EP1150684A1 - Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes - Google Patents

Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes

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Publication number
EP1150684A1
EP1150684A1 EP00911738A EP00911738A EP1150684A1 EP 1150684 A1 EP1150684 A1 EP 1150684A1 EP 00911738 A EP00911738 A EP 00911738A EP 00911738 A EP00911738 A EP 00911738A EP 1150684 A1 EP1150684 A1 EP 1150684A1
Authority
EP
European Patent Office
Prior art keywords
bone
resoφtive
agent
cement
cement dough
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00911738A
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German (de)
English (en)
Other versions
EP1150684A4 (fr
Inventor
John H. Healey
Gene R. Diresta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Memorial Sloan Kettering Cancer Center
Original Assignee
Sloan Kettering Institute for Cancer Research
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Filing date
Publication date
Application filed by Sloan Kettering Institute for Cancer Research filed Critical Sloan Kettering Institute for Cancer Research
Publication of EP1150684A1 publication Critical patent/EP1150684A1/fr
Publication of EP1150684A4 publication Critical patent/EP1150684A4/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • 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
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • 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
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • A61L2300/43—Hormones, e.g. dexamethasone
    • 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

Definitions

  • anti-resorptive bisphosphonates strongly bind to the hydroxyapatite of bone and remain bound indefinitely.
  • the inhibition mechanism involves prevention of osteoclasts and their precursors from recognizing the bisphosphonate-hydroxyapatite matrix (Papapoulos, S.E., Hoekman, K., Lowik, C.W.G. M., Vermeij, P., Bijvoet, O.L.M.," Application of an in vitro model and a clinical protocol in the assessment of the potency of a new bisphosphonate", J. Bone Min. Res., 4:5, 775-782, (1989)), and by other mechanisms still being elucidated.
  • Bisphosphonates are used systemically to halt generalized forms of bone resorption. Experimental attempts are underway to use these drugs to treat local problems such as bone pain in monostotic fibrous dysplasia and alveolar bone resorption, but these are rare indications for systemic therapy. Systemic administration of alendronate, a bisphosphonate, reportedly inhibited osteolysis associated with wear debris in a canine un-cemented hip arthroplasty model (Shanbhag et al, supra).
  • Bisphosphonates do not interfere with the underlying mechanism of debris induced osteolysis. Bisphosphonates impede the osteoclast activity.
  • anti-reso ⁇ tive agents have heretofore been used systemically to treat diseases that induce osteolytic processes.
  • the anti-reso ⁇ tive agents are distributed to bone via its capillary network in proportion to its blood flow.
  • the amount of drug that reach sites adjacent to bone cement is lower than that adjacent to normal bone.
  • the medullary blood supply of bone is compromised by the reaming of the femoral canal in hip replacement surgery and other arthroplasty procedures.
  • PMMA Cement Polymethyl methacrylate (PMMA) cement is effective for anchoring a prosthesis to bone.
  • PMMA Polymethyl methacrylate
  • a bone-cement dough selected from the group consisting of an organic bone-cement dough, an inorganic bone-cement dough, and a composite bone-cement dough and (b) an anti-reso ⁇ tive amount of one or more proteinaceous or a hormonal anti-reso ⁇ tive agents.
  • Fig. 2 is a graph depicting compression strength vs. drug level for an etidronate disodium-loaded PMMA cement.
  • Inorganic cements include calcium hydroxyapatite (may be prepared according to Hayek et al. Inorganic Synth. 7, 63-69 (1963)), Apatite- Wollostonite glass ceramic (Nippon Electric Glass Co., see Kawanabe et al. J. Bone Joint Surg. 80-B:3. 527-530) and hydraulic calcium phosphate (prepared as described in Bohner et al. J. Pharm. Sci. 86:5, 565-572 (1997)).
  • Composite cements are mixtures of organic or inorganic materials or salts with organic or inorganic binders. Suitable organic and inorganic binders include the organic and inorganic bone cements described above.
  • Bone cements are generally prepared by mixing bone-cement components to give a bone-cement dough, which is particularly useful for reducing a bone void in a patient. After the bone void is reduced, the bone-cement dough can harden or cure to a bone cement.
