EP0831756A1 - Composition a base de ciment de bisphosphonate permettant d'eviter le relachement aseptique des protheses orthopediques - Google Patents

Composition a base de ciment de bisphosphonate permettant d'eviter le relachement aseptique des protheses orthopediques

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Publication number
EP0831756A1
EP0831756A1 EP96917041A EP96917041A EP0831756A1 EP 0831756 A1 EP0831756 A1 EP 0831756A1 EP 96917041 A EP96917041 A EP 96917041A EP 96917041 A EP96917041 A EP 96917041A EP 0831756 A1 EP0831756 A1 EP 0831756A1
Authority
EP
European Patent Office
Prior art keywords
cement
bone
bisphosphonate
alendronate
salt
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Withdrawn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
EP96917041A
Other languages
German (de)
English (en)
Inventor
Hamish Simpson
Nick Athanasou
Ashley J. Yates
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0831756A1 publication Critical patent/EP0831756A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • 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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • 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
    • A61F2/30—Joints
    • A61F2/46—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
    • A61F2002/4631—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor the prosthesis being specially adapted for being cemented
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the instant invention relates to the use of bisphosphonate salts, e.g., alendronate, in an acrylate-based polymer bone cement such as polymethylmethacrylate (PMMA), to prevent periprosthetic bone loss and failure of a joint prosthesis and in arthroplasty patients having an orthopedic implant device.
  • bisphosphonate salts e.g., alendronate
  • PMMA polymethylmethacrylate
  • a bone resorption inhibitor into the implant cement, which binds (fixates) the device to the supporting trabecular or cortical bone in the cavity in which the bone is inserted.
  • the presence of a bone resorption inhibitor should sufficiently inhibit bone resorption in the periprosthetic area of the implant device to obviate replacement surgery.
  • Most of the currently new bone resorption inhibitors are non-estrogenic therapeutic agents in the class of bisphosphonates.
  • US Patent No. 4,621,077, issued Nov. 4, 1986 to Rosini and Staibano discloses pharmaceutical compositions comprising (4- amino-l-hydroxybutylidene-l,l -bisphosphonic acid (ABP) or a water-soluble (sodium, aniline or lysine) salt thereof.
  • ABSP (4- amino-l-hydroxybutylidene-l,l -bisphosphonic acid
  • Alendronate, 4-amino-l-hydroxybutylidene-l,l- bisphosphonic acid monosodium trihydrate is a known bone resorption inhibitor and is described in U.S. Patents 4,922,007 and
  • Clodronate (dichloromethylene)bisphosphonic acid disodium salt (Proctor and Gamble, is described in Belgium Patent
  • Tiludronate ([(4-chlorophenyl)thiomethylene]- bisphosphonic acid) (Sanofi) is described in U.S. Patent 4,876,248 issued October 24, 1989.
  • CGP 42'446 being 2-(imidazol-l-yl)-hydroxyethyl- idene-l,l-bisphosphonic acid is a Ciba Geigy compound and is described in Bone and Mineral, Abstracts, Supplement 1 to Vol 25, April 1994, S61 , Article 12, by A. Pataki et al. Ibandronate, BM 21.0995 (l-Hydroxy-3-(methylpentyl- amino)-propylidene-bisphosphonate) by Boehringer-Mannheim - is described in U.S. Patent 4,927,814 issued May 22, 1990.
  • Mildronate a derivative of pamidronate, 3-(N,N- dimethyl)amino-l -hydroxy-propylidene-bisphosphonic acid, dimethyl-APD, is described in Bone and Mineral, Abstracts, Supplement 1 to Vol 25, April 1994, S79, Article 78, by D. Gonzalez et al.
  • piridronate Another Proctor and Gamble compound, piridronate.
  • [2-(2-pyridinyl)ethylidene]-bisphosphonic acid, monosodium salt is described in USP 4,761 ,406 as having bone resorption inhibition activity.
