Hyaluronic acid-based gels including lidocaine

• US 10,391,202 B2
• Filed: 11/09/2018
• Issued: 08/27/2019
• Est. Priority Date: 08/04/2008
• Status: Active Grant

• Current Assignee: Allergan Industrie SAS (Abbvie Incorporated)
• Original Assignee: Allergan Industrie SAS (Abbvie Incorporated)
• Inventors: Lebreton, Pierre F.
• Primary Examiner(s): Soroush, Ali
• Application Number:
  US16/186,451
• Publication Number:
  US 20190076580A1
• Time in Patent Office: 291 Days
• 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 at a concentration of about 0.3% by weight of the soft tissue filler combined with the HA component;

wherein the stable, sterile soft tissue filler is made by a process comprising;

providing the HA component;

adjusting the pH of the HA component to an adjusted pH above about 7.2;

adding a solution containing lidocaine to the HA component having the adjusted pH to obtain a soft tissue filler; and

heat sterilizing the soft tissue filler to obtain a stable, sterile soft tissue filler.

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 particles of crosslinked HA in a relatively fluidic medium of uncrosslinked HA.

5. The soft tissue filler of claim 1, wherein the adjusting the pH comprises adjusting the pH above about 7.5.

6. The soft tissue filler of claim 1, wherein the step of providing a HA component comprises providing dry uncrosslinked NaHA material and hydrating the dry uncrosslinked NaHA material in an alkaline solution to obtain an alkaline, NaHA gel.

7. The soft tissue filler of claim 6, wherein the alkaline NaHA gel has a pH greater than about 8.0.

8. The soft tissue filler of claim 6, wherein the alkaline NaHA gel has a pH greater than about 10.0.

9. 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 the crosslinked HA component;

wherein the soft tissue filler is stable after heat sterilization at between about 120°

C. and about 130°

C.;

wherein the soft tissue filler has a pH of about 7; and

wherein the stable, sterile soft tissue filler is made by a process comprising;

providing the HA component crosslinked with BDDE;

adding a solution containing lidocaine to the HA component crosslinked with BDDE to obtain a soft tissue filler; and

heat sterilizing the soft tissue filler to obtain a stable, sterile soft tissue filler.

10. The soft tissue filler of claim 9, wherein the HA component comprises at least about 15% uncrosslinked HA by volume.

11. The soft tissue filler of claim 9, wherein the HA component comprises at least about 20% uncrosslinked HA by volume.

12. The soft tissue filler of claim 9, wherein the HA component comprises particles of crosslinked HA in a relatively fluidic medium of uncrosslinked HA.

13. The soft tissue filler of claim 9, wherein the process further comprises adjusting the pH of the HA component to an adjusted pH above about 7.5.

14. The soft tissue filler of claim 9, wherein the step of providing a HA component crosslinked with BDDE comprises the steps of providing dry uncrosslinked NaHA material and hydrating the dry uncrosslinked NaHA material in an alkaline solution to obtain an alkaline, uncrosslinked NaHA gel.

15. The soft tissue filler of claim 14, wherein the alkaline uncrosslinked NaHA gel has a pH greater than about 8.0.

16. The soft tissue filler of claim 14, wherein the alkaline uncrosslinked NaHA gel has a pH greater than about 10.0.

17. A sterile, stable injectable soft tissue filler composition comprising:

a mixture of soluble form hyaluronic acid (HA), crosslinked HA, and lidocaine in an amount effective to mitigate pain upon injection of the composition, the crosslinked HA being crosslinked with 1,4-butanediol diglycidyl ether (BDDE);

the composition having a HA concentration of between about 20 mg/ml and about 30 mg/ml;

wherein the sterile, stable injectable soft tissue filler composition is made by a process comprising;

providing the soluble form HA and crosslinked HA;

adjusting the pH of the soluble form HA and crosslinked HA;

adding a solution containing lidocaine to the soluble form HA and crosslinked HA having the adjusted pH to obtain a HA-based injectable soft tissue filler composition; and

heat sterilizing the HA-based injectable soft tissue filler composition to obtain the sterile, stable injectable soft tissue filler composition.

18. The soft tissue filler composition of claim 17, wherein the soluble form HA and crosslinked HA comprises at least about 15% soluble form HA by volume.

19. The soft tissue filler composition of claim 17, wherein the soluble form HA and crosslinked HA comprises at least about 20% soluble form HA by volume.

20. The soft tissue filler composition of claim 17, wherein the soluble form HA and crosslinked HA comprises particles of crosslinked HA in a relatively fluidic medium of the soluble form HA.

21. The soft tissue filler composition of claim 17, wherein the adjusting the pH comprises adjusting the pH above about 7.5.

22. The soft tissue filler composition of claim 17, wherein the step of providing the soluble form HA and crosslinked HA comprises the steps of providing dry uncrosslinked NaHA material and hydrating the dry uncrosslinked NaHA material in an alkaline solution to obtain an alkaline uncrosslinked NaHA gel.

23. The soft tissue filler composition of claim 22, wherein the alkaline uncrosslinked NaHA gel has a pH greater than about 8.0.

24. The soft tissue filler composition of claim 22, wherein the alkaline uncrosslinked NaHA gel has a pH greater than about 10.0.

25. A sterile, stable injectable soft tissue filler composition comprising:

a mixture of soluble form hyaluronic acid (HA), crosslinked HA, and lidocaine in an amount effective to mitigate pain upon injection of the composition, the crosslinked HA being crosslinked with 1,4-butanediol diglycidyl ether (BDDE); and

the lidocaine of the mixture being present in a concentration of about 0.3% by weight of the composition;

wherein the sterile, stable injectable soft tissue filler composition is made by a process comprising;

providing the soluble form HA and crosslinked HA;

adjusting the pH of the soluble form HA and crosslinked HA to an adjusted pH above about 7.2;

adding a solution containing lidocaine to the soluble form HA and crosslinked HA having the adjusted pH to obtain a HA-based injectable soft tissue filler composition; and

heat sterilizing the HA-based injectable soft tissue filler composition to obtain the sterile, stable injectable soft tissue filler composition.

26. The soft tissue filler composition of claim 25, wherein the soluble form HA is present in an amount of about 10% to about 20% by volume.

27. The soft tissue filler composition of claim 25, wherein the adjusted pH is above about 7.5.

28. The soft tissue filler composition of claim 25, wherein the step of providing the HA crosslinked with BDDE comprises the steps of providing dry uncrosslinked NaHA material and hydrating the dry uncrosslinked NaHA material in an alkaline solution to obtain an alkaline, uncrosslinked NaHA gel.

29. The soft tissue filler composition of claim 28, wherein the alkaline uncrosslinked NaHA gel has a pH greater than about 8.0.

30. The soft tissue filler composition of claim 28, wherein the alkaline uncrosslinked NaHA gel has a pH greater than about 10.0.