Low sweel tissue adhesive and sealant formulations

• US 10,207,021 B2
• Filed: 06/12/2017
• Issued: 02/19/2019
• Est. Priority Date: 07/29/2013
• Status: Expired due to Fees

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Jenkins, Lauri L., Dilucclo, Robert C.
• Primary Examiner(s): Arnold, Ernst V
• Application Number:
  US15/620,745
• Publication Number:
  US 20170274117A1
• Time in Patent Office: 617 Days
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

A hydrogel tissue adhesive formed by reacting an aldehyde-functionalized dextran containing pendant aldehyde groups with a multi-arm polyethylene glycol amine is described. The hydrogel exhibits little to no swell upon exposure to physiological conditions. The hydrogel may be useful as a tissue adhesive or sealant for medical applications that require a low swell hydrogel to inhibit complications, such as fibrosis, including scar formation or surgical adhesions.

Claims

1. A kit for forming a hydrogel comprising:

(a) a first aqueous solution or dispersion comprising one or more aldehyde-functionalized dextrans containing pendant aldehyde groups that are attached to dextran via one of the ring hydroxyl groups, said aldehyde-functionalized dextrans having a weight-average molecular weight of about 10,000 to about 20,000 Da and an equivalent weight per aldehyde group of about 226 to about 170 Da; and

(b) a second aqueous solution or dispersion comprising one or more polyethylene glycols having eight arms, substantially each arm of which is terminated with at least one primary amine group, wherein the polyethylene glycols have a number-average molecular weight of about 9,000 to about 11,000 Da;

wherein

(i) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 5 wt % to about 20 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 10 wt % to about 18 wt %;

or

(ii) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 5 wt % to about 10 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 10 wt % to about 20 wt %,

wherein the mean swell of samples of a hydrogel formed by mixing the first aqueous solution or dispersion and the second aqueous solution or dispersion is less than 10% as measured by forming a mixture of the first aqueous solution or dispersion and the second aqueous solution or dispersion using a dual barrel syringe with a 16 stage mixing tip, injecting the mixture directly into a piece of plastic tubing having an internal diameter of about 4 mm, allowing the hydrogel to gel, removing the hydrogel from the tubing by slitting the tubing open, thereby obtaining a cylindrical hydrogel, cutting the cylindrical hydrogel into pieces having a length of approximately 10 mm, placing each piece inside a separate piece of plastic tubing with an internal diameter of about 5 mm and a length of about 20 mm, placing each piece of tubing into a separate 20 mL lass vial containing phosphate-buffered saline, capping the lids of the glass vial and sealing the lids with tape, placing the glass vials in an incubator at 37°

C. on their sides to maintain the cylindrical hydrogels in a horizontal position, removing the vials from the incubator at intervals, and measuring the length of the hydrogels wherein the swell of a sample is the percentage increase in the length of the hydrogel relative to its initial length, and wherein measurements are performed using a ruler to the nearest 0.5 mm.

2. The kit of claim 1, wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185 Da.

3. The kit of claim 1, wherein the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 5 wt % to about 10 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 10 wt % to about 18 wt %.

4. The kit of claim 1, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 13,000 to about 17,000 Da.

5. The kit of claim 1, wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 222 to about 189 Da.

6. The kit of claim 1, wherein the polyethylene glycols have a number-average molecular weight of about 9,500 to about 10,500 Da.

7. The kit of claim 1, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Da and an equivalent weight per aldehyde group of about 177 Da, wherein the polyethylene glycols have a number-average molecular weight of about 10,000 Da, and wherein the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 10 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 15 wt %.

8. The kit of claim 1, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Da and an equivalent weight per aldehyde group of about 177 Da, wherein the polyethylene glycols has a number-average molecular weight of about 10,000 Da, and wherein the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 15 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 15 wt %.

