Microgel Compositions

Abstract

This invention relates to microgel compositions, and in particular, to gel compositions formed by binding a plurality of individual microgel particles together. The present invention also relates to processes for the preparation of these compositions and their use for particular applications, especially medical applications such as the repair of damaged, degenerated or inappropriately formed load-bearing tissue (such as, for example, intervertebral discs).

1 - 20 . (canceled) 
     
     
         21 . A method of treating damaged or degenerated soft tissue in a subject, the method comprising administering by injection, to the damaged or degenerated soft tissue or into a joint containing the damaged or degenerated soft tissue, a plurality of swellable microgel particles, and binding adjacent microgel particles together by either:
 (i) swelling the microgel particles in the presence of a free radical initiator, and in situ free radically coupling vinyl-containing moieties grafted onto the surfaces of the microgel particles; and/or   (ii) swelling the microgel particles in the presence of a water soluble cross-linking monomer, and in situ polymerizing the cross-linking monomer to form a cross-linked polymer network that interpenetrates and binds together adjacent microgel particles.   
     
     
         22 . The method as claimed in  claim 21 , wherein the microgel particles are pH responsive microgel particles having a capacity to undergo a pH-triggered transition from a collapsed configuration into a swollen configuration in response to a pH change from a pH between 5.0 to 6.6 to a pH between 6.6 and 8. 
     
     
         23 . The method as claimed in  claim 22 , wherein the pH-responsive microgel particles are administered at a pH between 6.6 and 8 to the damaged or degenerated soft tissue or into the joint containing the damaged or degenerated soft tissue. 
     
     
         24 . The method as claimed in  claim 21 , wherein each microgel particle comprises a copolymer defined by formula I:
   Poly(HM- co —P— co —X)  (I)
   
       wherein:
 P is a pH-responsive co-monomer; 
 X is a functional cross-linking co-monomer; and 
 HM is a hydrophobic co-monomer. 
 
     
     
         25 . The method as claimed in  claim 24 , wherein each microgel particle comprises a polymer selected from poly(ethylacrylate/methacrylic acid/ethyleneglycol dimethacrylate), poly(methylmethacrylate/methacrylic acid/ethyleneglycol dimethacrylate), poly(ethylacrylate/methacrylic acid/1,4-butanediol diacrylate) or poly(methylmethacrylate/methacrylic acid/1,4-butanediol diacrylate). 
     
     
         26 . The method as claimed in  claim 25 , wherein each microgel particle comprises poly(methylmethacrylate/methacrylic acid/ethyleneglycol dimethacrylate). 
     
     
         27 . The method as claimed in  claim 21 , wherein each vinyl containing moiety is a group of the formula L-B, wherein L is a bond or linking group and B is a group comprising a vinyl functional group. 
     
     
         28 . The method as claimed in  claim 27 , wherein each microgel particle is a pre-formed microgel particle having a plurality of vinyl-containing moieties grafted onto the surface thereof, wherein each vinyl containing moiety is a group of the formula -L-B, wherein L is a bond or linking group; and B is a group comprising a vinyl functional group. 
     
     
         29 . The method as claimed in  claim 28 , wherein and the plurality of vinyl-containing moieties grafted onto the surface of each microgel particle is present at a concentration of between 3.0 and 30 mol. % with respect to all of the co-monomers of the microgel particle. 
     
     
         30 . The method as claimed in  claim 28 , wherein the plurality of vinyl-containing moieties each having the formula -L-B is grafted to the surface of each pre-formed microgel particle by a reaction between the pre-formed microgel particle and a compound of formula Z-L-B, wherein Z is a reactive group which reacts with a functional group present on the surface of the pre-formed microgel particle to thereby graft the plurality of vinyl-containing moieties each having the formula -L-B onto the surface of the pre-formed microgel particle. 
     
     
         31 . The method as claimed in  claim 28 , wherein each vinyl-containing moiety of formula -L-B is further defined by the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 L is a functionalised (1-3C)alkylene chain comprising one or more functional groups selected from —O—, —C(O)—, —C(O)O—, —OC(O)—, —NRa—, —NRa—C(O)—, or —C(O)—NRa—, wherein Ra is H or (1-2C)alkyl; and 
 R 1 , R 2  and R 3  are selected from H or (1-3C)alkyl. 
 
