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.

Claims

1. A pharmaceutically acceptable amide of a compound corresponding to the formula (I):
A-[P(O)(OH).sub.2].sub.p  (I), wherein: A is A.sub.1, wherein A.sub.l is a residue of a linear, branched or cyclic, saturated or unsaturated, hydrocarbon with n carbon atoms, carrying p phosphonic acid groups, wherein said residue is substituted by hydroxyl and/or carboxyl or said residue is unsubstituted, and wherein said residue is interrupted by one or more oxygen and/or sulphur and/or nitrogen atoms or said residue is not interrupted, and wherein n is a number from 4 to 70, and p is 3 to 6; or A is A.sub.2, wherein 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 3 to 6.

2. The amide of claim 1, wherein A is A.sub.1, and A.sub.1 is a saturated hydrocarbon residue of the formula —(C.sub.nH.sub.2n+2−p)—, wherein n is 4 to 70.

3. The amide of claim 1, wherein n is 4 to 40.

4. The amide of claim 1, wherein n is 4 to 22.

5. The amide of claim 1, wherein p is 3 or 4.

6. The amide of claim 1, wherein the compound of formula (I) is selected from the group consisting of 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, and nonane-1,5,5,9-tetraphosphonic acid.

7. The amide of claim 1, wherein the compound of formula (I) is a Transforming Growth Factor beta (TGF-β) as defined by the members of the superfamily of growth factors, wherein a peptide chain has been modified to contain p alkylphosphonic acid amide groups.

8. The amide of claim 7, wherein the compound of formula (I) is a Transforming Growth Factor beta (TGF-β) selected from the group consisting of TGF-β1, TGF -β2, TGF-β3, TGF-β4, and TGF-β5, wherein the peptide chain has been modified to contain p alkylphosphonic acid amide groups.

9. The amide of claim 1, wherein the compound of formula (I) is a Bone Morphogenic Protein (BMP), wherein a peptide chain has been modified to contain p alkylphosphonic acid amide groups.

10. The amide of claim 9, wherein the compound of formula (I) is a Bone Morphogenic Protein (BMP) selected from the group consisting of BMP-2, BMP-3, BMP -4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, and BMP-13, wherein the peptide chain has been modified to contain p alkylphosphonic acid amide groups.

11. The amide of 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 p alkylphosphonic acid amide groups.

12. The amide of claim 11, wherein the compound of formula (I) is an amino acid 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 p alkylphosphonic acid amide groups.

13. The amide of claim 1, wherein the compound of formula (I) is an RGD-containing peptide, which has been modified to contain p alkylphosphonic acid amide groups.

14. The amide of claim 13, wherein the compound of formula (I) is an RGD-containing peptide selected from the group consisting of an RGDS-peptide, a GRGDS-peptide, an RGDV-peptide, an RGDE-peptide, and an RGDT-peptide, wherein the RGD-containing peptide has been modified to contain p alkylphosphonic acid amide groups.

15. A pharmaceutically acceptable amide of a compound corresponding to the formula (I):
A-[P(O)(OH).sub.2].sub.p  (I), wherein A is a residue of a linear, branched or cyclic, saturated or unsaturated, hydrocarbon with n carbon atoms, carrying p phosphonic acid groups, wherein said residue is substituted by hydroxyl and/or carboxyl or said residue is unsubstituted, and wherein said residue is interrupted by one or more oxygen and/or sulphur and/or nitrogen atoms or said residue is not interrupted, and wherein n is a number from 1 to 70, and p is 2.

16. The amide of claim 15, wherein A is a saturated hydrocarbon residue of the formula —(C.sub.nH.sub.2n+2−p)—, wherein n is 1 to 70.

17. The amide of claim 15, wherein n is 11 to 70.

18. The amide of claim 15, wherein n is 11 to 40.

19. The amide of claim 15, wherein n is 11 to 22.

Description

EXAMPLE 1

(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).

(2) 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.

(3) 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

(4) 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.

(5) B) The implant as produced in chapter A) above is then put into an aqueous solution of (i) methylenediphosphonic acid [1.5×10.sup.−3 mol per 10 ml of distilled water], (ii) ethane-1,1,2-triphosphonic acid [1.2×10.sup.−3 mol per 10 ml, in distilled water], (iii) propane-1,1,3,3-tetraphosphonic acid [6.2×10.sup.−4 mol per 10 ml, in distilled water], (iv) 1-hydroxyethylidenediphosphonic acid [1.4×10.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.

(6) 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.

(7) TABLE-US-00001 TABLE 1 Total protein synthesis* after Collagen* after Number of cells* 8 days (cpm† × 8 days (% of after 4 days 10.sup.4 per million total protein) Preparation (±SEM) cells) (±SEM) (±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 Test 32560 (±2485) 87842 (±3161) 2.74 (±0.18) *the numbers are given as an average value from three measurements for each test. †cpm = counts per minute from radio labeled proteins.

(8) The results illustrate the improved osteogenesis of the implants according to the present invention compared to the non treated implants.

EXAMPLE 3

(9) 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

(10) 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

(11) 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.