US20100197636A1 - Injectable calcium-phosphate cement releasing a bone resorption inhibitor - Google Patents

Injectable calcium-phosphate cement releasing a bone resorption inhibitor Download PDF

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US20100197636A1
US20100197636A1 US12/527,228 US52722808A US2010197636A1 US 20100197636 A1 US20100197636 A1 US 20100197636A1 US 52722808 A US52722808 A US 52722808A US 2010197636 A1 US2010197636 A1 US 2010197636A1
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calcium
cement
salt
solid phase
bisphosphonic acid
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Jean-Michel Bouler
Bruno Bujoli
Pascal Janvier
Ibrahim Khairoun
Jean-Noël Argenson
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Centre National de la Recherche Scientifique CNRS
Universite de Nantes
Graftys SA
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Centre National de la Recherche Scientifique CNRS
Universite de Nantes
Graftys SA
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    • 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
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/831—Preparations for artificial teeth, for filling teeth or for capping teeth comprising non-metallic elements or compounds thereof, e.g. carbon
    • A61K6/838—Phosphorus compounds, 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0052—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with an inorganic matrix
    • A61L24/0063—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
    • A61L27/20—Polysaccharides
    • 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
    • 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
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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 invention relates to a macroporous, resorbable and injectable apatitic calcium-phosphate cement with a high compressive strength useful as bone cement and releasing a bone resorption inhibitor.
  • Bone is a composite of biopolymers, principally collagen, and an inorganic component identified as carbonate hydroxyapatite, approximated as (Ca,Mg,Na,M) 10 (PO 4 ,CO 3 ,HPO 4 ) 6 (OH,Cl) 2 .
  • Deregulation of the bone activity of an individual is the cause of many bone pathologies such as osteoporosis, Paget's disease or osteolytic tumors. Taking into account, in particular, the increase in human life expectancy, osteoporosis has become a public health problem and much research has been undertaken to remedy it. Since the bone pathologies under consideration are caused by an imbalance in bone remodeling to the benefit of the activity of the osteoclasts, one of the routes of treatment envisioned consisted in reducing the activity of the osteoclasts, in order to slow down the degradation of the bone material.
  • the gem-bisphosphonic acids that are used at the present time for the treatment of bone lesions are used systemically and, as a result, give rise to a few undesirable side effects. They can cause renal disorders and jaw osteonecrosis (Eckert A. W., Cancer Treatment Reviews, 2006, in the press) when they are administered intravenously, and digestive system-disorders, especially oesophagi or stomach ulcers, when they are administered orally [(Lin J. H., Bone 1996; 18; 75-85) or (Thiébauld D. et al., Osteoporos Int. 1994; 76-73)].
  • Another drawback of the oral administration lies in the low level of absorption of the active principle onto bone material.
  • implant materials have been used to repair, restore, and augment bone.
  • the most commonly used implants include autologous bone, synthetic polymers and inert metals. Protocols using these materials have significant disadvantages that can include patient pain, risk of infection during operations, lack of biocompatibility, cost, and the risk that the inserted hardware can further damage the bone. Therefore, a major goal of biomaterial scientists has been to develop novel bone substitutes that can be used as alternatives to these conventional techniques for skeletal repair.
  • Bone cements such as cements based on polymethylmethacrylate (PMMA) offer certain advantages in avoiding the use of solid implants, but also have several disadvantages.
  • Methacrylates and methacrylic acid are known irritants to living tissues, and when PMMA-based cements are cured in vivo, free radicals are generated, which can damage surrounding tissues.
  • the polymerization reaction for these materials is highly exothermic, and the heat evolved during curing can damage tissues. In addition, these materials are not biodegradable.
  • CPC have the following advantages: malleability allowing them to adapt to the defect's site and shape.
  • the introduction of injectable calcium phosphate cements greatly improved the handling and delivery of the cements and opened up areas of new applications for the CPC.
  • CPC systems consist of a powder and a liquid component.
  • the powder component is usually made up of one or more calcium phosphate compounds with or without additional calcium salts.
