Injectable hybrid alginate hydrogels and uses thereof

Patent metadata

Field	Value
Publication number	US-2020277449-A1
Application number	US-201816647225-A
Country	US
Kind code	A1
Filing date	Sep 17, 2018
Priority date	Sep 15, 2017
Publication date	Sep 3, 2020
Grant date	—

Abstract

The invention relates to a hybrid hydrogel, in particular degradable or non-degradable, comprising a first hydrogel polymer of formula (I) in association with an alginate hydrogel polymer, and optionally organosilica particles in particular degradable or non-degradable nanoparticles, or porous silicon particles; pharmaceutical, veterinary and/or cosmetic compositions thereof; and uses thereof as a medicament. The invention notably relates to the use of such hybrid hydrogel in the treatment of fistulas and physiological leaks/leakages, notably in the gastrointestinal tract. The present invention finds applications in the therapeutic and diagnostic medical technical fields and also in cosmetic and veterinary technical fields.

First claim

1 . A hybrid hydrogel comprising:
A) A first hydrogel polymer comprising monomers of formula (I):

wherein
n is an integer representing the number of monomers (I) in the hydrogel polymer;
for each occurrence of the bracketed structure n, Y independently represents:
a molecular crosslinker for connecting at least a monomer of formula (I) in the framework to at least another monomer of formula (I) in another framework through a linker having the following structure:
*-R 1 -L 1 -R 2 -*;

wherein:
each occurrence of *-R 1 -L 1 -R 2 -* independently represents a responsively cleavable moiety or a non-cleavable moiety;
each occurrence of * denotes a point of attachment of the linker to a monomer of formula (I) in the hydrogel's framework;
L 1 represents a responsively cleavable covalent bond, a moiety containing a responsively cleavable covalent bond and/or a stable covalent bond;
R 1 and R 2 independently represent an optionally substituted C1-20 alkylenyl moiety, an optionally substituted C1-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, —C≡C— or an optionally substituted phenyl moiety, wherein the C1-20 alkylenyl, C1-20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6 alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, C1-6alkyl, —NO 2 , —CN, isocyano, —ORp, —N(Rp)2 wherein each occurrence of Rp independently represents H or C1-6alkyl;
wherein *-R 1 -L 1 -R 2 -* may independently comprise sugar derivatives such as mannose, hyaluronic acid derivatives, collagene, aminoacids or peptides;

or
a group of formula
*-R 7 (R 8 )-*

wherein
the * symbols denote the points of attachment of Y within the monomer backbone of formula (I);
R 7 represents N,
R 8 represents an optionally substituted C1-20 alkyl, C1-20alkenyl or C1-20alkynyl moiety, a C1-20 alkyl optionally substituted with carboxyl moiety, an optionally substituted C1-20heteroalkyl moiety, an optionally substituted C1-20alkylphenyl moiety or an optionally substituted phenyl moiety, wherein each of the foregoing C1-20 alkyl, C1-20alkenyl, C1-20alkynyl, C1-20heteroalkyl or C1-20alkylphenyl moieties may bear one or more substituents selected from halogen, —OR, —CO 2 R or —N(Rp)2; where R may represent H or C1-6alkyl and each occurrence of Rp may independently represent H or C1-6alkyl; and the phenyl moiety may bear one or more substituents independently selected from halogen, C1-6alkyl, —NO 2 , —CN, isocyano, —ORp, —N(Rp)2 wherein each occurrence of Rp independently represents H, C1-6alkyl or C1-6 alkoxy; wherein R 8 may be optionally crosslinked to another monomer of formula (I) in another hydrogel polymer chain; or
a hyaluronic acid, alginic acid, peptide, cellulose, amino acid, sugar such as glucose, lactose or mannose derivatives, or oligonucleotide moiety;
for each occurrence of the bracketed structure n, R 10 independently represents an optionally substituted C1-20 alkylenyl moiety, wherein the C1-20 alkylenyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6alkyl;
for each occurrence of the bracketed structure n, R 11 and R 12 independently represent H, an optionally substituted C1-20 alkyl, C1-20alkenyl or C1-20alkynyl moiety, an optionally substituted C1-20heteroalkyl moiety, or an optionally substituted phenyl moiety, wherein each of the foregoing C1-20 alkyl, C1-20alkenyl, C1-20alkynyl or C1-20heteroalkyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, C1-6alkyl, —NO 2 , —CN, isocyano, —ORp, —N(Rp)2 wherein each occurrence of Rp independently represents H or C1-6alkyl;
for each occurrence of the bracketed structure n, X independently represents an optionally substituted C1-20 alkylenyl moiety, wherein the C1-20 alkylenyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6alkyl; and
B) at least a polysaccharide-based hydrogel, preferably an alginate-based hydrogel, preferably a hydrogel based on an alginate polymer having formula (II):

