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EP-3433284-B1 - MODIFIED HYALURONIC ACID, METHOD FOR MAKING SAME AND USES THEREOF

EP3433284B1EP 3433284 B1EP3433284 B1EP 3433284B1EP-3433284-B1

Inventors

  • KRAUSE, ANDREAS
  • LINKO, ALEXANDER
  • VILLAIN, FRANCK

Dates

Publication Date
20260506
Application Date
20170321

Claims (15)

  1. A glycerol-modified, uncrosslinked 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, 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.
  2. The HA derivative of claim 1, wherein said polyglycerol structure of two or more multi-ether-bonded glycerol residues is in the form of a dendrimetric hyperbranched polyglycerol structure.
  3. The HA derivative of claim 1 or 2, wherein the HA derivative is HA or a salt thereof having an average molecular weight of 1.0 x 10 4 Da to 4.0 x 10 6 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, particularly between 5 and 50, of said glycerol-containing moieties per 100 repeating disaccharide unit of the HA.
  4. A method for making a hyaluronic acid (HA) derivative or a salt thereof as defined in any one of claims 1 to 3, comprising the steps of: (a) solubilizing HA in an aqueous alkaline solution to obtain solubilized HA, (b) adding glycidol to the solubilized HA of step (a), (c) reacting glycidol and HA to obtain a glycerol-modified HA derivative and, (d) isolating the glycerol-modified HA derivative.
  5. The method of claim 4, wherein step (d) comprises the following sub-steps: (d1) neutralizing a reaction mixture resulting from step (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.
  6. An uncrosslinked hyaluronic acid (HA) derivative or a salt thereof obtainable by the method according to claim 5.
  7. Use of the hyaluronic acid (HA) derivative or salt thereof as defined in any one of claims 1 to 3 and 6 for preparing a dermal filler composition.
  8. A dermal filler composition comprising crosslinked hyaluronic acid (HA) or a salt thereof and a HA derivative or a salt thereof as defined in any one of claims 1 to 3 and 6.
  9. The dermal filler composition of claim 8, 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.
  10. The dermal filler composition of claim 8 or 9, wherein the crosslinked HA is crosslinked with 1,4-butanediol diglycidyl ether (BDDE).
  11. The dermal filler composition of any one of claims 8 to 10, 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 preferably comprises a local anaesthetic agent such as lidocaine.
  12. A method of preparing a dermal filler composition as defined in any one of claims 8 to 11, comprising the steps of: (i) providing a hyaluronic acid (HA) derivative or a salt thereof as defined in any one of claims 1 to 3 and 6, (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.
  13. A kit, comprising a dermal filler composition according to any one of claims 8 to 11 and, optionally, instructions for use.
  14. Use of a dermal filler composition according to any one of claims 8 to 11 for cosmetic applications, including cosmetic treatments 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, and chin.
  15. A non-therapeutic 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 any one of claims 8 to 11.

Description

FIELD OF THE INVENTION 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. BACKGROUND OF THE INVENTION Hyaluronic acid (HA) is a naturally occurring, non-immunogenic glycosaminoglycan composed of linked repeating units of N-acetyl-D-glucosamine and D-glucuronic acid ([α-1,4-D-glucuronic acid-β-1,3-N-acetyl-D-glucosamine]n). Due to its high water-binding capacity and unique viscoelastic properties, HA is used in numerous applications, such as for drug delivery and tissue engineering, in therapy (e.g., as a supplement of joint fluid in arthritis or as a promoter of wound healing), and for cosmetic uses. In the last several years, HA has been increasingly used in dermal fillers because they offer aesthetic improvements previously only achievable with surgery, but at lower cost and in a more convenient and safe manner. Today, HA is the most widely used degradable dermal filler material in both Europe and the USA. Since HA is quickly degraded and reabsorbed by the body, the HA is usually cross-linked to increase the in vivo residence time to about 6 to 18 months. The cross-linking can be conducted by a number of strategies, including diepoxy, carbodiimide-mediated, aldehyde, and divinyl sulfone crosslinking, with 1,4-butanediol diglycidyl ether (BDDE) being the "golden standard". Dermal fillers based on crosslinked HA are used to restore facial volume, create youthful facial contours, add volume to lips and cheeks, fill in creases and lines, smooth out and reduce the appearance of fine lines, wrinkles, and folds (e.g., nasolabial folds, glabellar lines, marionette lines, and oral commissures), among others. The cosmetic/aesthetic treatment is performed in a nonsurgical setting and effects subside over time, as the hyaluronic acid is absorbed by the body. It is further known in the art to modify HA in many different ways to alter the mechanical and/or chemical properties of HA-based fillers depending on the specific use. Chemical modifications are also used to prepare HA derivatives which are capable of in vivo polymerization, either spontaneously or in the presence of an external trigger like UV light or heat. The three functional groups of HA that can be modified are the primary and secondary hydroxyl groups, the glucuronic acid carbonic acid group, and the N-acetyl group (following deamination). Chemical modification of HA extends and improves the physical properties, thereby creating new degrees of freedom compared to the conventional BDDE cross-linked HA gels whose properties (e.g., high vs. low viscosity or monophasic/cohesive vs. biphasic/particulate) are primarily governed by the amount of HA and the degree of cross-linking. CN 104194008 A relates to a cross-linked HA gel microparticle that is prepared by a process involving crosslinking natural HA to form a film material, performing a second crosslinking on one side of the film material, and shear granulating the material to obtain microparticles. US 2012/095206 A1 describes a method for producing a cross-linked HA comprising a high temperature crosslinking step at 35-60°C using, e.g., BBDE as a crosslinking agent, followed by further cross-linking at low temperature of 10-30°C (see abstract and claims). Nobuhiko et al. (J. Control. Release 25:133-143, 1993) concerns the regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid. There are disclosed heterogeneous structured devices consisting of lipid microspheres in degradable matrices of hyaluronic acid crosslinked with polyglycerol polyglycidyl ether (PGPGE). US 2010/0035838 A1 discloses a combined cross-linking approach where HA is reacted in the presence of a BDDE cross-linking agent and glycidol as a masking agent to prepare a cross-linked HA gel having resistance to enzymatic degradation under physiological conditions. Since both epoxide compounds (i.e. BDDE and glycidol) are present during the cross-linking process, the process results in an undefined polymer network. WO 2014/152632 A1 describes a HA-based composition suitable for use as a hydrophilic medical device coating. The composition is the reaction product of HA and a modified glycidol carbamate (GC) epoxide structure. EP 2 537 867 A1 discloses a modified HA comprising a glycerin skeleton-containing group of formula -O-CH2-CHOH-CH2-OR1, wherein R1 represents a linear or branched alkyl group, or a linear or b