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US-12617905-B2 - Crosslinked alginic acid

US12617905B2US 12617905 B2US12617905 B2US 12617905B2US-12617905-B2

Abstract

Provided are novel alginic acid derivatives and a novel crosslinked alginic acid. The alginic acid derivatives are represented by formula (I) and formula (II). The novel crosslinked alginic acid obtained by Huisgen reaction using an alginic acid derivative of formula (I) and an alginic acid derivative of formula (II).

Inventors

  • Shoji Furusako
  • Tsutomu Satoh
  • Tomohiro NARUMI

Assignees

  • MOCHIDA PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20220616
Priority Date
20191218

Claims (9)

  1. 1 . A crosslinked alginic acid obtained by performing a crosslinking reaction using an alginic acid derivative of formula (I) below comprising a cyclic alkyne group (Akn) introduced via an amide bond and a divalent linker (-L 1 -) at any one or more carboxyl groups of alginic acid and an alginic acid derivative of formula (II) below comprising an azide group introduced via an amide bond and a divalent linker (-L 2 -) at any one or more carboxyl groups of alginic acid: in formula (I), (ALG) consists of alginic acid; —NHCO— is an amide bond via any carboxyl group of alginic acid; -L 1 - is a linker selected from the group consisting of partial structural formulae shown in the following tables, excluding the parts outside the broken lines at both ends of each formula: TABLE 51-1 No. —L 1 — (L1- 1) m1 = 1-6 n1 = 2-6 (L1- 2a) m2a = 1-6 n2a = 2-6 p2a = 2-6 (L1- 2b) m2b = 1-6 n2b = 2-6 p2b = 2-6 (L1- 3) m3 = 1-6 n3 = 1-6 p3 = 2-6 (L1- 4a) m4a = 2-6 n4a = 2-6 (L1- 4b) m4b = 0-6 n4b = 2-6 (L1- 5a) m5a = 1-6 n5a = 2-6 p5a = 2-6 q5a = 1-6 (L1- 5b) m5b = 1-6 n5b = 1-6 p5b = 2-6 q5b = 1-6 (L1- 6a) m6a = 1-6 n6a = 0-6 p6a = 2-6 (L1- 6b) m6b = 1-6 n6b = 1-6 p6b = 2-6 TABLE 51-2 No. —L 1 — (L1- 7) m7 = 1-6 n7 = 1-6 (L1- 8a) m8a = 2-6 n8a = 1-6 R 1 = H, Me, Et, Bn (L1- 8b) m8b = 1-6 n8b = 1-6 R 1 = H, Me, Et, Bn (L1- 9a) m9a = 1-6 n9a = 2-6 p9a = 2-6 (L1- 9b) m9b = 1-6 n9b = 1-6 p9b = 2-6 (L1- 10) m10 = 1-6 n10 = 2-6 p10 = 1-6 R 2 = H, Me, Et, Bn (L1- 11) m11 = 2-6 (L1- 12) m12 = 1-6 n12 = 0-6 p12 = 1-6 and Akn is a cyclic alkyne group selected from the group consisting of partial structural formulae shown in the following table, excluding the part to the right of the broken line in each formula: TABLE 52 No. Akn (AK-1) (AK-2) (AK-3) (AK-4) (AK-5) (AK-6) (AK-7) (AK-8) (AK-9) (AK-10) (AK-11) (AK-12) in formula (II), (ALG) consists of alginic acid; —NHCO— is an amide bond via any carboxyl group of alginic acid; and -L 2 - is a linker selected from the group consisting of partial structural formulae shown in the following tables, excluding the parts outside the broken lines at both ends of each formula: TABLE 53-1 No. —L 2 (L2- 1) x1 = 2-6 (L2- 2a) x2 = 2-6 x2a = 2-6 y2a = 2-6 (L2- 2b) x2b = 1-6 y2b = 2-6 (L2- 3) x3 = 2-6 y3 = 1-6 (L2- 4) x4 = 1-6 y4 = 1-6 z4 = 1-6 (L2- 5a) x5a = 0-4 y5a = 2-6 (L2- 5b) x5b = 0-4 y5b = 1-6 (L2- 6a) x6a = 1-6 y6a = 2-6 z6a = 2-6 v6a = 1-6 (L2- 6b) x6b = 1-6 y6b = 1-6 z6b = 2-6 v6b = 1-6 TABLE 53-2 No. -L 2 - (L2- 7a) x7a = 1-6 y7a = 1-6 z7a = 2-6 (L2- 7b) x7b = 1-6 y7b = 1-6 z7b = 1-6 (L2- 8a) x8a = 0-4 y8a = 2-6 z8a = 3-6 (L2- 8b) x8b = 0-4 y8b = 1-6 z8b = 3-6 (L2- 9a) x9a = 0-4 y9a = 2-6 z9a = 1-6 (L2- 9b) x9b = 0-4 z9b = 1-6 y9b = 1-6 (L2- 10) x10 = 2-6 y10 = 2-6 with the proviso that crosslinked alginic acids obtained by performing a crosslinking reaction using a derivative in which -L 1 - is any one linker selected from the group consisting of (L1-1), (L1-2a), (L1-2b), (L1-11) or (L1-12) in the alginic acid derivative of formula (I) and a derivative in which -L 2 - is the linker (L2-10) in the alginic acid derivative of formula (II) are excluded.
