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1. WO2018134268 - INJECTABLE HYDROGELS AND USES THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1. A hydro el 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:

^-Li-R2-*;

wherein:

each occurrence of '"'-R'-Li-R2-* 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;

each occurrence of Li independently a responsively cleavable covalent bond, a moiety containing a responsively cleavable covalent bond and/or a stable covalent bond;

R1 and R2, for each occurrence, independently represent an optionally substituted Cl- 20 alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C≡C- or an optionally substituted phenyl moiety, wherein the CI -20 alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or CI -6 alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or C l- 6alkyl;

wherein '"'-R'-Li-R2-* may independently comprise sugar derivatives such as mannose, hyaluronic acid derivatives, collagene, aminoacids or peptides;

or

a group of formula


wherein

the * symbols denote the points of attachment of Y within the monomer backbone of formula (I);

R7 represents N,

R8 represents an optionally substituted CI -20 alkyl, Cl-20alkenyl or Cl-20alkynyl moiety, a CI -20 alkyl optionally substituted with carboxyl moiety, an optionally substituted Cl-20heteroalkyl moiety, an optionally substituted Cl-20alkylphenyl moiety or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20alkenyl, Cl-20alkynyl, Cl-20heteroalkyl or Cl-20alkylphenyl moieties may bear one or more substituents selected from halogen, -OR, -CO2R or -N(Rp)2; where R may represent H or Cl-6alkyl and each occurrence of Rp may independently represent H or Cl-6alkyl; and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -NO2, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H, Cl-6alkyl or CI -6 alkoxy; wherein R8 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, Rio independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl;

for each occurrence of the bracketed structure n, Rn and R12 independently represent H, an optionally substituted CI -20 alkyl, Cl-20alkenyl or Cl-20alkynyl moiety, an optionally substituted Cl-20heteroalkyl moiety, or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20alkenyl, Cl-20alkynyl or Cl-20heteroalkyl moiety may bear one or more substituents selected from halogen

or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -NO2, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl;

for each occurrence of the bracketed structure n, X independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl;

wherein at least a subset of occurrences of Y in the hydrogel polymer bears or comprises at least one organosilica particle wherein the organosilica matrix may be porous (preferably mesoporous) and contains responsively cleavable bonds within the organosilica framework.

2. Hydrogel according to claim 1, wherein at least in a subset of bracketed structures n:

Li represents independently a responsively cleavable covalent bond selected from:


Disulfide Diselenide Anhydride Ester Amide Imine


Acetal/ketal rea Thiourea Hydrazone Oxyme Boronic acid

derivatives


Carbamoyl Thioketal

a light-induced breakable group or a photo -responsive group; or

'"'-R'-Li-R2-* independently 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 independently represents for each occurrence a C1-C3 alkylenyl moiety, or -N(Rz)-wherein Rz represents H or Cl-6alkyl;

iii) a light-induced cleavable linker having formula:

wherein ql and q2 independently represent an integer from 1 to 6, preferably from 1 to 3. For example, ql and q2 may both represent an integer from 1 to 6, preferably from 1 to 3, more preferably ql = 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. Hydrogel according to claim 1, wherein in the linker having the structure '"'-R'-Li-R2- *, R1 and R2 are identical, and each represent -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or phenyl.

Hydrogel according to any one of claims 1 to 3 wherein in the group of formula *- Rv(Rs)-*,

R7 is N and

R8 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 Cl-6alkyl.

6. Hydrogel according to any one of claims 1 to 5 wherein at least a subset of occurrences of Y in the hydrogel polymer represents *-N(R8)-* wherein R8 represents a Cl-20alkyl or Cl-20heteroalkyl moiety, preferably Cl-6alkyl or Cl-6heteroalkyl, most preferably

Cl-6alkyl, bearing:

(i) a disintegratable organosilica nanoparticle; or

(ii) a disintegratable 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 macro mo lecule(s) or macromolecule cluster(s) within the nanocapsule is/are preferably in an active conformation;

wherein the organosilica matrix of the organosilica nanoparticle or nanocapsule contains responsively cleavable bridges #-R3-L2-R4-# between Si atoms within the organosilica framework;

preferably the organosilica matrix of the disintegratable organosilica nanoparticle or core/shell nanocapsule may be porous, most preferably mesoporous;

wherein:

each occurrence of # denotes a point of attachment to a Si atom in the organosilica material's framework;

L2 represents a responsively cleavable covalent bond; and

R3 and R4 independently represent an optionally substituted CI -20 alkylenyl moiety, an optionally substituted CI -20 heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C≡C- or an optionally substituted phenyl moiety, wherein the Cl-20alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, - N(RP)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl; and

wherein the nanoparticle or nanocapsule outer surface may comprise one or more groups of formula

#-R5R6

wherein

each occurrence of # denotes a point of attachment to a Si atom at the outer surface of the hybrid organosilica material's framework;

each occurrence of R5 independently represents an optionally substituted Cl- 20alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C≡C- or an optionally substituted phenyl moiety, wherein the Cl-20alkylenyl, Cl-20heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl; and

each occurrence of R6 independently represents -OR, -SR or -N(Rf)2; preferably -N(Rf)2; wherein each occurrence of R and Rf independently represents H or Cl-6alkyl.