     
     
         32 . The method as claimed in  claim 31 , wherein each vinyl-containing moiety is grafted to the surface of a pre-formed microgel particle via coupling glycidyl methacrylate to carboxylic acid groups on the surface of the pre-formed microgel particle. 
     
     
         33 . The method as claimed in  claim 21 , wherein the water-soluble cross-linking monomer is a water-soluble cross-linking monomer comprising two or more vinyl containing moieties. 
     
     
         34 . The method as claimed in  claim 33 , wherein the water-soluble cross-linking monomer has the following formula:— 
       
         
           
           
               
               
           
         
       
       wherein:
 (a) R 21 , R 22 , R 23 , R 31 , R 32  and R 33  may be independently selected from a group consisting of H; CH 3 ; a linear or branched alkyl group; or a N-alkyl group of up to 10 C units; and wherein (b) R 24  may be independently selected from a group consisting of:— 
 (i) —C(═O)—O—R 34 —O—C(═O)—, wherein R 34  may comprise —CH 2 —, —CH 2 CH 2 — or a linear or branched alkyl group, such as a methylene chain, which may be up to 20 C chains in length; or —C 6 H 4 —; or C 6 H 3 R 35 , wherein R 35  comprises substituents such alkyl, for example, CH 3 ; a halogen group; or an amide group; or other di- or tri-substituted phenyl groups containing more than one of these substitutents; 
 (ii) —C(═O)—O—R 36 —C(═O)—, wherein R 36  may be —(CH 2 CH 2 O) n — wherein n may be from 1 to 30; 
 (iii) —C(═O)—O—R 37 R 38 R 37 —, wherein R 37  may comprise degradable ester linkages, for example lactone, —[(CH 2 ) 5 C(═O)—O] m —, lactide, —[CH(CH 3 )C(═O)—O] m —, glycolide, —[CH 2 C(═O)—O] m —, wherein m may be from 1 to 50, and wherein R 38  may be —(CH 2 CH 2 O) n —, wherein n may be from 1 to 30; 
 (iv) —C(═O)—O—R 39 —, wherein R 39  may comprise degradable ester linkages, for example lactone, [(CH 2 ) 5 C(═O)—O] m —, lactide, [CH(CH 3 )C(═O)—O] m —, glycolide, [CH 2 C(═O)—O] m —, wherein m is between to 100; 
 (v) allylacrylates, for example —C(═O)—O—R 40 —, wherein R 40  may be —CH 2 —, —CH 2 CH 2 — or a linear, or branched, methylene chain up to 20 C chains in length, or —C 6 H 4 —, C 6 H 3 R 41 , wherein R 41  may comprise substituents, such as alkyl, CH 3 , a halogen or an amide group or other di- or tri-substituted phenyl groups containing more than one of these substitutents; 
 (vi) vinylbenzenes, for example C 6 H 4  or C 6 H 3 R 42  wherein R 42  comprises substituents, such as alkyl; CH 3 ; a halogen or an amide group (see (iii) above); or other substituted phenyl groups containing more than one of these substitutents; 
 (vii) acrylamides, for example C(═O)—NR 43 —R 44 —NR 45 C(═O)—, wherein R 43  and R 44  may be independently selected from a group consisting of H; CH 3 ; a linear or branched alkyl group; a dialkyl group; a N-alkylgroup, of up to 10 C units; and wherein R 44  may comprise —CH 2 —, —CH 2 CH 2 — or a linear, or branched, methylene chain up to 20 C chains in length; or —C 6 H 4 —, C 6 H 3 R 40  wherein R 40  comprises substituents, such as alkyl; CH 3 ; a halogen or an amide group or other di- or tri-substituted phenyl groups containing more than one of these substitutents; 
 (viii) trifunctional cross-linking monomers, wherein R 24  comprises any of the groups listed in (b), as well as R 21 R 22 C═CR 23 , where R 21 , R 22  and R 23  are described in (a); 
 (ix) tetrafunctional cross-linking monomers, wherein R 24  comprises any of the groups listed in (b), as well as R 21 R 22 C═CR 23  and R 31 R 32 C═CR 33 , wherein R 21 , R 22 , R 23 , R 31 , R 32  and R 33  are described in (a); and 
 (x) wherein R 24  may contain any combination of the groups listed in (b). 
 
