Process for efficient cross-linking of hyaluronic acid
A process for manufacturing a cross-linked hyaluronic acid (HA) gel product is comprising the steps of: (a) preparing an aqueous mixture of HA and a cross-linking agent selected from multiepoxides and diepoxides; wherein the HA is dissolved in an aqueous solution containing 1-10% (w/w) inorganic hydroxide; and wherein the dissolved HA constitutes more than 10% (w/w) of the final mixture; and (b) subjecting the aqueous mixture to cross-linking conditions to allow the dissolved HA to react with the cross-linking agent so as to obtain a cross-linked HA gel product.
1. A cross-linked hyaluronic acid (HA) gel product comprising HA molecules crosslinked by a crosslinker selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane, wherein:
the cross-linked HA gel product does not comprise any glycosaminoglycans other than HA;
the cross-linked HA gel product has a degree of modification (MoD) of 1.21% to 4%; and
the cross-linked HA gel product has an elastic modulus (G′) of 1000 to 1200 Pa, wherein G′ is measured at 0.1 Hz under a strain of 0.1% for an HA concentration of 20 mg/g at room temperature.
2. The cross-linked HA gel product according to claim 1 , wherein the cross-linked HA gel product has a degree of modification (MoD) of 1.5% to 4%.
3. The cross-linked HA gel product according to claim 1 , wherein the cross-linked HA gel product has a gel content (GelC) of 90% or greater.
4. The cross-linked HA gel product according to claim 1 , wherein the cross-linked HA gel product has a gel content (GelC) of 95% or greater.
5. The cross-linked HA gel product according to claim 1 , wherein the diepoxide crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).
6. The cross-linked HA gel product according to claim 1 , further comprising a local anesthetic, anti-inflammatory drug, antibiotic, bone growth factor, or cells.
7. The cross-linked HA gel product according to claim 1 , further comprising lidocaine.
8. The cross-linked HA gel product according to claim 1 , wherein the cross-linked HA gel product comprises gel particles or gel fibers having a size of more than 0.1 mm.
9. An implant comprising:
a cross-linked hyaluronic acid (HA) gel product comprising HA molecules crosslinked by a crosslinker selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane;
water; and
a buffering agent,
wherein:
the cross-linked HA gel product does not comprise any glycosaminoglycans other than HA;
the cross-linked HA gel product has a degree of modification (MoD) of 1.21% to 4%;
the cross-linked HA gel product has an elastic modulus (G′) of 1000 to 1200 Pa, wherein G′ is measured at 0.1 Hz under a strain of 0.1% for an HA concentration of 20 mg/g at room temperature.
10. The implant according to claim 9 , wherein the cross-linked HA gel product has a degree of modification (MoD) of 1.5% to 4%.
11. The implant according to claim 9 , wherein the cross-linked HA gel product has a gel content (GelC) of 90% or greater.
12. The implant according to claim 9 , further comprising a local anesthetic, anti-inflammatory drug, antibiotic, bone growth factor, or cells.
13. The implant according to claim 9 , further comprising lidocaine.
14. The implant according to claim 9 , wherein the diepoxide crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).
15. The implant according to claim 9 , wherein the cross-linked HA gel product comprises gel particles or gel fibers having a size of more than 0.1 mm.
16. A pre-filled syringe comprising:
a cross-linked hyaluronic acid (HA) gel product comprising HA molecules crosslinked by a crosslinker selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane;
water; and
a buffering agent,
wherein:
the cross-linked HA gel product does not comprise any glycosaminoglycans other than HA;
the cross-linked HA gel product has a degree of modification (MoD) of 1.21% to 4%; and
the cross-linked HA gel product has an elastic modulus (G′) of 1000 to 1200 Pa, wherein G′ is measured at 0.1 Hz under a strain of 0.1% for an HA concentration of 20 mg/g at room temperature.
17. The pre-filled syringe of claim 16 , further comprising a local anesthetic, anti-inflammatory drug, antibiotic, bone growth factor, or cells.
18. The pre-filled syringe of claim 16 , further comprising lidocaine.
19. The pre-filled syringe of claim 16 , wherein the cross-linked HA gel product comprises gel particles or gel fibers having a size of more than 0.1 mm.