Mineral-polymer hybrid composition

Abstract

Self-forming hybrid compositions consisting in admixed liquid and solid components enable the formation of bio-materials. The present invention proposes a) a thermo-sensitive self-forming liquid component, being water-based and containing at least a polycationic polymer such as chitosan, and an organic mono-phosphate source, which is a solution at a pH ranging from 6.5 to 7.4; b) a solid component being mineral and composed of at least one of calcium, fluoride, strontium, carbonate and phosphate salts. Solid mineral salts preferentially have a recognized bioactive potential such as the calcium phosphate salts for bones. Both solid and liquid components are admixed to form an injectable liquid slurry or pre-gelled paste that turn in situ into a hybrid uniform gel-like bio-material.

What is claimed is:  
     
         1 . An in situ self-forming mineral-polymer hybrid composition composing: 
 a) a water-based and thermo-gelling liquid component comprising at least one hydrosoluble cationic polymer, one organic mono-phosphate source, and optionally one water-soluble organic mono-sulfonate, mono-sulfate or mono-carboxylate source; said liquid component having a pH between 6,5 and 7.4; and    b) a water non-soluble solid component comprising at least one of calcium, fluoride, strontium, carbonate and phosphate salts, said solid component having a particle size ranging from 5 to 1000 micrometers,    wherein said composition contains 50% weight to volume or less of the solid component and said liquid component and solid component are admixed together intimately to form a non-hardening thermo-gelling hybrid composition; said hybrid composition gelling at the body temperature.    
     
     
         2 . A composition according to  claim 1 , wherein said liquid component is prepared from organic and/or inorganic acids, including malic acid, propionic acid, phosphoric acid, organophosphoric acid, glycerophosphoric acid, lactic acid, hydrochloric acid, ascorbic acid, formic acid, acetic acid, and the like.  
     
     
         3 . A composition according to  claim 1 , wherein said polymer is a cationic hydrophilic polysaccharide bearing amino groups, including partially-deacetylated chitosans, and pure chitosan.  
     
     
         4 . A composition according to  claim 1 , wherein said polymer is a partially-deacetylated chitosan with a degree of deacetylation between 30 and 99%.  
     
     
         5 . A composition according to  claim 1 , wherein said liquid component comprises a second soluble polymer selected among polypeptides, cellulosics and synthetic polymers, including collagen, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose, hydroxymethyl propylcellulose, poly(ethylene oxide), poly(propylene oxide), poly(ethylene glycol), poly(vinyl pyrrolidone) poly(vinyl alcohol), or derivatives thereof, or a mixture thereof.  
     
     
         6 . A composition according to  claim 1 , wherein said organic mono-phosphate, mono-sulfonate, mono-sulfate and mono-carboxylate sources of said liquid component have a basic character and a pKa between 6.0 and 7,4.  
     
     
         7 . A composition according to  claim 1 , wherein said organic mono-phosphate source is 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 , 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 1 , K 2 PO 7 C 4 H 8 , Na 2 PO 6 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 9 C 6 H 11 , 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 CrH 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 , and KPO 6 C 10 H 12  and the like, and derivatives, or mixtures thereof.  
     
     
         8 . A composition according to  claim 1 , wherein said organic mono phosphate source is alpha-glycerophosphate, beta-glycerophosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate salt, or a mixture thereof.  
     
     
         9 . A composition according to  claim 1 , wherein said organic mono-sulfonate source is N-[carbamoylmethyl]-2-aminoethanesulfonate (ACES), N,N-bis[2-hydroxyethyl]-2-aminoethane-sulfonate (BES), 3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxypropane-sulfonate (DIPSO), N-[2-hydroxyethyl]piperazine-N′-3-propanesulfonate (HEPES), 2-[N-morpholino]ethane-sulfonate (MES), 4-[N-morpholino]-butanesulfonate (MOBS), 3-[N-morpholino]-2-hydroxypropanesulfonate (MOPSO), or N-tris[hydroxymethyl]methyl-2-aminoethanesulfonate (TES) or the like, or a mixture thereof.  
     
     
         10 . A composition according to  claim 1 , wherein said liquid component further comprises bis[2-hydroxyethyl]iminotris [hydroxymethyl]methane (BIS-TRIS) or Tris[hydroxymethyl]aminomethane (TRIZMA), or the like, or a mixture thereof.  
     
     
         11 . A composition according to  claim 1 , wherein said liquid component further comprises amino-acid residues or sequences, including histidine (HIS) or lysine (LYS) residues or sequences.  
     
     
         12 . A composition according to  claim 1 , wherein said liquid component comprises organic polyol ingredient including sugar-polyols, saccharide-polyols and glycols, such as glycerol, mannitol, sorbitol, ethylene glycol oligomers, propylene glycol oligomers, fructose, glucose, maltose, and the like.  
     
