Hyaluronic acid-based gels including lidocaine

• US 8,450,475 B2
• Filed: 02/26/2009
• Issued: 05/28/2013
• Est. Priority Date: 08/04/2008
• Status: Active Grant

• Current Assignee: Allergan Industrie SAS (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Lebreton, Pierre F.
• Primary Examiner(s): Soroush, Ali
• Application Number:
  US12/393,768
• Publication Number:
  US 20100028437A1
• Time in Patent Office: 1,552 Days
• Field of Search: 536/124, 514/54, 424/484, 424/488
• US Class Current: 536/124
• CPC Class Codes: A61K 2800/91 Injection
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 8/0241 Containing particulates characterized by their shape and/or structure see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes
• CPC Class Codes: A61K 8/375 the alcohol moiety containing more than one hydroxy group
• CPC Class Codes: A61K 8/42 Amides
• CPC Class Codes: A61K 8/735 Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 2/0023 Heat
• CPC Class Codes: A61L 2/0029 Radiation
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 23/00 : Anaesthetics
• CPC Class Codes: A61P 23/02 : Local anaesthetics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61Q 19/001 : Preparations for care of the lips
• CPC Class Codes: A61Q 19/08 : Anti-ageing preparations
• CPC Class Codes: C08L 5/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

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.

Claims

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%.