  2. 2 . The crosslinked alginic acid according to claim 1 , wherein any carboxyl group of a first alginic acid of formula (I) and any carboxyl group of a second alginic acid of formula (II) are crosslinked together via the following formula (III-L): wherein in formula (III-L), the —CONH— and —NHCO— at either end are amide bonds via any carboxyl group of alginic acid; -L 1 - is defined above; -L 2 - is defined above; and X is a cyclic group selected from the group consisting of partial structural formulae shown in the following tables, excluding the parts outside the broken lines at both ends of each formula: TABLE 57-1 No. X No. X (TZ-1) (TZ-1-r) (TZ-2) (TZ-2-r) (TZ-3) (TZ-3-r) (TZ-4) (TZ-4-r) (TZ-5) (TZ-5-r) (TZ-6) (TZ-6-r) TABLE 57-2 No. X No. X (TZ-7) (TZ-7-r) (TZ-8) (TZ-8-r) (TZ-9) (TZ-9-r) (TZ-10) (TZ-10-r) (TZ-11) (TZ-11-r) (TZ-12) (TZ-12-r) with the proviso that in formula (III-L) the linker (L2-10) is excluded from the corresponding -L 2 - when -L 1 - is any one linker selected from the group consisting of (L1-1), (L1-2a), (L1-2b), (L1-11) and (L1-12).
  3. 3 . A crosslinked alginic acid structure obtained by mixing the alginic acid derivative of formula (I) and the alginic acid derivative of formula (II) according to claim 1 to obtain a mixed solution that is then dripped into a solution containing a divalent metal ion.
  4. 4 . The crosslinked alginic acid structure according to claim 3 , wherein the structure is obtained via both chemical crosslinking by triazole rings formed by a Huisgen reaction and ionic crosslinking partially formed by a divalent metal ion.
  5. 5 . The crosslinked alginic acid structure according to claim 3 , wherein the structure is obtained by subjecting the alginic acid derivative of formula (I) and the alginic acid derivative by of formula (II) to ionic crosslinking by a divalent metal ion and chemical crosslinking by a Huisgen reaction.
  6. 6 . The crosslinked alginic acid structure according to claim 3 , wherein the chemical crosslinking formed by performing a Huisgen reaction using the alginic acid derivative of formula (I) and the alginic acid derivative of formula (II) has the structure of formula (III-L) below: wherein in formula (III-L), the —CONH— and —NHCO— at either end are amide bonds via any carboxyl group of alginic acid; -L 1 - is defined above; -L 2 - is defined above; and X is a cyclic group selected from the group consisting of partial structural formulae shown in the following tables, excluding the parts outside the broken lines at both ends of each formula: TABLE 57-1 No. X No. X (TZ-1) (TZ-1-r) (TZ-2) (TZ-2-r) (TZ-3) (TZ-3-r) (TZ-4) (TZ-4-r) (TZ-5) (TZ-5-r) (TZ-6) (TZ-6-r) TABLE 57-2 No. X No. X (TZ-7) (TZ-7-r) (TZ-8) (TZ-8-r) (TZ-9) (TZ-9-r) (TZ-10) (TZ-10-r) (TZ-11) (TZ-11-r) (TZ-12) (TZ-12-r) with the proviso that in formula (III-L) the linker (L2-10) is excluded from the corresponding -L 2 - when -L 1 - is any one linker selected from the group consisting of (L1-1), (L1-2a), (L1-2b), (L1-11) and (L1-12).
  7. 7 . The crosslinked alginic acid structure according to claim 3 , wherein the structure is beads or a semi-spherical gel.
  8. 8 . The crosslinked alginic acid according to claim 1 , wherein the crosslinked alginic acid has biocompatibility.
  9. 9 . The crosslinked alginic acid structure according to claim 3 , wherein the structure has biocompatibility.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a Continuation of PCT International Application No. PCT/JP2020/047100, filed on Dec. 17, 2020, which claims priority under 35 U.S.C. 119(a) to Patent Application No. 2019-227866, filed in Japan on Dec. 18, 2019, all of which are hereby expressly incorporated by reference into the present application. TECHNICAL FIELD The present invention relates to novel alginic acid derivatives, to a novel crosslinked alginic acid, a novel crosslinked alginic acid structure, and methods of manufacturing these. BACKGROUND ART Alginic acid, a high-molecular-weight acidic polysaccharide molecule that is extracted from the cell walls of natural brown algae such as Lessonia, Macrocystis, Laminaria, Ascophyllum, Durvillea, Ecklonia cava, Eisenia bicyclis and Saccharina japonica, is a linear heteropolymer of two kinds of uronic acid, β-D-mannuronate (M component) and its C-5 epimer