12. A method for applying a row swell coating using the kit according to claim 1 to an anatomical site on tissue of a living organism comprising the steps of:

applying to the site (a) aldehyde-functionalized dextrans containing pendant aldehyde groups, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 10,000 to about 20,000 Da and an equivalent weight per aldehyde group of about 226 to about 170 Da;

followed by

(b) polyethylene glycols having eight arms, substantially each arm of which is terminated with at least one primary amine group, wherein the polyethylene glycols have a number-average molecular weight of about 9,000 to about 11,000 Da,

or (b) followed by (a), or premixing (a) and (b) and applying the resulting mixture to the site before the resulting mixture completely cures; and

wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 2;

1 to about 1;

4.

13. The method of claim 12, wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185 Da.

14. The method of claim 12, wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 1:

1 to about 5;

18.

15. The method of claim 12, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 13,000 to about 17,000 Da.

16. The method of claim 12, wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 222 to about 189 Da.

17. The method of claim 12, wherein the polyethylene glycols have a number-average molecular weight of about 9,500 to about 10,500 Da.

18. The method of claim 12, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Da and a degree of aldehyde substitution of about 108%, wherein the polyethylene glycols have a number-average molecular weight of about 10,000 Da, and wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 1:

1.5.

19. The method of claim 12, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Da and a degree of aldehyde substitution of about 108%, wherein the polyethylene glycols has a number-average molecular weight of about 10,000 Da, and wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 1:

1.

20. The method of claim 12, wherein the site is tissue involved in or affected by a surgical procedure.

21. The method of claim 20, wherein the surgical procedure is lumbar laminectomy, laminotomy, discectomy, flexor tendon surgery, spinal fusion, joint replacement or repair, abdominal procedures, gynecological procedures, musculoskeletal surgeries, thoracic surgeries, cranial surgeries, ocular surgeries, oral surgeries or implants.

9. A dried hydrogel formed by a process comprising the steps of:

combining in a solvent (a) one or more aldehyde-functionalized dextrans containing pendant aldehyde groups, said aldehyde-functionalized dextrans having a weight-average molecular weight of about 10,000 to about 20,000 Da and an equivalent weight per aldehyde group of about 226 to about 170 Da, and (b) one or more polyethylene glycols having eight arms, substantially each arm of the which is terminated with at least one primary amine group, said polyethylene glycols having a number-average molecular weight of about 9,000 to about 11,000 Da, to form a hydrogel;

wherein

(i) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the solvent is about 5 wt % to about 20 wt % and the total concentration of the polyethylene glycols in the solvent is about 10 wt % to about 18 wt %;

or

(ii) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the solvent is about 5 wt % to about 10 wt % and the total concentration of the polyethylene glycols in the solvent is about 10 wt % to about 20 wt %; and

treating said hydrogel to remove at least a portion of said solvent to form the dried hydrogel, and

wherein the mean swell of samples of a hydrogel formed by mixing the first aqueous solution or dispersion and the second aqueous solution or dispersion is less than 10% as measured by forming a mixture of the first aqueous solution or dispersion and the second aqueous solution or dispersion using a dual barrel syringe with a 16 stage mixing tip, injecting the mixture directly into a piece of plastic tubing having an internal diameter of about 4 mm, allowing the hydrogel to gel, removing the hydrogel from the tubing by slitting the tubing open, thereby obtaining a cylindrical hydrogel, cutting the cylindrical hydrogel into Pieces having a length of approximately 10 mm, placing each piece inside a separate piece of plastic tubing with an internal diameter of about 5 mm and a length of about 20 mm, placing each piece of tubing into a separate 20 mL glass vial containing phosphate-buffered saline, capping the lids of the glass vial and sealing the lids with tape, placing the glass vials in an incubator at 37°

C. on their sides to maintain the cylindrical hydrogels in a horizontal position, removing the vials from the incubator at intervals, and measuring the length of the hydrogels, wherein the swell of a sample is the percentage increase in the length of the hydrogel relative to its initial length, and wherein measurements are performed using a ruler to the nearest 0.5 mm.

10. The dried hydrogel of claim 9, wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185 Da.

11. The dried hydrogel of claim 9 wherein said dried hydrogel is in the form of a film.