Hydroxyapatite is a member of the apatite group of minerals and has the chemical formula CaaO (PO4) 6 (OH) 2. It is, essentially, a calcium phosphate including hydroxide having a Ca: P ratio of 1.67: 1.

Hydroxyapatite is currently of much interest in the biomedical field due to its well established bioactivity. It has, for example, been used in various dental materials and in various medical applications, such as artificial joints and bones and as bone fillers. The material is, however, limited in its application because of its inadequate mechanical properties and thus has mainly been used for low load applications.

Attempts to enhance the mechanical properties of hydroxyapatite have generally been based upon the development of compaction methods and also the choice and control of grain size. Sintering aids have also previously been suggested for improving the mechanical properties of hydroxyapatite, but these have been single phase materials, such as CuO and Alz03.

EP-A-577,342 discloses compositions comprising hydroxyapatite and a biocompatible glass based upon CaO and P205 *

We have now developed sintered hydroxyapatite compositions which are biocompatible and which have enhanced mechanical properties, and also a method for the preparation of these compositions.

Accordingly, the present invention provides a sintered enhanced hydroxyapatite material which comprises hydroxyapatite, a biocompatible glass based upon CaO and P20, contained in an amount of less than 10% by weight based on the weight of hydroxyapatite and a source of F ions.

The present invention also provides a method for the preparation of a material as defined above which comprises sintering a mixture of hydrcxyapatite, a biocompatible glass based upon CaO and P205, and a source of F-ions at a temperature of above 1200°C.

The present invention further provides a bone implant or bone filler which comprises a material as defined above.

The present t invention additionally provides an artificial joint which comprises a coating of a material as defined above on at least a part of a metal or alloy joint.

The present invention also provides a composition such as a bone cement or dental cement which comprises a material as defined above together with a pharmaceutically acceptable diluent or carrier.

The present invention additionally provides a material or composition as defined abeve for use in a method of treatment of the human or animal body by surgery or therapy.

In the preparation of the composite of the present invention, the biocompatible glass acts as a sintering aid and is contained in an amount of less than 10% by weight, preferably an amour. t of from 2.5 to 5% by weight, more preferably from 2.5 to 4% by weight, based on the weight of the hydroxyapatite.

By the term"biocompatible glass"as used herein is meant that the glass does not contain any metal ions which are not tolerated by the body (except for Ale+, provided that the amount is small).

Suitable biocompatible glasses for use in the present invention are, for example, a two oxide CaO-P205 glass, a three oxide CaO-P2Os-Na2O glass, or a four oxide CaO-PzOs-Na2O-Al203. Other components may be incorporated into the biocompatible glass based upon CaO and P20 ;, provided that the metals of the oxide used in the formation thereof are compatible with the body.

The preferred biocompatible glass for use in the present invention is a two oxide Cas-po glass. The mole ratio o-CaO to P205 in these glasses may vary within wide limits but preferably is from 20: 80 to 80: 20 mol %. The glass having a mole ratio of CaO: P2O ; of about 50: 50 is particularly preferred. If CaF2, or any other compound containing calcium, is used as the source of F-ions, the amount of Ca in this compound is added to the amount of CaO when determining the above ratio. Thus by using such a compound the amount of CaO in the glass may be reduced if appropriate.

The source of F'ions enhances the properties of the material. In particular it improves the strength properties such as the flexural bend strength. The materials disclosed in EP-A-577,342 have a flexural bend strength of up to about 80 to 90 MPa. However, the materials of the present invention have an increased flexural bend strength of, for example, up to about 120 to 160 MPa. This enables the materials to be used in surgical techniques where the materials of EP-A-577,342 could not be used, such as in spinal surgery.

The source of F'ions should not contain any metal ions which are not tolerated by the body. It is, for example, an alkali metal or alkaline earth metal fluoride such as CaF2, NaF or MgF2, preferably CaF2.

The source of F'ions may be contained in the material of the present invention in an amount of up to, for example, 40% by weight, based on the weight of hydroxyapatite. The F'ions themselves may be contained in the material in an amount of up to, for example, 20% by weight, preferably up to 5% by weight, more preferably 1 to 2.5% by weight, most preferably 1.25 to 2% by weight, based on the weight of the hydroxyapatite.

