Aldehyde-modified hyaluronic acid, method for preparing same and applications thereof
AssigneeMERZ PHARMA GmbH & CO. KGaA
InventorsPatrick Plitt, Colin Drabe, Sibylle Mueller, Radovan Vukicevic, Jens Neubauer, Charlotte Reither
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Abstract
A modified hyaluronic acid derivative is described having the —CH2-OH group of the N-acetyl-D-glucosamine unit (GlcNAc) modified to an aldehyde group having the structure —CH2-O—CH2-CHO where the degree of modification is 1.0% to 15.0% for preparing a crosslinked hydrogel for use in aesthetic applications. The modified hyaluronic acid derivative is prepared by reacting a glycerol-modified hyaluronic acid with an oxidizing agent such as periodate.
Claims17
A modified hyaluronic acid derivative, wherein the —CH2—OH group of at least one N-acetyl-D-glucosamine unit is modified into an aldehyde group having a structure —CH2—O—CH2—CHO, wherein the degree of modification is 2.0% to 6.9%, the degree of modification being defined as the number of —CH2—O—CH2—CHO groups divided by the total number of N-acetyl-D-glucosamine units present in the modified hyaluronic acid derivative, wherein the number of aldehyde groups having the structure —CH2—O—CH2—CHO of the at least one N-acetyl-D-glucosamine unit divided by the total number of aldehyde groups present in the modified hyaluronic acid derivative is from 0.95 to 1, wherein the modified hyaluronic acid derivative has a weight average molecular weight of 0.4 MDa to 1.3 MDa, and wherein the modified hyaluronic acid derivative comprises at least one disaccharide unit of the following structure
- wherein Ac denotes —C(O)CH3 and R is selected from the group consisting of hydrogen, an alkali metal ion and an alkaline earth metal ion, and further comprises at least one disaccharide unit of the following structure
- wherein Ac denotes —C(O)CH3, R1, R2, R3 and R4 are independently selected from the group consisting of H and —CH2—CHO, and R5 is selected the group consisting of from hydrogen, an alkali metal ion, an alkaline earth metal ion, and —CH2—CHO, wherein, at least one of R1, R2, R3, R4 and R5 is —CH2—CHO and, if R1 is —CH2—CHO, at least one of R2, R3, R4, and R5 is —CH2—CHO.
A modified hyaluronic acid derivative obtained by a method comprising:
- a) providing a glycerol-modified hyaluronic acid, wherein a —CH2—OH group of at least one N-acetyl-D-glucosamine unit is modified into a group of the following formula —CH2—O—CH2—CHOH—CH2OH;
- b) dissolving the glycerol-modified hyaluronic acid in an aqueous medium to obtain solubilized glycerol-modified hyaluronic acid;
- and
- c) reacting said solubilized glycerol-modified hyaluronic acid with an oxidizing agent, optionally a periodate, optionally sodium periodate, to convert at least a part of said —CH2—O—CH2—CHOH—CH2OH groups into aldehyde groups having the formula —CH2—O—CH2—CHO, thereby obtaining a modified hyaluronic acid derivative, wherein c) is performed for a duration of 5 to 65 minutes, and wherein the degree of modification is 2.0% to 6.9%, the degree of modification being defined as the number of —CH2—O—CH2—CHO groups divided by the total number of N-acetyl-D-glucosamine units present in the modified hyaluronic acid derivative;
- wherein the number of aldehyde groups having the structure —CH2—O—CH2—CHO of the at least one N-acetyl-D-glucosamine unit divided by the total number of aldehyde groups present in the modified hyaluronic acid derivative is from 0.95 to 1, wherein the modified hyaluronic acid derivative has a weight average molecular weight of 0.4 MDa to 1.3 MDa, and wherein the modified hyaluronic acid derivative comprises at least one disaccharide unit of the following structure
- wherein Ac denotes —C(O)CH3 and R is selected from the group consisting of hydrogen, an alkali metal ion and an alkaline earth metal ion, and further comprises at least one disaccharide unit of the following structure
- wherein Ac denotes —C(O)CH3, R1, R2, R3 and R4 are independently selected from the group consisting of H and —CH2—CHO, and R5 is selected from the group consisting of hydrogen, an alkali metal ion, an alkaline earth metal ion, and —CH2 —CHO, wherein, at least one of R1, R2, R3, R4 and R5 is —CH2—CHO and, if R1 is —CH2—CHO, at least one of R2, R3, R4 and R5 is —CH2—CHO.
Dependencies are inferred from the claim text.