Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
  • A61L27/04—Metals or alloys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/28—Bones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/42—Phosphorus; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/001—Use of materials characterised by their function or physical properties
  • A61L24/0015—Medicaments; Biocides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
  • A61L27/12—Phosphorus-containing materials, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
  • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses

Definitions

• the present invention is related to an anti-bacterial preparation for treating bone. More specifically, the present invention is related to an antibacterial preparation for treating bone which is a lithium-containing calcium- based material .
• infections then, lies in killing bacteria that come near the device before they form an attachment.
• the proposed antibacterial implants include polymeric systems ( Alt et al, Biomaterials Volume 25, Issue 18, August 2004, Pages 4383-4391; Shi et al., Biomaterials Volume 27, Issue 11 , April 2006, Pages 2440-2449; Marks et al., The Journal of Bone and Joint Surgery. American Volume 1976, 58(3): 358-64), metallic systems (Visai et al., Int J Artif Organs.2011 Sep; 34(9): 929-46;
• a primary objective of the present invention is to provide anti-bacterial preparation for treating a bone.
• the present invention is also aimed to provide a process for preparing the anti-bacterial preparation, and a method of using the anti-bacterial preparation in treating a bone.
• the anti-bacterial preparation provided according to the present invention comprises a solid component comprising a lithium compound and a calcium compound, wherein the anti-bacterial preparation shows an improved antibacterial ability in comparison with a preparation containing the calcium compound but free of the lithium compound .
• a Hanks' solution with the anti-bacterial preparation of the present invention immersed therein with a ratio of solution : anti-bacterial preparation 1 0 cc/g exhibits a pH value of not less 1 0.
• the anti-bacterial preparation contains about 5-80%, more preferably about 10-70% of the lithium compound, based on the weight of the solid component.
• the lithium compound is a lithium salt, lithium oxide, lithium amide (L1N H2), lithium hydroxide or lithium halide; and more preferably lithium carbonate, lithium sulfate, lithium phosphate, lithium oxide, lithium fluoride, lithium acetate, lithium bromide, lithium hydroxide, lithium nitrate, lithium nitrite, lithium iodide, lithium molybdate (U2M0O4), lithium tetraborate (Li2B 4 O7), lithium citrate tetrahydrate (L13C6H5O7.4H2O), or l ithium stearate (UC18H35O2); and most preferably lithium carbonate, or lithium phosphate.
• Li2B 4 O7 lithium citrate tetrahydrate
• U13C6H5O7.4H2O lithium citrate tetrahydrate
• U18H35O2 l ithium stearate
• the solid component is a powder component comprising the lithium compound and the calcium compound, wherein the calcium compound is selected from the group consisting of a calcium phosphate, calcium sulfate, calcium oxide, calcium carbonate, calcium hydroxide, calcium magnesium phosphate, calcium nitrate, calcium citrate, calcium chloride and a mixture thereof; and more preferably the calcium compound is a calcium sulfate, a calcium phosphate source, or a mixture thereof.
• the calcium phosphate is tetracalcium phosphate (TTCP), dicalcium phosphate, tricalcium phosphate, monocalcium phosphate or a mixture thereof.
• the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dehydrate (CSD), anhydrous calcium sulfate, or a mixture thereof.
• the anti-bacterial preparation further comprises a setting liquid component with a liquid to powder ratio of 0.20 ml/g to 0.80 ml/g, when the solid component is the powder component.
• the present invention also provides a method for treating a subject comprising forming a bone cement paste by mixing the powder component and the setting liquid component of the anti-bacterial preparation of the present invention; and filling a hole or cavity in a bone with said bone cement paste wh ich sets hard in the hole or cavity in need of said treatment.
• the solid component is a block, or granules or pieces obtained by breaking up said block.
• the block comprises the lithium compound and the calcium compound, wherein the calcium compound is selected from the group consisting of calcium phosphate, calcium sulfate, calcium oxide, calcium carbonate, calcium hydroxide, calcium magnesium phosphate, hydroxyapitite, or a mixture thereof, and preferably is selected from the group consisting of tetracalcium phosphate, dicalcium phosphate, hydroxyapitite, calcium sulfate dihydrate, calcium sulfate hemihydrate, or a mixture thereof.
