EP1066065A1 - Biociments presentant des proprietes ameliorees - Google Patents

Biociments presentant des proprietes ameliorees

Info

Publication number
EP1066065A1
EP1066065A1 EP99910351A EP99910351A EP1066065A1 EP 1066065 A1 EP1066065 A1 EP 1066065A1 EP 99910351 A EP99910351 A EP 99910351A EP 99910351 A EP99910351 A EP 99910351A EP 1066065 A1 EP1066065 A1 EP 1066065A1
Authority
EP
European Patent Office
Prior art keywords
tcp
mixture according
hpo
cahpo
phosphate
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Withdrawn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
EP99910351A
Other languages
German (de)
English (en)
Inventor
Robert Wenz
Ferdinand Clemens Maria Driessens
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 Patent GmbH
Original Assignee
Merck Patent GmbH
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 Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1066065A1 publication Critical patent/EP1066065A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials

Definitions

  • the invention relates to biodegradable calcium phosphate cements, in particular mixtures of calcium phosphate-containing powders of different stoichiometric compositions with improved properties.
  • the mixtures according to the invention all contain tricalcium phosphate (TCP) and one or more other phosphate-containing inorganic compounds in different compositions, the TCP fraction being in a well-defined particle size range.
  • TCP tricalcium phosphate
  • Naturally occurring bone material consists of calcium phosphate with a hydroxyapatite structure.
  • the composition of bone minerals does not correspond to the ideal stoichiometric composition of crystalline hydroxyapatite (Ca ⁇ o (PO 4 ) 6 (OH) 2 ), but usually has a non-stoichiometric composition, which is due to the incorporation of other anions such as carbonate or Hydrogen phosphate instead of orthophosphate but also caused by other cations such as sodium, potassium or magnesium instead of calcium.
  • Biodegradable calcium phosphate cements are attracting increasing interest in traumatology and orthopedics due to the limited availability of autogenous bone and the problem of bioburden with allogeneic bone.
  • a disadvantage of many available synthetic bone substitutes based on calcium and phosphorus is essentially seen in the fact that they are not degradable.
  • TCP tricalcium phosphate
  • DCP dicalcium phosphate
  • TTCP tetracalcium phosphate
  • Such cements are known for example from US 4,518,430, US 4,612,053, US 4,678,355, US 4,880,610, US 5,053,212, US 5,152,836, US 5,605,713, EP 0416 761, EP 0 543 765, EP 0664 133 or of WO 96/36562.
  • a cement is also known from the prior art, consisting of .alpha.-TCP and .beta.-TCP and a small amount of precipitated serving as a seed - 3 -
  • the initially paste-like mixture is hardened by interlocking the crystals of calcium-deficient hydroxyapatite that precipitate during the setting process.
  • the properties of the known hydroxyapatites or calcium phosphate cements in particular their physiological acceptance, the required bioresorbability and ability to be replaced by newly generated natural bone tissue or stimulation of their growth, as well as some of their physical properties, such as, for example, B. compression strength and curing times depend on the more or less pronounced degree of crystallization, the particle size and the porosity that can be achieved in the manufacture.
  • the present invention provides such cements with special properties.
  • the problem underlying the invention was in particular whether new cements with improved properties can be obtained by varying the grinding or the particle size of a TCP mixture together with admixtures of other inorganic phosphate compounds.
  • the present invention thus relates to a mixture of powders which is suitable for the production of resorbable calcium phosphate cements and, in addition to tricalcium phosphate (TCP), contains at least one other phosphate-containing inorganic compound which is characterized in that the TCP particles have the following particle size distribution: 30 - 90%: 0.1 - 40 ⁇ m and 10 - 70%: 40 - 300 ⁇ m.