  • bone-cement components are those materials that when admixed initially form a bone-cement dough. Bone-cement components are optionally mixed in the presence of additional chemicals, solvents, ingredients or materials.
  • a bone-cement dough is a moldable, pliable, ductile, or deformable composition that can be manually molded by the skilled artisan to a desired shape.
  • C 12 alkyl acrylates e.g., methyl acrylate, ethyl acrylate, propyl acrylate, tso-propyl acrylate, n-butyl acrylate, sec-butyl acrylate, tso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, heptyl acrylate, 2-heptyl acrylate, 2-ethylhexyl acrylate, 2-ethylbutyl acrylate, dodecyl acrylate, hexadecyl acrylate, 2-ethoxyethyl acrylate, isobornyl acrylate, cyclohexyl acrylate); C r C, 2 -alkyl methacrylates (e.g., methyl methacrylate, ethyl methacrylate, propyl methacrylate, /so-propyl methacrylate,
  • polymethyl methacrylate is the polymer component and methyl methacrylate is the monomer component.
  • the polymer component is an acrylic, such as PMMA, it is preferably in the form of small polymer beads or amo ⁇ hous particles.
  • the polymer component is PMMA powder, it generally has the consistency of flour. For example, in a typical PMMA
  • the polymer component may comprise a mixture a particle sizes where about 65 to about 70 percent polymer particles have an average diameter of about 25 microns, and about 30 to about 35 percent of the polymer beads are about 13 to about 17 microns in diameter.
  • the desired particle sizes and distributions are readily obtained by sifting through the appropriate screen mesh (e.g., see United States Patent No. 4,341,691,
  • accelerators for use with the invention, include but are not limited to, amines, such as p-toluidine, ⁇ , ⁇ -hydroxypropyl-p-toluidine, N,N-dimethyl-p-arninophenethanol, trihexylamine, and trioctylamine; polyamines, such as 0 N,N,N',N'-tetramethylethylenediamine; barbituric acids, such as dimethyl barbituric acid and diethyl barbituric acid; and dimethylamino-benzene-sulphonamide; or mixtures thereof.
  • amines such as p-toluidine, ⁇ , ⁇ -hydroxypropyl-p-toluidine, N,N-dimethyl-p-arninophenethanol, trihexylamine, and trioctylamine
  • polyamines such as 0 N,N,N',N'-tetramethylethylenediamine
  • barbituric acids such as dimethyl barbituri
  • the stabilizer advantageously prevents premature polymerization, which can occur when the liquid monomer component and the polymer component are mixed in the presence of heat, light or other materials.
  • stabilizers suitable for use with the 5 invention include, but are not limited to, hydroquinones and alkylated hydroquinones, such as toluhydroquinone, methyl-tert-butylhydroquinone, 2,5-di-t-butylhydroquinone 2,6-di- tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4- hydroxyanisole, 3 ,5-di-tert-butyl-4-hydroxyanisole, 3 ,5-di-
  • the composition of the polymer component of a preferable bone cement comprises about 80 to about 100 percent (by weight) poly methyl methacrylate, preferably about 90 percent; and optionally about 9 to about 11 percent (by weight) barium sulfate, U.S.P., preferably about 10 percent.
  • the barium sulfate when present, provides radiopacity so that the cement appears visible in X-ray-sensitive film when developed.
  • the polymer component optionally comprises a polymerization initiator, such as benzoyl peroxide, in an amount of about 0.5 to about 1 percent by weight, preferably about 0.75 percent, for initiating a free-radical polymerization process upon mixing the polymer and liquid monomer components.
  • the ratio of the liquid monomer component to the polymer component is about one milliliter of the liquid monomer component to about two grams of the polymeric component.
  • the liquid monomer is added to the polymer component.
  • the resulting mixture is stirred until a bone-cement dough is formed that preferably does not adhere to rubber gloves.
  • the bone-cement dough is then kneaded to the consistency amenable to digital application to bone or injection into a bone void formed, for example, by drilling into a bone.
