ANTIBIOTIC-GRAFTED ALUMINA CERAMIC MATRIX

Abstract

The object of the invention is a porous alumina ceramic matrix grafted with an antibiotic, in particular vancoymicin, as well as its use in therapy. The invention also relates to a prosthesis or an implant using this matrix. The invention also relates to a method for preparing a matrix according to the invention.

Claims

1.-12. (canceled)

13. A porous alumina ceramic matrix grafted with an antibiotic.

14. The matrix according to claim 13, wherein the porosity of the matrix is between 40 and 80%.

15. The matrix according to claim 13, wherein the pore size is from 100 to 900 m.

16. The matrix according to claim 13, wherein the porosity is open.

17. The matrix according to claim 13, wherein the mechanical resistance to compression is between 20 and 60 MPa.

18. The matrix according to claim 13, wherein the ceramic matrix has a volume porosity of 45 to 75%, and a pore size of 100 to 900 m, wherein the ceramic is obtained by impregnation of a foam, pre-sintering at a temperature above 1200 C., superpregnation with a slip, and sintering at a temperature above 1500 C.

19. The matrix according to claim 13, wherein the antibiotic is chosen from: beta-lactamases, in particular amoxicillin, oxacillin, cloxacillin, ceftriaxone, cefotaxime, ceftazidime, piperacillin, imipenen, ertapenem, ceftaroline, aztreonam, cefepime, cefazolin; clofazimine; glycopeptides, in particular vancomycin, its derivatives, teicoplanin; and lipoglycopeptides, in particular dalbavancin, oritavancin, telavancin, daptomycin.

20. The matrix according to claim 19, wherein the antibiotic is vancomycin or a derivative.

21. The matrix according to claim 13, for reducing and/or preventing bacterial proliferation and/or the formation of bacterial biofilm.

22. The matrix according to claim 13, for use in therapy or prophylaxis.

23. The matrix according to claim 13, for use in the treatment of bone infections or bone cancers.

24. The matrix according to claim 13, for use in therapy as blocks of bone fillings, blocks of corpectomy, cages or intersomatic wedges of the cervical or lumbar spine, cervical wedges, calcaneus wedges, osteotomy wedges such as the addition of tibial wedges, derotation wedges such as anterior tibual tuberosity, compensation, valgization, reconstruction and filling blocks, pins, fixation and arthrodesis wedges and pivots, drill pellets, arthrodesis blocks ensuring the maintenance of natural space or intersomatic interline, special reconstruction implants: sinus filling block, orbit floor and ceiling, craniotomy plugs, filling implants and maxillofacial rehab plates, and any anatomical part on which it is possible to reinsert nerves or facia lata tissues.

25. The matrix according to claim 13 forming a prosthesis or an implant.

26. A method of preparing a porous alumina ceramic matrix grafted with an antibiotic, comprising the following steps: reaction of a diacid on the alumina ceramic matrix; formation of an ester; and transamidification by reaction on an amino group of the antibiotic.

27. The method of preparing a matrix according to claim 26, wherein the ester is an N-hydroxysuccinimide ester.

28. The method of preparing a matrix according to claim 26, wherein the ester is formed in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0035] FIG. 1 represents vancomycin and the reactive amine site (vancosamine) thereof during grafting, and located opposite the effective part of the molecule that is represented with the interactions.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0036] The invention is now described in more detail and in a non-limiting manner in the description below.

Matrix

[0037] The matrix used in the present invention is a porous ceramic based on alumina Al.sub.2O.sub.3.

[0038] The (open) porosity of this ceramic may, in particular, be between 40 and 80%, preferably between 60 and 70%, advantageously about 65%

[0039] The pore size is typically from 100 to 900 m, preferably from 200 to 600 m, more preferably about 400 m.

[0040] The porosity/pore size is measured by mercury porosimetry. The porosity is defined by the difference between the volume occupied by the pores and the total volume, wherein the total volume is the sum of the volume of the pores and of the alumina. The weight of alumina is defined by the volume and the density, wherein, by weighing the sample and knowing its total volume, one can determine by difference the volume of pores and therefore the (open) porosity.

[0041] The size of the ceramic matrix is variable and may range from a few millimeters to several centimeters or even tens of centimeters; the volume may be between 1 and 250 cm.sup.3, for example between 5 and 100 cm.sup.3.

[0042] The mechanical resistance to compression is advantageously between 20 and 60 MPa, advantageously greater than 40 MPa.

[0043] Any known method for the preparation of porous alumina may generally be used. One may, in particular, use a method comprising the following steps: [0044] (A) supply of a pore-forming material (of the foam type, for example polyurethane foam, that is used, in particular, to regulate the porosity and the size of the pores) and impregnation of the pore-forming material with a suspension of alumina ceramic particles (alumina slip), possibly mixed with various organic additives such as binders, plasticizers and dispersants; [0045] (B) drying in an oven; [0046] (C) heat treatment at low temperature (below 700 C.) to remove the foam and organic constituents from the suspension; then [0047] (D) sintering at a temperature above 1500 C., for example above 1600 C.

[0048] The method described in patent application FR2823674 may advantageously be used.