  • Quaternary nitrogen derivatives of piridronate, including NE-58051 , NE-58095, NE-58043, NE-10244, NE-1-0446 are described in Bone and Mineral, Abstracts, Supplement 1 to Vol 25, April 1994, S65, Article 24, by F. H.Ebetino et al.
  • the article, "Monatschefte" 99, 2016 (1968) by F. Kasparet describes the synthesis of etidronate. (1-hydroxy- ethylidene)bisphosphonic acid, disodium salt, (Proctor and Gamble).
  • US Patent No. 4,446,052 issued May 1, 1984 to Sunberg and Benedict, discloses a gel comprising di[(3-amino-l- hydroxy-propylidene)- 1 , 1 -bisphosphonic acidjtricalcium salt in water.
  • the gel is disclosed to be useful for the treatment of certain disorders of calcium metabolism in warm blooded animals.
  • a bone implant cement to optimally prevent excessive bone resorption in the periprosthetic area of an implant device, i.e., the bone area which is in contact and close proximity to the cement surface, to retard the aseptic loosening and failure of the device and thereby to prevent the pain, morbidity and cost associated with this condition.
  • a bisphosphonate salt can be used in a bone fixation cement for patients for the prevention of failure of joint prostheses, e.g., for the hip or knee.
  • Administration of a fixation cement containing a bisphosphonate, e.g., alendronate can provide extended therapeutic action and prevent the periprosthetic bone resorption process and thereby maintain the integrity of the total prosthetic structure.
  • a bone implant cement comprising a pharmaceutically acceptable polymeric carrier and an effective amount of a bisphosphonate bone resorption inhibitor.
  • the bisphosphonate applicable in the cement includes the free acids, and pharmaceutically acceptable salts, e.g., sodium, potassium, ammonium, calcium, magnesium and barium salts of: alendronate, clodronate, tiludronate, YM 175, ibandronate (BM 21.0995), risedronate, piridronate, pamidronate, or combinations thereof.
  • pharmaceutically acceptable salts e.g., sodium, potassium, ammonium, calcium, magnesium and barium salts of: alendronate, clodronate, tiludronate, YM 175, ibandronate (BM 21.0995), risedronate, piridronate, pamidronate, or combinations thereof.
  • step (b) adding the cement from step (a) to the bone cavity; (c) implanting the joint prosthesis into the bone cavity.
  • the bisphosphonates described above are useful in the invention cement.
  • Very useful are the sodium, potassium and calcium salts of residronate, clodronate, tiludronate and alendronate and particularly useful are the sodium and calcium salts of alendronate, i.e., monosodium alendronate trihydrate, disodium alendronate, anhydrous monosodium alendronate, di[(3-amino-l- hydroxypropylidene)- 1 ,1 -bisphosphonic acid]tricalcium, [(4-amino- 1 -hydroxybutyli dene)- 1 ,1 -bisphosphonic acidjmonocalcium salt, (ABP)Ca, di[(4-amino- 1 -hydroxybutylidene)- 1 , 1 -bisphosphonic acid]monocalcium salt, (ABP)2Ca, and tri[(4-amino-l -hydroxy ⁇ butylidene
  • the cement disclosed herein can be used to treat human subjects at the time of insertion of a prosthesis, i.e., a medical implant device.
  • the method described herein involves the administration of a bisphosphonate fixation cement in an osteogenically effective amount to inhibit bone reso ⁇ tion in the periprosthetic bone area of a medical implant device.
  • peripheral bone area as used herein is meant the area of bone which is in contact with the medical implant device, including the cement, or in the immediate proximity thereof.
  • sodium alendronate as used herein, is meant alendronate, being 4-amino-l -hydroxybutylidene- 1,1- bisphosphonic acid monosodium trihydrate.
  • calcium alendronate as used herein, is meant the above four listed insoluble calcium salts.
  • Very useful bisphosphonates salt in the invention are alendronate and calcium alendronate.
  • insoluble is meant that the aqueous solubility of the bisphosphonate, calcium alendronate, at room temperature is not appreciable.
  • inhibittion of bone reso ⁇ tion refers to prevention of bone loss, especially the inhibition of removal of existing bone either from the mineral phase and/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity.