• the present invention also provides a method for treating a subject comprising implanting said block, said granules or said pieces of the antibacterial preparation of the present invention in said subject in need of said treatment.
• the anti-bacterial preparation further comprises a lithium retarding agent which slows down the lithium compound releasing from said anti-bacterial preparation .
• the lithium retarding agent is poly(acrylic acid).
• the inventive antibacterial agent (lithium compound) is not an antibiotic and thus is free from all kinds of antibiotic-related side effects.
• the inventive antibacterial lithium compound can gradually dissolve from an implant after it is implanted, keeping bacteria from approaching the implant. Furthermore, the dissolution rate of the antibacterial lithium compound can be adjusted to avoid its concentration being too high, causing negative response of the surrounding tissues, or being too low, causing insufficient antibacterial effect.
• the effective antibacterial duration can be adjusted to avoid being too long or too short. Unlike those implant devices incorporating permanent antibacterial agents such as metallic antibacterial agents, the duration of the present inventive antibacterial preparation can be so designed that, at the end of the desired antibacterial duration (the majority of antibacterial agent has been released), the biocompatibility of the implant will readily increase to a normal, acceptable level .
• Figure 1 shows antibacterial zones of TTCP/DCPA/CSH/Li samples prepared according to the present invention and TTCP/DCPA/CSH/alkal ine metal salt samples.
• Figures 2 to 5 show antibacterial zones of TTCP/DCPA/CSH/Li/PAA blocks prepared according to the present invention immersed in Hanks' solution for one, two, three and five days, respectively.
• Figure 6 shows antibacterial zones of CaCO3 Ca2P2O7 Li blocks prepared according to the present invention without immersion .
• Preferred embodiments of the present invention include but not limited to the following items: 1.
• An anti-bacterial formula for treating a bony site comprising a calcium (Ca) source and a lithium (Li) source.
• the anti-bacterial formula of Item 1 contains about 5-80%, more preferably about 1 0-70% of the lithium source, based on the weight of the calcium source and the lithium source.
• the lithium source in Item 1 is selected from the group consisting of lithium carbonate, lithium sulfate, lithium phosphate, lithium oxide, lithium fluoride, lithium acetate, lithium bromide, lithium hydroxide, lithium nitrate, lithium nitrite, lith ium iodide, lithium molybdate (U2M0O4), lithium amide (L1N H2), lithium tetraborate (Li2B 4 O7), l ithium citrate tetrahydrate (U3C6H5O7.4H2O), lithium stearate (UC18H35O2).
• the lithium source in Item 2 is lithium carbonate and/or lithium phosphate.
• the calcium source in Item 1 is calcium phosphate, calcium sulfate, calcium oxide, calcium carbonate, calcium hydroxide, calcium magnesium phosphate, calcium nitrate, calcium citrate, calcium chloride, or a m ixture thereof.
• the calcium phosphate in Item 5 is tetracalcium phosphate (TTCP), dicalcium phosphate, tricalcium phosphate (TCP), hydroxyapatite (HA), or a mixture thereof.
• TTCP tetracalcium phosphate
• TCP tricalcium phosphate
• HA hydroxyapatite
• the dicalcium phosphate in Item 6 is dicalcium phosphate anhdydrous
• the calcium sulfate in Item 5 is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD), anhydrous calcium sulfate, or a mixture thereof.
• the calcium source in Item 5 comprises calcium phosphate and calcium
• the calcium phosphate in Item 9 comprises tetracalcium phosphate (TTCP).
• the calcium phosphate in Item 1 0 further comprises dicalcium phosphate.
• the dicalcium phosphate in Item 1 1 is dicalcium phosphate anhdydrous
• the calcium sulfate in Item 9 comprises calcium sulfate hemihydrate (CSH). 14.
• the anti-bacterial formula in Item 1 further comprises a lithium retarding
• the lithium retarding agent in Item 14 is poly(acrylic acid) (PAA).
• the anti-bacterial formula in Item 15 comprises, based on the total weight of the anti-bacterial preparation, 0.01-5% of poly(acrylic acid) having a
• n 50 - 50000, preferably 1000-5000, and more preferably 1500-2500.