wherein each occurrence of Z independently represents a counterion such as Ca, Mg, Na, K, Li, Rb and m, 1, p are independently integers.

2 . Hybrid hydrogel according to claim 1 , wherein at least in a subset of bracketed structures n:
L 1 represents independently a responsively cleavable covalent bond selected from:

a light-induced breakable group or a photo-responsive group; or
*-R 1 -L 2 -R 2 -* represents:
i) a pH-cleavable linker comprising to imine groups conjugated with an aromatic group such as phenyl, preferably a linker comprising a para di-imino phenyl group;
ii) a pH-cleavable linker of formula:

wherein each occurrence of q independently represents an integer, for example 1-6; and
D represents independently for each occurrence a C1-C3 alkylenyl moiety, or —N(Rz)— wherein Rz represents H or C1-6alkyl;
iii) a light-induced cleavable linker having formula:

wherein q1 and q2 independently represent an integer from 1 to 6, preferably from 1 to 3. For example, q1 and q2 may both represent an integer from 1 to 6, preferably from 1 to 3, more preferably q1=q2=3; or

iv) a responsively cleavable moiety selected from:

v) a moiety comprising a sugar derivative such as mannose, a hyaluronic acid derivative, collagene, an aminoacid or a peptide moiety.

3 . Hybrid hydrogel according to claim 1 , wherein in the linker having the structure *-R 1 -L 1 -R 2 -*, R 1 and R 2 are identical, and each represent —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, or phenyl.

4 . Hybrid hydrogel according to any one of claims 1 to 3 wherein in the group of formula
*-R 7 (R 8 )-*,
R 7 is N and
R 8 represents a C1-C6 alkyl substituted with a carboxyl moiety, a C1-C6 alkyl substituted with one or more hydroxyl groups, C1-C6 alkoxy, C1-C6 alkyl substituted with —N(Rp)2 wherein each occurrence of Rp independently represents a C1-6alkyl.

5 . Hybrid hydrogel according to any one of claims 1 to 4 wherein in the group of formula *-R 7 (R 8 )-*, R 7 may be may be N and and R 8 may be independently selected from the group comprising:

6 . Hybrid hydrogel according to any one of claims 1 to 5 wherein at least a subset of occurrences of Y in the first hydrogel polymer represents *-N(R 8 )-* wherein R 8 represents a C1-20alkyl or C1-20heteroalkyl moiety, preferably C1-6alkyl or C1-6heteroalkyl, most preferably C1-6alkyl, bearing:
(i) an organosilica nanoparticle; or
(ii) an organosilica nanocapsule having a core/shell structure, and a molecule of interest or bioactive macromolecule or bioactive macromolecule cluster encapsulated within said nanocapsule, wherein the bioactive macromolecule(s) or macromolecule cluster(s) within the nanocapsule

Assignees

• Univ Strasbourg
• Centre Nat Rech Scient
• Ihu Strasbourg Institut Hospitalo Univ De Strasbourg

Inventors

• De Cola Luisa
• Perretta Silvana
• Alonci Giuseppe
• Riva Pietro
• Piantanida Etienne
• Guerriero Ludovica

Classifications

• A61K8/733

  Alginic acid; Salts thereof · CPC title

• C08G73/028

  Polyamidoamines · CPC title

• C08J2305/04

  Alginic acid; Derivatives thereof · CPC title

• C08J2377/00

  Characterised by the use of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Derivatives of such polymers · CPC title

• A61Q19/00

  Preparations for care of the skin · CPC title