U.S. patent number RE43,793 [Application Number 13/213,472] was granted by the patent office on 2012-11-06 for endosseous implant.
This patent grant is currently assigned to Ecole Polytechnique Federale de Lausanne, Universite de Geneve. Invention is credited to Bjorn-Owe Aronsson, Pierre Descouts, Michael Gratzel, Peter Pechy, Carine Viorney.
United States Patent |
RE43,793 |
Descouts , et al. |
November 6, 2012 |
Endosseous implant
Abstract
Endosseous implant to be applied to a human or animal bone,
wherein the surface of the implant is made from titanium or a
titanium alloy, said implant having a smooth or rough surface
texture, which is characterized in that said surface has been
treated with at least one selected organic phosphonate compound or
a pharmaceutically acceptable salt or ester or an amide thereof;
process for producing said implants.
Inventors: |
Descouts; Pierre (Neydens,
FR), Aronsson; Bjorn-Owe (Veyrier, CH),
Gratzel; Michael (St. Sulpice, CH), Viorney;
Carine (Carantec, FR), Pechy; Peter (Lausanne,
CH) |
Assignee: |
Universite de Geneve (Geneva,
CH)
Ecole Polytechnique Federale de Lausanne (Lausanne,
CH)
|
Family
ID: |
8164167 |
Appl.
No.: |
13/213,472 |
Filed: |
November 19, 2001 |
PCT
Filed: |
November 19, 2001 |
PCT No.: |
PCT/EP01/13364 |
371(c)(1),(2),(4) Date: |
August 28, 2003 |
PCT
Pub. No.: |
WO02/40074 |
PCT
Pub. Date: |
May 23, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
10432026 |
Aug 28, 2003 |
7727540 |
Jun 1, 2010 |
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Foreign Application Priority Data
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Nov 20, 2000 [WO] |
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PCT/EP00/11510 |
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Current U.S.
Class: |
424/422;
433/201.1; 623/23.57; 606/76 |
Current CPC
Class: |
C07F
9/572 (20130101); C07F 9/4046 (20130101); C07F
9/3843 (20130101); C07F 9/3808 (20130101); A61L
27/32 (20130101); A61C 8/0012 (20130101); A61P
19/00 (20180101); A61L 27/06 (20130101); A61F
2/30767 (20130101); A61L 27/10 (20130101); C07F
9/6561 (20130101); C07F 9/58 (20130101); C07F
9/3865 (20130101); C07F 9/6506 (20130101); A61F
2/28 (20130101); C07F 9/3873 (20130101); A61F
2310/00598 (20130101); A61F 2310/00407 (20130101); A61F
2310/0088 (20130101); A61F 2310/00485 (20130101); A61F
2310/00053 (20130101); A61F 2310/00089 (20130101); A61F
2310/00431 (20130101); A61L 2430/02 (20130101); A61F
2310/0073 (20130101); A61F 2310/00856 (20130101); A61F
2310/00544 (20130101); A61F 2310/00023 (20130101); A61F
2310/00017 (20130101); A61F 2310/00029 (20130101); A61F
2310/00443 (20130101); A61F 2310/00449 (20130101); A61F
2310/00059 (20130101); A61F 2310/00413 (20130101); A61F
2310/00796 (20130101); A61F 2310/00748 (20130101); A61F
2310/00928 (20130101); A61F 2310/00616 (20130101); A61F
2310/00976 (20130101); A61F 2310/00401 (20130101); A61C
2008/0046 (20130101); A61F 2/0095 (20130101); A61F
2310/00095 (20130101); A61F 2310/00131 (20130101); A61F
2310/00491 (20130101); A61F 2310/00047 (20130101) |
Current International
Class: |
A61C
8/00 (20060101); A61F 2/28 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 860 213 |
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Aug 1998 |
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EP |
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92 09697 |
|
Jun 1992 |
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WO |
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97/14716 |
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Apr 1997 |
|
WO |
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98/52619 |
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Nov 1998 |
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WO |
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99 11202 |
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Mar 1999 |
|
WO |
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99/31126 |
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Jun 1999 |
|
WO |
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02/13872 |
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Feb 2002 |
|
WO |
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02/14350 |
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Feb 2002 |
|
WO |
|
Other References
Carine Viornery, "Surface functionalization of titanium with
phosphonated ligands to improve bone bonding", These No. 2309,
Lausanne, EPFL, 2000. cited by other .
Abstract of A. Sewing et al., "Cell Culture Study on Biomimetic
Coatings and Adhesion Peptides as Functionalized Coating for Dental
Implants", Conference at 16th European Conference on Biomaterials,
Sep. 12-14, 2001, London, UK. cited by other .
Abstract of S. Ro.beta.ler et al., "Biomimetic Coatings
Functionalized with Adhesion Peptides for Dental Implants",
Conference at 16th European Conference on Biomaterials, Sep. 12-14,
2001, London, UK. cited by other .