7. Hydrogel according to any one of claims 1 to 6 wherein

Rio represents CH- or CH-CH2; and

Rii and R12 independently represent H or C1-C6 alkyl.

Hydrogel according to 6 wherein at least a subset of nanocapsules bound to the hydrogel polymer are further crosslinked via one or more #-R5R6 groups to another hydrogel polymer of formula I.

A hydrogel according to claim 6 or 8 wherein the nanoencapsulated molecule is selected from proteins, enzymes, antibodies, peptides, DNA, RNA, PNA, gene fragments and small molecules with or without pharmaceutical activity; preferably proteins, enzymes, antibodies, peptides, DNA, RNA, PNA and gene fragments.

10. A hydrogel according to any one of claims 6 to 9, wherein L2 represents independently a responsively cleavable covalent bond selected from:


Disulfide Diselenide Anh dride Amide Imine


Acetal/ketal rea Thiourea Hydrazone Oxyme Boronic acid

derivatives


Carbamoyl Thioketal

a light breakable group or a photo-responsive group, or

#-R3-L2-R4-# 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 independently represents for each occurrence a C1-C3 alkylenyl moiety, or -N(Rz)-wherein Rz represents H or Cl-6alkyl;

iii) a light-induced cleavable linker having formula:

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

iv) a responsively cleavable moiety selected from:


1 1. A hydrogel of any one of claims 1 to 10, wherein the organosilica particles bound to the hydroegl polymer has a diameter between 25 nanometers and 500 nanometers.

12. A pharmaceutical or cosmetic composition comprising a hydrogel of any one of claims 1 to 1 1, and a pharmaceutically or cosmetically acceptable carrier.

13. A method for preparing a hydrogel of any one of claims 1 to 1 1, comprising steps of:

a) dissolving in water or alcoholic solutions:

a monomer precursor of formula (IV)


at least one molecular crosslinker precursor having the structure A-R'-Li- R2-A,

disintegratable organosilica nanoparticles bearing amino-containing tether groups at the outer surface; or disintegratable organosilica core/shell nanocapsules bearing amino-containing tether groups at the outer surface and encapsulating a bioactive macromolecule or bioactive macromolecule cluster, and/or another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity; wherein the bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule is preferably in active conformation; and Optionally, a selected precursor of formula B-R8

b) Stirring the solution obtained in step a), at any appropriate temperature, thereby allowing the polymerization carried out to form the hydrogel,

c) Optionally adding a suitable organic solvent, thereby precipitating the hydrogel;

wherein:

each occurrence of A independently represents a nucleophilic moiety, preferably - N(Rf)2 wherein each occurrence of Rf may represent H or Cl-6alkyl;

B independently represents a nucleophilic moiety, preferably -N(Rf)2 wherein each occurrence of Rf may represent H or Cl-6alkyl;

Li independently represents a responsively cleavable covalent bond, a moiety containing a responsively cleavable covalent bond and/or a stable covalent bond; and

R1 and R2 independently represent an optionally substituted CI -20 alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C≡C- or an optionally substituted phenyl moiety, wherein the Cl-20 alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or C 1 -6 alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl; wherein '"'-R'-Li-R2-* may independently comprise a sugar derivative such as mannose, a hyaluronic acid derivative, collagene, an aminoacid or a peptide moiety;

Rio independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl;

Ri i and R12 independently represent an optionally substituted CI -20 alkyl, Cl-20alkenyl or Cl-20alkynyl moiety, an optionally substituted Cl-20heteroalkyl moiety, or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20alkenyl, Cl-20alkynyl or Cl-20heteroalkyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -NO2, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl;

X independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl; and

R8 may independently represent:

- an optionally substituted CI -20 alkyl moiety, a CI -20 alkyl optionally substituted with carboxyl moiety, an optionally substituted Cl-20heteroalkyl moiety, an optionally substituted Cl-20alkylphenyl moiety or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20heteroalkyl or Cl-20alkylphenyl moieties may bear one or more substituents selected from halogen, -OR, -CO2R or -N(Rp)2 where R may represent H or Cl-6alkyl, and each occurrence of Rp may independently represent H or Cl-6alkyl; and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H, Cl-6alkyl or CI -6 alkoxy;

the residue of the corresponding amino acid H2NR8;