α-L-guluronate (G component), connected by 1-4 linkages. Specifically, in terms of its chemical structure it is a block copolymer made up of homopolymer blocks of mannuronic acid (MM), homopolymer blocks of guluronic acid (GG), and randomly arranged blocks of mannuronic acid and guluronic acid (MG), in complex combination with arbitrary permutations and proportions. Alginic acid is widely used in such fields as medicine, biotechnology, cosmetics, fibers, paper and foodstuffs. While monovalent alkali metal salts of alginic acid (such as sodium alginate) are water soluble, divalent alkali earth metal salts of alginic acid (such as calcium alginate) have the property of being gelled (insolubilized) by crosslinking with metal ions, and these properties have been used to modify or mold these into suitable forms for various applications. To investigate ways of modifying or molding polysaccharides (such as hyaluronic acid, chondroitin sulfate and alginic acid) into various materials and improving their physical properties (such as strength and swelling properties), much research has already been done into crosslinked polysaccharides crosslinked by covalent bonds. Methods of obtaining crosslinked polysaccharides include (1) crosslinking methods using aldehyde crosslinking agents such as formaldehyde (Patent Literature 1: WO 2011/028031A), (2) self-crosslinking methods via carboxyl groups and hydroxyl groups in polysaccharides (Patent Literature 2: WO 1989/10941A), and (3) crosslinking methods using homo-bifunctional crosslinking agents (diepoxides, divinylsulfones, diamines, dihydrazines, etc.) or hetero-bifunctional crosslinking agents (epihalohydrins, etc.) (Patent Literature 3: WO 2009/073437A). Other known methods include (4) methods of crosslinking by light exposure after introduction of a photoreactive group (such as cinnamic acid, substituted cinnamic acid, acrylic acid, maleic acid, fumaric acid, furyl acrylic acid, thiophen acrylic acid, cinnamylidene acetic acid, sorbic acid, thymine or coumarin) (Patent Literatures 4 and 5: WO 2005/026214A, and JP H 09-87236A) and (5) methods of crosslinking by disulfide bonds between polysaccharides having introduced thiol groups, and methods of crosslinking by a Michael addition reaction using a polysaccharide having an introduced thiol group and a polysaccharide having an introduced maleimide group (Patent Literature 6: WO 2008/071058A). Another method of crosslinking by covalent binding between polysaccharides is (6) a method of crosslinking by a Huisgen reaction (1,3-dipolar cycloaddition reaction) using a polysaccharide having an introduced alkyne group and a polysaccharide having an introduced azide. Crosslinked polysaccharides obtained by subjecting polysaccharides to a Huisgen reaction are disclosed in (i) WO 2008/031525A (Patent Literature 7), (ii), WO 2012/165462A (Patent Literature 8), (iii) WO 2015/020206A (Patent Literature 9), (iv) CN 106140040A (Patent Literature 10), and (v) WO 2019/240219A (Patent Literature 13). However, (i) Patent Literature 7 relates to a crosslinked polysaccharide obtained by performing a Huisgen reaction in the presence of a copper catalyst on a chain-like alkyne group and azide group introduced via linkers into a first polysaccharide (hyaluronic acid) and a second polysaccharide selected from chondroitin, sulfated dermatan, alginic acid or its salt and the like, and does not disclose the novel crosslinked alginic acid described below. Meanwhile, (ii) Patent Literature 8 relates to a crosslinked polysaccharide obtained using polysaccharides selected from hyaluronic acid, carboxymethyl dextran, cellulose derivatives and chitosan as first and second polysaccharides (the first and second polysaccharide may be the same or different) by performing a Huisgen reaction on a cyclic alkyne group and azide group introduced into the respective polysaccharides via linkers (by ester bonds between the polysaccharides and the linkers), and does not disclose the novel crosslinked alginic acid described below. Furthermore, (iii) Patent