  • Other additives are included in small amounts to adjust setting times, increase injectability, reduce cohesion or swelling time, and/or introduce macroporosity.
  • FR-2715853 describes compositions for biomaterials for resorption/substitution of support tissues, comprising a mineral phase composed of BCP or calcium-titanium-phosphate, and a liquid aqueous phase comprising an aqueous solution of a cellulose-based polymer. These injectable compositions contain no active principle.
  • Noninjectable bone substitutes which are in the form of implants, are also known.
  • H. Denissen et al. J. Periodontal, Vol. 71, No. 2, February 2000, pp. 280-2966 describes implants of hydroxyapatite modified by absorption of a particular gem-bisphosphonic acid, namely (3-dimethylamino-1-hydroxypropylidene)-1,1-bisphosphonic acid, or olpadronate.
  • the in situ release of the acid is said to promote bone reconstruction.
  • hydroxyapatite itself has the drawback of being very poorly resorbable.
  • the international application WO03/074098 describes a modified phosphocalcic compound obtained by the addition of a gem-bisphosphonic acid or an alkali metal or alkaline-earth metal salt thereof to a suspension of a precursor phosphocalcic compound in ultrapure water, by stirring the reaction medium at room temperature, and then recovering the pellet by centrifugation, washing the pellet with ultrapure water, followed by filtering and drying in air at room temperature.
  • WO03/074098 also describes a suspension of the so obtained modified phosphocalcic compound in a solution or an hydrogel and the use of the so obtained injectable composition for the treatment of osteoporosis and osteolytic tumors.
  • the inventors of WO03/074098 thus recommend a local administration of a gem-bisphosphonic acid, the phosphocalcic phase providing a source of calcium and of phosphate required for stimulation of the bone remodelling.
  • the present applicant has now surprisingly found a method of producing a calcium-phosphate bone cement i.e. an auto-hardening cement, having a compressive strength close to bone, being resorbable for its substitution by new bone material and presenting a release of a gem-bisphosphonic compound, i.e. a bisphosphonic acid or a salt thereof, which allows a regulation of bone remodelling.
  • a calcium-phosphate bone cement i.e. an auto-hardening cement
  • a compressive strength close to bone being resorbable for its substitution by new bone material and presenting a release of a gem-bisphosphonic compound, i.e. a bisphosphonic acid or a salt thereof, which allows a regulation of bone remodelling.
  • the present inventors have shown that it is possible to obtain an auto-hardening calcium-phosphate cement comprising a gem-bisphosphonic compound with a setting time suitable for a chirurgical use while said gem-bisphosphonic compound shows a setting retarder activity.
  • the phosphonate groups of the gem-bisphosphonic compounds compete with phosphate groups of the cement paste in the following setting reaction. Consequently, the final product, its setting time and hardness are modified.
  • the initial calcium phosphate compound In presence of the liquid phase, the initial calcium phosphate compound is partially hydrolysed. Ca 2+ and PO 4 2 ⁇ ions are released. Bisphosphonic compounds chelate to Ca 2+ ions and may hamper the apatite precipitation (see reaction below):
  • the present inventors have shown that it is possible to obtain a resorbable calcium-phosphate cement comprising a gem-bisphosphonic compound. This is an unexpected technical effect since the introduction of a gem-bisphosphonic compound was thought to reduce the resorbability potential of phosphocalcic compounds in general.
  • the present inventors have shown that it is possible to obtain a calcium-phosphate cement releasing a gem-bisphosphonic compound which is thus able to have its inhibitor activity locally on the osteoclasts. This allows solving the secondary effects of an oral administration. Moreover, the dosage used in the cement (for example: 4 mg/implanted site) is much lower than the dosage used for an oral administration (10-70 mg/day during several months). Furthermore, it has been shown (Clin Cancer Res. 2006 15; 12(20 Pt 2):6222s-6230s, ChemMedChem. 2006 February; 1(2):267-73) that bone has a very high affinity for gem-bisphosphonic compounds. Thus, the gem-bisphosphonic compounds released by the cement according to the invention will be immediately absorbed by bone close around the implantation site and all the dose released will be trapped.