     
         13 . A composition according to  claim 1 , wherein, said liquid component comprises water-soluble phosphate or carbonate salts, or a mixture thereof.  
     
     
         14 . A composition according to  claim 1 , wherein said liquid component has an intrinsic viscosity ranging between 5 and 100,000 mPa.s at 21° C.  
     
     
         15 . A composition according to  claim 1 , wherein said liquid component forms a homogeneous solid aqueous gel-like material at a temperature between 25 and 60° C.  
     
     
         16 . A composition according to  claim 1 , wherein said solid component comprises calcium phosphate, calcium sulfate, calcium carbonate, calcium titanate, calcium acetate, calcium glycerophosphate, calcium gluconate, calcium propionate compounds, or the like, or a mixture thereof.  
     
     
         17 . A composition according to  claim 1 , wherein said solid component comprises at least one calcium phosphate selected from the group consisting of Ca(H 2 PO 4 ) 2 .H 2 O, CaHPO 4 .2H 2 O, CaHPO 4 , CaZn 3 (PO 4 ) 2 , CaZnPO 4 , CaNaPO 4 , Ca 2 PO 4 Cl, alpha-Ca 3 (PO 4 ) 2 , beta-Ca 3 (PO 4 ) 2 , Ca 3 (PO 4 ) 2 .H 2 O, Ca 4 (PO 4 ) 2 O, Ca 8 H 2 (PO 4 ) 6 .5H 2 0, Ca 9 (HPO 4 )(PO 4 ) 5 OH, Ca 10 (PO 4 ) 6 (OH) 2-2x O x , and Ca 10 (PO 4 ) 6 (OH) 2 , and derivatives thereof.  
     
     
         18 . A composition according to  claim 1 , wherein said solid component comprises hydroxyapatite and tricalcium phosphate.  
     
     
         19 . A composition according to  claim 1 , wherein said solid component comprises hydroxyapatite and alpha- or beta-tricalcium phosphate, or any combination thereof.  
     
     
         20 . A composition according to  claim 1 , wherein said solid component comprises from 5 to 95% wt. of hydroxyapatite and 90 to 5% wt. of alpha- or beta-tricalcium phosphate.  
     
     
         21 . A composition according to  claim 1 , wherein said solid component comprises from 45-65% wt. of hydroxyapapite and 36-55% wt. of alpha- or beta-tricalcium phosphate.  
     
     
         22 . A composition according to  claim 1 , wherein said solid component comprises natural mineral components including hard-tissue, enamel or dental apatite, coral or nacre.  
     
     
         23 . A composition according to  claim 1 , wherein said solid component comprises additionally a carbonate compound selected from 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 (PN 4 ) 4.5 (CO 3 ) 2.5 , Ca 9 (PO 4 ) 4.5 (CO 3 ) 1.5  and the like.  
     
     
         24 . A composition according to  claim 1 , wherein said solid component comprises additionally a carbonated calcium phosphate.  
     
     
         25 . A composition according to  claim 1 , wherein said solid component comprises additionally a fluoride compound selected from NaF, Na 2 Si 6 F, KF, KSi 6 BF, CaF 2 , MgF 2 , ZnF 2 , sodium fluorophosphates, and the like.  
     
     
         26 . A composition according to  claim 1 , wherein said solid component comprises additionally a fluorinated calcium phosphate.  
     
     
         27 . A composition according to  claim 1 , wherein said solid component comprises additionally a strontium compound.  
     
     
         28 . A composition according to  claim 1 , wherein said solid component comproses additionally a strontium containing calcium phosphate.  
     
     
         29 . A composition according to  claim 1 , wherein said solid component comprises natural or synthetic solid components including mineral or ceramic materials, bioglasses, polymeric or biopolymeric materials, and the like.  
     
     
         30 . A composition according to  claim 1 , wherein said solid component and said liquid component have a solid/liquid weight ratio between 0.05 and 2.0 g/mL.  
     
     
         31 . A composition according to  claim 1 , wherein said hybrid composition or liquid component or solid component is- admixed with autologous materials selected from a group comprising cortical or cortico-cancellous bone, whole blood and blood components, bone marrow, cells isolated from tissues, stroma cells, or hematopoietic cells.  
     
     
         32 . A composition according to  claim 1 , which further comprises osteoinductive agents selected from the group consisting of growth factors, hormones, individual osteoinductive proteins and mixtures of osteoinductive proteins.  
     
     
         33 . A composition according to  claim 1 , which further comprises bone derived materials including demineralized bone matrix (DBM) or powder (DBP).  
     
     
         34 . A composition according to  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.  
     