  • TCP tricalcium phosphate
  • the mixtures according to the invention must always contain TCP.
  • TCP mainly occurs in two different crystal modifications ⁇ and ⁇ .
  • the mixtures contain ⁇ -TCP, with up to 60% ⁇ -TCP being admixed.
  • the invention thus relates to a mixture in which TCP is 40 to 100% in the ⁇ -form ( ⁇ -TCP) and 0 to 60% in the ⁇ -form ( ⁇ -TCP). If one speaks of TCP in the preceding or in the following, this mixture of ⁇ - and ß-TCP is always understood by definition.
  • the invention relates in particular to mixtures in which 30 to 70% of the TCP particles have a particle size between 0.1 to 7 ⁇ m.
  • the invention also relates to mixtures in which 10 to 60% of the TCP particles have a particle size between 40 to 100 ⁇ m. - 5 -
  • Corresponding mixtures which have the following particle size distribution of the TCP particles are particularly preferred: 30-50%: 1-7 ⁇ m 20-40%: 7-40 ⁇ m and 10-50%: 40-100 ⁇ m.
  • the size and property of the remaining phosphate-containing compounds play a role in the mixture.
  • at least 50% of these non-TCP particles should have a size between 10 and 100 ⁇ m. In general, these particles must not be too fine but not too coarse.
  • the proportion of these non-TCP connections in the mixtures according to the invention is 1-85%, preferably 5 to 60%.
  • Suitable compounds that can be added to TCP are generally all inorganic compounds that contain calcium and phosphate. Particularly suitable compounds are disclosed in EP 543 765. The compounds selected from the following group are preferred: Ca (H 2 PO 4 ) 2 H 2 O, CaHPO 4 , CaHPO 4 - * 2H 2 O, Ca 8 (HPO 4 ) 2 (PO 4 ) 4 - 5H 2 O, Ca 9 (HPO 4 ) (PO 4 ) 5 OH, Ca 10 (PO 4 ) 6 (OH) 2 , carbonate-containing apatite, CaCO 3 , Ca (OH) 2 , MgHPO -3H 2 O, Mg 3 (PO 4 ) 2 , CaNaPO 4 , Cai ⁇ Na (PO 4 ) 2 , CaKPO 4 , Ca 2 PO 4 Cl, Ca 2 NaK (PO 4 ) 2 , Ca 10 (PO 4 ) 6 Cl 2 , ZnHPO 4 -4H 2 O and Zn 3 (PO 4 ) 2 ,
  • TCP 70-99% Ca ⁇ 0 (PO 4 ) 6 (OH) 2 : 1-10%; CaCO 3 : 10-20%; - 6 -
  • TCP 70-99% Ca 8 (HPO 4) 2 (PO 4) 4 ⁇ 5H 2 O: 1-10%, CaCO 3: 10-20%;
  • TCP 40-99% Ca ⁇ 0 (PO 4 ) 6 (OH) 2 : 1-10%; CaHPO 4 : 1-50%;
  • TCP 40-99% Ca 8 (HPO 4 ) 2 (PO 4 ) 4 "5H 2 O: 1-10%, CaHPO 4 : 1-50%;
  • TCP 20-99% Ca 10 (PO 4 ) 6 (OH) 2 : 1-10%; CaHPO 4 : 1-50%,
  • the mixtures according to the present invention may also contain known curing accelerators. Disodium hydrogen phosphate is preferred.
  • the TCP-containing biocements of the present invention are particularly advantageous if the magnesium content in the starting materials is not more than about 0.13% and the sodium content is not more than about 0.2%.
  • antibiotics z. B from the aminoglycoside series such as gentamicin, or cefazolin, clindamycin palmitate, in particular clindamycin phosphate or disinfectant to avoid germ colonization during implantation.
  • antibiotics / disinfectants are not only mixed into the cements, but also eluted from them.
  • the mixing in of antibiotics / disinfectants should not adversely affect the mechanical properties or the processing properties of the cements, for example with regard to the curing times, in accordance with the intended application.
  • disinfectants are acridines, especially biguanides such as chlorhexidine and here again especially Polyhexanidum (Lavasept ®), are suitable. Furthermore, through the interference and progressive release of antibiotics and / or disinfectants from resorbable calcium phosphate cements, this biomaterial, after surgical debridement, can be implanted in areas at risk of infection. Furthermore, the treatment of osteomyelitis, which is characterized by chronic infection and bone necrosis, is facilitated because the osteomyelitis can possibly be remedied by a one-sided operation.
  • resorbable biocements e.g. increase the cellular activity of the bone surrounding the cement, in the sense of an increased resorption of the cement and replacement thereof by the body's own bone or formation of a composite of the body's own bone and non-resorbed portions of the cement or active substances in the sense of chemotherapeutic agents, which loosen a stabilizing cement seal prevent after tumor resection by nearby tumor cells.