  • inhibitor of bone reso ⁇ tion refers to agents that prevent bone loss by the direct or indirect alteration of osteoclast formation or activity.
  • osteoogenically effective means that amount which decreases the turnover of mature bone.
  • an osteogenically effective dose is also “pharmaceutically effective.”
  • subject refers to a living vertebrate animal such as a mammal in need of treatment, i.e., in need of an implant device
  • preventing shall mean providing a subject with an amount of a bisphosphonate in a bone cement sufficient to act prophylactically on the bone cavity and the periprosthetic bone area to prevent the loosening of the implant device.
  • cement is meant to encompass the mixed cement composition containing all of the ingredients and components prior to, during, and after complete “curing”, i.e., during early stages of monomer polymerization, at partial polymerization and complete polymerization.
  • cement can include the kneaded precured mass containing unpolymerized methylmethacrylate just prior to insertion into the bone cavity, the inserted mass just after insertion, and the fully polymerized cement , i.e., "fully cured", inside the bone cavity in contact with the prosthetic bone and the implant device after sufficient time for complete curing, e.g., 15-20 minutes.
  • PMMA polymethylmethacrylate
  • a solid acrylate polymer part which is generally a sterile package containing fully polymerized polymer, e.g., PMMA beads of substantially uniform small particle size of about 5-20 microns average diameter, and a catalyst, e.g., a solid aromatic peroxide such as benzoyl peroxide, present in about in one weight percent or less; and a second part, containing the acrylate monomer, which is generally a sterilized ampoule containing the acrylate or methacrylate monomer, e.g., methylmethacrylate, and an initiator, e.g., an N,N-disubstituted aromatic amine such as N,N-dimethyl-p-toluidine, present in about one weight percent or less.
  • a solid acrylate polymer part which is generally a sterile package containing fully polymerized polymer, e.g., PMMA beads of substantially uniform small particle size of about 5-20 microns average diameter, and a catalyst,
  • the second part can also contain a small quantity of a monomer stabilizer e.g., hydroquinone or a dicarboxylic acid, such as ascorbic acid in about 0.02 weight percent or less of the composition.
  • a monomer stabilizer e.g., hydroquinone or a dicarboxylic acid
  • ascorbic acid in about 0.02 weight percent or less of the composition.
  • a small amount of ethyl alcohol in about one weight percent or less can also be present to help solubilize the ascorbic acid.
  • the polymer powder part can also contain a radiopaquing agent, e.g., zirconium oxide or barium sulfate, present in about 5-15 weight percent of the composition, to distinguish the cement from bone during subsequent X-ray analysis and monitoring of the implanted device.
  • a radiopaquing agent e.g., zirconium oxide or barium sulfate
  • Both the polymer powder and monomer parts can also contain a non-toxic pigmented coloring agent e.g., chlorophyll, present in less than 0.1 weight percent, to enable easy identification in the surgical room during handling and preparation.
  • a non-toxic pigmented coloring agent e.g., chlorophyll
  • an antibiotic can be included in the polymer powder part, e.g., gentamicin sulfate, or tetracycline, present in about 1-2 weight percent or less, to prevent bacterial infection in the periprosthetic area.
  • the separately packaged polymer powder can be sterilized prior to use with, e.g., gamma radiation; the monomer can be sterilized by e.g., sterile microfiltration; and the package containing the polymer part can be sterilized by e.g., ethylene oxide.
  • the contents of the polymer powder and monomer parts are mixed in an area having an exhaust system in the surgical room just prior to application. All sterile instruments are used in the mixing procedure.