Thesis of Martin Kantlehner, Techincal University of Munich, 2000.
cited by other.
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Primary Examiner: Wax; Robert A
Assistant Examiner: Al-Awadi; Danah
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
L.L.P.
Claims
The invention claimed is:
1. An endosseous implant suitable for application to a human or
animal bone, said implant having a surface made from titanium or a
titanium alloy, said surface having a smooth or rough texture,
wherein said surface has a layer formed thereon of at least one
pharmaceutically acceptable organic compound or an ester.[., an
amide.]. or a salt thereof, corresponding to the general formula
(I): A-[P(O)(OH).sub.2].sub.p (I), wherein A means A.sub.1, and
A.sub.1 is a residue of a linear, branched or cyclic, saturated or
unsaturated, hydrocarbon residue with n carbon atoms, wherein n is
a number from 1 to 70, whereby said residue is not interrupted or
is interrupted by one or more oxygen and/or nitrogen atoms, wherein
each residue A.sub.1 carries p phosphonic acid groups, and when n
is 1 and p is 2: A is --CH.sub.2--, or when n is 1: p is 3 or 4, or
when n is 2 to 10: p is 2, provided each phosphonic acid group or
phosphonic acid ester group is bound to a different carbon atom
within the same molecule; or when n is 2 to 10: p is 3, 4, 5 or 6;
or when n is 11 to 70: p is 2, 3, 4, 5 or 6; or A means A.sub.2 and
A.sub.2 is a residue of an amino acid or of a sequence of amino
acids respectively of a protein or of a polypeptide; or a residue
of a specific drug molecule, wherein each residue A.sub.2 carries p
phosphonic acid groups, and p is 1 to 6 when A.sub.2 is a residue
of an amino acid or of a sequence of amino acids respectively of a
protein or of a polypeptide; or p is 1 or 3-6 when A.sub.2 is a
residue of a specific drug molecule originally not bearing any
phosphonate group, optionally falling under the definition given
for A.sub.1.
2. The implant according to claim 1, wherein A.sub.1 is a saturated
hydrocarbon residue of the formula --(C.sub.nH.sub.2n+2-p)--,
wherein n means 1 to 70.
3. The implant according to claim 1, wherein the pharmaceutically
acceptable salt is an alkali salt.
4. The implant according to claim 1, wherein the pharmaceutically
acceptable ester is an alkyl phosphonate.[., or an ethyl
acetate.]..
5. The implant according to claim 1, wherein the compound of
formula (I) is a polyphosphonic acid.
6. The implant according to claim 4, wherein the compound of
formula (I) is an ester.
7. The implant according to claim 1, wherein the compound of
formula (I) is a Transforming Growth Factor beta (TGF-.beta.) as
defined by the members of the superfamily of growth factors,
wherein each time the peptide chain has been modified to contain at
least one alkylphosphonic acid group or a derivative thereof.
8. The implant according to claim 1, wherein the compound of
formula (I) is a Bone Morphogenic Protein (BMP), wherein the
peptide chain has been modified to contain at least one
alkylphosphonic acid group or a derivative thereof.
9. The implant according to claim 1, wherein the compound of
formula (I) is 2-amino-4,4-bis-(diethoxy-phosphoryl)-butyric acid,
2-amino-5-(diethoxy-phosphoryl)-pentanoic acid and/or
2-amino-4-phosphonobutyric acid.
10. The implant according to claim 1, wherein the compound of
formula (I) is one of the principal twenty amino acids, wherein the
amino acid has been modified to contain at least one
alkylphosphonic acid group or a derivative thereof.
11. The implant according to claim 1, wherein the compound of
formula (I) is a RGD-containing peptide, which has been modified to
contain at least one alkyl-phosphonic acid group or derivative
thereof.
12. A process for producing the implant according to claim 1, which
comprises treating said surface with at least one organic compound
of formula (I) or an ester.[., an amide.]., a salt or a mixture
thereof.
13. The implant according to claim 1, in the form of screws,
plates, nails, pins or specially formed parts which may be used as
prostheses in orthopaedics, for replacing or strengthening broken
or diseased bones, in dentistry, for anchoring artificial teeth, or
for anchoring of bone anchored hearing prosthesis into the skeletal
structure of humans and animals.
14. The implant according to claim 13, wherein said implant is
packed with a plastic or metallic packaging material.
15. The implant according to claim 14, wherein said packaging is
filled with pure water containing an inorganic salt and/or a
compound of the formula (I) or a salt thereof.
16. The implant according to claim 1, wherein n is a number from 1
to 40.
17. The implant according to claim 1, wherein n is a number from 1
to 22.
18. The implant according to claim 1, wherein when n is 1, p is
3.
19. The implant according to claim 1, wherein when n is 2, p is 3,
4 or 5.
20. The implant according to claim 1, wherein when n is 2, p is 3
or 4.
21. The implant according to claim 1, wherein when n is 11 to 70, p
is 2, 3, 4 or 5.
