# US 2021/0330859 A1 · Hydrogels and method of making the same

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- Number: US 2021/0330859 A1
- Document ID: US20210330859A1
- Status: Published application
- Kind: A1
- Application number: 17/366,762
- Filed: 2021-07-02
- Published: 2021-10-28
- Earliest claimed: 2019-01-07
- Assignees: Regeltec, Inc.
- Applicants: ReGelTec, Inc.
- Inventors: Anthony LOWMAN; Thomas P. SCHAER; Peter WILSON; Erik BREWER; Nigel Gordon SMITH
- Web page: https://patentgrep.com/patent/US20210330859A1

## CPC

- A61L 27/26: Mixtures of macromolecular compounds
- A61L 27/025: {Other specific inorganic materials not covered by A61L27/04 - A61L27/12}
- A61L 27/52: Hydrogels or hydrocolloids
- A61L 2400/06: Flowable or injectable implant compositions
- A61L 2430/34: for soft tissue reconstruction
- A61L 2430/38: for reconstruction of the spine, vertebrae or intervertebral discs
- C08K 2003/3045: {Sulfates}
- C08L 29/04: Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
- C08L 39/06: Homopolymers or copolymers of N-vinyl-pyrrolidones
- C08L 71/02: Polyalkylene oxides
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- C08K: Use of inorganic or non-macromolecular organic substances as compounding ingredients (paints, inks, varnishes, dyes, polishes, adhesives C09)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

The present disclosure relates to hydrogels and their use for repairing or supplementing body tissue. The hydrogels are capable of safe injection into patients through fine gauge needles and are suitable for repairing, supplementing, or replacing the nucleus pulposus of an intervertebral disc. Methods of manufacturing and methods of using the hydrogels of the present disclosure to repair or replace tissues are also disclosed.

## Claims

### Claim 1

A hydrogel, comprising:
about 12 wt. % to about 22 wt. % of polyvinyl alcohol;
about 0.12 wt. percent to about 0.22 wt. % of polyvinylpyrrolidone;
about 12 wt. % to about 22 wt. % non-functionalized polyethylene glycol having a Mw of about 800 Da to about 2,000 Da, wherein the hydrogel does not contain a chemically crosslinked polymer.

### Claim 2 (depends on 1)

The hydrogel of claim 1, wherein at a temperature from about 45° C. to about 65° C. the hydrogel is capable of injection through a 16 cm length, 17 gauge needle at an injection rate of at least 0.5 cc per minute using an injection pressure of less than about 200 psi.

### Claim 3 (depends on 1, 2)

The hydrogel of any one of claims 1-2, wherein the non-functionalized polyethylene glycol has an Mw of about 800 Da to about 1,200 Da.

### Claim 4 (depends on 1, 2, 3)

The hydrogel of any one of claims 1-3, wherein the non-functionalized polyethylene glycol has a Mw of about 900 Da to about 1,100 Da.

### Claim 5 (depends on 1, 2, 3, 4)

The hydrogel of any one of claims 1-4, wherein the non-functionalized polyethylene glycol has a Mw of about 1,000 Da.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The hydrogel of any one of claims 1-5, further comprising a contrast agent.

### Claim 7 (depends on 6)

The hydrogel of claim 6, wherein the contrast agent is barium sulfate.

### Claim 8 (depends on 6)

The hydrogel of claim 6, wherein the contrast agent is silver sulfate.

### Claim 9 (depends on 6, 7, 8)

The hydrogel of any one of claims 6-8, wherein the hydrogel comprises about 9 wt. % to about 19 wt. % of the contrast agent.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The hydrogel of any one of claims 1-9, wherein
the polyvinyl alcohol has an Mw of about 135,000 Da to about 155,000 Da;
the non-functionalized polyethylene glycol has an Mw of about 800 Da to about 1,200 Da; and
the polyvinylpyrrolidone has an Mw of about 35,000 Da to about 45,000 Da.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The hydrogel of any one of claims 1-10, wherein the viscosity of the hydrogel is about 10 Pa·s at a temperature of about 65° C.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The hydrogel of any one of claims 1-10, wherein the viscosity of the hydrogel is 8±2 Pa·s at a temperature of about 65° C.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The hydrogel of any one of claims 1-12, wherein the Young's modulus of the hydrogel is about 0.25 MPa.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The hydrogel of any one of claims 1-12, wherein the Young's modulus of the hydrogel is 0.2±0.05 MPa.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The hydrogel of any one of claims 1-14, wherein V/V0 of the hydrogel is about 1.0 to about 1.2 determined according to the 7-day swelling test method in ASTM F2789-10.

