Mineral-polymer hybrid composition

Abstract

The present invention relates to self-setting compositions consisting in admixed liquid and solid components enable the formation of hardened bio-materials having a broad range of properties and performances. The present invention proposes a) a thermo-sensitive self-gelling liquid component, being water-based, comprising at least a polycationic and a phosphate source, wherein the liquid component is a thermo-gelling solution at a pH ranging from 6.5 to 7.4; b) a powder component consisting in at least two calcium phosphate sources. The preferred calcium phosphate source includes apatites, tricalcium phosphates, tetracalcium phosphates and dicalcium phosphates. Both solid and liquid components are admixed to form a flowable slurry that sets in situ into a hardened calcium phosphate based bio-material.

What is claimed is:  
     
         1 . An injectable self-setting composition comprising: 
 a) a water-based liquid component comprising at least one cationic polymer and one mono-phosphate salt; said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character and being free of insoluble particles; and    b) a powder component comprising at least two calcium phosphate sources selected from apatites and apatitic calcium phosphates, octacalcium phosphates, amorphous calcium phosphates, tetracalcium phosphates, tricalcium phosphates, dicalcium phosphates and monocalcium phosphates,    wherein when said components of step a) and b) are intimately and uniformly mixed together, said components of step a) and b) form an injectable thermo-setting slurry, said slurry when heated turns into a solid material.    
     
     
         2 . The composition of  claim 1 , wherein said cationic polymer is a polysaccharide, a polypeptide or a synthetic polymer.  
     
     
         3 . The composition of  claim 1 , wherein said cationic polymer has a concentration in said liquid component between 0.1 and 5.0% wt.  
     
     
         4 . The composition of  claim 1 , wherein said cationic polymer is chitosan or collagen, or a mixture of chitosan and collagen.  
     
     
         5 . The composition of  claim 1 , wherein said cationic polymer is a partially-deacetylated chitin or chitosan with a degree of deacetylation between 30 and 99%.  
     
     
         6 . The composition of  claim 1 , wherein said cationic polymer is a polylysine.  
     
     
         7 . The composition of  claim 1 , wherein said monophosphate salt has a basic character.  
     
     
         8 . The composition of  claim 1 , wherein said liquid component comprises a first phosphate source selected from the group consisting of Na 2 PO 4 C 3 H 5 (OH) 2 , Fe 2 PO 4 C 3 H 5 (OH) 2 , K 2 PO 4 C 3 H 5 (OH) 2 , MgPO 4 C 3 H 5 (OH) 2 , MnPO 4 C 3 H 5 (OH) 2 , Ca 2 PO 4 C 3 H 5 (OH) 2 , Na 2 PO 7 C 3 H 7 , Na 2 PO 7 C 4 H 7 , K 2 PO 7 C 4 H 7 , NaPO 7 C 4 H 8 , K 2 PO 7 C 4 H 8 , Na 2 PO 8 C 5 H 9 , K 2 PO 8 C 5 H 9 , NaPO 8 C 5 H 10 , KPO 8 C 5 H 10 , Na 2 PO 9 C 6 H 11 , NaPO 9 C 6 H 12 , K 2 PO 8 C 6 H 14 , KPO 9 C 6 H 12 , Na 2 PO 8 C 6 H 13 , K 2 PO 8 C 6 H 13 , NaPO 8 C 6 H 14 , KPO 8 C 6 H 14 , Na 2 PO 9 C 6 H 12 , K 2 PO 9 C 6 H 12 , NaPO 9 C 6 H 13 , KPO 9 C 6 H 13 , Na 2 PO 8 C 10 H 11 , K 2 PO 8 C 10 H 11 , NaPO 8 C 10 H 12 , KPO 8 C 10 H 12  and the like, or a derivative thereof.  
     
     
         9 . The composition of  claim 1 , wherein said monophosphate salt is a sodium, magnesium, potassium, ferric and/or calcium alpha- or beta-glycerophosphate salt, or a mixture thereof.  
     
     
         10 . The composition of  claim 1 , wherein said monophosphate salt is glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate or fructose-6-phosphate salt, or a mixture thereof.  
     
     
         11 . The composition of  claim 1 , wherein said liquid component has a pH between 6.8 and 7.2.  
     
     
         12 . The composition of  claim 1 , wherein said liquid component has a viscosity superior to 200 mPa.s.  
     
     
         13 . The composition of  claim 1 , wherein said liquid component further comprises at least one other water-soluble polymer selected from the group consisting of polypeptides, cellulosics and synthetic polymers, including methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propylcellulose, poly(ethylene oxide), poly(propylene oxide), poly(ethylene glycol), poly(vinylpyrrolidone), poly(vinyl alcohol), and derivatives thereof.  
     