  • the monomer is added to the polymer powder during mixing at room temperature being careful not to entrap air and create air voids. Care must be taken in handling the monomer since it is volatile and flammable.
  • the polymerization of the monomer begins which binds together the polymer producing a dough-like mass over a 1-2 minute period.
  • the mass is kneaded to a desirable consistency and then placed into the bone cavity, which has been previously washed with cold saline soution and dried, under a slight pressure, by sterile gloved hand, sterile spatula, or by a syringe applicator to force the cement into the spongy areas of the bone to eliminate "air pockets" between the bone cavity and the cement.
  • the reason for this is that the cement is not an adhesive and depends upon mechanical interlock of bone, cement and implant surfaces for good fixation.
  • the implant device is then firmly inserted into the bone cavity and the excess cement removed. The implant is held firmly in place until complete curing occurs in about a 7-8 minute period. The rest of the arthroplastic structure is then assembled.
  • the cement useful herein contains a bisphosphonate admixed with a polymeric base.
  • polymers that can be used as the polymeric base for fixation of bone implants are polyacrylic acid ester and polymethylacrylic acid ester types, e.g., polymethacrylate and polymethylmethacrylate, including copolymers of polyacrylic acid ester/polymethacrylic acid ester, and copolymers with polyalkyl- methylmethacrylate.
  • Specific polymers include: polyalkylmethacrylates including polymethylmethacrylate (PMMA) and polyethylmethacrylate, polymethacrylate, polymethylmeth- acrylate/polymethacrylate copolymers, copolymers of methyl ⁇ methacrylate including methylmethacrylate/n-decylmeth- aery late/isobornylmethacry late, copolymers and mixtures thereof the above polymers, and the like.
  • PMMA polymethylmethacrylate
  • polyethylmethacrylate polymethacrylate
  • polymethylmeth- acrylate/polymethacrylate copolymers copolymers of methyl ⁇ methacrylate including methylmethacrylate/n-decylmeth- aery late/isobornylmethacry late
  • copolymers and mixtures thereof the above polymers and the like.
  • a very useful polymer is polymethylmethacrylate.
  • an effective amount of biphosphonate in the cement necessary to achieve therapeutic effectiveness will vary with the age, size, sex and condition of the subject, the nature and severity of the disorder to be treated, and the like; thus, a precise effective amount is best determined by the caregiver.
  • an effective amount of biphosphonate is about 0.005 to 10 weight percent of the total cement composition and a particularly useful range is 0.1 to 2 weight percent.
  • the method of the invention is useful for preventing defects and disorders in the periprosthetic area of the joint prosthesis which can result in a weakened or loosened structure and/or pain.
  • the bisphosphonate-containing cement may be implanted directly at the site to be treated, for example, by injection or surgical implantation.
  • Bisphosphonate delivered in cement is useful for maintaining implant fixation, by preventing or delaying the onset of aseptic loosening.
  • Solubility of the disodium salt in water is about 200mg/ml as compared to the free acid which is 8 mg/ml.
  • the solution pH of the disodium salt at 50 mg/ml. is 8.7, as compared to the free acid which is pH 2.2 at 8 mg/ml.
  • the hemipentahydrate salt can be heated between 100-150 degrees C. for 1 -4 hours to produce the hemihydrate.
  • the hemihydrate salt can be heated from 150-250 degrees C. for 1 -4 hours to produce the anhydrous salt.
  • the obtained titled salt displays a unique X-ray diffraction pattern.
  • Solubility of the anhydrous monosodium salt in water is about 300 mg/ml as compared to the free acid which is 8 mg/ml.
  • the trihydrate precipitates out of the aqueous solution.
  • the solution pH of the monosodium salt at 40 mg/ml. is 4.4, as compared to the free acid which is pH 2.2 at 8 mg/ml.