• the anti-bacterial formula in Item 1 further comprises a pore-forming agent, thereby pores form in vivo after dissolution of said pore-forming agent.
• the pore-forming agent in Item 17 is selected from the group consisting of LiCI, KCI, NaCI, MgC , CaC , NalOs, Kl, NasPO4, K3PO4, Na2COs, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC4H4O6), potassium carbonate, potassium gluconate (KC6H11O7), potassium-sodium tartrate (KNaC4H 4 O6-4H2O), potassium sulfate (K2SO4), sodium sulfate, sodium lactate and mannitol.
• LiCI LiCI, KCI, NaCI, MgC , CaC , NalOs, Kl, NasPO4, K3PO4, Na2COs
• amino acid-sodium salt amino acid-potassium salt
• glucose polysaccharide
• fatty acid-sodium salt
• the pore-forming agent in Item 18 is about 10-80% in volume, preferably
• the anti-bacterial formula in Item 1 is in powder form, cement form, dense block (pre-molded) form, dense granule form, porous block (pre-molded) form, porous granule form, or a mixture thereof.
• the anti-bacterial formula in cement form in Item 20 further comprises a setting liquid agent, thereby mixing said calcium source, said lithium source, and said setting liquid agent, a cement paste can be formed.
• the setting liquid agent in Item 21 comprises ammonium ion (NH4 + ) in a concentration of about 0.01 M to about 2 M.
• the setting liquid agent in Item 22 is a solution of NH4H2PO4, (NH4)2HPO4, (NH4)3PO4-3H2O, (NH4)3PO4, or a mixture thereof.
• the setting liquid agent in Item 23 is a solution of (NH4)2HPO4.
• the liquid-to-powder ratio in Item 24 is about 0.1 cc/g to about 1.0 cc/g, preferably about 0.2 cc/g to about 0.8 cc/g. 26.
• the anti-bacterial formula in dense block (pre-molded) form in Item 20 is prepared by a method comprising preparing a cement paste by mixing a cement powder and a setting liquid agent in Item 21; shaping the paste in a mold; and removing the mold to form a dense block.
• the method in Item 26 further comprises pressurizing said paste in said mold before said paste becomes set to remove a portion of liquid from said paste, so that a liquid-to-powder ratio of said paste decreases, wherein the pressure applied to the paste in the mold is from about 1 MPa to 500 MPa, preferably from 100 MPa to 500 MPa.
• the method in Item 26 further comprises impregnating the dense block with an impregnating liquid for a period of time, so that a compressive strength of the resulting impregnated block removed from the impregnating liquid is increased compared to that of said block without said impregnating treatment.
• the impregnating liquid in Item 28 is a phosphate-containing solution having a phosphate concentration from about 0.1 M to about 3M.
• the anti-bacterial formula in dense granule form in Item 20 is prepared by a method comprising preparing a cement paste by mixing a cement powder and a setting liquid agent in Item 21; shaping the paste in a mold; removing the mold to form a dense block; and crushing said dense block into dense granules.
• the method in Item 30 further comprises pressurizing said paste in said mold before said paste becomes set to remove a portion of liquid from said paste, so that a liquid-to-powder ratio of said paste decreases, wherein the pressure applied to the paste in the mold is from about 1 MPa to 500 MPa, preferably from 100 MPa to 500 MPa.
• the method in Item 30 further comprises impregnating the dense granules with an impregnating liquid for a period of time, so that a compressive strength of the resulting impregnated dense granules removed from the impregnating liquid is increased compared to that of said granules without said impregnating treatment.
• the impregnating liquid in Item 32 is a phosphate-containing solution having a phosphate concentration from about 0.1 M to about 3M.
• the anti-bacterial formula in porous block form in Item 20 is prepared by a method comprising preparing a cement paste by mixing a cement powder and a setting liquid agent in Item (21), wherein a pore-forming agent is added into the cement; shaping the paste in a mold; removing the mold to form a block article; and immersing said block article in an immersing liquid to dissolve at least a portion of said pore-forming agent in the immersing liquid, creating pores therein, so that a porous block is formed, and preferably the porous block has a porosity of 50-90 vol%.
