VISCOELASTIC GELS AS NOVEL FILLERS

• US 20120190644A1
• Filed: 08/25/2010
• Published: 07/26/2012
• Est. Priority Date: 08/27/2009
• Status: Active Grant

• Current Assignee: Fidia Farmaceutici s.p.a (P.&R. S.p.A)
• Original Assignee: Fidia Farmaceutici s.p.a (P.&R. S.p.A)
• Inventors: D'este, Matteo, Renier, Davide
• Granted Patent: US 8,846,640 B2
• Time in Patent Office: Days
• US Class Current: 514/54
• 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 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• 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 17/10 Anti-acne agents
• CPC Class Codes: C08B 37/0003 General processes for their isolation or fractionation, e.g. purification or extraction from biomass
• 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 3/005 Processes for mixing polymers
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08J 3/14 by precipitation from solutions C08J3/122 takes precedence
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: C08L 2205/02 containing two or more polymers of the same C08L -group
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Biomaterials obtainable by mixing

• • the autocrosslinked derivative of hyaluronic acid (ACP) with
  • the derivative (HBC) of hyaluronic acid crosslinked with 1,4-butanediol diglycidyl ether (BDDE) in the weight ratio of between 10:90 and 90:10 as novel fillers.

Claims

1. Biomaterials obtainable by mixing

the autocrosslinked derivative of hyaluronic acid (ACP) with

the derivative (HBC) of hyaluronic acid crosslinked with 1,4-butanediol diglycidyl ether (BDDE)

in the weight ratio of between 10:

90 and 90;

10 as novel fillers and/or as body shaping products.

3. Biomaterials as claimed in claims 1-2, preferably in the weight ratio of 90:

10 to 50;

50, as biorevitalising fillers.

4. Biomaterials as claimed in claims 1-2, in the weight ratio of 10:

90 to 50;

50 with a volume-enhancing effect.

5. Biomaterials as claimed in claim 4, preferably in the weight ratio of 25:

75.

12. Biomaterials as claimed in claim 1 or 2, wherein the vehicle is saline solution.

13. Biomaterials as claimed in claim 1 or 2, containing lidocaine.

15. Use of the biomaterials claimed in claim 1 or 2 as new fillers and/or as new products for body shaping in the treatment of skin blemishes, in dermatology, in dermocosmetology and/or in aesthetic surgery.

2. Biomaterials obtainable by mixing

hyaluronic acid hexadecylamide (HYADD) with

the derivative (HBC) of hyaluronic acid crosslinked with 1,4-butanediol diglycidyl ether (BDDE)

in the weight ratio of between 10:

90 and 90;

10 as novel fillers and/or as body shaping products.

6. Process for the preparation and purification of the HBC derivative comprising the following steps:

a. Dissolution in alkaline solution of diepoxide BDDE in a stoichiometric ratio from 2.5 to 25% in moles of the repetitive units of hyaluronic acid, followed by

b. Dispersion of hyaluronic acid (HA) in the solution referred to in paragraph a), at room temperature.

c. Triggering of the reaction by heat activation, the solution referred to in paragraph b) being heated at a temperature of between 35 and 55°

C. for between 2 and 36 hours.

d. Extrusion of the mass obtained through a metal sieve, to reduce it to particles with a size of approx. 600 μ

m.

e. Hydration of the gel obtained by diluting it with water by a factor of 3 to 20.

f. Correction of pH to neutral with an aqueous solution of HCl

g. Precipitation with a water-soluble organic solvent such as ethanol, methanol, isopropanol, n-propanol, dioxane, acetonitrile, acetone and/or mixtures thereof until the product is obtained in powder form

h. Washing with organic solvents such as ethanol, methanol, isopropanol, n-propanol, dioxane, acetonitrile, acetone and/or mixtures thereof containing water.

i. Drying under vacuum until the residual solvents under 400 ppm have been eliminated and an HBC powder is obtained.

7. Process of mixing ACP or HYADD with HBC prepared as described in claim 6, comprising the following steps:

a. Mixing of ACP or HYADD powder with HBC powder in the ACP or HYADD;

HBC ratio of between 90;

10 and 10;

90.

b. Hydration with saline solution or phosphate buffer, leading to a total HA concentration of between 12 and 27 mg/ml.

c. Extrusion at a temperature of between 25 and 65°

C. through a sieve with a mesh of between 50 and 500 μ

m.

d. Syringe filling.

e. Sterilisation by heat from saturated steam at a temperature of between 120 and 124°

C. for at least 10 min.

10. Process as claimed in claims 6-9, wherein the HA used for the preparation of the HBC, ACP and HYADD derivatives has a mean molecular weight of between 400 and 3×

10⁶ Da, preferably between 1×

10⁵ Da and 1×

10⁶ Da, and more preferably between 200,000 and 1×

10⁶ Da.

8. Process for the preparation and purification of the HBC derivative comprising the following steps:

a. Dissolution in alkaline solution of diepoxide BDDE in a stoichiometric ratio from 2.5 to 25% in moles of the repetitive units of hyaluronic acid, followed by

b. Dispersion of HA in the solution referred to in paragraph a), at room temperature.

c. Triggering of the reaction by heat activation, the solution referred to in paragraph b) being heated at a temperature of between 35 and 55°

C. for between 2 and 36 hours.

d. Correction of pH to neutral with an aqueous solution of HCl.

e. Hydration of the gel obtained by diluting it with water by a factor of 3 to 20.

9. Process of mixing ACP or HYADD with HBC prepared as described in claim 8, comprising the following steps:

a. Mixing of ACP or HYADD gel or powder with HBC in gel form in an ACP or HYADD;

HBC ratio of between 90;

10 and 10;

90.

b. Crushing and homogenisation by passing through a filter with a particulate matter retention coefficient of between 25 and 150 μ

m.

c. Syringe filling.

d. Heat sterilisation with saturated steam at a temperature of between 120 and 124°

C. for at least 10 min.

11. Biomaterials obtained as claimed in claims 8-9, wherein the ACP:

HBC weight ratio is 25;

75.

14. Biomaterials as claimed in claim 11, containing lidocaine, wherein the vehicle consists of saline solution.