The source of F-ions may be present in the material either separately or incorporated in the biocompatible glass.

The total weight of the glass and source of F'ions is, for example, up to 50% by weight, preferably up to 10% by weight, based on the weight of

the hydroxyapatite.

The method for the preparation of the enhanced hydroxyapatite material comprises sintering the aforesaid mixture of hydroxyapatite, biocompatible glass based upon CaO and P2O5 and source of F'ions at a temperature of above 1200°C, preferably at a temperature of from 1250° to 1350°C. The source of F'ions may be, for example, incorporated in the biocompatible glass before the sintering. Generally, the mixture to be sintered will be in a very fine particulate form with the particles having a particle size of less than 100 micrometres, preferably less than 75 micrometres, more preferably less than 10 micrometres.

The enhanced hydroxyapatite materials of the present invention have improved mechanical properties as compared to hydroxyapatite without the source of F'ions addition. We believe that the F-ions diffuse into the structure and are interstitial in the composite structure, as indicated by an increase in unit cell dimensions as measured by X-ray diffraction.

The materials of the present invention may also increase osteoblast cell proliferation in vitro, as demonstrated by growing cells directly on the material surface and measuring the number of cells at different times.

The enhanced hydroxyapatites of the present invention may be used in any of the dental and medical applications for which unmodified hydroxyapatite or glass modified hydroxyapatite have previously been used. There may also be additional dental and medical

fields in which the hydroxyapatite composites of the present invention may be used which are not open to the unmodified hydroxyapatite. Examples of fields where the enhanced hydroxyapatite materials of the present invention may be used are as bone implants, where an implant of the enhanced hydroxyapatite material may be used, or as bone fillers where a powdered composition may be used as a filling material. The hydroxyapatite composite may also be used in the formation of artificial joints in which a coating of the hydroxyapatite composite is applied to at least a part of a metal or alloy joint.

The present invention also includes within its scope a composition which comprises an enhanced hydroxyapatite material as hereinbefore defined together with a pharmaceutically acceptable diluent or carrier. Such compositions find use as bone cements or dental cements. Other applications of the enhanced hydroxyapatite materials of the present invention in the medical and dental field will be readily appreciated by those skilled in the art.

The present invention will be further described with reference to the following Examples.

Preparation Examcle 1 Phosphate based glasses were produced from reagent grade chemicals heated at 1300°C in an alumina crucible for 1 hour. The following

compositions were prepared, in mole percent. Glass A Glass B Glass C Glass D Glass $ P205 75 75 75 63. 75 63.75 CaO 25 15 20 21. 25 21.25 MgO 0 0 0 5 10 CaF 0 10 5 10 5 Example 1 Each glass was coarsely reduced to a sand type particle and milled in a porcelain ball mill pot for 24 hours. After milling its particle size was less than 100 micrometres and its median particle size, Do5 was 6 to 9 micrometres according to Laser Diffraction analysis using a Malvern Mastersizer Ms-20. To hydroxyapatite powder each of the glass powders was added, in amounts of 2.5% and 4.0% by weight, with methanol (350 ml of methanol/200g of material) and the powders were wet milled together for a further 24 hours. Following the milling process, the slip was poured and oven dried. The dried powder was then auto sieved to a particle size of less than 75 micrometres.

Particle size distribution profiles were carried out after milling.

30mm diameter discs, using 4g of powder, were uniaxially pressed at 288 MPa and fired at a 4°C/min ramp rate up to 1200° to 1350°C, with a one hour hold time at this temperature, followed by natural cooling inside the furnace.

The flexural bending strengths for the compositions are given in Table 1 below.

Flexural bending strength measurements were obtained for each sample from a 4-point biaxial bending test in a concentric ring jig with a 20 mm supporting span and a 10 mm loading span at a cross head speed of 5 mm/min on 10 specimens.

The concentric ring test eliminates many problems associated with the fracture induced by the edges of the samples although it gives lower results when compared with conventional bending tests. Fracture toughness measurements were performed using an indentation technique proposed by Laugier, J. Mater. Sci., 1987, 6, 355-356, using a 9.8 N load.