     
     
         35 . The method as claimed in  claim 33 , wherein the water-soluble cross-linking monomer is or comprises allylmethacrylate or divinylbenzene. 
     
     
         36 . The method as claimed in  claim 33 , wherein the water-soluble cross-linking monomer is or comprises butanediol diacrylate. 
     
     
         37 . The method as claimed in  claim 33 , wherein the water-soluble cross-linking monomer is or comprises ethyleneglycol dimethacrylate. 
     
     
         38 . The method as claimed in  claim 33 , wherein the water-soluble cross-linking monomer is or comprises poly(ethyleneglycol)dimethacrylate with a molar mass in the range of 200 to 1000 g/mol. 
     
     
         39 . The method as claimed in  claim 21 , wherein the microgel particles are injected along with a free radical initiator and/or an accelerator. 
     
     
         40 . The method as claimed in  claim 39 , wherein the free radical initiator has the general formula [M]S 2 O 8   2− , wherein M is a cation. 
     
     
         41 . The method as claimed in  claim 40 , wherein the free radical initiator is ammonium persulfate, (NH 4   + ) 2 S 2 O 8   2− . 
     
     
         42 . The method as claimed in  claim 39 , wherein the accelerator is selected from TEMED (1,2-bis(dimethylamino)ethane, N,N,N′,N′-Tetramethylethylenediamine) and ascorbic acid. 
     
     
         43 . The method as claimed in  claim 42 , wherein the accelerator is ascorbic acid. 
     
     
         44 . The method as claimed in  claim 39 , wherein the microgel particles are injected along with ammonium persulfate and ascorbic acid. 
     
     
         45 . The method as claimed in  claim 21 , wherein a physiologically acceptable buffer solution is co-administered with the microgel particles. 
     
     
         46 . The method as claimed in  claim 45 , wherein the physiologically acceptable buffer solution and microgel particles are mixed together to swell just prior to administration. 
     
     
         47 . The method as claimed in  claim 21 , wherein the damaged or degenerated soft tissue or the joint containing the damaged or degenerated soft tissue is selected from the group consisting of intervertebral discs, nucleus pulposus (NP) of intervertebral discs, articular joints, articular elbow joints, articular knee joints, articular hip joints, articular wrist joints, articular shoulder joints, articular ankle joints, joints present in a finger, and joints present in a thumb. 
     
     
         48 . The method as claimed in  claim 21 , wherein the method is performed to repair and/or replace damaged or degenerated soft tissue. 
     
     
         49 . The method as claimed in  claim 21 , wherein the microgel particles are present at a concentration of 10-20 wt % when administered to the damaged or degenerated soft tissue or the joint containing the damaged or degenerated soft tissue. 
     
     
         50 . The method as claimed in  claim 21 , wherein the microgel particles are in a swollen configuration at the physiological pH of the damaged or degenerated soft tissue or joint containing the damaged or degenerated soft tissue. 
     
     
         51 . A doubly-crosslinked microgel composition comprising a plurality of swollen microgel particles, wherein adjacent microgel particles are bound together by either:
 (i) covalent cross-links therebetween formed by the free radical reaction between vinyl-containing moieties grafted onto the surfaces of the microgel particles; and/or   (ii) a cross-linked polymer network that interpenetrates adjacent microgel particles and thereby binds the particles together, wherein the polymer network is formed by the polymerisation of a water soluble cross-linking monomer.   
     
     
         52 . A process of preparing the doubly-cross-linked microgel composition as claimed in  claim 51 , the process comprising binding adjacent microgel particles together by either:
 (i) swelling the microgel particles in the presence of a free radical initiator, and in situ free radically coupling vinyl-containing moieties grafted onto the surfaces of the microgel particles; and/or   (ii) swelling the microgel particles in the presence of a water soluble cross-linking monomer, and in situ polymerizing the cross-linking monomer to form a cross-linked polymer network that interpenetrates and binds together adjacent microgel particles.   
     
     
         53 . A method of treating a damaged or degenerated nucleus pulposus, the method comprising administering by injection, to the damaged or degenerated nucleus pulposus, at least one nucleus pulposus cell and/or at least one stem cell and/or at least one mammalian cell. 
     
     
         54 . The method as claimed in  claim 53 , further comprising administering by injection, to the damaged or degenerated nucleus pulposus, collagen and/or proteoglycans.