• the method in Item 34 further comprises pressurizing said paste in said mold before said paste becomes set to remove a portion of liquid from said paste, so that a liquid-to-powder ratio of said paste decreases, wherein the pressure applied to the paste in the mold is from about 1 MPa to 500 MPa, preferably from 100 MPa to 500 MPa.
• the method in Item 34 further comprises impregnating the porous block with an impregnating liquid for a period of time, so that a compressive strength of the resulting impregnated porous block removed from the impregnating liquid is increased compared to that of said porous block without said impregnating treatment.
• the impregnating liquid in Item 36 is a phosphate-containing solution having a phosphate concentration from about 0.1 M to about 3M.
• the anti-bacterial formula in porous granule form in Item 20 is prepared by a method comprising preparing a cement paste by mixing a cement powder and a setting liquid agent in Item 21, wherein a pore-forming agent is added into the cement; shaping the paste in a mold; removing the mold to form a block article; immersing said block article in an immersing liquid to dissolve at least a portion of said pore-forming agent in the immersing liquid, creating pores therein, so that a porous block is formed, and preferably the porous block has a porosity of 50-90 vol%; and crushing said porous block into porous granules. 39.
• the anti-bacterial formula in porous granule form in Item 20 is prepared by a method comprising preparing a cement paste by mixing a cement powder and a setting liquid agent in Item 21, wherein a pore-forming agent is added into the cement; shaping the paste in a mold; removing the mold to form a dense block article; crushing said dense block article into dense granules; and immersing said dense granules in an immersing liquid to dissolve at least a portion of said pore-forming agent in the immersing liquid, creating pores therein, so that porous granules are formed, and preferably the porous granules have a porosity of 50-90 vol%.
• the methods in Items 38 or 39 further comprise pressurizing said paste in said mold before said paste becomes set to remove a portion of liquid from said paste, so that a liquid-to-powder ratio of said paste decreases, wherein the pressure applied to the paste in the mold is from about 1 MPa to 500 MPa, preferably from 100 MPa to 500 MPa.
• the methods in Item 38 or 39 further comprise impregnating the porous block with an impregnating liquid for a period of time, so that a compressive strength of the resulting impregnated porous granules removed from the impregnating liquid is increased compared to that of said porous granules without said impregnating treatment.
• the impregnating liquid in Item 41 is a phosphate-containing solution having a phosphate concentration from about 0.1 M to about 3M.
• the pore-forming agent in Items 34 or 38 is selected from the group
• K6H11O7 potassium-sodium tartrate
• KNaC4H 4 O6-4H2O potassium sulfate
• K2SO4 sodium sulfate
• sodium lactate sodium lactate and mannitol.
• the anti-bacterial formula in Item 1 further comprises a growth factor, a BMP, living cells, or a drug.
• the bony site in Item 1 is an orthopedic site or a dental site.
• the orthopedic site or dental site in Item 45 is a fractured site, a diseased site, or an infected site.
• the diseased site in Item 46 is a gum-diseased site.
• TTCP tetracalcium phosphate
• DCPA dicalcium phosphate anhydrous
• PAA poly(acrylic acid)
• the TTCP powder was fabricated in-house from the reaction of dicalcium pyrophosphate (Ca2P2O7) (Alfa, USA) and calcium carbonate (CaCO3)
• TTCP powder was prepared by mixing Ca2P2Oz powder with CaCO3 powder uniformly for 1 2 hours.
• the mixing ratio of Ca2P2Oz powder to CaCO3 powder was 1 : 1 .27 (weight ratio) and the powder mixture was heated to 1400°C to allow two powders to react to form TTCP.
• TTCP and DCPA powders were uniformly mixed in a ball miller in a molar ratio of 1 : 1 to obtain a TTCP/DCPA mixed powder.
• TTCP and CSH powders were uniformly mixed in a ball miller to obtain a TTCP/CSH mixed powder.
• TTCP/DCPA mixed powder in a molar ratio of 1 :1
• CSH powder uniformly mixed in a ball miller to obtain a TTCP/DCPA/CSH mixed powder.