  • suitable pharmaceutical active ingredients are growth factors, such as FGF (Fibroblast Growth Factor), BMP (Bone Morphogenetic Protein) or TGF-ß (Tissue Growth Factor) or other active ingredients such as prostaglandins or substances that influence prostaglandin metabolism, active substances that interact with the metabolism the thyroid or parathyroid glands interact or also chemotherapeutic agents, such as Metothrexate.
  • growth factors such as FGF (Fibroblast Growth Factor), BMP (Bone Morphogenetic Protein) or TGF-ß (Tissue Growth Factor)
  • active ingredients such as prostaglandins or substances that influence prostaglandin metabolism, active substances that interact with the metabolism the thyroid or parathyroid glands interact or also chemotherapeutic agents, such as Metothrexate.
  • the invention thus also relates to mixtures which additionally contain one or more active pharmaceutical ingredients or one or more disinfectants. - 8th -
  • the mixtures according to the invention must be mixed with an aqueous liquid, so that apatite structures or apatite-like masses set or form in accordance with the reaction equation mentioned at the beginning.
  • advantageous properties are obtained after the powder mixtures have been mixed with the aqueous liquids. These properties are characterized in that the paste obtained after the solid and liquid phase have been mixed enables certain processing options, such as modeling and injectability, in specific time intervals in a temperature-dependent manner.
  • aqueous liquids such.
  • physiological saline body fluids such as blood or serum, or aqueous buffers in question.
  • the additives such as pharmacological active substances or hardening accelerators, can not only be added to the TCP powder, but can also be added to the biocement to be mixed in aqueous solution. This is then available as a creamy suspension or paste and can be easily inserted into the intended locations or defective bone structures.
  • the invention thus also relates to a corresponding mixture in the form of an aqueous solution, paste or suspension and its use for the production of biodegradable implantable synthetic bone materials.
  • the mixed and setting mixtures according to the invention are distinguished in particular by a desired compression strength of 30 MPa and more, which, depending on the composition of the mixture according to the invention, is achieved after only very short curing times between two and ten, preferably between three and six hours, while in the prior art
  • curing times of 15 to 30 hours are the rule and the strength only slightly exceeds 30 MPa.
  • compression strengths of 40 to 50 MPa can even be achieved with the mixtures according to the invention.
  • Fig. 1 Antibiotic elution from biocement D batches:
  • Paragraphs I to V correspond to the identically labeled curves in the figure.
  • Fig. 2 Gentamicin release from H, B, F, .D cement release in ⁇ g
  • Example 1 ⁇ -TCP was produced by a firing process at 1350 ° C. for 4 hours and then cooling in room air, a 2: 1 molar mixture of CaHPO 4 and CaCO 3 .
  • the reaction product obtained contained less than 10% ⁇ -TCP.
  • the ⁇ -TCP was ground, sieved and mixed in such a way that about 50% had a particle size between 0.1 and 7 ⁇ m, about 25% between 7 and 25 ⁇ m and a further 25% between 25 and 80 ⁇ m.
  • the OCP was produced according to the method of LeGeros (Calzif. Tiss. Int. 37 (1985) 194-197).
  • Biozement H mixture of ⁇ -TCP and PHA
  • Biocement F mixture of ⁇ -TCP, DCP and PHA
  • Biocement D mixture of ⁇ -TCP, DCP, CaCO 3 and PHA
  • Bio-cement H-OCP Mixture of ⁇ -TCP and OCP
  • Biozement F-OCP Mixture of ⁇ -TCP, DCP and OCP
  • Biozement D-OCP Mixture of ⁇ -TCP, DCP, CaCO 3 and OCP
  • the numbers of the mixing ratios are in grams.
  • the liquid used to mix the powders is a 4% solution of Na 2 HPO 4 in water.
  • the liquid / powder ratio is 0.30 ml / g powder. - 11 -
  • the beginning (initial) hardening (t,) and the time to reach the final hardness (t f ) were determined at room temperature (20 ⁇ 1 ° C) and at 37 ⁇ 1 ° C according to ASTM standards using Gilmoore needles.