  • a “cement” is the result of the setting of a paste resulting from the mixing of a pulverulent solid phase and a liquid phase.
  • the “setting” of a cement means the hand-off auto-hardening at room or body temperature of the paste resulting from the mixing of the solid phase and the liquid phase.
  • An “injectable cement” means a cement paste sufficiently fluid to flow through a needle with a diameter of a few millimetres, preferably between 1 and 5 mm.
  • a “calcium phosphate cement” is a cement wherein the pulverulent solid phase is made of a calcium phosphate compound or a mixture of calcium and/or phosphate compounds.
  • An “apatitic” calcium phosphate cement crystallises in the hexagonal system having the formula Ca 5x (PO 4 ) 3x ,(OH, Cl, F) x with x ⁇ 1.
  • the present invention relates to a method for preparing an injectable calcium-phosphate bone cement releasing a gem-bisphosphonic derivative comprising the addition of a gem-bisphosphonic compound or a calcium precursor modified with a gem-bisphosphonic derivative, in the solid phase or in the liquid phase, wherein the gem-bisphosphonic derivative amount is up to 2.5% by weight in respect to the weight of solid phase.
  • the gem-bisphosphonic derivative amount and the way to incorporate it in the preparation method according to the invention is an essential feature in order to provide a cement according to the invention with an initial setting time suitable for a surgical use, i.e. lower than 1 hour, preferably lower than 30 min.
  • the bisphosphonic acids or salts thereof that may be used as gem-bisphosphonic compounds correspond to the formula:
  • X or Y represents, independently of each other, H or an alkali metal or alkaline-earth metal cation, and any organic or inorganic cation of biological interest.
  • R 1 represents H, OH or a halogen
  • R 2 represents a hydrogen or a halogen, an alkyl radical, an aminoalkyl radical in which the amino group optionally bears an alkyl substituent, an alkylamino radical, an alkyl radical bearing an aromatic substituent comprising at least one N atom, an alkyl radical bearing an aromatic thioether group.
  • R 2 is an alkyl radical
  • alkyls containing from 1 to 6 carbon atoms are preferred.
  • R 2 is an aminoalkyl radical
  • radicals NH 2 (CH 2 ) n — in which n is less than 6 are preferred.
  • R 2 is an alkylaminoalkyl radical
  • the preferred radicals are radicals R′R′′N(CH 2 ) m — in which R′ and R′′ represent, independently of each other, H or an alkyl radical containing up to 5 carbon atoms, and m is less than 6.
  • R is an alkylamino radical
  • the radicals RCNH— in which RC is a cycloalkyl containing from 3 to 7 carbon atoms are preferred.
  • R 2 is an alkyl radical bearing an aromatic substituent comprising at least one N atom
  • alkyls containing up to 3 carbon atoms and bearing one pyridyl or imidazolyl group are preferred.
  • R 2 is an alkyl radical bearing an aromatic thioether group
  • alkyls containing up to 3 carbon atoms and bearing a phenylthio group in which the phenyl group optionally bears a halogen substituent are preferred.
  • a salt of a bisphosphonic acid may be an organic or mineral salt, preferably an alkali metal or alkaline-earth metal salt.
  • a gem-bisphosphonic compound used in the method according to the invention is selected from the group consisting of etidronate, clodronate, pamidronate, alendronate, risedronate, tiludronate, ibandronate, zoledronate, nemonate, olpadronate, and neridronate.
  • the gem-bisphosphonic derivative amount is preferably up to 0.3% by weight in respect to the weight of solid phase.
  • the gem-bisphosphonic compound amount is preferably up to 5% by weight in respect to the weight of solid phase.
  • the gem-bisphosphonic compound amount is preferably up to 0.15% by weight in respect to the weight of solid phase.
  • the chemical association of the gem-bisphosphonic compound may be obtained by adding a gem-bisphosphonic acid or an alkali metal or alkaline-earth metal salt or and any organic or inorganic cation of biological interest thereof to a suspension of a precursor phosphocalcic compound, in a solvent preferably an aqueous medium (e.g. ultrapure water), by stirring the reaction medium at room temperature, and then recovering the formed compound by centrifugation.