• Li compound(s) for example, lithium carbonate, lithium phosphate, lithium sulfate, or lithium oxide
• TTCP, TTCP/DCPA, TTCP/CSH or TTCP/DCPA/CSH were uniformly mixed in a ball miller to obtain a TTCP/Li compound, TTCP/DCPA/Li compound, TTCP/CSH/Li compound or TTCP/DCPA/CSH/Li compound mixed powder.
• PAA poly(acrylic acid)
• a series of TTCP/Li compound, TTCP/DCPA/Li compound, TTCP/CSH/Li compound and TTCP/DCPA/CSH/Li compound cement pastes with and without PAA were respectively prepared by mixing appropriate amounts of each mixed powders and ( ⁇ ⁇ 4 setting solutions with and without PAA addition at appropriate L/P ratios.
• the working time of cement paste was determined by the time after that the cement paste was no longer workable.
• the setting time of cement paste was measured according to the standard method set forth in ISO 1 566 for dental zinc phosphate cements. The cement is considered set when a 400 gm weight loaded onto a Vicat needle with a 1 mm diameter tip fails to make a perceptible circular indentation on the surface of the cement.
• TTCP/Li compound Preparation of TTCP/Li compound, TTCP/DCPA/Li compound, TTCP/CSH/Li compound and TTCP/DCPA/CSH/Li compound blocks and granules with and without PAA
• TTCP/Li compound, TTCP/DCPA/Li compound, TTCP/CSH/Li compound or TTCP/DCPA/CSH/Li compound mixed powder were mixed with (NH 4 )2HPO4 setting solution with or without PAA with a desirable L/P ratio to form a cement paste.
• the paste Prior to being fully hardened, the paste was placed in a mold under a desirable pressure (e.g ., 450 Kgf or 1 56 MPa) to squeeze a portion of the liquid out of the paste.
• a desirable pressure e.g ., 450 Kgf or 1 56 MPa
• some block samples were further impregnated in an impregnation solution (for example, 1 -3 M (NH 4 ) 2 HPO4 or K2HPO4) at a desirable temperature (for example, 0-50°C) for a desirable period of time (for example, 1 day) to increase strength, followed by drying in an oven (for example, at 50°C for 1 day).
• the block was crushed into granules with a desirable particle size distribution range.
• the mold can be tailor-made to produce a block with a desirable shape and geometry.
• the cytotoxicity test was performed according to ISO 1 0993-5.
• the extraction method was used .
• N IH/3T3 fibroblasts seeding density 5000 per well
• DMEM Dulbecco's modified essential medium
• bovine serum (1 0%)
• PSF PSF
• An extract was prepared by immersing a hardened cement paste in the culture medium at a ratio of 0.1 (g/ml) at 37°C for 24h and then collecting the liquid by centrifugation .
• the extract was added to the 96 well microplate (1 00 ⁇ per well) incubated in a 5% CO2 humidified atmosphere at 37°C.
• the extract was sucked out and then a mixture of the culture medium (1 00 ⁇ ) and WST-1 (1 0 ⁇ ) was added to the wells and incubated for 1 h at 37°C.
• Cell viability was measured by using the WST-1 assay. This is a colorimetric assay of mitochondrial dehydrogenase activity where the absorbance at 450 nm is proportional to the amount of dehydrogenase activity in the cell.
• TSA Tryptic Soy Agar
• SA staphylococcus aureus
• PBS phosphate buffered saline
• Antibacterial tests were conducted on a series of commercially pure lithium compounds, including L12SO4, L13PO4, U2CO3, U2O, and LiF.
• Samples were either dry-molded under a pressure of 450 kgf into a 3 mm high, 6 mm dia. cylinder without being mixed with a setting solution, or wet- molded under 1.4 MPa into a 3 mm high, 6 mm dia. cylinder with being mixed with a 0.6 M ( ⁇ ⁇ 4 setting solution at L/P ratios 0.2-0.6 (0.20 for L12SO4, 0.25 for L13PO4, 0.60 for U2CO3) Results:
• the TTCP/L12CO3 powder was mixed with 0.6M (NH4)2HPO4 setting solution containing 3, 5, or 10 vol% PAA solution at L/P ratio of 0.45 cc/g to obtain a TTCP/Li/PAA cement paste.