  • the compression strength was determined using a Lloyd type LR50K material testing machine after 1, 2, 4, 18 and 65 hours of immersion in Ringer's solution.
  • the reaction product was determined by means of X-ray diffractometry.
  • DCP is preferred in particular whose Ca / P ratio is> than 1.45.
  • Antibiotics / disinfectants in liquid preparation and as a solid were mixed into the cements obtained and the release behavior was determined.
  • a phosphate buffer according to Sörensen, pH 7.4 at 37 ° C was used as the elution solution.
  • Mixtures of cements with antibiotics / disinfectants were determined for their hardening properties based on ASTM standards. X-ray diffractometry showed that CaHPO 4 did not react in the cements F-OCP and D-OCP and that calcium-deficient-hydroxyapatite was formed despite the addition of OCP as a seed.
  • Biocement t (20 ° Q t, (37 ° Q t f (20 ° C t f (37 ° C) ⁇ -TCP 31 (1) 4.5 (0.25) 51 (1) 7 (0.5)
  • F-OCP 10 (0.5) 3.5 (0.25) 16.5 (1) 4.5 (0.25)
  • the results show that the problem underlying the invention has been solved.
  • the initial and final curing time is reduced by adding OCP and pHA compared to ⁇ -TCP (with 10% ß-TCP content).
  • the shift in the hardening kinetics towards shorter times is particularly pronounced at low temperatures, whereas the effect appears only very slightly at body temperature.
  • This is particularly advantageous for the processing properties of the cement obtained, because a sufficiently long processing time is guaranteed at room temperature, whereas the hardening at body temperature does not become too short and the cement introduced can therefore still be modeled. It can be seen from the data on the compressive strength of the bio-cements demonstrated here by way of example that the final strength is generally reached after 6 hours and that the bio-cements D and D-OCP achieve strengths of up to 50 MPa.
  • Example 3 The next task on which the invention is based, namely the mixing in and progressive release of active substances from the cements, for example an antibiotic for implant protection or for combating infection, is demonstrated below as being solved.
  • the release kinetics of the selected bio-cement D with different antibiotics as well as the release kinetics of different bio-cements with gentamicin are shown in Figures 1 and 2. - 13 -
  • the mixing of antibiotics / disinfectants does not adversely affect the hardening kinetics or the strength in relation to the desired effect of the antibiotic release.
  • biocement H, F and D with gentamicin sulfate powder at a liquid-powder ratio of 0.30 using Na 2 HPO 4 or gentamicin sulfate solution as a liquid at 37 ° C. are shown.
  • the stated strength values were determined after 20 hours.
  • the values tj and tf are measured in minutes and refer to the measurements with the Gilmoore needle.
  • the cohesion time (CT) was measured at room temperature and is given in minutes.
  • the percentage of ⁇ / ß-TCP is essentially determined by the percentage by weight of Mg and Na in the starting material. -14-
  • stamping is also influenced by the relative Ca / P ratio.
  • the following table provides an overview of the influence of Mg and Na on the phase composition of TCP:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Surgery (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne des ciments de phosphate de calcium biodégradables, notamment des mélanges de poudres, renfermant du phosphate de calcium, dans différentes compositions stoechiométriques, présentant des propriétés améliorées. Lesdits mélanges contiennent tous du phosphate tricalcique (TCP) et au moins un autre composé inorganique renfermant du phosphate dans différentes compositions, la proportion de TCP étant présente dans une plage de dimensions de particules bien définie.
EP99910351A 1998-03-27 1999-03-17 Biociments presentant des proprietes ameliorees Withdrawn EP1066065A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19813614 1998-03-27
DE19813614A DE19813614A1 (de) 1998-03-27 1998-03-27 Bio-Zemente mit verbesserten Eigenschaften
PCT/EP1999/001738 WO1999049906A1 (fr) 1998-03-27 1999-03-17 Biociments presentant des proprietes ameliorees