22. The implant according to claim 1, wherein when n is 11 to 70, p
is 2, 3 or 4.
23. The implant according to claim 1, wherein A.sub.2 is a residue
of the superfamily of Transforming Growth Factor beta
(TGF-.beta.).
24. The implant according to claim 1, wherein p is 1, 2, 3 or 4
when A.sub.2 is a residue of an amino acid or of a sequence of
amino acids respectively of a protein or a polypeptide.
25. The implant according to claim 1, wherein p is 1, 2 or 3 when
A.sub.2 is a residue of an amino acid or of a sequence of amino
acids respectively of a protein or a polypeptide.
26. The implant according to claim 1, wherein p is 1 when A.sub.2
is a residue of a specific drug molecule originally not bearing any
phosphonate group, optionally falling under the definition given
for A.sub.1.
27. The implant according to claim 2, wherein n is 1 to 40.
28. The implant according to claim 2, wherein n is 1 to 22.
29. The implant according to claim 3, wherein the salt is a sodium
or potassium salt.
30. The implant according to claim 5, wherein the polyphosphonic
acid is selected from the group consisting of methylenediphosphonic
acid, ethane-1,2-diphosphonic acid, propane-1,3-diphosphonic acid,
.[.propane-1,3-diphosphonic acid,.]. ethane-1,1,2-triphosphonic
acid, butane-1,1,4-triphosphonic acid, pentane-1,1,5-triphosphonic
acid, pentane-2,2,5-triphosphonic acid, hexane-2,2,6-triphosphonic
acid, pentane-1,1,5,5-tetraphosphonic acid,
heptane-1,4,4,7-tetraphosphonic acid,
propane-1,1,3,3-tetraphosphonic acid,
.[.nonane-1,5,5,9-tetraphosphonic acid,.]. an ester thereof, a salt
thereof, and a mixture thereof.
31. The implant according to claim 6, wherein the ester is selected
from the group consisting of tetra isopropyl
methylenediphosphonate, hexaethyl ethane-1,1,2-triphosphonate,
hexaisopropyl butane-1,1,4-triphosphonate, hexaisopropyl
pentane-1,1,5-triphosphonate, hexaisopropyl
pentane-2,2,5-triphosphonate, hexaisopropyl
hexane-2,2,6-triphosphonate, octaisopropyl
propane-1,1,3,3-tetraphosphonate.[.,.]. .Iadd.and
.Iaddend.octaisopropyl heptane-1,4,4,7-tetraphosphonate .[.and
octaisopropyl nonane-1,5,5,9-tetraphosphonate.]..
32. The implant according to claim 7, wherein the compound of
formula (I) is a Transforming Growth Factor beta (TGF-.beta.) as
defined by the members of the superfamily of growth factors,
selected from the group consisting of TGF-.beta.1, TGF-.beta.2,
TGF-.beta.3, TGF-.beta.4 and TGF-.beta.5, wherein each time the
peptide chain has been modified to contain at least one
alkylphosphonic acid group or an ester.[., an amide.]. or a salt
thereof.
33. The implant according to claim 8, wherein the compound of
formula (I) is a Bone Morphogenic Protein (BMP), selected from the
group consisting of BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5,
BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12
and BMP-13, wherein the peptide chain has been modified to contain
at least one alkylphosphonic acid group or an ester.[., an amide.].
or a salt thereof.
34. The implant according to claim 10, wherein the compound of
formula (I) is selected from the group consisting of arginine,
glycine, aspartic acid, alanine, valine, proline, serine,
threonine, cysteine and lysine, wherein the amino acid has been
modified to contain at least one alkylphosphonic acid group or an
ester.[., an amide.]. or a salt thereof.
35. The implant according to claim 11, wherein the compound of
formula (I) is selected from the group consisting of a
RGDS-peptide, a GRGDS-peptide, a RGDV-peptide, a RGDE-peptide, a
RGDT-peptide, and a mixture thereof, which has been modified to
contain at least one alkyl-phosphonic acid group or an ester.[., an
amide.]. or a salt thereof.
36. The implant according to claim 14, wherein said implant is
packed with a plastic or metallic packaging material, into an air
tight packaging which is evacuated or filled with an inert gas or
an inert liquid.
37. The implant according to claim 36, wherein said air tight
packaging is filled with pure water containing an inorganic alkali
salt and/or a compound of the formula (I) or a salt thereof in a
concentration of from about 1.0.times.10.sup.-5 mol/10 ml to
5.times.10.sup.-2 mol/10 ml, of the water.
38. The implant according to claim 36, wherein said air tight
packaging is filled with pure water containing an inorganic alkali
salt and/or a compound of the formula (I) or a salt thereof in a
concentration of from about 5.times.10.sup.-4 mol/10 ml to
2.0.times.10.sup.-2 mol/10 ml of the water.
Description
.Iadd.This application is a reissue application of U.S. application
Ser. No. 10/432,026, filed Aug. 28, 2003, which issued as U.S. Pat.