  • a connecting portion of a prosthetic device can be inserted in the bone-cement dough-containing bone. The bone-cement dough cures, bonding the prosthetic device to the bone.
  • the liquid monomer component When the liquid monomer component is mixed with the polymer component, initially, the liquid monomer wets the polymer component. Since the polymer component is generally at least partially soluble in the liquid monomer, the solid polymer beads partially begin to dissolve or swell in the liquid monomer.
  • the polymerization reaction preferably starts as soon as the two components are mixed. During the next 2 to 4 minutes, the polymerization process proceeds, changing the viscosity of the initial mixture from a syrup-like consistency (relatively lower viscosity) to a dough-like consistency (relatively higher viscosity).
  • PMMA for example, can serve as a matrix appropriate to both support a prosthetic implant and deliver the anti-reso ⁇ tive agent to adjacent bone osteoclast activity and thus minimize the osteolytic bone reso ⁇ tion.
  • PMMA bone cements can be obtained by following known methods (e.g., United States Patent Nos. 4,064,566; 4,341,691; 4,554,686; 5,334,626; 5,795,922; and 4,791,150, all of which are inco ⁇ orated herein by reference) or instructions or package inserts accompanying commercial PMMA bone cement kits, e.g., "SIMPLEX®”, “PALACOS®”, “Zimmer®”, or "C.M.W®”). These bone cements can be impregnated with an anti-reso ⁇ tive agent mixing the anti-reso ⁇ tive agent into either the polymer component or the liquid monomer component at room temperature before the two components are mixed.
  • an anti-reso ⁇ tive agent mixing the anti-reso ⁇ tive agent into either the polymer component or the liquid monomer component at room temperature before the two components are mixed.
  • the anti-reso ⁇ tive agent may be impregnated in the bone cement by thoroughly mixing freshly made bone-cement dough with anti-reso ⁇ tive agent.
  • the anti-reso ⁇ tive agent can be applied to the surface of a bone-cement dough (organic, inorganic, or composite cements) by contacting pre-mixed bone-cement dough with the anti-reso ⁇ tive agent.
  • a bone-cement dough organic, inorganic, or composite cements
  • the bone-cement dough is formed in the shape of a sphere and contacted with the anti-reso ⁇ tive agent, preferably a bisphosphonate, by rolling the dough sphere in the anti -reso ⁇ tive agent, preferably in particulate form, until the external surface of the sphere is covered with the anti-reso ⁇ tive agent.
  • the sphere is covered with the anti- reso ⁇ tive agent such that it is approximately evenly distributed over the surface of the sphere.
  • the sphere is covered to the extent that it does not pick up more anti- reso ⁇ tive agent with further rolling.
  • about 60 grams (about 50 cm 3 ) of bone- cement dough may be prepared from a standard PMMA bone cement kit according manufacture's instructions.
  • the resulting dough can be divided into 10 spheres (about 6g and about 5 cm 3 each) and rolled in the anti-reso ⁇ tive agent, preferably a bisphosphonate, until the sphere is covered with the anti-reso ⁇ tive agent evenly distributed on the sphere's surface.
  • the anti-reso ⁇ tive agent is impregnated in the bone-cement dough or applied to the surface of the bone-cement dough in an anti-reso ⁇ tive amount.
  • an "anti- reso ⁇ tive amount” means an amount of the anti-reso ⁇ tive agent sufficient to prevent loosening of the bone cement from the living bone to which it is attached for an extended period of time, preferably, about 2 to about 4 years, more preferably about 5 to about 10 years, most preferably, about 11 to about 50 years and, optimally, for the life of the patient. Detecting whether the bone cement loosens from the living bone can be readily accomplished by well-known methods. For example, a radiologist or other skilled artisan can detect loosening of the bone cement by performing Gruen-zone analysis of the bone cement/bone bond and then measuring the thickness of the radiolucent line between the bone cement and the bone.
  • the amount of the anti-reso ⁇ tive agent that is impregnated in the bone cement is dependent on the type of bone cement and anti-reso ⁇ tive agent.