• the TTCP/Li/PAA block samples were prepared from pressure-molding the TTCP/Li/PAA cement paste under a pressure of 450 kgf. Table 3. Average diameters (mm) of antibacterial zones of TTCP/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• Sample with setting solution containing 3 vol% PAA shows an antibacterial zone of 1 1 .4 mm after being immersed in Hanks' solution for 1 d; 1 0.3 mm for 2d; 8.5 mm for 3d .
• Sample with setting solution containing 5 vol% PAA shows an antibacterial zone 1 1 .5 mm after being immersed in Hanks' solution for 1 d; 1 1 .4 mm for 2d; 1 1 .2 mm for 3d .
• Sample with setting solution containing 1 0 vol% PAA shows an anti-bacterial zone 1 2.6 mm after being immersed in Hanks' solution for 1 d; 1 2.5 mm for 2d; 1 1 .7 mm for 3d; 6.7 mm for 5d .
• Table 4 Average pH values of Hanks' solutions wherein TTCP/Li/PAA blocks were immersed for different periods of time (days).
• a highly porous structure is developed in the implant material that can increase the bioresorption rate of the implant.
• the TTCP/DCPA/Li compound powder was mixed with 0.6 M (NH 4 )2H PO4 setting solution with L/P ratio of 0.35 to obtain a TTCP/DCPA/Li cement paste.
• the 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 1 .4 MPa.
• Sample containing 90 wt% TTCP/DCPA and 1 0 wt% L12O shows an antibacterial zone of 22 mm .
• TTCP/DCPA/Li/PAA blocks were prepared by mixing appropriate amounts of TTCP/DCPA powders (1 : 1 in molar ratio) and U2CO3 powder
• TTCP/DCPA/Li/PAA cement paste The 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf.
• Table 8 Average diameters (mm) of antibacterial zones of TTCP/DCPA/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• Sample with setting solution containing 5 vol% PAA shows an antibacterial zone 1 2.7 mm after being immersed in Hanks' solution for 1 d; 1 0.6 mm for 2d; 1 0.9 mm for 3d; 7.3 mm for 5d .
• Sample with setting solution containing 1 0vol% PAA shows an anti-bacterial zone 1 1 .9 mm after being immersed in Hanks' solution for 1 d; 1 1 .5 mm for 2d; 1 0.6 mm for 3d; 8.8 mm for 5d; 6.9 mm for 7d .
• Table 9 Average pH values of Hanks' solutions wherein TTCP/DCPA/Li/PAA blocks were immersed for different periods of time (days).
• Table 1 Average weight loss percentages (%) of TTCP/DCPA/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• TTCP/DCPA/Li/KCI block samples Antibacterial tests were conducted on TTCP/DCPA/Li/KCI block samples.
• the mixed powder was mixed with 0.6M ( ⁇ ⁇ 4 setting solution at L/P ratio of 0.50 cc/g to obtain a TTCP/DCPA/Li/KCI cement paste.
• the 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf.
• TTCP/CSH/Li/PAA blocks were prepared by mixing appropriate amounts of TTCP/CSH powder (65 : 35 by weight) and L12CO3 powder
• TTCP/CSH : L12CO3 1 : 1 by weight
• the TTCP/CSH/Li powder was mixed with 0.6 M ( ⁇ ⁇ 4 setting solution containing 3, 5, or 1 0 vol% PAA solution with L/P ratio of 0.35 to obtain a
• TTCP/CSH/Li/PAA cement paste The 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf.
• Table 1 Average diameters (mm) of antibacterial zones of TTCP/CSH/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• the measured antibacterial zones include 6 mm dia. sample
• Sample with setting solution containing 1 0 vol% PAA shows an anti-bacterial zone 1 3.0 mm after being immersed in Hanks' solution for 1 d; 1 0.0 mm for 2d; 1 1 .0 mm for 3d .
• Table 1 3. Average pH values of Hanks' solution wherein TTCP/CSH/Li/PAA blocks were immersed for different periods of time (days).