No. 7,727,540, issued Jun. 1, 2010, which is a national stage
application of International Application No. PCT/EP01/13364, filed
Nov. 19, 2001, which claims priority to International Application
No. PCT/EP00/11510, filed Nov. 20, 2000. .Iaddend.
The present invention relates to a metallic endosseous implant made
from titanium or a titanium alloy to be applied to a human or
animal bone, said implant having a smooth or rough surface texture,
and wherein said surface has been treated with at least one
selected organic compound carrying one or more phosphonic acid
group [--P(O)(OH).sub.2] or a derivative thereof, preferably as a
pharmaceutically acceptable salt or ester or amide thereof. It has
been shown that such chemically modified surface surprisingly
enhances the bone bonding strength. Implants according to the
present invention may be used as prostheses in medicine, more
specifically in orthopaedics, for replacing or strengthening broken
or diseased bones, and in dentistry, for anchoring artificial teeth
and for anchoring of bone anchored hearing prosthesis.
Implants which are used as prostheses in medicine for replacing or
strengthening broken or diseased bones or as artificial teeth are
known. These implants must be made of a non-corrosive material and
must be compatible with the surrounding tissue without producing
immunologic reactions effecting rejection by the body. In the
following. the terms "surface" or "contact surface" refer to the
titanium or a titanium alloy implant surface not yet treated
according to the present invention and the term "modified surface"
to the surface treated according to the present invention.
It is known that to implant devices in the form of screws, plates,
nails, pins, and specially formed parts into the skeletal structure
of humans and animals as artificial prosthetic is a means for
permanent replacement of missing structural parts or as permanent
anchoring devices. An excellent "osseointegration " is required for
those situations where the implanted device should remain
permanently adhered to the contacting bone surface.
It is generally known to use titanium metal or titanium alloys for
such implants. When carefully produced, the titanium implant with
its surface oxide exhibits biocompatibility in the sense that it
remains passive for bone regeneration and does not per se induce
adverse reactions such as inflammation or soft tissue generation or
encapsulation. The interface obtained between the implant and the
bone tissue normally consists of a protein layer of about 100 nm to
1 .mu.m thickness preventing the bone tissue from being in direct
molecular contact with the implant.
The actual state of the art for endosseous implants is based on
different approaches, for example (i) the creation of a suitable
roughness of the implant surface giving a mechanical interlocking
between bone and implant and/or (ii) coating the titanium or
titanium alloy surface of the implant, e.g. with an artificial
hydroxyapatite for improving the healing process and the
bone-implant intimate contact.
It is known that a high surface roughness on titanium implants
increases the mechanical stability of the implant in the bone
tissue. Mechanical surface treatment significantly alters the
topography, while the surface chemistry remains substantially
unchanged. The disadvantages of an implant with a high surface
roughness are that a purely mechanical anchoring is very sensible
to micromotions which may lead to a deterioration of the mechanical
anchorage and that the osseointegration time of the implant is
relatively long.
Coating the surface of the implant with an artificial
hydroxyapatite decreases the osseointegration time. However, it is
very difficult, if not impossible, to produce hydroxyapatite
coatings with a long term stability on load bearing implants. The
interface between the coating and the implant is often disrupted or
the coatings are flaked off.
U.S. Pat. No. 5,733,564 suggests to use selected bisphosphonates
which are known drug substances for the promotion of bone tissue
formation by coating titanium metal surfaces of prostheses or
implants with these compounds.
It has now been found that if the surface of a titanium or a
titanium alloy endosseous implant has been treated with at least
one selected organic compound as defined herein below carrying one
or more phosphonic acid groups or a derivative thereof, preferably
an ester, an amide or a salt thereof, as defined herein below, said
surface shows a surprisingly improved bone bonding strength and a
surprisingly shortened osseointegration time compared to the non
treated surface and does not have the disadvantages as known for
surfaces having a hydroxyapatite coating.