  • the anti- reso ⁇ tive agent is present in an amount of about 1 microgram to about 11 grams per 60 grams of bone-cement dough, preferably, about 0J grams to about 10 grams per 60 grams of cement dough, and is more preferably about 0.5 grams per 60 grams of bone-cement dough.
  • Anti-reso ⁇ tive agent levels higher than these may be used until the cement's chemical or mechanical properties are compromised relative to anti-reso ⁇ tive agent-free cement controls, or until local elution drug levels comprise bone remodeling processes.
  • the anti- reso ⁇ tive agent preferably a bisphosphonate
  • the bone-cement dough can be impregnated with an anti-reso ⁇ tive agent in an amount of from about 1 microgram to about 5 milligrams of the anti -reso ⁇ tive agent per 60 grams of bone-cement dough, preferably about 2 microgram to about 0J milligrams of the anti-reso ⁇ tive agent per 60 grams of bone-cement dough.
  • the amount of anti-reso ⁇ tive agent impregnated in the bone-cement dough is that amount used for antibiotic drugs impregnated in bone cement (e.g., Duncan et al, Instructional Course Lectures, 44, 305-313, (1996); Wininger et al, Antimicrobial Agents and Chemotherapy, 40: 12, 2675-2679, (1996); Elson et al, J. Bone Joint Surg., 59-B:2. 200-205, (1977); Baker et al, J. Bone Surg, 70-A:10. 1551-1557, (1988), all of which are inco ⁇ orated herein by reference).
  • antibiotic drugs impregnated in bone cement e.g., Duncan et al, Instructional Course Lectures, 44, 305-313, (1996); Wininger et al, Antimicrobial Agents and Chemotherapy, 40: 12, 2675-2679, (1996); Elson et al, J. Bone Joint Surg., 59-B:2.
  • the final level of the anti-reso ⁇ tive agent impregnated in the bone-cement dough will be determined by the skilled artisan and will be subject to the nature and potency of the ant-reso ⁇ tive agent; the type of bone cement dough, particularly the relationship of its mechanical strength versus the amount of anti-reso ⁇ tive agent; and the physical conditions required to make the bone-cement dough (e.g., time, temperature, etc.).
  • the anti-reso ⁇ tive agent When the anti-reso ⁇ tive agent is to be applied to the surface of bone-cement dough (organic, inorganic, or composite cements) by contacting bone-cement dough with the anti- reso ⁇ tive agent, the anti-reso ⁇ tive agent is preferably contacted with the bone-cement dough until the dough surface will no longer pick up any of the anti-reso ⁇ tive agent.
  • the temperature stability of the anti-reso ⁇ tive agent should be considered.
  • PMMA for example, reaches temperatures of 70 °C during its polymerization. This is high enough to inactivate many organic molecules, e.g., proteins, etc.
  • Another consideration is the hydration state of the anti-reso ⁇ tive agent and its impact on cement polymerization or setting; for example, the PMMA polymerization reaction is adversely impacted by water inco ⁇ orated within anti- reso ⁇ tive salt molecules.
  • anti-reso ⁇ tion agents can chemically interfere with or be inactivated by the reaction chemistry of the cement during its polymerization or setting.
  • the bone cement which contains an anti-reso ⁇ tive agent according to the present invention, can be made by pre-mixing an anti-reso ⁇ tive agent, such as a bisphosphonate with, for example, a methyl methacrylate powder before adding a catalyst.
  • an anti-reso ⁇ tive agent such as a bisphosphonate
  • a methyl methacrylate powder before adding a catalyst.
  • the bone cement can made with the anti-reso ⁇ tive agent, such as a bisphosphonate, impregnated therein, admixed with the anti-reso ⁇ tive agent, or one such as a surgeon (or other skilled artisan) can prepare the bone-cement dough at the time of use, e.g., in the operating or medical procedure room. Formation of bone-cement dough according to these methods overcomes the heretofore difficult problem of reducing the longevity of joint replacements.
  • the anti-reso ⁇ tive agent such as a bisphosphonate
  • the bone-cement dough can be loaded into a syringe while still quite fluid for injection into the prepared area.
  • the bone-cement dough can be kneaded for about several more minutes then it is of the proper consistency to be formed into a suitable shape for placement in the attachment site.