     
         35 . A composition according to  claim 1 , which further comprises at least one bone morphogenic proteins (BMP), sialoproteins, osteonectin, osteopontin, osteocalcin, calcitonin, or a mixture thereof.  
     
     
         36 . A composition according to  claim 1 , which further comprises anti-resorptive, antibiotic, antiviral, antitumor, and/or immunosupressive agent.  
     
     
         37 . Use of a composition according to any one of  claims 1  to  36 , as a gelling composition to correct a defect, cavity or interface of a tissue, or in a body cavity, and turned in situ into a gel-like filling material.  
     
     
         38 . Use of a composition according to any one of  claims 1  to  36 , as a gel-like material to fulfill a defect, cavity or interface of a tissue, or in a body cavity.  
     
     
         39 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered and is completely self-formed in a defect, cavity or interface of one or more bones.  
     
     
         40 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered and completely self-formed in a defect, cavity or interface of a cortical, corticocancellous or cancellous part of a bone.  
     
     
         41 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered and completely self-formed in a defect, cavity or interface between tissue parts or fragments of a fractured bone.  
     
     
         42 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered and completely self-formed in a defect, cavity or interface at the metaphyseal or diaphyseal region of a bone.  
     
     
         43 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered and is completely self-formed in a defect, cavity or interface of a hyaline cartilage tissue.  
     
     
         44 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered and completely self-formed in a defect, cavity or interface of a fibro-cartilage tissue.  
     
     
         45 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is injected or extruded percutaneously or endoscopically into a defect, cavity or interface of a tissue or a body cavity through a cannula, catheter, trocar or needle.  
     
     
         46 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is applied and gelled during the course of an open surgical operation.  
     
     
         47 . Use of a composition according to any one of  claims 1  to  36 , wherein said hybrid composition is administered during the course of a repairing, reconstructing or replacing treatment in dental, plastic, cranio-maxillofacial or orthopaedic surgery.  
     
     
         48 . An in situ self-forming mineral-polymer hybrid composition comprising: 
 a) a liquid component, comprising at least 0.5% w/v of a chitosan, 2.0% w/v of a glycerophosphate; said liquid component having a pH between 6.5 and 7.4; and    b) a solid component comprising at least one apatite and one tricalcium phosphate, said solid component having a particle size ranging from 5 to 1000 micrometers,    wherein said composition contains 50% weight to volume or less of the solid component and said liquid component and solid component are admixed together intimately to form a non-hardening thermo-gelling hybrid composition; said hybrid composition gelling at the body temperature.    
     
     
         49 . A composition according to  claim 48 , wherein said liquid component additionnally comprises 0 to 10% w/v of at least one of glycerol, sorbitol, mannitol, ethylene glycol oligomers or polymers, and propylene glycol oligomers or polymers.  
     
     
         50 . A composition according to  claim 48 , wherein said liquid component is admixed with autologous blood, blood component or bone marrow, said autologous blood, blood component or bone marrow being at a concentration ranging from 0 to 25% w/v.  
     
     
         51 . A composition according to  claim 48 , wherein said solid component is a dry mixture of at least hydroxyapatite and beta-tricalcium phosphate.  
     
     
         52 . A composition according to  claim 48 , wherein said solid component additionnally comprises at least a strontium containing calcium phosphate.  
     
     
         53 . A composition according to  claim 48 , wherein said solid component additionnally comprises 0 to 25% w/v of dry crunched autologous spongy bone.  
     
     
         54 . A composition according to  claim 48 , wherein said solid component additionnally comprises 0 to 55% w/v of dry demineralized bone material.  
     
     
         55 . A method of preparation of an in situ self-forming mineral-polymer hybrid composition as described in any one of  claims 1  to  36  and  48  to  54 , comprising the step of: 
 a) preparing a first water-based liquid sub-component comprising at least one hydrosoluble cationic polymer, and preferably at least 0.5% w/v of a chitosan, said first sub-component being stable and stored below 10° C.;  
 b) preparing a second water-based liquid sub-component comprising at least one organic mono-phosphate source, and optionally one water-soluble organic mono-sulfonate, mono sulfate or mono-carboxylate source;  
 c) preparing a solid component comprising at least one of calcium, fluoride, strontium, carbonate and phosphate salts, such as apatite and one tricalcium phosphate;  
 d) admixing homogeneously said second liquid sub-component with said solid component into a stable water-based dispersion, said dispersion being stable and stored at room temperature or below; and  
 e) admixing said first liquid component and said stable dispersion together intimately to form a non-hardening thermo-gelling hybrid composition,  
 said hybrid composition having a pH between 6.5 and 7.4, being injectable, gelling at the body temperature and being applicable to any defect, cavity or anatomical structure of body's tissues.