### Claim 16

A method of repairing or supplementing a tissue in a patient in need thereof, comprising:
(a) melting a hydrogel in a container, wherein the hydrogel comprises:
about 12 wt. % to about 22 wt. % of polyvinyl alcohol;
about 0.12 wt. percent to about 0.22 wt. % of polyvinylpyrrolidone;
about 12 wt. % to about 22 wt. % non-functionalized polyethylene glycol having a Mw of about 800 Da to about 2,000 Da, wherein the hydrogel does not contain a chemically crosslinked polymer; and
a solvent;
(b) heating the step (a) mixture to from about 65° C. to about 80° C.,
(c) inserting a 15 gauge or smaller needle into the tissue in need of repair or supplement;
(d) connecting the needle to the container and
(e) injecting a therapeutically effective amount of the step (b) mixture into the tissue to provide a tissue implant.

### Claim 17 (depends on 16)

The method of claim 16, wherein the tissue is the nucleus of an intervertebral disc.

### Claim 18 (depends on 16, 17)

The method of any one of claims 16-17, wherein the needle is a 17 gauge needle.

### Claim 19 (depends on 16, 17)

The method of any one of claims 16-17, wherein the needle is an 18 gauge needle.

### Claim 20 (depends on 16, 17, 18, 19)

The method of any one of claims 16-19, wherein the injection rate of the hydrogel into the tissue is at least 2.5 cc per minute.

### Claim 21 (depends on 16, 17, 18, 19, 20)

The method of any one of claims 16-20, wherein the tissue implant has a Young's modulus of between about 0.1 to 1.0 MPa.

### Claim 22 (depends on 16, 17, 18, 19, 20, 21)

The method of any one of claims 16-21, wherein the therapeutically effective amount of the step (b) mixture is from about 0.1 cc to about 12.0 cc.

### Claim 23 (depends on 16, 17, 18, 19, 20, 21)

The method of any one of claims 16-21, wherein the therapeutically effective amount of the step (b) mixture is from about 3.0 cc to about 6.0 cc.

### Claim 24 (depends on 16, 17, 18, 19, 20, 21)

The method of any one of claims 16-21, wherein the therapeutically effective amount of the step (b) mixture is from about 6.0 cc to about 8.0 cc.

### Claim 25 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24)

The method of any one of claims 16-24, further comprising:
inserting the container into an injector before heating the hydrogel in the container.

### Claim 26 (depends on 25)

The method of claim 25, wherein the injector includes a heater assembly, the melting of step (a) and the heating of step (b) including melting and heating the hydrogel via the heater assembly.

### Claim 27 (depends on 25)

The method of claim 25, wherein the injector includes an actuator, the injecting of step (e) including transitioning the actuator from a first state to a second state.

### Claim 28 (depends on 27)

The method of claim 27, wherein transitioning the actuator from the first state to the second state includes moving a plunger from a proximal position within the syringe to a distal position within the syringe.

### Claim 29 (depends on 27, 28)

The method of claim 27 or 28, wherein the actuator is configured to transition from the first state to the second state in response to being rotated relative to the syringe.

### Claim 30 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 16-29, wherein the hydrogel of step (a) is heated to about 121° C. to melt the hydrogel.

### Claim 31 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The method of any one of claims 16-30, wherein the non-functionalized polyethylene glycol has an Mw of about 800 Da to about 1,200 Da

### Claim 32 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The method of any one of claims 16-31, wherein the non-functionalized polyethylene glycol has a Mw of about 900 Da to about 1,100 Da.

### Claim 33 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The method of any one of claims 16-32, wherein the non-functionalized polyethylene glycol has a Mw of about 1,000 Da.

### Claim 34 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any one of claims 16-33, wherein the solvent is water.

### Claim 35 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The method of any of claims 16-34, wherein the hydrogel further comprises a contrast agent.

### Claim 36 (depends on 35)

The method of claim 35, wherein the contrast agent is barium sulfate.

### Claim 37 (depends on 35, 36)

The method of any one of claims 35-36, wherein the hydrogel comprises about 9 wt. % to about 19 wt. % of the contrast agent

### Claim 38 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

The method of any one of claims 16-37, wherein the hydrogel comprises:
the polyvinyl alcohol has an Mw of about 135,000 Da to about 155,000 Da;
the non-functionalized polyethylene glycol has an Mw of about 800 Da to about 1,200 Da; and
the polyvinylpyrrolidone has an Mw of about 35,000 Da to about 45,000 Da.

### Claim 39 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)

The method of any one of claims 16-38, wherein the viscosity of the hydrogel is about 10 Pa·s at a temperature of about 65° C.

### Claim 40 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)

The method of any one of claims 16-39, wherein the viscosity of the hydrogel is 8±2 Pa·s at a temperature of about 65° C.

### Claim 41 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The method of any one of claims 16-40, wherein the Young's modulus of the hydrogel is about 0.25 MPa.

### Claim 42 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)

The method of any one of claims 16-41, wherein the Young's modulus of the hydrogel is 0.2±0.05 MPa.

### Claim 43 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The method of any of claims 16-42, wherein the therapeutically effective amount of the step (b) mixture is determined by observing the implant in real time as it is injected using radiographic imaging.

