Sterile hyaluronic acid polymer compositions and related methods
The present application provides sterile hyaluronic polymer compositions than are useful, e.g., as medical devices, biomedical adhesives, and sealants. Generally, provided are sterile dry compositions comprising a thiol-derivatized hyaluronic acid and one or more stabilizing excipients. Also provided are related kits and methods. The compositions described herein are particularly robust to sterilizing irradiation, and substantially maintain both their molecular weight and gelation parameters such as gelation time after sterilization, such that such sterile compositions are capable of hydrogel formation.
1. A sterile dry polymer composition prepared by terminal sterilizing irradiation and that is soluble in aqueous solution, said composition comprising a thiol-derivatized hyaluronic acid and stabilizing excipients selected from ascorbic acid, and at least one of dithiothreitol, ethylenediamine tetraacetic acid (EDTA), or sucrose, wherein said thiol-derivatized hyaluronic acid has a molecular weight in the range of 50,000 daltons to 1,000,000 daltons as determined by multi-angle light scattering and is capable of crosslinking to form a hydrogel wherein significant cross-linking due to the terminal stabilizing radiation is inhibited by the presence of the stabilizers in the composition.
2. The sterile dry polymer composition of claim 1 , wherein the thiol-derivatized hyaluronic acid has a defined molecular weight prior to sterilization, and a molecular weight after sterilization by 20 kGy irradiation that is within 60% of the defined molecular weight.
3. The sterile dry polymer composition of claim 1 or claim 2 , comprising dithiothreitol and ethylenediamine tetraacetic acid in addition to ascorbic acid.
4. The sterile dry polymer composition of claim 3 , further comprising sucrose.
5. The sterile dry polymer composition of claim 1 or 2 , comprising one or more of the following amounts of stabilizing excipient on a per weight basis relative to the thiol-derivatized hyaluronic acid: from about 1.0×10 −3 to 0.10 times dithiothreitol, from about 2.1×10 −3 to 0.20 times EDTA, from about 0.06 to 6 times sucrose, and from about 0.06 to 6 times ascorbic acid.
6. The sterile dry polymer composition of claim 1 , wherein said composition possesses an initial gelation time that changes by no more than about ±25% upon storage at 25° C. in a sealed foil pouch for a period of one month.
7. The sterile dry polymer composition of claim 6 , comprising one or more of the following amounts of stabilizing excipient on a per weight basis relative to the thiol-derivatized hyaluronic acid: from about 1.0×10 −3 to 0.10 times dithiothreitol, from about 2.1×10 −3 to 0.20 times EDTA, from about 0.06 to 6 times sucrose, and from about 0.06 to 6 times ascorbic acid.
8. The sterile dry polymer composition of any one of claims 1 , 2 , or 6 , wherein the thiol-derivatized hyaluronic acid is carboxymethyl-hyaluronic acid-dithiobis(propanoic dihydrazide) (CM-HA-DTPH).
9. The sterile dry polymer composition of any one of claims 1 , 2 , or 6 , wherein the thiol-derivatized hyaluronic acid is not crosslinked or is lightly crosslinked.
10. The sterile dry polymer composition of any one of claims 1 , 2 , or 6 , wherein the thiol-derivatized hyaluronic acid has a molecular weight ranging from about 90,000 daltons to about 300,000 daltons.
11. The sterile dry polymer composition of claim 1 in an electron-beam or gamma ray-permeable container.
12. A method for forming the sterile dry polymer composition of claim 4 , said method comprising:
providing a sealed container comprising a dry polymer composition comprised of a thiol-derivatized hyaluronic acid, ascorbic acid, dithiothreitol, ethylenediamine tetraacetic acid (EDTA), or sucrose, wherein said composition possesses an initial gelation time, and
subjecting the sealed container to electron beam or gamma irradiation at a dose and under conditions sufficient to sterilize the contents of said sealed container, to thereby provide a sterile dry polymer composition that is (i) soluble in aqueous solution and is capable of crosslinking to form a hydrogel, and (ii) possesses a gelation time that is changed by no more than about ±25% upon storage at 25° C. in a sealed foil pouch for a period of one month.
13. A method for forming the sterile dry polymer composition of claim 1 , said method comprising:
providing a sealed container comprising a dry polymer composition comprised of a thiol-derivatized hyaluronic acid and stabilizing excipients selected from ascorbic acid and at least one of dithiothreitol, ethylenediamine tetraacetic acid (EDTA), or sucrose, wherein said thiol-derivatized hyaluronic acid has a defined molecular weight as determined by multi-angle light scattering, and
subjecting the sealed container to electron beam or gamma irradiation at a dose and under conditions sufficient to sterilize the contents of said sealed container, to thereby provide a sterile dry polymer composition that is soluble in aqueous solution and is capable of crosslinking to form a hydrogel, wherein the defined molecular weight of the thiol derivatized hyaluronic acid is in the range of 50,000 daltons to 1,000,000 daltons.
14. The method of claim 13 , wherein the thiol-derivatized hyaluronic acid has a molecular weight after sterilization by irradiation that is within 60% of the defined molecular weight prior to sterilization.
15. The method of any one of claims 13 - 12 , wherein said irradiation is electron beam irradiation at a dosage ranging from 0.5 to 10.0 MRad.
16. The method of claim 15 , wherein the electron beam irradiation dosage ranges from about 1.5 to 5.0 MRad.
17. The method of any one of claims 13 - 12 , wherein said irradiation is gamma irradiation at a dosage ranging from about 0.5-10.0 MRad.
18. The method of claim 17 , wherein the gamma irradiation is in a dosage range from about 1.5 to 5.0 MRad.
19. The method of any one of claims 13 - 12 wherein said thiol-derivatized hyaluronic acid polymer is selected from carboxymethyl-hyaluronic acid-dithiobis(propanoic dihydrazide.
20. A method for forming a hydrogel suitable for injecting or implanting onto bone, teeth, nerves, cartilage, artery, soft tissues or other tissues of a mammalian subject by mixing the sterile dry powder of claim 1 with a pharmaceutically acceptable buffer solution.