The materials were characterized by X-Ray Diffraction (XRD) and their microstructure analysed using SEM. In vitro tests were carried out in a phosphate buffered saline solution and samples were bending strength tested after 1 month.

SEM analysis showed that the hydroxyapatite/glass materials were very dense when sintered at 1250°C, or above.

Table 1<BR> Flexural bending strength for hydroxyapatite (HA) and hydroxyapatite/gl<BR> composites<BR> Biaxial Flexure (MPa) Material Sintering Temperature 1200°C 1250°C 1300°C 1350°C HA 27#4 54#14 54#17 46#10 HA + 2.5% A 37#9 59#13 113#20 96#25 HA + 4% A 36#10 101#13 105#13 103#10 HA + 2.5% B 53#7 88#8 106#42 159#32 HA + 4% B 34#10 54#10 99#20 108#10 HA + 2.5% C 46#7 72#13 90#26 86#34 HA + 4% C 40#10 62#10 112#17 106#14 HA + 2.5% D 56#13 81#17 126#20 116#17 HA + 4% D 85#14 104#13 130#13 114#10 HA + 2.5% E 81#17 91#20 133#13 130#10 HA + 4% E 50#10 101#17 112#16 111#17 The figures for HA and HA + glass are given for comparison.

Table 2 Hardness values for the different composites (in HV)kg/mm2or Composite Composition 1250°C 1300° 1350° 498.15#46.67507.77#39.74513.3#51.71 HA + 2.5% A 465. 7526. 54 469. 4659. 35 534. 2644.82 HA + 4% A 413.55#40.3 512.14#37.84 495.69#40. 99 HA + 2.5% B 441. 1335. 25 593. 8635. 04 57945.06 HA + 4% B 372. 0432. 72 579. 0828. 13 535. 9328.04 HA + 2.5% C 430.09#22.02 564.7#27.01 565.04#42. 85 HA + 4% C 317. 5432. 7 536. 5744. 49 524. 8436.52 HA + 2.5% D 533. 4230. 86 545. 7165. 36 554. 538.11 HA + 4% D 555.26#34.34 542.11#51.18 530.33#8. 63 HA + 2.5% E 544. 2651. 66 546. 0276. 75 502. 0346.31 HA + 4% E 425. 4879. 03 535. 3033. 98 474. 7858.81

Table 3 Hardness values for the different composites (in kg/mm2 or HV) Composite Composition 1200°C 1250°C 1300°C 1350°C HA 85. 4+4. 4 93. 1+0. 1 94+0. 3 93. 9+0.2 HA + 2.5% A 72.9#0.5 93.1#0.9 96.3#0.3 94.6#0. 2 HA + 4% A 74. 60. 4 92. 10. 7 97. 50. 7 97. 20.1 HA + 2.5% B 75. 90. 8 89. 61. 4 95. 13. 5 97. 90.8 HA + 4% B 73.9#0.3 86.7#0.4 97#1.6 98#0. 8 HA + 2.5% C 73.9#0.2 89.3#0.4 95.9#1.7 96.9#0. 9 HA + 4% C 76.3#0.4 90.2#0.9 95.9#1.6 95.8#2. 2 HA + 2.5% D 810. 2 961 961. 2 97. 70.6 HA + 4% D 88.1#0.9 96#0.2 96.2#1.1 97.2#0. 8 HA + 2.5% E 87.6#1.1 94.7#0.4 96.2#0.8 95.6#1. 6 HA E81.3#0.497#0.797.2#0.898.2#0.34% The hardness values are given in Table 2 below. Hardness was measured using Vickers indentation, load 300 g. The percentage of theoretical density measurements are given in Table 3 below. The values in Table 3 are calculated by taking data from a phase analysis and using the values for the theoretical density of the HA, «-TCP and -TCP phases, the theoretical density is calculated from Ritveld.

The actual density for the specimens is measured using the Archimedes principle in liquid mercury, and the percentage of theoretical density is

calculated.

A considerable improvement in the flexural strength was achieved by the incorporation of the source of F'ions during the sintering of hydroxyapatite.

A slight increase in weight of the samples was detected after immersion in saline for 1 month, which was related to the precipitation of crystals on the surface of the materials. No changes in the flexural strength were found after 1 month.