The present invention is defined in the claims. The present
invention specifically refers to an endosseous implant to be
applied to a human or animal bone, wherein the surface of the
implant is made from titanium or a titanium alloy, said implant
having a smooth or rough surface texture, which is characterized in
that said surface has been treated with at least one organic
compound corresponding to the general formula (I):
A-[P(O)(OH).sub.2].sub.p (I), or a pharmaceutically acceptable
derivative thereof, which is preferably an ester, an amide or a
salt thereof, wherein A means A.sub.1 or A.sub.2, and A.sub.1 is a
residue of a linear, branched or cyclic, saturated or unsaturated,
hydrocarbon residue with n carbon atoms, whereby said residue may
be substituted by hydroxyl and/or carboxyl and optionally further
interrupted by one or more oxygen and/or sulphur and/or nitrogen
atoms, carrying p phosphonic acid groups, wherein n is a number
from 1 to 70, preferably 1 to 40, preferably 1 to 22, and when n is
1 and p is 2: A is --CH.sub.2--, or when n is 1: p is 3 or 4,
preferably 3, or when n is 2 to 10: p is 2, provided each
phosphonic acid group or phosphonic acid ester group is bound to a
different carbon atom within the same molecule; or when n is 2 to
10: p is 3, 4, 5 or 6, preferably 3, 4 or 5, preferably 3 or 4; or
when n is 11 to 70: p is 2, 3, 4, 5 or 6, preferably 2, 3, 4 or 5,
preferably 2, 3 or 4; or A means A.sub.2 and A.sub.2 is a residue
of an amino acid or of a sequence of amino acids resp. of a protein
or of a polypeptide, preferably a residue of the superfamily of
Transforming Growth Factor beta (TGF-.beta.); or a residue of a
specific drug molecule, wherein each residue A.sub.2 carries p
phosphonic acid groups, and p is 1 to 6, preferably 1, 2, 3 or 4,
preferably 1, 2, or 3, when A.sub.2 is a residue of an amino acid
or of a sequence. of amino acids resp. of a protein or of a
polypeptide; or p is 1 or 3-6, preferably 1, when A.sub.2 is a
residue of a specific drug molecule originally not bearing any
phosphonic group, optionally falling under the definition given for
A.sub.1.
The present invention further refers to a process for producing the
implant according to the present invention which is characterized
in that said surface is treated with at least one organic compound
of formula (I) or a derivative thereof, which is preferably an
ester, an amide or a salt thereof.
It is assumed that the phosphonate compounds as specified herein,
especially as acids or salts, form a covalent bond with the surface
of the implant thereby improving the osseointegration properties of
said surface to a remarkable and unexpected extent. The present
invention however is not bound to this explanation.
A.sub.1 preferably is a saturated hydrocarbon residue of the
formula --(C.sub.nH.sub.2n+2-p)--, wherein n means 1 to 70,
preferably 1 to 40, preferably 1-22. Preferred is the free acid or
the salt form of the compound of formula (I), preferably where the
pharmaceutically acceptable salt is an alkali salt, preferably of
sodium or potassium salt. If the pharmaceutically acceptable ester
is used, the isopropyl phosphonate or ethyl phosphonate esters are
preferred, examples of such esters are: tetra isopropyl
methylenediphosphonate, hexaethyl ethane-1,1,2-triphosphonate,
hexaisopropyl butane-1,1,4-triphosphonate, hexaisopropyl
pentane-1,1,5-triphosphonate, hexaisopropyl
pentane-2,2,5-triphosphonate, hexaisopropyl
hexane-2,2,6-triphosphonate, octaisopropyl
propane-1,1,3,3-tetraphosphonate, octaisopropyl
heptane-1,4,4,7-tetraphosphonate, octaisopropyl
nonane-1,5,5,9-tetraphosphonate.
The metallic surface of the endosseous implant to be treated
according to the present invention may be made from titanium or a
titanium alloy as known to be used for the production of endosseous
implants. Titanium alloys may be made from titanium and any other
metal known to form an alloy with titanium, such as chromium,
niobium, tantalum, vanadium, zirconium, aluminium, cobalt, nickel
and/or stainless steels. Such titanium metal alloys for making
implants are known per se and are described for example in Breme et
al., Metals as Biomaterials, pp. 1-71 (1998) the contents of which
are incorporated herein by reference.
Implants according to the present invention may be in the form of
screws, plates, nails, pins, and specially formed parts and may be
used as prostheses in medicine, more specifically in orthopaedics,
for replacing or strengthening broken or diseased bones, and in
dentistry, for anchoring artificial teeth and for anchoring of bone
anchored hearing prosthesis into the skeletal structure of humans
and animals. The surface area of the implant which is to be bound
to the body tissue resp. bones, may have a smooth or rough surface
texture. Such surface textures are known and can be obtained for
example by treating the surface mechanically and/or with acids
and/or electrolytically and/or with a glow-discharge plasma and/or
plasma spraying and/or or by electro machining. Such materials and
processes have been described in different publications, for
example in B. -O. Aronsson et al., J. Biomed. Mater. Res. 35
(1997), pp. 49f., the contents of which are incorporated herein by
reference.
Examples of compounds of formula (I) wherein A is a residue of a
saturated hydrocarbon are polyphosphonic acids such as
methylenediphosphonic acid, ethane-1,2-diphosphonic acid,
propane-1,3-diphosphonic acid, propane-1,3-diphosphonic acid,
ethane-1,1,2-triphosphonic acid, butane-1,1,4-triphosphonic acid,
pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,
hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic
acid, heptane-1,4,4,7-tetraphosphonic acid,
propane-1,1,3,3-tetraphosphonic acid, or
nonane-1,5,5,9-tetraphosphonic acid.