• Table 14 Average weight loss percentages (%) of TTCP/CSH/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• TTCP/DCPA/CSH/Li block samples were prepared by mixing appropriate amounts of TTCP/DCPA/CSH powder and L12CO3 powder
• TTCP/DCPA/CSH : L12CO3 1 : 1 by weight
• the mixed powder containing 65 wt% TTCP/DCPA powder and 35 wt% CSH powder is designated "TTCP/DCPA/CSH sample 65/35" or simply "65/35"; the mixed powder
• the "65/357alkaline metal salt mixed powder was mixed with 0.6 M ( ⁇ ⁇ 4 setting solution with L/P ratio of 0.35 g/cc to obtain a TTCP/DCPA/CSH/alkaline metal salt cement paste.
• the 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf.
• FIG. 1 shows the results of the antibacterial tests for the
• TTCP/DCPA/CSH/Li samples TTCP/DCPA/CSH/alkaline metal salt samples.
• the "55/457Li2CO3 powder was mixed with 0.6 M (NH4)2HPO4 setting solution with L/P ratio of 0.35 g/cc to obtain a TTCP/DCPA/CSH/Li salt cement paste.
• the 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 1 .4 MPa.
• TTCP/DCPA/CSH/Li salt cement paste The 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf. The TTCP/DCPA/CSH/Li salt block samples were subsequently heated to 400°C for 1 h or 2h .
• TTCP/DCPA/CSH/Li/PAA block samples Immersion, pH measurement, weight loss, cytotoxicity and antibacterial tests were conducted on a variety of TTCP/DCPA/CSH/Li/PAA block samples.
• the TTCP/DCPA/CSH/Li/PAA blocks were prepared by mixing appropriate amounts of TTCP/DCPA/CSH powder and L12CO3 powder with a desired TTCP/DCPA/CSH powder and L12CO3 powder with a desired
• the mixed powder containing 65 wt% TTCP/DCPA powder and 35 wt% CSH powder is designated "TTCP/DCPA/CSH sample 65/35" or simply "65/35";
• the mixed powder containing 45 wt% TTCP/DCPA powder and 55 wt% CSH powder is designated "TTCP/DCPA/CSH sample 45/55" or simply "45/55"; and so forth .
• TTCP/DCPA:CSH 65:35 by weight
• U2CO3 powder TTCP/DCPA/CSH/Li mixed powder
• the resulting TTCP/DCPA/CSH/Li powder was mixed with 0.6 M (NH 4 )2H PO4 setting solution containing 3 vol% PAA solution with L/P ratio of 0.35 cc/g to obtain a TTCP/DCPA/CSH/Li/PAA cement paste.
• the 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf. Results :
• TTCP/DCPA/CSH/Li/PAA blocks were prepared by mixing
• the resulting TTCP/DCPA/CSH/Li powder was mixed with 0.6 M ( ⁇ ⁇ 4 setting solution containing 3, 5, or 1 0 vol% PAA solution with L/P ratio of 0.35 to obtain a TTCP/DCPA/CSH/Li/PAA cement paste.
• the 3 mm high, 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf.
• Figs. 2 to 5 show the TTCP/DCPA/CSH/Li/PAA blocks prepared above immersed in Hanks' solution for one, two, three and five days, respectively.
• TTCP/DCPA/CSH/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• the measured antibacterial zones include 6 mm dia. sample
• Sample with setting solution containing 5 vol% PAA shows an antibacterial zone 1 0.7 mm after being immersed in Hanks' solution for 1 d; 1 0.0 mm for 2d; 6.7 mm for 3d .
• Sample with setting solution containing 1 0vol% PAA shows an anti-bacterial zone 1 1 .0 mm after being immersed in Hanks' solution for 1 d; 1 0.0 mm for 2d; 1 0.0 mm for 3d; 9.0 mm for 5d; 7.5 mm for 7d .
• TTCP/DCPA/CSH/Li/PAA blocks were immersed for different periods of time
• Table 1 9. Average weight loss percentages (%) of TTCP/DCPA/CSH/Li/PAA blocks immersed in Hanks' solution for different periods of time (days).