  • the bone-cement dough is added to the bone void within about three or four minutes following its preparation. Even then, the resulting bone cement to bone bond is generally stronger if the cement and prosthesis are placed into the prepared site early within this time period rather than later. However, bleeding can occur until there is sufficient counte ⁇ ressure to resist it, late in the stiffening of the cement.
  • the skilled artisan may need to balance the competing concerns of maximum cement interdigitation and minimizing bleeding at the cement-bone interface. The sooner after its preparation the bone-cement dough is applied, the less viscous it is, and the more likely that it will flow into surface irregularities and projecting cavities.
  • the prosthesis is then advantageously held in the proper position for several more minutes while the bone-cement dough continues to harden.
  • the types of grafts for use in the present invention include allogeneic bone grafts, autografic bone grafts and xenografic bone grafts.
  • the types of allogeneic bone grafts for use in the present invention include the following:
  • an allogeneic bone graft from a cadaver which can be obtained, for example, from a bone bank;
  • demineralization such as by using 6N HC1, to leave only the protein portion of the bone, or
  • demineralized allogeneic bone grafts in combination with vehicles such as glycerine or formulated into temperature sensitive putty to best treat surfaces or cavities requiring bone reducers.
  • an autografic bone graft is a bone structure taken from one portion of the skeleton of an individual to be grafted to another portion of the skeleton of that individual, for example, a bone segment taken from the iliac bone of a patient to be grafted to the spine of the patient.
  • a xenografic bone graft is a bone structure taken from one species and transplanted to a different species.
  • Iontophoresis enhances simple diffusion of the anti-reso ⁇ tive agent by the use of an electric-field gradient across the bone. This provides high local concentrations of the anti-reso ⁇ tive agent to prevent premature reso ⁇ tion of the graft before the intended healing can occur.
  • the procedures and apparatus for carrying out iontophoresis are described in United States Patent Nos. 5,668,120, 5,730,715, and 5,735,810, all three of which are inco ⁇ orated herein by reference, and can be adapted for use in the present invention.
  • the graft is then removed from the vehicle and washed with water.
  • Bone grafting is a common procedure in skeletal reconstructive and trauma surgery to reestablish the integrity of the skeleton. It provides (1) structural support to the skeleton, principally through cortical grafts and (2) bone healing assistance to the skeleton via osteoinduction, osteoconduction, and cellular mechanisms. Various techniques are used to bridge gaps between and reduce cavities in bone. Different materials are chosen to obtain the optimal clinical combination of healing potential, biocompatibility, and convenience.
  • graft choices include an autografic bone grafts, allografts, xenografic bone grafts, or other sources.
  • Other graft choices include naturally- occurring materials such as coral, or alloplastic materials.
  • inorganic materials include, but are not limited to, hydroxyapatite and tricalcium phosphate synthetic implants that are readily available source material. These can be mixed with protein constituents of bone such as collagen to redcue defects and heal bones. Such materials are easily sculpted to fit the defect or impacted into a cavity.
  • the most often-used technique for reconstructing damaged bone tissue involves initially preparing the bone tissue by cutting and drilling the bone tissue so that it conforms to the shape of the securement portion of a prosthesis. Then, a number of shallow holes are generally drilled or cut into the surfaces of the bone tissue adjacent to the prosthesis in order to form projecting cavities into which bone-cement dough will flow so as to form a strong mechanical interlock between the bone cement and the bone tissue.
  • the prepared bone surfaces are then thoroughly cleansed of all blood, fatty marrow tissue, bone fragments, and the like, so that the bone-cement dough conforms to all of the surface irregularities of the prepared bone tissue. Finally, particularly in the case of acrylic polymeric cements, the two components of the unpolymerized bone cement are mixed.
  • estrogen like compounds suitable for use with the invention include but are not limited to triphenylethylenes, such as tamoxifen and its derivatives, toremifene, droloxifene, and idoxifene; benzothiophenes, such as raloxifene and LY353381; chromans such as levormeloxifene; naphthalenes, such as CP336J56; and dihydronapthylenes, such as nafoxidine.