  • the compound may then be purified by washing with ultrapure water, followed by filtering and drying in air at room temperature.
  • the calcium precursor is chosen:
  • “Ultrapure water” means water having a resistivity in the region of 18 M ⁇ cm.
  • the stirring at room temperature is preferably maintained for a period of between 1 hour and 72 hours, for example for 48 hours.
  • the nature of the stirring and the particle size of the calcium precursor may have an effect on the proportion of gem-bisphosphonic compound that may be grafted. It is thus preferable, when a given particle size has been selected for the calcium precursor, to adapt the stirring so as not to modify said particle size.
  • the calcium precursor modified with a gem-bisphosphonic compound and used in the method according to the invention is calcium-deficient apatite (CDA), ⁇ -TCP, DCPD, or CaCO 3 .
  • the present invention further relates to an injectable apatitic calcium-phosphate bone cement releasing a gem-bisphosphonic compound obtainable according to the method of the present invention as described above.
  • CPC's are materials consisting of a liquid phase being water or an aqueous solution and a pulverulent solid phase containing one or more solid compounds of calcium and/or phosphate salts so that if liquid and solid phases are mixed in an appropriate ratio they form a paste which at room or body temperature sets by precipitation of one or more other solid compounds, of which at least one is a calcium phosphate.
  • CPCs according to the invention are of the CDHA (calcium-deficient hydroxyapatite) type.
  • the CPC according to the invention is injectable. Indeed, in recent years, the occurrence of osteoporotic fractures has dramatically increased. Considering the lack of adequate treatment and the increasing number of elderly people, this trend is expected to continue. Osteoporotic fractures are often very difficult to repair, because the bone is very weak. It is therefore not possible to insert screws to hold osteosynthesis plates. A way to solve the problem is to inject a CPC into the osteoporotic bone to reinforce it.
  • Calcium and/or phosphate compounds useful in the invention as a component of the solid phase include hydroxyapatite (HA) Ca 10 (PO 4 ) 6 (OH) 2 ; amorphous calcium phosphate (ACP), Ca x (PO 4 )y.H 2 O; monocalcium phosphate monohydrate (MCPH), CaH 4 (PO 4 ) 2 .H 2 O; dicalcium phosphate dihydrate (DCPD), CaHPO 4 .2H 2 O, also called brushite; dicalcium phosphate anhydrous (DCPA), CaHPO 4 ; precipitated or calcium-deficient apatite (CDA), (Ca,Na) 10 (PO 4 ,HPO 4 ) 6 (OH) 2 ; alpha- or beta-tricalcium phosphate ( ⁇ -TCP, ⁇ -TCP), Ca 3 (PO 4 ) 2 ; tetracalcium phosphate (TTCP), Ca 4 P 2 O 9 , and calcium carbonate, CaCO 3 .
  • a pulverulent solid phase comprising one or more calcium and/or phosphate compounds selected from the group consisting of HA, ⁇ -TCP, ⁇ -TCP, ACP, MCPH, DCPA, CDA, CaCO 3 , and mixtures thereof, is preferred.
  • the solid phase can also comprise at least one synthetic polymer or biopolymer (e.g. HPMC).
  • HPMC synthetic polymer or biopolymer
  • a pulverulent solid phase comprising ⁇ -TCP is more preferred.
  • ⁇ -TCP has the formula ⁇ -Ca 3 (PO 4 ) 2 .
  • ⁇ -TCP is easily transformed into calcium-deficient hydroxyapatite (CDA) in aqueous solution. This property is used to form apatitic CPCs.
  • An ⁇ -TCP preferred amount is comprised between 5% and 100%, more preferably 30% and 80%, and most preferably 30% and 70% of the solid phase.
  • a preferred pulverulent solid phase consists in a mixture of ⁇ -TCP, DCPA, CDA and CaCO 3 .
  • Another preferred pulverulent solid phase consists in a mixture of ⁇ -TCP, DCPD, CDA, MCPH, and a biopolymer such as HPMC (hydroxypropylmethylcellulose).