• the resulting TTCP/DCPA/CSH/Li salt powder was mixed with 0.6 M, 1 M, 2 M or 3 M ( ⁇ ⁇ 4 setting solution containing 1 0 vol% PAA solution with a L/P ratio ranging from 0.35 g/cc to 0.7 g/cc to obtain a
• TTCP/DCPA/CSH/Li salt /PAA cement paste The resulting paste was injected into 37°C water using a 5 cc syringe attaching with or without a surgical needle to test the injectability of the cement pastes.
• the amount of residual cement cement remaining in the syringe after normal hand-injection was measured and considered as an index of injectability of the cement. (The higher amount of residual cement indicates the lower injectability)
• TTCP/DCPA/CSH/Li salt /PAA cement paste through a 5 cc syringe attached with a 1 1 cm long, 0.6 mm inner d ia . "1 8G" stainless steel needle.
• the CaCOs/Ca2P2O7/Li salt m ixed powder was m ixed with 0.6 M (N H 4 )2HPO4 setting solution with L/P ratio of 0.35 g/cc to obtain a CaCO3/Ca2P2O7/Li salt cement paste.
• the 3 mm h igh , 6 mm dia. block samples were prepared from pressure-molding the cement paste under a pressure of 450 kgf. The block samples were heated to 600°C for 1 h or 3h .
• Figure 6 shows antibacterial zones of CaCO3 Ca2P2O7 Li blocks prepared accord ing to the present invention without immersion .
• UV-sterilized sample (either granule or cement) to be tested was put in a 1 2-well plate, wherein was added 1 ml Tryptone Soya Broth (TSB) with 1 0 6 live S. aureusbacteria in each well (concentration : 1 0 6 colony-forming units (CFU) per ml).
• S. aureusbacteria were cultured with the sample anaerobically at 37°C. One cultured without sample was considered as a positive control in each study group.
• TSA Tryptone Soya Agar
• broth of each well was sequentially diluted and plated .
• the growth of bacteria was evaluated after cultivation on agar plates at 37°C for 24 h .
• the 24h antimicrobial activity values of L13PO4 salt samples with 0.06-0.1 2 g L13PO4 salt in 1 ml TSB are in the range of about 97.4-98.9%.
• the 24h antimicrobial activity value of the sample with 0.14 g L13PO4 salt in 1 ml TSB reaches 99.8% .
• the 24h antimicrobial activity value increases with increasing L13PO4 salt content.
• the 24h antimicrobial activity value of the sample containing 50 wt% L13PO4 reaches 1 00%.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Inorganic Chemistry (AREA)
• Transplantation (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Dermatology (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Surgery (AREA)
• Molecular Biology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Materials Engineering (AREA)
• Communicable Diseases (AREA)
• Physical Education & Sports Medicine (AREA)
• Oncology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Rheumatology (AREA)
• Materials For Medical Uses (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (1)

Family

ID=49512698

Family Applications (1)

Country Status (7)

Families Citing this family (4)

Citations (4)

Family Cites Families (18)

• 2013
  • 2013-05-06 WO PCT/US2013/039661 patent/WO2013169633A1/en not_active Ceased
  • 2013-05-06 US US13/887,416 patent/US10207023B2/en active Active
  • 2013-05-06 KR KR1020207012751A patent/KR20200050477A/ko not_active Ceased
  • 2013-05-06 JP JP2015511567A patent/JP6174684B2/ja active Active
  • 2013-05-06 KR KR1020147031072A patent/KR20150004826A/ko not_active Ceased
  • 2013-05-06 CN CN201380023551.3A patent/CN104302300B/zh active Active
  • 2013-05-06 EP EP13787118.2A patent/EP2846811B1/en active Active
  • 2013-05-06 KR KR1020207015455A patent/KR102214257B1/ko active Active
  • 2013-05-06 TW TW102116122A patent/TWI630003B/zh active
  • 2013-05-06 CN CN201711401529.4A patent/CN107982574B/zh active Active
• 2018
  • 2018-12-18 US US16/223,773 patent/US20190117826A1/en not_active Abandoned

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events