Hyaluronic acid-based gels including lidocaine
Disclosed herein are soft tissue fillers, for example, dermal and subdermal fillers, based on hyaluronic acids and pharmaceutically acceptable salts thereof. In one aspect, hyaluronic acid-based compositions described herein include a therapeutically effective amount of at least one anesthetic agent, for example, lidocaine. The present hyaluronic acid-based compositions including lidocaine have an enhanced stability, relative to conventional compositions including lidocaine, for example when subjected to sterilization techniques or when stored for long periods of time. Methods and processes of preparing such hyaluronic acid-based compositions are also provided.
1. A stable, sterile soft tissue filler comprising:
a hyaluronic acid (HA) component comprising HA crosslinked with 1,4-butanediol diglycidyl ether (BDDE), and uncrosslinked HA, wherein the HA component comprises greater than about 10% uncrosslinked HA by volume; and
lidocaine combined with said crosslinked HA component.
2. The soft tissue filler of claim 1 wherein the HA component comprises at least about 15% uncrosslinked HA by volume.
3. The soft tissue filler of claim 1 wherein the HA component comprises at least about 20% uncrosslinked HA by volume.
4. The soft tissue filler of claim 1 wherein the HA component comprises a first portion of crosslinked HA and a second portion of uncrosslinked HA.
5. The soft tissue filler of claim 4 wherein the first portion has degree of crosslinking of less than about 6%.
6. The soft tissue filler of claim 4 wherein the HA component has a degree of crosslinking of less than about 5%.
7. The soft tissue filler of claim 4 wherein the HA component has a degree of crosslinking of about 2%.
8. The soft tissue filler of claim 1 wherein the lidocaine is at a concentration of between about 0.1% and about 5% by weight of said soft tissue filler.
9. The soft tissue filler of claim 1 wherein the HA component comprises particles of crosslinked HA in a relatively fluidic medium of uncrosslinked HA.
10. A method of preparing a stable, sterile soft tissue filler, the method comprising the steps of:
providing a hyaluronic acid (HA) component crosslinked with 1,4-butanediol diglycidyl ether (BDDE), wherein the HA component further comprises uncrosslinked HA at a concentration of at least about 10% of the weight of the HA component;
adjusting the pH of said HA component to an adjusted pH above about 7.2; and
adding a solution containing lidocaine to said HA component having said adjusted pH to obtain a HA-based soft tissue filler that is stable after being subjected to heat sterilization.
11. The method of claim 10 wherein said adjusted pH is above about 7.5.
12. The method of claim 10 wherein said step of providing a HA component comprises the steps of providing dry uncrosslinked NaHA material and hydrating said dry uncrosslinked NaHA material in an alkaline solution to obtain an alkaline, uncrosslinked NaHA gel.
13. The method of claim 12 wherein said alkaline, uncrosslinked NaHA gel has a pH greater than about 8.0.
14. The method of claim 12 wherein said alkaline, uncrosslinked NaHA gel has a pH greater than about 10.
15. The method of claim 10 wherein the HA component comprises greater than about 10% uncrosslinked HA.
16. The method of claim 10 wherein the HA component comprises at least about 20% uncrosslinked HA.
17. The method of claim 10 wherein the HA component has a degree of crosslinking of less than about 5%.
18. A stable, sterile soft tissue filler comprising:
a hyaluronic acid (HA) component crosslinked with 1,4-butanediol diglycidyl ether (BDDE), said HA component having a degree of crosslinking of less than about 5% and uncrosslinked HA in an amount of at least about 10% by volume of the HA component; and
lidocaine having a concentration of about 0.3% by weight of said soft tissue filler;
wherein the soft tissue filler has been heat sterilized.
19. A stable, sterile soft tissue filler composition comprising:
a hyaluronic acid (HA) material crosslinked with 1,4-butanediol diglycidyl ether (BDDE), said HA material including a high molecular weight HA component and a low molecular weight HA component and having a degree of crosslinking of less than about 5%;
free HA at a concentration of at least about 10% by volume of the soft tissue filler composition; and
lidocaine having a concentration between about 0.1% and about 5.0% by weight of the soft tissue filler composition.
20. The composition of claim 19 wherein the high molecular weight HA component has a molecular weight of between about 1.0 MDa and about 4.0 MDa.
21. The composition of claim 19 wherein the high molecular weight HA component has a molecular weight of about 2.0 MDa.
22. The composition of claim 19 wherein the high molecular weight HA component has a molecular weight of about 2.8 MDa.
23. The composition of claim 19 wherein the high molecular weight HA component has a molecular weight of at least about 1.0 MDa and the low molecular weight HA has a molecular weight of less than about 1.0 MDa.
24. The composition of claim 23 wherein the low molecular weight HA component has a molecular weight of between about 0.2 MDa and less than 1.0 MDa.
25. The composition of claim 23 wherein the low molecular weight HA component has a molecular weight of between about 0.3 MDa and less than 0.75 MDa.
26. The composition of claim 19 wherein the HA material comprises about 90% by weight of the low molecular weight HA component and about 10% by weight of the high molecular weight HA component.
27. A stable, sterile soft tissue filler composition comprising:
a 1,4-butanediol diglycidyl ether (BDDE)-crosslinked hyaluronic acid (HA) having a degree of crosslinking of about 2% to about 20%;
at least 10% free HA by volume; and
about 0.1% to about 5% lidocaine by weight of the composition.
28. The composition of claim 27 , wherein the free HA is about 20% or less of the HA by volume.
29. The composition of claim 27 , wherein the free HA is about 10% to about 20% of the composition by volume.
30. The composition of claim 27 , wherein the composition is prepared by adding free HA to crosslinked HA.
31. A heat-sterilized, stable dermal filler comprising:
a hyaluronic acid (HA) comprising both crosslinked HA and uncrosslinked HA, the crosslinked HA being crosslinked with 1,4-butanediol diglycidyl ether (BDDE) and having a degree of crosslinking of less than about 5%; and
lidocaine at a concentration of about 0.3% by weight of said dermal filler;
the dermal filler having a pH of about 7.
32. The dermal filler of claim 31 having a HA concentration of between about 20 mg/mL to about 30 mg/mL.
33. The dermal filler of claim 31 wherein the HA comprises at least about 10% to about 20% of the uncrosslinked HA by volume.
34. A stable, sterile soft tissue filler comprising:
a hyaluronic acid (HA) component comprising HA crosslinked with 1,4-butanediol diglycidyl ether (BDDE), and uncrosslinked HA; and
lidocaine at a concentration of about 0.3% by weight of the soft tissue filler combined with said crosslinked HA component;
wherein the soft tissue filler is stable after heat sterilization at between about 120 degrees C. and about 130 degrees C.; and
wherein the soft tissue filler has a pH of about 7.
35. The soft tissue filler of claim 34 having a HA concentration of between about 20 mg/mL to about 30 mg/mL.
36. The soft tissue filler of claim 34 wherein the HA comprises at least about 10% to about 20% of the uncrosslinked HA by volume.
37. The soft tissue filler of claim 34 wherein the crosslinked HA has a degree of crosslinking of less than about 5%.