  • the liquid phase may consist of one or more aqueous solutions containing one or several of the components of Table I, wherein said component may be chosen among the respective compounds are mixtures thereof shown in Table I.
  • the concentrations of aqueous solutions of the compounds described above as liquid phases are between about 0.1% and about 5% by weight.
  • a preferred liquid phase consists in a Na 2 HPO 4 aqueous solution, a NaH 2 PO 4 aqueous solution or a citric acid solution. More preferably, the liquid phase consists in a Na 2 HPO 4 aqueous solution.
  • a solution of about 0.5% to about 5% by weight of Na 2 HPO 4 in distilled water, a solution of about 0.5% to about 5% by weight of NaH 2 PO 4 in distilled water or a solution of about 0.5% to about 5% by weight of citric acid in distilled water can be used.
  • the pH of the liquid phase should be between about 5 to about 10, preferably between about 5 and about 9, most preferably between about 5 and about 7.
  • the liquid phase/solid phase (L/S) ratio is between about 0.20 to about 0.9 ml/g, more preferably between about 0.25 to about 0.8 ml/g, still preferably between about 0.25 to about 0.45 ml/g, the most preferably about 0.30 to about 0.45 ml/g.
  • the liquid phase/solid phase (L/S) ratio is between about 0.25 ml/g and about 0.9 ml/g; more preferably between about 0.30 ml/g and about 0.45 ml/g, the liquid phase being an aqueous Na 2 HPO 4 solution.
  • the liquid phase/solid phase (L/S) ratio is between about 0.25 ml/g and about 0.9 ml/g; more preferably between about 0.30 ml/g and about 0.45 ml/g, the liquid phase being an aqueous NaH 2 PO 4 solution.
  • the liquid phase/solid phase (L/S) ratio is between about 0.20 ml/g and about 0.8 ml/g; more preferably between about 0.25 ml/g and about 0.30 ml/g, the liquid phase being an aqueous citric acid solution.
  • the setting time of a CPC depends on the composition of the powder and liquid components, the powder-to-liquid ratio, proportion of the calcium phosphate components and the particle sizes of the powder components.
  • the setting time of the cement is an important property of the cement. If the setting time is too fast, the surgeon does not have time to use the cement before it is hard. If the setting time is too long, the surgeon must wait until he/she can close the wound.
  • the setting time is usually measured on a moulded sample with a Gillmore needle apparatus.
  • This test basically measures when the hydrating cement paste develops some finite value of resistance to penetration. It defines an initial setting time and a final setting time based on the time at which a needle of particular size and weight either penetrates a cement paste sample to a given depth or fails to penetrate a cement paste sample.
  • the Gillmore needle apparatus consists in two needles with a different diameter and a different weight. The first needle with the biggest diameter and the lowest weight measures the initial setting time and the second one with the lowest diameter and the highest weight measures the final setting time (C266 ASTM standard).
  • the initial setting time of the cement according to the invention is suitable for a chirurgical use, i.e. lower than 1 hour, preferably lower than about 45 min.
  • it is comprised between about 10 min and about 45 min, more preferably about 15 min and about 40 min, most preferably between about 20 min and about 35 min.
  • the final setting time of the cement according to the invention is comprised between about 40 min and about 3 h, preferably about 40 min and about 2 h, most preferably between about 40 min and about 1 h.
  • the compressive strength of the hardened cement according to the invention is above about 10 MPa, preferably above about 20 MPa.
  • the cement In order to prevent any extravasation of the cement into the tissues surrounding bone, it is very important to visualise the cement.
  • the easiest way is to increase the radio-opacity of the cement, for example by means of contrasting agents.
  • metallic powders of tantalum, titanium or tungsten can be used.
  • liquid agents in partially bioresorbable cements such as iodine compounds as iopamidol, iohexyl and iotrolan.
  • barium sulphate is used.
  • a further object of the invention is the use of an injectable CPC according to the invention to fill a bony defect or fracture caused by trauma, osteoporosis, osteolytic tumours, and articular or dental prostheses surgeries.
  • This method of treatment comprises the introduction in the bony defect or fracture through a needle of an injectable CPC according to the invention.