Examples of compounds of formula (I) wherein A is a residue of a
protein resp. polypeptide in the form of a Transforming Growth
Factor beta (TGF-.beta.) in which are included the all members of
the superfamily of growth factors and particularly the TGF-.beta.1,
TGF-.beta.2, TGF-.beta.3, TGF-.beta.4, and TGF-.beta.5 as described
for example in A. B. Roberts, M. B. Sporn, Handbook of Experimental
Pharmacology, 95 (1990) pp. 419-472 or D. M. Kingsley, Genes and
Development 8 (1994) p. 133-146, and references therein, where the
peptide chain has been modified to contain an alkylphosphonic acid
group or a derivative thereof, which is preferably an ester, an
amide or a salt thereof. In this sense the compound of formula (I)
represents a Transforming Growth Factor beta (TGF-.beta.) as
defined by the members of the superfamily of growth factors,
preferably the TGF-.beta.1, TGF-.beta.2, TGF-.beta.3, TGF-.beta.4,
and TGF-.beta.5, wherein each time the peptide chain has been
modified to contain at least one alkylphosphonic acid group or a
derivative thereof, which is preferably an ester, an amide or a
salt thereof.
Examples of compounds of formula (I) wherein A is a residue of a
Bone Morphogenic Protein (BMP) (being a subfamily to the TGF
family) e.g., the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5,
BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12,
BMP-13, as found for example in J. M. Wozney et. al., Science 242
(1988) 1528-1534; A. J. Celeste et al., Proc. Natl. Acad. Sci. USA
87 (1990) 9843-9847; E. Ozkaynak et al., J. Biol. Chem. 267 (1992)
25220-25227; Takao et al., Biochem. Biophys. Res. Com. 219 (1996)
656-662; WO 93/00432; WO 94/26893; WO 94/26892; WO 95/16035 and
references therein, where the peptide chain has been modified to
contain an alkylphosphonic acid group or a derivative thereof,
which is preferably an ester, an amide or a salt thereof. These
compounds are incorporated herein by reference. In this sense the
compound of formula (I) represents a Bone Morphogenic Protein
(BMP), preferably the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5,
BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12,
BMP-13, wherein the peptide chain has been modified to contain at
least one alkylphosphonic acid group or a derivative thereof, which
is preferably an ester, an amide or a salt thereof.
Examples of compounds of formula (I) wherein A is a residue of an
amino acid are 2-amino-4,4-bis-(diethoxyphosphoryl)-butyric acid as
described for example in O. Fabulet et al., Phosphorus, Sulphur
Silicon and Related Elements, 101, 225-234 (1995);
2-amino-5-(diethoxyphosphoryl)-pentanoic acid as described for
example in I. G. Andronova et al., Russ. J. Gen. Chem. 66,
1068-1071 (1996); 2-amino-4-phosphonobutyric acid as described for
example in X. Y. Jiao et al., Synth. Commun. 22, 1179-1186 (1992)
and references therein. Further examples are all the principal
twenty amino acids as described for example in L. Stryer,
Biochemistry, 3rd edition (1988), pp. 17-22, where the amino acid
is modified in an analogous way with an alkylphosphonic acid group
or a derivative thereof, which is preferably an ester, an amide or
a salt thereof, preferably wherein the compound of formula (I) is
one of the principal twenty amino acids, preferably arginine,
glycine, aspartic acid, alanine, valine, proline, serine,
threonine, cysteine or lysine, wherein the amino acid has been
modified to contain at least one alkylphossphonic acid group or a
derivative thereof, said derivative being preferably an ester, an
amide or a salt thereof. These compounds are incorporated herein by
reference.
Examples of compounds of formula (I) wherein A is a residue of a
peptide comprise but are not limited to RGD-containing peptides,
RGDS-peptides, GRGDS-peptides, RGDV-peptides, RGDE-peptides, and/or
RGDT-peptides. Such peptides are described for example in Y.
Hirano, J. Biomed. Materials Res., 25 (1991), pp. 1523-1534 or in
WO 98/52619 and references therein. Included within the scope of
the present invention are also similar peptides known to have
specific biological activities such as cell attachment or cell
attachment prevention, and which are prepared in analogy with the
peptides as mentioned above. In this sense the compound of formula
(I) is a RGD-containing peptide, preferably a RGDS-peptide, a
GRGDS-peptide, a RGDV-peptide, a RGDE-peptide, and/or a
RGDT-peptide, which has been modified to contain at least one
alkylphosphonic acid group or a derivative thereof, which is
preferably an ester, an amide or a salt thereof.
Preferred compounds of formula (I) are those containing a residue
A.sub.2 as defined above, preferably a residue of an amino acid or
of a sequence of amino acids resp. of a protein or of a
polypeptide, preferably a residue of the superfamily of
Transforming Growth Factor beta (TGF-.beta.), preferably a Bone
Morphogenic Protein (BMP).