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 Cl-6alkyl;

a C1-C6 alkyl substituted with -N(Rp)2 wherein each occurrence of Rp independently represents a Cl-6alkyl;

a C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a CI alkyl;

a Cl-20alkylphenyl moiety optionally substituted with one or more -OR wherein

R may represent H or Cl-6alkyl;

a group of any one of the following formulae:


a hyaluronic acid, alginic acid, peptide, cellulose, amino acid, sugar (for example glucose, lactose or mannose derivatives) or oligonucleotide moiety; or

a C 1 -20alkyl or C 1 -20heteroalkyl moiety, preferably C 1 -6alkyl or C 1 -6heteroalkyl, most preferably Cl-6alkyl, bearing an organosilica particle, preferably organosilica nanoparticles or core-shell nanocapsules, preferably the organosilica matrix may be porous, most preferably mesoporous, and may contain responsively cleavable bonds L2 or responsively cleavable linkers #-R3-L2-R4-# within the organosilica framework as defined in claim 6.

The method of claim 13, wherein the monomer precursor is of formula (IV a)


15. The method of claim 13 or 14, wherein the linker Li and '"'-R'-Li-R2-* are as defined in claim 2.

The method of any one of claims 13 to 15 wherein the molecular crosslinker precursor is of formula


The method of any one of claims 13 to 16 wherein the selected precursor of formula B-


18. A hydrogel covalently conjugated to disintegratable organosilica nanoparticles or disintegratable organosilica nanocapsules having a core/shell structure, obtainable by a method of any one of claims 13 to 17.

19. A hydrogel of any one of claims 1 to 11 or a pharmaceutical composition of claim 12, for use as medicament.

20. Hydrogel according to claim 19 for use in sealing a wound, for enhancing tissue regeneration, as fillers for example for submucosal fluid cushion for surgery, tissue reconstitution in a subject-in-need thereof, for the treatment of diabetes, for the treatment of spinal cord injury.

21. Hydrogel according to claim 19 for use as a medicament for the treatment of cancer, preferably tumor, more preferably for the resection of solid tumors.

22. A method for sealing acute and/or chronic wounds and/or perforation in a subject-in- need thereof, the method comprising administering to the subject a therapeutically effective amount of a hydrogel of any one of claims 1 to 11 or a pharmaceutical composition of claim 12, thereby sealing the wound and/or perforation.

23. A method for treating a disease, preferably cancer tumor, in a subject-in-need thereof, the method comprising administering to the subject a therapeutically effective amount of a hydrogel of any one of claims 1 to 11 or a pharmaceutical composition of claim 12, thereby treating the disease in the subject.

24. Use of a hydrogel of any one of claims 1 to 11, in a cosmetic composition.

25. Use of a hydrogel of any one of claims 1 to 11 or a cosmetic composition of claim 24, for delivering a cosmetically bioactive macromolecule to the skin.

26. Use according to claim 24 or 25, wherein the cosmetically bioactive macromolecule is collagen, keratin, elastin, calcitonin, hyaluronic acid, aminoacids, retinol, antioxidants, vitamins or silk proteins.

27. A method for systemically delivering a drug, or a bioactive macromolecule in a biologically active form, to a subject in need thereof, the method comprising, administering to the subject a therapeutically effective amount of a hydrogel of any one of claims 1 to 11 or a pharmaceutical composition of claim 12.

28. The method of claim 27, wherein said bioactive macromolecule is selected from proteins, oligonucleotides, antibodies, peptides, PNA, DNA, R A, gene fragments, a hormone, a growth factor, a protease, an extra-cellular matrix protein, an enzyme, an infectious viral protein, an antisense oligonucleotide, a dsR A, a ribozyme, a DNAzyme, antibiotics, antinflammatory, steroids, chemiotherapeutics.

29. A unit dosage form for local delivery of a molecule to a tissue of a subject, the unit dosage form comprising, a therapeutically effective amount of a hydrogel of any one of claims 1 to 11 or a pharmaceutical composition of claim 12, wherein said macromolecule is selected from proteins, oligonucleotides, antibodies, peptides, PNA, DNA, RNA, gene fragments, a hormone, a growth factor, a protease, an extra-cellular matrix protein, an enzyme, an infectious viral protein, an antisense oligonucleotide, a dsRNA, a ribozyme and a DNAzyme.

A delivery system for enhancing wound healing, tissue regeneration and/or tissue regeneration in vivo, said system comprising a hydrogel of any one of claims 1 to 11 or a pharmaceutical composition of claim 12.