     
         14 . The composition of  claim 1 , wherein said liquid component further comprises at least one organic polyol, including sugar-polyol, saccharide-polyol and glycol, selected from the group consisting of glycerol, mannitol, sorbitol, ethylene glycol oligomers, propylene glycol oligomers, saccharose, fructose, glucose, maltose, and the like.  
     
     
         15 . The composition of  claim 1 , wherein said liquid component further comprises at least one water-soluble amino acid having a basic character and a pKa between 6.5 and 8.5.  
     
     
         16 . The composition of  claim 1 , wherein said liquid component further comprises a water-soluble sulfonate or carboxylate salt having a basic character and a pKa between 6.5 and 8.5.  
     
     
         17 . The composition of  claim 1 , wherein the liquid component and the powder component has a ratio liquid/powder component from 0.05 to 1.50 mug.  
     
     
         18 . The composition of  claim 1 , wherein the composition has a final molar ratio of calcium/phosphorus between 1.20 and 1.80.  
     
     
         19 . The composition of  claim 1 , wherein said powder component comprises alpha-tricalcium phosphate and an apatitic calcium phosphate.  
     
     
         20 . The composition of  claim 1 , wherein said powder component comprises alpha-tricalcium phosphate, dicalcium phosphate and an apatitic calcium phosphate.  
     
     
         21 . The composition of  claim 1 , wherein said powder component comprises alpha-tricalcium, monocalcium phosphate and an apatitic calcium phosphate.  
     
     
         22 . The composition of  claim 1 , wherein said powder component comprises at least alpha-tricalcium phosphate and an amorphous calcium phosphate.  
     
     
         23 . The composition of  claim 1 , wherein said powder component comprises tetracalcium phosphate and dicalcium phosphate.  
     
     
         24 . The composition of  claim 1 , wherein said powder component comprises tetracalcium phosphate and monocalcium phosphate.  
     
     
         25 . The composition of  claim 1 , wherein said powder component comprises less than 40% wt. of an apatitic calcium phosphate.  
     
     
         26 . The composition of  claim 1 , wherein said powder component further comprises at least one fluoride selected from the group consisting of NaF, Na 2 Si 6 F, KF, KSi 6 F, CaF 2 , MgF 2 , ZnF 2 , and sodium fluorophosphates, and the like, or derivatives thereof.  
     
     
         27 . The composition of  claim 1 , wherein said powder component further comprises at least one carbonate selected from the group consisting of Na 2 CO 3 , CaCO 3 , K 2 CO 3 , MgCO 3 , ZnCO 3 , Ca 9 K(PO 4 ) 5 (CO 3 ) 2 , Ca 8.5 Na 1.5 (PO 4 ) 4.5 (CO 3 ) 2.5 , Ca 9 (PO 4 ) 4.5 (CO 3 ) 1.5 , and the like.  
     
     
         28 . The composition of  claim 1 , wherein said powder component comprises a strontium salt including strontium carbonate.  
     
     
         29 . The composition of  claim 1 , wherein said powder component comprises at least one calcium phosphate selected from the group consisting of fluoride, strontium, carbonate, magnesium, zinc, and barium containing calcium phosphates.  
     
     
         30 . The composition of  claim 1 , wherein said powder component comprises at least one inorganic salt including sodium phosphates and disodium glycerophosphate, or the like.  
     
     
         31 . The composition of  claim 1 , wherein said powder component comprises at least one organic salt including oxalate, citrate, malate, gluconate, lactate, lactobionate, or the like.  
     
     
         32 . The composition of  claim 1 , wherein said powder component comprises at least one organic salt including oxalic, citric, malic, gluconic, lactic, lactobionic acids, or the like.  
     
     
         33 . The composition of  claim 1 , wherein said powder component is a powder having a size ranging from 0.1 to 100 micrometers.  
     
     
         34 . The composition of  claim 1 , further comprising a bioactive ingredient such as a drug, a protein, a peptide, a synthetic molecule or an inorganic molecule.  
     
     
         35 . The composition of  claim 1 , which further comprises at least one osteoinductive agent selected from the group consisting of hormones, bone proteins and mixtures of osteoinductive proteins, demineralized bone matrix (DBM) or powder (DBP), bone morphogenic proteins (BMP), sialoproteins, osteonectin, osteopontin, osteocalcin, calcitonin.  
     
     
         36 . The composition of  claim 1 , which further comprises at least one growth factor selected from the group consisting of IGF, EGF, a-FGF, b-FGF, PDGF-A, PDGF-B and TGF-beta.  
     
     
         37 . The composition of  claim 1 , which further comprises an antiresorptive, antibiotic, antiviral, antitumor, or an immunosupressive agent.  
     
     
         38 . Use of the composition of  claim 1  for injection into a defect, cavity or interface of a body's tissue, said composition setting in situ into a hardened filling material.  
     
     
         39 . Use of the composition of  claim 1  for injection into a defect, cavity or interface of a cancellous, cortical or corticocancellous bone, said composition setting in situ into a hardened filling material.  
     