  • percutaneous vertebroplasty This consists of a percutaneous puncture method to stabilize and straighten vertebral collapse of the thoracic and lumbar spinal column, most often as a result of osteoporosis.
  • a very painful vertebral collapse can occur in the region of the thoracic (TSC) and lumbar (LSC) spinal column as a result of the reduced load-bearing capacity of the skeletal frame. This results in more or less distinct deformation of the vertebrae, and even in vertebral collapse. Both cases are easily recognizable by x-ray. Even a complete vertebral collapse and distinct deformation of the entire spinal column is possible.
  • TSC thoracic
  • LSC lumbar
  • a thin puncture needle is inserted to the vertebra, e.g. under x-ray guidance.
  • the bone can be punctured by the needle without risk.
  • fluid bone cement is injected into the vertebra via the puncture needle; after the cement hardens, the vertebra is stabilized (vertebroplasty). If the vertebra is severely deformed (e.g. in the case of a wedge-like formation), the collapsed vertebra is straightened before the cement is injected.
  • a balloon is hereby inserted into the vertebra via the puncture needle and inflated with fluid under high pressure. Following a successful straightening, the balloon is removed and the resulting cavity is filled with bone cement (balloon-kyphoplasty).
  • a further object of the invention is the use of an injectable CPC according to the invention to fill a tooth defect.
  • a supplementary object of the invention is a kit for preparing an injectable calcium-phosphate bone cement releasing a gem-bisphosphonic derivative according to any of claims 8 to 10 comprising a gem-bisphosphonic derivative or a calcium precursor modified with a gem-bisphosphonic compound, a solid phase and a liquid phase.
  • FIG. 1 31 P VACP MAS NMR spectrum of modified CDA [10.4 wt % alendronate], showing the alendronate component associated to CDA (see example 1). The spectra were recorded at a spinning frequency of 12 kHz and a magnetic field of 7.0 T.
  • FIG. 2 31 P MAS spectra of cements (see example 5) after a one week setting time.
  • reference no alendronate added
  • solid alendronate powder mixed with the cement solid component
  • solution alendronate dissolved in the cement liquid component
  • CDA alendronate chemically associated to the CDA component
  • FIG. 3 (upper view) 31 P single pulse MAS-NMR spectrum of modified ⁇ -TCP [4.7 wt % alendronate], (bottom view) 31 P VACP MAS NMR spectrum of modified ⁇ -TCP [4.7 wt % alendronate] (see example 2).
  • FIG. 4 Scanning Electron Microscopy (observation in the backscattered electron mode) view of a ewe vertebral body implanted with a 3 g-dose of unloaded CPC, 12 weeks after implantation.
  • FIG. 5 Scanning Electron Microscopy (observation in the backscattered electron mode) view of a ewe vertebral body implanted with a 3 g-dose of alendronate-loaded CPC (0.13 wt %), 12 weeks after implantation (see example 8).
  • a suspension of calcium phosphate was prepared by introducing 100 mg of CDA into 8.75 ml of ultrapure water mixed with 1.25 ml of a 0.02 mol.l ⁇ 1 sodium alendronate aqueous solution. The suspension was placed in a tube maintained at room temperature, and was stirred with a rotary stirrer at 16 rpm for 5 days. The suspension was then centrifuged and the most part of the supernatant was removed. The solid residue was filtered off, washed several times with small portions of ultrapure water, and then dried at room temperature. The resulting solid contained 7.4 wt % alendronate.
  • the bisphosphonate can also be chemically associated to one of the other components of the solid phase (CaCO 3 , DCPA, ⁇ -TCP . . . ).
  • a suspension of the calcium phosphate support was prepared by introducing 100 mg of ⁇ -TCP into 8.75 ml of ultrapure water mixed with 1.25 ml of a 0.02 mol.l ⁇ 1 sodium alendronate aqueous solution. The suspension was placed in a tube maintained at room temperature, and was stirred with a rotary stirrer at 16 rpm for 2 days. The suspension was then centrifuged and the most part of the supernatant was removed. The solid residue was filtered off, washed several times with small portions of ultrapure water, and then dried at room temperature. The resulting solid contained 4.7 wt % alendronate.