  • triphenylethylenes such as tamoxifen and its derivatives, toremifene, droloxifene, and idoxifene
  • benzothiophenes such as raloxifene and LY353381
  • chromans such as levormeloxifene
  • naphthalenes such as CP336J56
  • dihydronapthylenes such as nafoxidine.
  • cytokine means a low molecular weigh hormone-like protein secreted by cells, which cells regulate the intensity and duration of the immune response.
  • cyctokines include but are not limited to, interleukins (e.g., II- 1 to
  • R 1 and R 2 are independently, hydrogen, an alkali metal, an alkaline earth metal, a C,-C 4 quaternary ammonium cation, C]-C 10 alkyl, C,-C 10 unsaturated alkyl, aryl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, benzyl, or/>-nitrophenyl;
  • R 3 is hydrogen, chloro, amino, or hydroxy;
  • R 4 and R 5 are independently hydrogen, C C 4 alkyl, or C 2 -C 4 unsaturated alkyl; n is an integer ranging from 1 to 7; X is -NH-, -O-, or -S-; y is 0 or 1 ; and R 6 is hydrogen, -NH 2 , -N(R 7 )(R 7 ), -N + (R 7 )(R 7 )(R 7 ), a 5- to 7-membered aryl or cycloalkyl group, or a 5- to 7-membered heteroaryl or heterocycloalkyl group having from 1 to 3 heteroatoms one or more of which, when nitrogen, is optionally quaternary; each R 7 is independently hydrogen or a C r C 4 alkyl group; and when R° is -N + (R 7 )(R 7 )(R 7 ) or a 5- to 7-membered heteroaryl or heterocycloalkyl group having from 1 to 3 heteroatoms one
  • alkyl group means a straight or branched chain monovalent radical comprised of hydrogen and carbon atoms having no unsaturation, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, heptyl, octyl, and the like which rings may be unsubstituted or substituted by one or more suitable substituents as defined above.
  • an "unsaturated alkyl group” means a straight or branched chain monovalent radical comprised of hydrogen and carbon atoms having one or more double bonds therein, conjugated or unconjugated, such as allyl, butenyl, pentenyl, hexenyl, heptenyl, butadienyl, pentadienyl, hexadienyl, and the like, which rings may be unsubstituted or substituted by one or more suitable substituents as defined above.
  • heterocycloalkyl group means a monocyclic radical comprising carbon atoms, preferably 4 to 6 ring carbon atoms, and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation, which may be unsubstituted or substituted by one or more suitable substituents.
  • unsubstituted heterocycloalkyl groups include pyrrolidenyl, piperidinyl, piperazinyl, mo ⁇ holinyl, and pyranyl.
  • Other preferred bisphosphonates useful in the present invention are represented by formula II below:
  • bisphosphonates for use in the present invention include, but are not limited to risedronate, ibandronate, zoledronate, olpadronate, icandronate, and neridronate (6- amino- 1 -hydroxyexilidene-1, 1 -bisphosphonate); 1 -hydroxyethane- 1 , 1 -bisphosphonic acid; dichloromethane bisphosphonic acid;
  • esters include those wherein the hydrogen of one or more of the hydroxyl groups of the above bisphosphonates is replaced by C,-C 10 alkyl, C,-C 10 unsaturated alkyl, aryl, 2-chloroethyl, 2,2,2-trichloroethyl, 2JJ-trifluoroethyl, benzyl, j-nitrophenyl;

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
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  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Cette invention se rapporte à des ciments osseux anti-résorption, qui comprennent une quantité anti-résorption d'un ou plusieurs agents anti-résorption, cet agent étant constitué de préférence par un bisphosphonate. Ces ciments osseux anti-résorption servent à réduire les vides osseux et à fixer des prothèses à l'os. Cette invention se rapporte également à des implants osseux allogènes, autogreffés et xénogreffés, qui contiennent une quantité anti-résorption d'un agent anti-résorption, tel qu'un bisphophonate. Ces greffes osseuses anti-résorption sont utiles pour la chirurgie osseuse reconstructive.