Antibiotic Active Ingredient

[0049] The antibiotic to be grafted is an antibiotic having an accessible amine functional group and having an action on the bacterial wall. Antibiotics having an action on the wall on the bacteria are preferred to those having an action inside the bacteria.

[0050] Antibiotics may be chosen from the following non-exhaustive list: [0051] beta-lactamases, in particular amoxicillin, oxacillin, cloxacillin, ceftriaxone, cefotaxime, ceftazidime, piperacillin, imipenen, ertapenem, ceftaroline, aztreonam, cefepime, cefazolin; [0052] clofazimine; [0053] glycopeptides, in particular vancomycin, its derivatives, teicoplanin; [0054] lipoglycopeptides, in particular dalbavancin, oritavancin, telavancin, daptomycin.

[0055] The preferred antibiotic is vancomycin and its derivatives.

[0056] According to the present invention, the antibiotic is present on the surface of the ceramic matrix, wherein the surface may be the internal surface of the alumina ceramic. The antibiotic is grafted via covalent bonds.

Grafting Method

[0057] The grafting method makes it possible to link the antibiotic via spacers with an amine functional group on the surface of the alumina ceramic.

[0058] The first step involves contacting a diacid in an appropriate solvent. The solvent may be tetrahydrofuran (THF). The diacid may be an aliphatic diacid comprising, apart from the acid functions, from 4 to 14 carbon atoms, for example 8, and may be 1,10-decanedicarboxylic acid. The excess solvent is removed by thorough evaporation. This first step results in the grafting of the spacers on the surface using two hydroxyl groups present on the surface.

[0059] The second step is the formation of an N-hydroxysuccinimide (NHS) ester. The acid-modified ceramic is placed in a solution of N-hydroxysuccinimide (NHS) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), in a buffer, for example, of 2-(N-morpholino)ethanesulfonic (MES) acid, for example at room temperature for a time between 10 minutes and 2 hours. The EDC/NHS combination is known for the binding of biomolecules. An NHS ester is obtained at the end of this second step.

[0060] The third step is the coupling of the antibiotic. An accessible amine function, based on the application of the principles of steric hindrance, will then react with the NHS ester to form an amide bond, by transamidation. The reaction solvent may be the MES buffer or an organic solvent such as ethanol. The reaction temperature may be, for example, at room temperature. The reaction time may be, for example, between 1 and 48 hours. The pellets are then washed, for example using the same solvent, then cleaned and dried in the conventional manner.

[0061] In the case of vancomycin, the reactive site is the glucose-related vancosamine function. This reactive part is identified in FIG. 1, with the indication of the interactions between vancomycin and the D-ala-D-ala residues of the peptidoclycan of the bacterial wall.

Applications.

[0062] The invention finds application in a large number of uses, in particular in traumatology for reconstructions of fractures, in orthopedics as filling elements, or as implants (for fusion of the spine, etc.), for osteotomies through addition, and for reconstructions, (for example maxillofacial) and, in particular, for interventions in the context of treatment of bone cancers, of a primary or secondary nature.

[0063] The invention allows the production of numerous bone substitutes and implants, which may be used, for example, as addition wedges or for bone filling throughout the entire skeleton.

[0064] Exemplary applications may be cited such as bone filling blocks, corpectomy blocks, cages or intersomatic wedges of the cervical or lumbar spine, cervical wedges, calcaneus wedges, osteotomy wedges (e.g. tibial addition wedges), derotation wedges (e.g. anterior tibial tuberosity), compensation, valgization, reconstruction and filling blocks, fixing and arthrodesis wedges and pivots, drill bit pellets, arthrodesis blocks ensuring maintenance of the natural space or intersomatic interline, special reconstruction implants: sinus filling block, orbit floor and ceiling, craniotomy plugs, bone filling implants whatever the location of the skeleton, and generally any anatomically-shaped part on which it is possible to reinsert nerves or facia lata tissues wherever the location of implantation on the skeleton.

[0065] The grafting of the antibiotic such as vancomycin on the ceramic reduces the risk of colonization of the material by germs sensitive to vancomycin. The grafted vancomycin interacts with the D-ala-D-ala produced by the bacteria and prevents bacterial transpeptidases (penicillin-binding protein) from forming the peptidoglycan. Therefore, the bacteria cannot form its wall and is lysed.

[0066] A particular interest of the invention is long-term protection of the implant to avoid colonization (i) during implantation but, also, (ii) over time given the covalent grafting of the molecule.

EXAMPLE

[0067] The following example illustrates the invention without limiting it.

[0068] Step 1:

[0069] Alumina ceramic pellets were placed in a solution of 1,10-decanedicarboxylic acid in dry THF (tetrahydrofuran) at room temperature. The excess solvent was removed by placing in the oven.

[0070] This first step results in the grafting of the spacers on the surface using two hydroxyl groups present on this surface.

[0071] Step 2:

[0072] The pellets modified by 1,10-decanedicarboxylic acid were then placed in a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) in a 2-(N-morpholino)ethanesulfonic (MES) acid buffer at room temperature to obtain an NHS ester.

[0073] Step 3:

[0074] Finally, the vancomycin was allowed to react with the pellets from the previous step in the MES buffer. The pellets were then washed with MES buffer and cleaned in an ultrasonic bath.

[0075] FIG. 1 shows the vancomycin molecule with the reaction amine, vancosamine.