The following steps are recommended to be taken for producing the
implant according to the present invention, i.e. for treating the
surface of the implant with at least one compound of formula (I)
above. The implant is first cleaned in a cleaning bath for removing
unwanted molecules resp. impurities from the surface. Preferably
the implant is first treated with a degreasing agent, for example
an organic solvent such as alcohol, chloroform, and another organic
solvent and/or an inorganic detergent such as an aqueous alkaline
solution based on sodium hydroxide or potassium hydroxide.
Subsequently, the implant is carefully rinsed in pure water,
preferably in distilled ultra-pure water, having preferably a
conductivity resistance of at least 15 Mohm*cm. After cleaning and
rinsing, the implant is dried with flowing nitrogen gas or flowing
dry or hot air and stored under controlled conditions.
Alternatively after degreasing the implant can be further treated
in a glow-discharge plasma for cleaning the surface. The clean
surface of the implant is then treated with at least one compound
of formula (I) or an ester or a salt thereof, i.e. with at least
one such compound or a mixture thereof. The compound or the mixture
of said compounds is brought onto the surface of the implant by any
suitable means, like brushing, spraying, dipping or evaporation,
including glow-discharge plasma assisted vapour deposition. The
phosphonic acid compound or the ester or the salt thereof is
preferably dissolved in a polar solvent, so that a solution with a
concentration of from about 1.0.times.10.sup.-5 mol/10 ml to
5.times.10.sup.-2 mol/10 ml, preferably from about
5.times.10.sup.-4 mol/10 ml to 2.0.times.10.sup.-2 mol/10 ml with
reference to the weight of the solvent is obtained. Preferably the
concentration is such that a partial or full (1% to 100%,
preferably 50% to 100% of a) monomolecular layer is formed on the
implant surface. The preferred solvent is pure distilled water. The
implant is left in contact with the solution for a sufficiently
long time, preferably for a few minutes up to a few hours. After
that the implant is carefully rinsed with pure water and packed
with a plastic or metallic clean packaging material preferably into
an air tight packaging which preferably is evacuated or filled with
an inert gas such as nitrogen or an inert liquid such as pure water
as defined herein above. Said pure water may contain inorganic
salts, preferably alkali salts, such as alkali chlorides, sulfates,
phosphates, phosphonates, preferably the sodium and/or potassium
salts, and/or compounds of the formula (I) or an ester or a salt
thereof, preferably in a concentration of from about
1.0.times.10.sup.-5 mol/10 ml to 5.times.10.sup.-2 mol/10 ml,
preferably from about 5.times.10.sup.-4 mol/10 ml to
2.0.times.10.sup.-2 mol/10 ml of solvent, which preferably is
distilled water.
Analytical investigations, e.g. X-ray Photoelectron Spectroscopy
analysis (XPS) or NMR, have shown that on contacting the phosphonic
acid compound of formula (I) with the titanium surface of the
implant, immediate adsorption takes place. A strong bond is formed
between the surface and the phosphonic acid compound so that a
chemical surface modification is obtained. Several different alkane
polyphosphonic acids as mentioned herein above were synthesized.
Dental implants produced with these compounds according to the
present invention have shown excellent results.
The compounds according to the general formula (I), wherein p is 3
to 6, preferably 3 or 4, and n is 4 to 70, preferably 4 to 40,
preferably 4 to 22, the salts or esters or amides thereof are new.
Examples of such compounds are butane-1,1,4-triphosphonic acid,
pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,
hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic
acid, heptane-1,4,4,7-tetraphosphonic acid, or
nonane-1,5,5,9-tetraphosphonic acid.
The compounds hexaisopropyl butane-1,1,4-triphosphonate and
octaisopropyl heptane-1,4,4,7-tetraphosphonate, resp. a mixture of
these compounds, are obtained in that an alkalimetal, preferably
sodium, tetra lower alkyl methylenediphosphonate, preferably
tetraisopropyl methylenediphosphonate, is reacting with at least a
stoichiometric amount of a dihalomethane, preferably
dibromomethane, in the presence of an organic solvent having no
active hydrogen atoms, preferably dry hexane or benzene or
toluene.
The reaction is preferably carried out at a temperature within the
range of 30.degree. C. to 125.degree. C., preferably 40.degree. C.
to 110.degree. C., until the reaction is completed, which generally
is within a time period of 10 to 48 hours, preferably 18 to 36
hours.
To the reaction product is then added the purified product of
triisopropylphosphite that has been reacted with
diisopropyl-3-bromopropane. The obtained mixture of compounds can
then be separated in a conventional manner, for example by column
chromatography
In an analogous way, by reacting 1,4-dibromobutane in excess molar
ratio in the range 1:6 to 1:0.5 with triisopropylphosphite,
surprisingly the new compounds hexaisopropyl
pentane-1,1,5-triphosphonate and octaisopropyl
nonane-1,5,5,9-tetraphosphonate are produced. Further, in an
analogous way the hexaisopropyl pentane-2,2,5-triphosphonate and
hexaisopropyl hexane-2,2,6-triphosphonate were obtained by reacting
equal parts of tetraisopropylethane-1,1-diphosphonate with
diisopropyl-3-bromopropylphosphonate.