EP00911738A 1999-02-09 2000-02-09 Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes Withdrawn EP1150684A4 (fr)

Applications Claiming Priority (3)

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US11926099P 1999-02-09 1999-02-09
US119260P 1999-02-09
PCT/US2000/003285 WO2000047214A1 (fr) 1999-02-09 2000-02-09 Ciments osseux anti-resorption et implants osseux allogenes, autogreffes et xenogreffes

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EP1150684A1 true EP1150684A1 (fr) 2001-11-07
EP1150684A4 EP1150684A4 (fr) 2005-06-15

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JP (1) JP2002536123A (fr)
AU (1) AU776555B2 (fr)
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US6410043B1 (en) 1998-05-07 2002-06-25 The University Of Tennessee Research Corporation Method for chemoprevention of prostate cancer
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AU2002349211A1 (en) * 2001-11-29 2003-06-10 John E Davies Resorption-controlled bone implants
FR2836681B1 (fr) * 2002-03-04 2004-06-18 Centre Nat Rech Scient Compose phosphocalcique modifie, composition injectable le contenant
IL153699A (en) 2002-12-26 2008-11-26 Prochon Biotech Ltd The composition for transplantation basically
GB0307834D0 (en) * 2003-04-04 2003-05-14 Ta Contrast Ab Composition
AU2004296178B2 (en) 2003-12-04 2011-03-24 The United States Of America As Represented By The Department Of Veterans Affairs Gallium inhibits biofilm formation
JP5167538B2 (ja) * 2005-05-16 2013-03-21 国立大学法人 東京医科歯科大学 骨セメントおよび歯科補綴物
EP1926459B1 (fr) 2005-09-19 2015-01-07 Histogenics Corporation Matrice support de cellules dont la densite des pores et la porosite sont definies specifiquement de maniere uniforme verticalement et organisees de maniere non aleatoire, et procede de preparation de celle-ci
EP1958649A1 (fr) * 2007-02-14 2008-08-20 Graftys Ciment calcium-phosphate injectable libérant un inhibiteur de la résorption osseuse
WO2009006921A1 (fr) * 2007-07-10 2009-01-15 Barrera Jose Bouza Substance microporeuse pour implant chirurgical
WO2009134856A2 (fr) * 2008-04-30 2009-11-05 Genta Incorporated Compositions pharmaceutiques à base de gallium et procédés associés
EP2228080A1 (fr) * 2009-03-03 2010-09-15 Graftys Biomatériaux de phosphate de calcium au gallium
WO2013043529A1 (fr) * 2011-09-19 2013-03-28 Emory University Activation de la voie de la protéine morphogénétique osseuse, compositions pour ossification et méthodes associées
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
DE102016209988A1 (de) * 2016-06-07 2017-12-07 Heraeus Medical Gmbh Pastenförmiger Zweikomponenten-Polymethylmethacrylat-Knochenzement
CN109010909A (zh) * 2018-09-05 2018-12-18 杭州市萧山区中医院 聚甲基丙烯酸甲酯复合红霉素骨水泥用于防治假体周围骨溶解和炎症反应的应用
CN109010334A (zh) * 2018-09-05 2018-12-18 杭州市萧山区中医院 聚甲基丙烯酸甲酯复合辛伐他汀骨水泥用于制备假体周围骨溶解和炎症反应的药物中的应用
CN111321403B (zh) * 2020-03-10 2022-03-11 河北北方学院 一种基于多巴胺的锌表面载镓-氧化石墨烯复合涂层的制备方法
CN113181425A (zh) * 2021-04-28 2021-07-30 北京邦塞科技有限公司 骨水泥固相粉料、骨水泥及其制备方法和应用
CN114984310B (zh) * 2022-06-30 2023-09-08 西安理工大学 一种抗溃散吸水膨胀有机-无机复合骨水泥及其制备方法

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WO2000047214A1 (fr) 2000-08-17
AU3358800A (en) 2000-08-29
EP1150684A4 (fr) 2005-06-15
CA2360319A1 (fr) 2000-08-17
AU776555B2 (en) 2004-09-16
WO2000047214A9 (fr) 2002-04-11
JP2002536123A (ja) 2002-10-29

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