Cyclodextrin-grafted cross-linked hyaluronic acid complexed with active drug substances and uses thereof

Patent metadata

Field	Value
Publication number	US-10988600-B2
Application number	US-201716312079-A
Country	US
Kind code	B2
Filing date	Jun 20, 2017
Priority date	Jun 23, 2016
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

A hyaluronic acid product is comprising a cross-linked hyaluronic acid and one or more cyclodextrin molecules, and further comprising a guest molecule capable of forming a guest-host complex with the aminocyclodextrin molecule acting as a host, wherein the guest molecule is a retinoid, preferably adapalene, or a RAM BA. The hyaluronic acid is cross-linked by ether bonds, and the one or more cyclodextrin molecules are grafted onto the cross-linked hyaluronic acid by amide bonds, preferably using a triazine-based coupling reagent.

First claim

The invention claimed is:

1. A hyaluronic acid product comprising:
(a) a cross-linked hyaluronic acid and one or more aminocyclodextrin host molecules, wherein the hyaluronic acid is cross-linked by ether bonds and wherein the one or more aminocyclodextrin host molecules are grafted onto the cross-linked hyaluronic acid by direct amide bonds between an amino group of the one or more aminocyclodextrin host molecules and a carboxyl group of the cross-linked hyaluronic acid; and
(b) one or more guest molecules comprising 4-(2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl)ethyl)benzoic acid;
wherein the one or more guest molecules form a guest-host complex with the one or more aminocyclodextrin host molecules.

2. The hyaluronic acid product according to claim 1 , wherein the one or more aminocyclodextrin host molecules are constituted by 6-8 glucopyranoside units.

3. The hyaluronic acid product according to claim 2 , wherein the one or more aminocyclodextrin host molecules are selected from the group consisting of 2 aminocyclodextrin, 3-aminocyclodextrin, and 6-aminocyclodextrin.

4. The hyaluronic acid product according to claim 1 , wherein the one or more aminocyclodextrin host molecules and disaccharides of the cross-linked hyaluronic acid of the resulting hyaluronic acid product have a molar ratio of more than 2%.

5. The hyaluronic acid product according to claim 1 , wherein the hyaluronic acid product is in the form of gel particles having an average size in the range of 0.01-5 mm.

6. A process of preparing a formulation of one or more guest molecules that form a guest-host complex with one or more aminocyclodextrin host molecules, the process comprising:
(a) providing (i) hyaluronic acid and (ii) one or more aminocyclodextrin host molecules with the one or more guest molecules comprising 4-(2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl)ethyl)benzoic acid;
(b) cross-linking the hyaluronic acid by ether bonds using a bi- or polyfunctional cross-linking agent;
(c) grafting the one or more aminocyclodextrin host molecules onto the cross-linked hyaluronic acid by amide bonds; and
(d) bringing a solution of the one or more guest molecules into contact with the one or more aminocyclodextrin host molecules grafted onto the cross-linked hyaluronic acid under conditions allowing for the formation of the guest-host complex between the one or more aminocyclodextrin host molecules and the one or more guest molecules, and optionally
(e) recovering the guest-host complex bound to the cross-linked hyaluronic acid.

7. The process according to claim 6 , wherein an amino group of the aminocyclodextrin molecule forms said amide bond with a carboxyl group of the cross-linked hyaluronic acid.

8. The process according to claim 6 , wherein the grafting in (c) comprises:
(i) activating the carboxyl groups on the cross-linked hyaluronic acid with a triazine-based coupling reagent to form an activated cross-linked hyaluronic acid, and
(ii) coupling the one or more aminocyclodextrin molecules to the carboxyl groups of the activated cross-linked hyaluronic acid by amide bonds.

9. The process according to claim 6 , wherein said bi- or polyfunctional cross-linking agent is selected from the group consisting of: 1,4-butanediol diglycidyl ether (BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), and diepoxyoctane.

10. The process according to claim 6 , further comprising providing particles of the hyaluronic acid product having an average size in the range of 0.01-5 mm.

11. A product obtainable by the process according to claim 6 .

12. A method of cosmetically treating skin, the method comprising administering to the skin the hyaluronic acid product according to claim 1 .

13. The hyaluronic acid product according to claim 5 , wherein the hyaluronic acid product is in the form of gel particles having an average size in the range of 0.1-0.8 mm.

14. The hyaluronic acid product according to claim 1 , wherein the one or more aminocyclodextrin host molecules comprise methyl groups or hydroxypropyl groups.

15. The hyaluronic acid product according to claim 1 , wherein the one or more guest molecules are capable of being released from the guest-host complexes due to a change in pH that cleaves hydrogen or ionic bonds between the host and guest molecules.

16. The hyaluronic acid product according to claim 1 , wherein the one or more guest molecules are capable of being released from the guest-host complexes due to enzymatic cleavage of α-1,4 linkages between glucose monomers.

17. The hyaluronic acid product according to claim 4 , wherein the one or more aminocyclodextrin host molecules and disaccharides of the cross-linked hyaluronic acid of the resulting hyaluronic acid product have a molar ratio of more than 5%.

Assignees

• Galderma Sa
• Galderma Holding SA

Inventors

• Edsman Katarina
• Boiteau Jean-Guy

Classifications

• C08J2305/16

  Cyclodextrin; Derivatives thereof · CPC title

• C08B37/0072

  Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates · CPC title

• A61K8/735

  Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof · CPC title

• C08J3/12

  Powdering or granulating · CPC title

• C08B37/0012

  Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof · CPC title