### Claim 44 (depends on 43)

The method of claim 43, wherein the therapeutically effective amount is the amount of step (b) mixture that is injected before the radiographic image shows that the gel is going into an undesirable location.

### Claim 45 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The method of any of claims 16-42, wherein the therapeutically effective amount of step (b) mixture is determined by:
(a) injecting a hydrogel of the present disclosure to from about 120 psi to about 200 psi as determined by a pressure gauge on the delivery system;
(b) pausing the hydrogel injection;
(c) monitoring the pressure gauge for a pressure decrease below 120 psi to about 200 psi;
(d) injecting additional hydrogel until 120 psi to about 200 psi is achieved;
(e) repeating the steps (b)-(d) until the pressure decrease in less than about 10% of 120 psi to about 200 psi.

### Claim 46

. A method of manufacturing a hydrogel comprising:
(a) forming a mixture comprising polyvinyl alcohol, polyvinylpyrrolidone and water;
(b) heating the mixture of Step (a) to form a solution;
(c) heating non-functionalized polyethylene glycol (PEG) having a Mw of about 800 Da to about 2,000 Da;
(d) adding the heated PEG from step (c) to the heated mixture of step (b);
(e) cooling the mixture of step (d) to provide a hydrogel;
(f) conducting a phase separation to provide an aqueous supernatant and a hydrogel; and
(g) removing the aqueous supernatant to provide the hydrogel, wherein the hydrogel does not contain a chemically cross-linked polymer.

### Claim 47 (depends on 46)

The method of claim 46, wherein the heating of step (b) is from about 95° C. to about 120° C.

### Claim 48 (depends on 46, 47)

The method of any one of claims 46-47, wherein the heating of step (c) is from about 95° C. to about 120° C.

### Claim 49 (depends on 46, 47, 48)

The method of any one of claims 46-48, wherein the phase separation is conducted by centrifugation.

### Claim 50 (depends on 49)

The method claim 49, wherein the centrifugation is conducted at from about 4,000 g to about 6,000 g for from about 5 min to about 10 min.

### Claim 51 (depends on 49)

The method claim 49, wherein the centrifugation is conducted at about 4,300 g for about 10 min.

### Claim 52 (depends on 49, 50, 51)

The method of any one of claims 49-51, wherein the centrifugation is conducted at a speed and for a time that is sufficient to achieve phase separation but does not form a density gradient of suspended contrast agent.

### Claim 53 (depends on 46, 47, 48, 49, 50, 51, 52)

The method of any one of claims 46-52, wherein the mixture of step (a) further comprises a contrast agent.

### Claim 54 (depends on 53)

The method of claim 53, wherein the contrast agent is barium sulfate.

### Claim 55 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of any one of claims 46-54, wherein the mixture of step (e) comprises:
about 7 wt. % to about 17 wt. % of polyvinyl alcohol;
about 0.07 wt. % to about 0.17% of polyvinylpyrrolidone;
about 13 wt. % to about 23 wt. % of polyethylene glycol;
about 3 wt. % to about 13 wt. % of barium sulfate and
about 57 wt. % to about 67 wt. % of water.

### Claim 56 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of any one of claims 46-54, wherein the mixture of step (e) comprises:
about 9 wt. % to about 15 wt. % of polyvinyl alcohol;
about 0.09 wt. % to about 0.15% of polyvinylpyrrolidone;
about 15 wt. % to about 21 wt. % of polyethylene glycol;
about 5 wt. % to about 11 wt. % of barium sulfate and
about 59 wt. % to about 65 wt. % of water.

### Claim 57 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of any one of claims 46-54, wherein the mixture of step (e) comprises:
about 11 wt. % to about 13 wt. % of polyvinyl alcohol;
about 0.11 wt. % to about 0.13% of polyvinylpyrrolidone;
about 17 wt. % to about 19 wt. % of polyethylene glycol;
about 7 wt. % to about 9 wt. % of barium sulfate and
about 61 wt. % to about 63 wt. % of water.

### Claim 58 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)

The method of any one of claims 46-57, wherein the polyethylene glycol has an Mw of about 800 Da to about 2000 Da.

### Claim 59 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The method of any one of claims 46-58, wherein the polyethylene glycol has an Mw of about 1000 Da.

### Claim 60 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59)

The method of any one of claims 46-59, wherein the wt. % of the aqueous supernatant changes less than about 5 wt. % when the hydrogel is stored at 23° C. for 2 months.

### Claim 61 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60)

The method of any one of claims 46-60, wherein the hydrogel comprises:
about 12 wt. % to about 22 wt. % of polyvinyl alcohol;
about 0.12 wt. percent to about 0.22 wt. % of polyvinylpyrrolidone;
about 12 wt. % to about 22 wt. % non-functionalized polyethylene glycol having a Mw of about 800 Da to about 2,000 Da, wherein the hydrogel does not contain a chemically crosslinked polymer.

### Claim 62 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)

The hydrogel prepared by the method of any one of claim 46-61.