Modified hyaluronic acid, method for making same and uses thereof

• US 10,640,578 B2
• Filed: 03/21/2017
• Issued: 05/05/2020
• Est. Priority Date: 03/24/2016
• Status: Active Grant

• Current Assignee: Merz Pharma GmbH & Company Kgaa
• Original Assignee: Merz Pharma GmbH & Company Kgaa
• Inventors: Krause, Andreas, Linko, Alexander, Villain, Franck
• Primary Examiner(s): Arnold, Ernst V
• Application Number:
  US16/087,248
• Publication Number:
  US 20190100605A1
• Time in Patent Office: 1,141 Days
• CPC Class Codes: A61K 2800/91 Injection
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 8/735 Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• 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: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08J 2305/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08L 2203/02 for biomedical use
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The present invention generally relates to a modified hyaluronic acid (HA) and to a method for making same, more specifically to a (poly)glycerol-modified HA derivative prepared by grafting glycidol to HA. The present invention also relates to the use of the HA derivative for preparing a dermal filler composition, a hydrogel comprising cross-linked HA and the (poly)glycerol-modified HA derivative, and a method for preparing said hydrogel. Furthermore, the present invention relates to the use of the hydrogel as a cosmetic and/or aesthetic product, in particular as a dermal filler for tissue filling, replacing and/or augmenting.

Claims

1. An un-crosslinked glycerol-modified hyaluronic acid (HA) derivative or a salt thereof having at least the primary hydroxyl group at the C6 carbon atom of all or a part of the N-acetyl-D-glucosamine units of HA modified into ether-bonded glycerol-containing moieties.

2. The HA derivative of claim 1, wherein said glycerol-containing moiety that is bonded to the C6 carbon atom of HA via an ether bond is a single glycerol residue or a polyglycerol structure of two or more multi-ether-bonded glycerol residues.

3. The HA derivative of claim 1, wherein the HA derivative is HA or a salt thereof having an average molecular weight of 1.0×

10⁴ Da to 4.0×

10⁶ Da and/or wherein the glycerol-containing moieties are linked to the C6 carbon atom of N-acetyl-D-glucosamine units of HA in an amount such that said derivative comprises between 1 and 100 of said glycerol-containing moieties per 100 repeating disaccharide unit of the HA.

4. The HA derivative of claim 1, wherein said glycerol-containing moiety that is bonded to the C6 carbon atom of HA via an ether bond is a dendrimetric hyperbranched polyglycerol structure.

5. The HA derivative of claim 1, wherein the HA derivative is HA or a salt thereof having an average molecular weight of 1.0×

10⁴ Da to 4.0×

10⁶ Da and/or wherein the glycerol-containing moieties are linked to the C6 carbon atom of N-acetyl-D-glucosamine units of HA in an amount such that said derivative comprises between 5 and 50 of said glycerol-containing moieties per 100 repeating disaccharide unit of the HA.

6. A dermal filler composition comprising crosslinked hyaluronic acid (HA) or a salt thereof and the HA derivative or a salt thereof as defined in claim 1.

7. The dermal filler composition of claim 6, wherein the crosslinked HA is present at a concentration of 0.1% to 4.0% by weight/volume and/or wherein the HA derivative is present at a concentration of 0.1% to 30.0% by volume/volume.

8. The dermal filler composition of claim 6, wherein the crosslinked HA is crosslinked with 1,4-butanediol diglycidyl ether (BDDE).

9. The dermal filler composition of claim 6, further comprising one or more compounds selected from the group consisting of anesthetics, polyols, vitamins, amino acids, metals, antioxidants, hydroxyapatite particles, and mineral salts, wherein the composition optionally comprises a local anaesthetic agent optionally lidocaine.

10. The dermal filler composition of claim 6, wherein the crosslinked HA is present at a concentration of 1.0% to 3.0% by weight/volume and/or wherein the HA derivative is present at a concentration of 5% to 25% by volume/volume.

11. A kit, comprising a dermal filler composition according to claim 6 and, optionally, instructions for use.

12. A method for making a hyaluronic acid (HA) derivative or a salt thereof as defined in claim 1, comprising:

(a) solubilizing HA in an aqueous alkaline solution to obtain solubilized HA,

(b) adding glycidol to the solubilized HA of (a),

(c) reacting glycidol and HA to obtain a glycerol-modified HA derivative and,

(d) isolating the glycerol-modified HA derivative.

13. The method of claim 12, wherein (d) comprises the following:

(d1) neutralizing a reaction mixture resulting from (c) comprising the glycerol-modified HA derivative, and

(d2) isolating the glycerol-modified HA derivative from the neutralized reaction mixture to obtain the glycerol-modified HA derivative, or a salt thereof, in purified form.

14. A method of preparing a dermal filler composition as defined in claim 6, comprising:

(i) Providing the hyaluronic acid (HA) derivative or a salt thereof,

(ii) providing a crosslinked HA or a salt thereof,

(iii) combining the HA derivative or a salt thereof and the crosslinked HA or a salt thereof to obtain said dermal filler composition.

15. A method of cosmetic treatment comprising administering to a subject an effective amount of the dermal filler composition according to claim 6.

16. A method for replacing or filling of a biological tissue or increasing the volume of the biological tissue for cosmetic purposes, comprising administering to a subject in need thereof an effective amount of the injectable dermal filler composition according to claim 6.

17. The method of cosmetic treatment according to claim 16, wherein the cosmetic treatment comprises treatment of facial lines, facial wrinkles, glabellar lines, nasolabial folds, marionette lines, buccal commissures, peri-lip wrinkles, crow'"'"'s feet, subdermal support of the brows, malar and buccal fat pads, tear troughs, nose, lips, cheeks, peroral region, infraorbital region, facial asymmetries, jawlines, or chin.