  • PalacosTMR with Gentamicin base cement commercially available, including new formulations with bisphosphonates, e.g., alendronate and calcium alendronate.
  • Palacos is a registered trademark of Heraeus Kulzer GmbH Wehrheim, Germany, under license to Schering Plough, Suffolk, England. Part A (Polymer Powder
  • Sterilized polymer packet containing:
  • Methyl methacrylate (stabilized with hydroquinone) 18.40
  • Part B is added to Part A under sterile conditions with simple mixing and 1.186 grams (2 weight percent based on the weight of the cement composition prior to adding the bisphosphonate) of 4-amino-l -hydroxybutylidene- 1 ,1 -bisphosphonic acid monosodium trihydrate (alendronate) is added during the mixing step to achieve a uniform cement mixture containing: Ingredient Grams
  • bisphosphonate can be used, for example, to achieve 0.005 to 10 weight percentages of the bone reso ⁇ tion inhibitor in the cement composition.
  • Bisphosphonate drugs which prevent bone loss and/or add back lost bone can be evaluated in the ovariectomized rat.
  • This animal model is well established in the art (see, for example, Wronski, et al., (1985) "Calcif. Tissue Int.” 7:324-328; Kimmel, et al, (1990) "Calcif. Tissue Int.” 46:101-110; and Durbridge, et al., (1990) "Calcif. Tissue Int.” 47:383-387; these references are hereby inco ⁇ orated in their entirety).
  • Wronski, et al., ((1985) "Calcif. Tissue Int.” 45:179-183)) describe the association of bone loss and bone turnover in the ovariectomized rat.
  • the bisphosphonate salts applicable in the instant invention are active in this assay.
  • PMMA polymethyl-methacrylate
  • the opposite side of the rat tibia is treated at about the same time and in the same manner except that the PMMA contains up to about 2 percent by weight of alendronate, either as the calcium or sodium salt, or other pharmaceutically acceptable salt.
  • alendronate salt is inco ⁇ orated into the PMMA by simple mixing prior to polymerization until a uniform mixture is achieved.
  • the tibia containing the alendronate exhibits no substantial localized inflammation or osteolysis, but instead, exhibits new bone formation in the region of the PMMA particles.
  • the alendronate-containing PMMA prevents PMMA particle induced osteolysis and localized inflammation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Surgery (AREA)
  • Organic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un ciment d'os au bisphosphonate qui permet d'éviter la déperdition osseuse périprothétique et le relâchement aseptique d'une prothèse articulaire chez les patients. Ledit ciment contient un inhibiteur de résorption osseuse au bisphosphonate (par exemple du sel de sodium ou du sel de calcium d'alendronate), et un vecteur polymère pharmaceutiquement acceptable tel que le polyméthacrylate de méthyle.
EP96917041A 1995-06-06 1996-06-03 Composition a base de ciment de bisphosphonate permettant d'eviter le relachement aseptique des protheses orthopediques Withdrawn EP0831756A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US47040495A 1995-06-06 1995-06-06
US470404 1995-06-06
PCT/US1996/008515 WO1996039107A1 (fr) 1995-06-06 1996-06-03 Composition a base de ciment de bisphosphonate permettant d'eviter le relachement aseptique des protheses orthopediques

Publications (1)

Publication Number Publication Date
EP0831756A1 true EP0831756A1 (fr) 1998-04-01

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EP96917041A Withdrawn EP0831756A1 (fr) 1995-06-06 1996-06-03 Composition a base de ciment de bisphosphonate permettant d'eviter le relachement aseptique des protheses orthopediques

Country Status (5)

Country Link
EP (1) EP0831756A1 (fr)
JP (1) JPH11511041A (fr)
AU (1) AU5973496A (fr)
CA (1) CA2223450A1 (fr)
WO (1) WO1996039107A1 (fr)

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AU5973496A (en) 1996-12-24
WO1996039107A1 (fr) 1996-12-12
CA2223450A1 (fr) 1996-12-12
JPH11511041A (ja) 1999-09-28

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