Publications (1)

Publication Number Publication Date
EP1066065A1 true EP1066065A1 (fr) 2001-01-10

Family

ID=7862589

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99910351A Withdrawn EP1066065A1 (fr) 1998-03-27 1999-03-17 Biociments presentant des proprietes ameliorees

Country Status (10)

Country Link
EP (1) EP1066065A1 (fr)
JP (1) JP2002509766A (fr)
CN (1) CN1295485A (fr)
AU (1) AU2933699A (fr)
CA (1) CA2325740A1 (fr)
DE (1) DE19813614A1 (fr)
HU (1) HUP0101520A3 (fr)
PL (1) PL342733A1 (fr)
WO (1) WO1999049906A1 (fr)
ZA (1) ZA200006034B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106587681A (zh) * 2016-12-06 2017-04-26 南昌大学 一种新兴绿色建筑材料‑生物水泥的制备方法

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1153621A1 (fr) * 2000-05-12 2001-11-14 MERCK PATENT GmbH Biociments basés sur le mélange TCP-PHA présentant une résistance améliorée à la compression
AU2002213313B2 (en) 2000-10-16 2006-08-17 University Of South Carolina Biocompatible cement containing reactive calcium phosphate nanoparticles and methods for making and using such cement
JP2002291866A (ja) * 2001-04-03 2002-10-08 Ngk Spark Plug Co Ltd リン酸カルシウムセメント粉体及びリン酸カルシウムセメント
DE10249625B4 (de) * 2002-10-21 2005-08-04 BAM Bundesanstalt für Materialforschung und -prüfung Pulvergemisch für resorbierbare Calciumphosphat-Biozemente und ihre Verwendung
WO2007030616A2 (fr) 2005-09-09 2007-03-15 Wright Medical Technology, Inc. Ciment de substitution composite pour greffe osseuse et articles produits a partir de ce ciment
EP2077126A1 (fr) * 2008-01-07 2009-07-08 Graftys Ciment calcium-phosphate apatitique analgésique
JP5478872B2 (ja) * 2008-11-05 2014-04-23 国立大学法人東北大学 人工骨材
CN104837512B (zh) * 2012-01-31 2017-06-23 托莱多大学 可注射的、生物可降解的骨接合剂及其制造和使用方法
US9487443B2 (en) * 2014-03-14 2016-11-08 Ricoh Company, Ltd. Layer stack formation powder material, powder layer stack formation hardening liquid, layer stack formation material set, and layer stack object formation method

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668295A (en) * 1985-04-25 1987-05-26 University Of Dayton Surgical cements
DE3613213A1 (de) * 1986-04-18 1987-10-22 Merck Patent Gmbh Tricalciumphosphat fuer implantationsmaterialien
US5569442A (en) * 1994-11-04 1996-10-29 Norian Corporation Reactive tricalcium phosphate compositions and uses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9949906A1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106587681A (zh) * 2016-12-06 2017-04-26 南昌大学 一种新兴绿色建筑材料‑生物水泥的制备方法
CN106587681B (zh) * 2016-12-06 2019-04-12 南昌大学 一种绿色建筑材料-生物水泥的制备方法

Also Published As

Publication number Publication date
PL342733A1 (en) 2001-07-02
JP2002509766A (ja) 2002-04-02
CA2325740A1 (fr) 1999-10-07
AU2933699A (en) 1999-10-18
CN1295485A (zh) 2001-05-16
HUP0101520A2 (hu) 2001-11-28
HUP0101520A3 (en) 2001-12-28
DE19813614A1 (de) 1999-09-30
ZA200006034B (en) 2001-08-10
WO1999049906A1 (fr) 1999-10-07

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