  • the bisphosphonate can also be chemically associated to one of the other components of the solid phase.
  • a suspension of the calcium phosphate support was prepared by introducing 100 mg of DCPD into 9 ml of ultrapure water mixed with 1 ml of a 0.02 mol.l ⁇ 1 sodium alendronate aqueous solution. The suspension was placed in a tube maintained at room temperature, and was stirred with a rotary stirrer at 16 rpm for 2 days. The suspension was then centrifuged and the most part of the supernatant was removed. The solid residue was filtered off, washed several times with small portions of ultrapure water, and then dried at room temperature. The resulting solid contained 5.3 wt % alendronate.
  • the bisphosphonate can also be chemically associated to one of the other components of the solid phase.
  • a suspension of the calcium phosphate support was prepared by introducing 100 mg of CaCO 3 into 8.5 ml of ultrapure water mixed with 1.5 ml of a 0.02 mol.l ⁇ 1 sodium alendronate aqueous solution. The suspension was placed in a tube maintained at room temperature, and was stirred with a rotary stirrer at 16 rpm for 2 days. The suspension was then centrifuged and the most part of the supernatant was removed. The solid residue was filtered off, washed several times with small portions of ultrapure water, and then dried at room temperature. The resulting solid contained 5.0 wt % alendronate.
  • the solid phase of the cement consists of alpha-tertiary calcium phosphate ⁇ -TCP, CaHPO 4 , CaCO 3 and some precipitated hydroxyapatite CDA.
  • the solid phase composition is the same for all samples:
  • ⁇ -TCP was prepared by using an appropriate mixture of CaHPO 4 and CaCO 3 , heating it at 1300° C. for at least 6 h and quenching it in air down to room temperature.
  • the liquid/powder ratio L/P of cements was taken to be either 0.30 ml/g for samples prepared with Na 2 HPO 4 and NaH 2 PO 4 and 0.25 ml/g for samples prepared with citric acid.
  • the powders are finely ground during 10 minutes.
  • liquid phase is added dropwise and the two phases are mixed with a spatula or a pestle.
  • the cement samples obtained after 7 days incubation were studied using solid-state magic angle spinning (MAS) NMR spectrometry.
  • the experiments were carried out on a Bruker Advance 300 spectrometer, operating at 7.0 T ( 1 H and 31 P Larmor frequencies of 300 and 121.5 MHz), using 4 mm double-resonance and triple-resonance MAS probes.
  • the 31 P— ⁇ 1 H ⁇ cross-polarisation (CP) MAS experiments were performed using a ramped cross polarization with a contact time of 1 ms.
  • 1 H decoupling was achieved using the SPINAL64 sequence with a 1 H nutation frequency of 70 kHz.
  • the recycle delay was set to 2 s.
  • the 31 P single pulse spectra were thus obtained by recording a single scan after a delay of 600 s.
  • the solid phase of the cement consists of alpha-tertiary calcium phosphate ⁇ -TCP, DCPD, MCPH, HPMC and some precipitated hydroxyapatite CDA.
  • the solid phase composition is the same for all samples:
  • ⁇ -TCP was prepared by using an appropriate mixture of CaHPO 4 and CaCO 3 , heating it at 1300° C. for at least 6 h and quenching it in air down to room temperature.
  • the liquid phase chosen to prepare different cement formulations was 5% Na 2 HPO 4 by weight in water.
  • the liquid/powder ratio L/P of cements was taken to be 0.50 ml/g.
  • the powders are finely ground during 30 minutes.
  • liquid phase is added dropwise and the two phases are mixed with a spatula or a pestle.
  • the properties of the cements were studied using Vickers microindentation (maximal compressive strength), powder X-ray diffraction and 31 P solid state NMR (transformation ratio of ⁇ -TCP to CDA), and texture analyses (evaluation of the initial setting time).

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WO2016088915A1 (ko) * 2014-12-03 2016-06-09 한국기계연구원 골다공증 치료용 유효성분을 함유하는 경조직 재생용 지지체 및 이의 제조방법
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