     
         40 . Use of the composition of  claim 1  for injection into the metaphysis or diaphysis of a bone, said composition setting in situ into a filling hardened material.  
     
     
         41 . Use of the composition of  claim 1  for injection into a fractured bone, between the bone fragments of fractured bone, said composition setting in situ into a filling hardened material.  
     
     
         42 . An injectable self-setting composition comprising: 
 a) a liquid component, free of insoluble material, comprising, an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate; said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan having a final concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt having a final concentration ranging between 1.0 to 10.0% w/v, and    b) a powder component comprising a dry mixture of a tricalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound,    wherein when said components of step a) and b) are intimately and uniformly mixed together, said components of step a) and b) form an injectable thermo-setting slurry, said slurry when heated turns into a solid material.    
     
     
         43 . An injectable self-setting composition comprising: 
 a) a liquid component, free of insoluble particle, comprising an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate; said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan has a concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt has a concentration ranging between 1.0 to 10.0% w/v, and    b) a powder component comprising a dry mixture of a tetracalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound,    wherein when said components of step a) and b) are intimately and uniformly mixed together, said components of step a) and b) form an injectable thermo-setting slurry, said slurry once heated setting into a solid material.    
     
     
         44 . A composition as described in  claim 42  or  43 , wherein said inorganic salt is selected from carbonate, phosphate, strontium, fluoride salts, and the like.  
     
     
         45 . A composition as described in  claim 42  or  43 , wherein said organic salt is selected from citrate, malate, lactate, gluconate salts, and the like.  
     
     
         46 . A composition as described in  claim 42  or  43 , wherein said organic acid is selected from citric acid, malic acid, lactic acid, gluconic acid, and the like.  
     
     
         47 . A composition as described in  claim 42  or  43 , wherein said organic compound is selected from the group consisting of biological fluids and components, water-soluble or miscible organic polyols, drugs, amino-acids, proteins, and the like.  
     
     
         48 . A composition as described in  claim 42  or  43 , which further comprises a water-soluble or miscible organic polyol, including sugar-polyol, saccharide-polyol and glycol, selected from the group consisting of glycerol, mannitol, sorbitol, ethylene glycol oligomers, propylene glycol oligomers, saccharose, fructose, glucose, maltose, and the like.  
     
     
         49 . A composition as described in  claim 42  or  43 , which further comprises glucosamine and/or histidine.  
     
     
         50 . A composition as described in  claim 42  or  43 , which further comprises a strontium containing compound.  
     
     
         51 . A composition as described in  claim 42  or  43 , which further comprises a carbonate containing compound.  
     
     
         52 . A composition as described in  claim 42  or  43 , which further comprises a fluoride containing compound.  
     
     
         53 . Use of a composition as described in  claim 42  or  43  for injection into a defect, cavity or substance of a mammalian or human hard-tissue, said composition setting in situ.  
     
     
         54 . Use of a composition as described in  claim 42  or  43 , for injection in association with a permanent or biodegradable fixative device, said composition setting in situ.  
     
     
         55 . A method of preparation of an injectable self-setting composition, said method comprising the step of admixing a water-based liquid component comprising at least one cationic polymer and one monophosphate salt with a powder component comprising at least two calcium phosphate sources selected from apatites and apatitic calcium phosphates, octacalcium phosphates, amorphous calcium phosphates, tetracalcium phosphates, tricalcium phosphates, dicalcium phosphates and monocalcium phosphates, wherein said liquid component comprising at least one cationic polymer and one mono-phosphate salt; said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character and being free of insoluble particles, said admixing thus forming an injectable thermo-setting slurry, said slurry when heated turns into a solid material.  
     
     
         56 . A method of preparation of an injectable self-setting composition, said method comprising admixing a liquid component, free of insoluble material, comprising, an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate, with a powder component comprising a dry mixture of a tricalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound, said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan having a final concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt having a final concentration ranging between 1.0 to 10.0% w/v, said admixing thus forming an injectable thermo-setting slurry, said slurry when heated turns into a solid material.  
     
     
         57 . A method of preparation of an injectable self-setting composition, said method comprising admixing a liquid component, free of insoluble particle, comprising an organic and/or inorganic acid, a partially N-deacetylated chitosan and/or a collagen, and a glycerophosphate with a powder component comprising a dry mixture of a tetracalcium phosphate with a calcium deficient apatite or an octacalcium phosphate, and with at least one of an inorganic salt, an organic salt, an organic acid source and an organic compound, said liquid component having a pH ranging from 6.5 to 7.4, said liquid component having an endothermally gelling character, said partially N-deacetylated chitosan has a concentration ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt has a concentration ranging between 1.0 to 10.0% w/v, said admixing thus forming an injectable thermo-setting slurry, said slurry when heated turns into a solid material.