent, oβ-CD, the biocompatible photoinitiator, and optionally the medication as defined in claim 22,
exposing the solution to visible light to generate a hydrogel, and
if the medication was not included in the mixed solution: contacting the hydrogel with a solution of the medication, thereby allowing diffusion of the medication into the hydrogel,
drying the hydrogel.

### Claim 40 (depends on 22)

A hydrogel according to claim 22, for use in the treatment of musculoskeletal disorders, preferably for treatment of infection, inflammation, malignant processes, growth disorders, degenerative disorders, trauma, auto-immune diseases or treatment of pain arising from (surgical treatment of) these disorders.

### Claim 41 (depends on 40)

The hydrogel according to claim 40, which is prepared in vivo by administering, preferably injecting a combination of
(a) the biopolymer functionalized with functionalization agent mixed with the medication in liquid form (or encapsulated in microparticles) with
(b) a biopolymer functionalized with oβ-CD, and
wherein the combination is exposed to visible light in vivo, to generate the hydrogel in vivo.