The process is further characterised by that these products are
hydrolysed to produce the analogous acids by refluxing them in
molar excess of HCl for a time comprised within 1 to 12 hours,
preferably 1 to 6 hours. The compounds are then preferably dried
under vacuum over P.sub.2O.sub.5.
The following Examples illustrate but do not limit the present
invention.
EXAMPLE 1
Methylenediphosphonic acid was synthesized according to U.S. Pat.
No. 3,400,176 and B. A. Arbusov, Pure Appl. Chem. 9 (1967), pp.
307-353 and references therein. The compound was characterized by
NMR (.sup.1H, .sup.31P, .sup.13C) mass spectroscopic elemental
analysis and by its melting point. All these data are in accordance
with the literature O. T. Quimby et al., J. of Organomet. Chem. 13,
199-207 (1968).
Propane-1,1,3,3-tetraphosphonic acid was synthesized from
tetraisopropyl methylenediphosphonate. The tetraphosphonic acidic
solution was concentrated under vacuum, dried over P.sub.2O.sub.5
under vacuum. The .sup.1H, .sup.31P and .sup.13C NMR results
(D.sub.2O) are in accordance with the given literature data.
In an analogous manner propane-1,3-diphosphonic acid,
ethane-1,1,2-triphosphonic acid, butane-1,1,4-triphosphonic acid,
pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,
hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic
acid, heptane-1,4,4,7-tetraphosphonic acid, or
nonane-1,5,5,9-tetraphosphonic acid, are synthesized.
EXAMPLE 2
A) A sample made from titanium in the form of a circular plate of
14 mm in diameter, having a thickness of 1 mm, is produced in a
conventional manner. The sample surface is provided with a smooth
surface roughness by mechanical polishing with diamond paste
according to standard procedures. By Atomic force microscopy the
surface roughness was measured to a S.sub.rms value of ca 6 nm over
a surface area of 400 square microns.
B) The implant as produced in chapter A) above is then put into an
aqueous solution of (i) methylenediphosphonic acid
[1.5.times.10.sup.-3 mol per 10 ml of distilled water], (ii)
ethane-1,1,2-triphosphonic acid [1.2.times.10.sup.-3 mol per 10 ml,
in distilled water], (iii) propane-1,1,3,3-tetraphosphonic acid
[6.2.times.10.sup.-4 mol per 10 ml, in distilled water], (iv)
1-hydroxyethylidenediphosphonic acid [1.4.times.10.sup.-3 mol per
10 ml, in distilled water] and left there at room temperature for
15 minutes. The implant is then rinsed with pure water and
dried.
The implant prepared according to the preparations B(i), B(ii), and
B(iii) are plated with rat bone building cells, osteoblasts. The
osteogenesis is measured as (I) the cell proliferation and (II) the
bone protein synthesis. Comparative test results are given for the
untreated implant. The results are given in Table 1. Analogous
results are obtained for all the phosphonic acids given herein
above both on a smooth and on a rough surface. Analysis with XPS
and ToF-SIMS indicated that a molecular (mono) layer was formed on
a titanium surface as well as on a TiO.sub.2-surface.
TABLE-US-00001 TABLE 1 Total protein synthesis* after Number of
cells* 8 days (cpm.dagger. .times. Collagen* after 8 after 4 days
10.sup.4 per million days (% of total Preparation (.+-.SEM) cells)
(.+-.SEM) protein) (.+-.SEM) B(i) 36108 (.+-.2485) 94224 (.+-.8357)
3.18 (.+-.0.17) B(ii) 40773 (.+-.1263) 104503 (.+-.2863) 3.19
(.+-.0.10) B(iii) 37290 (.+-.2852) 92361 (.+-.8237) 2.30 (.+-.0.29)
Comparative 32560 (.+-.2485) 87842 (.+-.3161) 2.74 (.+-.0.18) Test
*the numbers are given as an average value from three measurements
for each test. .dagger.cpm = counts per minute from radio labeled
proteins.
The results illustrate the improved osteogenesis of the implants
according to the present invention compared to the non treated
implants.
EXAMPLE 3
Example 2 is repeated with the difference that the implant is
treated with ethane-1,1,3-triphosphonic acid which has been
modified by linking the amine terminus of a Glycine molecule to one
of the phosphonate groups.
EXAMPLE 4
Examples 2 is repeated with the difference that the implant is
treat with ethane-1,1,3-triphosphonic acid which is modified by
linking the amine terminus of a GRGDS cell binding polypeptide to
one of the phosphonate groups.
EXAMPLE 5
Examples 2 is repeated with the difference that the compound
according to formula (I) is ethane-1,1,3-triphosphonic acid which
is modified by linking the amine terminus (Methionine) of a human
Bone Morphogenic Protein type 2 (BMP-2) to one of the phosphonate
groups, which gives analogous test results as given in Table 1.
* * * * *