FR2697243A1 - Process for the preparation of microporous calcium phosphate parts comprising hydroxylapatite, with controlled microporosity, and parts obtained by this process. - Google Patents

Abstract

The invention concerns a process for the preparation of microporous calcium phosphate pieces comprising hydroxylapatite, having controlled microporosity, and the pieces so obtained. The process comprises three successive stages: a) densifying, by hot isostatic pressing at a pressure of 20 to 150 MPa, at a temperature T1 of 900 to 1200 DEG C, a calcium phosphate powder with an atomic ratio Ca/p of 1,600 to 1,666; and b) subjecting the densified piece to heat treatment at a temperature T2 of 900 DEG C to 1400 DEG C. In this process, the choice of pressure, the isostatic pressure and the temperatures T1 and T2 serve to adjust the microporosity of the piece and the ratio of the open microporosity to the total microporosity to produce characteristics suited to various applications in particular bone reconstruction.

Description

 Process for the preparation of microporous calcium phosphate parts comprising hydroxyapatite, microporosity control, and parts obtained by this close.

 The present invention relates to a process for the preparation of microporous calcium phosphate parts comprising hydroxylapatite.

 More specifically, it relates to obtaining calcium phosphate parts consisting of hydroxylapatite and possibly tricalcium phosphate, having porosity characteristics (pore size and shape, open porosity, closed porosity and pore volume) adapted to the uses. contemplated.

It is recalled that hydroxylapatite (PAH) is a calcium phosphate of formula
Ca 10 (PO 4) 6 (OH) 2 having a Ca / P atomic ratio of 1.666.

 It is the main constituent of bone mineral because it represents 95% by weight of this substance.

Hydroxylapatite can be prepared by chemical synthesis in the form of a powder, but the product of synthesis often has deviations from the stoichiometry corresponding to hydroxylapatite. This synthetic hydroxylapatite corresponds in fact to a mixture of hydroxylapatite having the formula given above and of tricalcium phosphate of formula Ca 3 (PO 4) 2. To obtain good mechanical properties and a satisfactory reactivity, it is preferable that the proportion of tricalcium phosphate does not lead to a Ca / P atomic ratio of less than 1,600. This synthetic hydroxylapatite or calcium phosphate can thus
correspond to the formula Ca10-x (P04) 6-x (HPO4) x (OH) 2-x in which x is such that O <x <0.4 which corresponds to a Ca / P atomic ratio of 1.600 to 1.666 .

Also, in the rest of this text, the term "calcium phosphate" will be used to designate products having an atomic ratio.
Ca / P from 1.600 to 1.666, especially those corresponding to this formula.

 Calcium phosphates of this type can find therapeutic applications, for example for bone or tissue reconstitution, and other applications for example as a stationary phase in preparative analytical chromatography or prepurification as well as in catalytic reactors.

Bone reconstitution from hydroxylapatite (PAH) is a known therapy in dentistry and reconstructive surgery, as described by Passuti et al in La Presse
Medical, 18, No. 1, January 7-14, 1989, p. 28-31, and by Lavernia et al in Ceramic Bulletin 70, No. 1, p. 95-100.

 In this technique, a therapeutic approach to stimulate regrowth of new bone tissue is to provide hydroxylapatite in the form of injectable granules. The transfer through the needle and the distribution in the area to be treated impose a good control of the sphericity, the size and the surface condition of the granules.

 For this use, the macroporosity is obtained by itself by the spacing of the granules. On the other hand, it is important to have a microporosity adapted to this therapy.

 The clinical use of these hydroxylapatites for volume-to-volume substitutions has limitations in dimensions and stresses related to their poor mechanical qualities.

 Furthermore, the use of I <AP in the form of injectable granules is only conceivable if the material is resistant to fragmentation and abrasion during transfers. Here again the mechanical strength is in question.

 The generally decreasing solidity, when the pore volume increases, a compromise must be found between porosity and mechanical strength.

 For these applications, especially for bone reconstitution, it is therefore important to have hydroxylapatite parts having suitable porosity characteristics.

Porous hydroxylapatite parts have two types of porosity
a macroporisity (pores of 100 to 600 μm) allowing the room to be rehabitated by bone tissue, and
an interconnected microporosity having pores of a few micrometers, which allows the solution and then the transfer of the calcium and phosphate ions and, more generally, the cells participating in the metabolism of bone synthesis, between the hydroxylapatite and the neoformed tissue.

 Macroporosity is conventionally obtained by adding pore-forming agents which are then removed.

 The microporosity is obtained by performing a partial densification of a hydroxylapatite powder, that is to say by voluntarily maintaining the temperature of the densification treatment below the sintering temperature.

 Generally, this densification or sintering is carried out at temperatures ranging from 1000 to 3500 ° C. by performing either natural sintering at a temperature of 1200 to 3000 ° C., or sintering under a load at a temperature of approximately 1000 ° C. either hot-isostatic compression sintering.

 With these methods, the microporous volume and the ratio of the open microporosity to the total microporosity can not be adjusted independently because this ratio depends on the total microporosity of the part as can be seen in the appended FIG.

 This FIG. 1 is a diagram representing the microporosity (in U) as a function of the relative density (in%) of hydroxylapatite parts obtained by natural sintering at temperatures ranging from 1000 to 3000 C.

In this figure, curve 1 refers to the total microporosity Pt, while curve 2 refers to the open microporosity PO. It is thus noted that for relative densities of less than 88%, that is to say a total microporosity Pt greater than 12%, the open microporosity
PO is very predominant. On the other hand, for relative densities greater than 91%, ie total microporosities of up to 9%, the open microporosity PO is practically non-existent and the microporosity closed.
Pf is largely preponderant.

 Also, since the sintering temperature makes it possible to act solely on the relative density, it is not possible to adjust by this sintering the percentage of open microporosity with respect to the total microporosity, this ratio being defined by the relative density, c that is, by the total microporosity.

 However, for some applications, it is desirable to have a predominant open microporosity with a relatively low total microporosity so as not to harm the mechanical characteristics of the part, because it becomes more fragile when the pore volume increases.

 With these known densification methods, it is also impossible to control the pore size of the hydroxylapatite parts. Generally, these pores have elongated shapes with numerous intersections of acute angle walls, which are comparable to critical defects, responsible for the low mechanical strength of the parts.

 The present invention specifically relates to a process for preparing a porous piece of calcium phosphate, which adjusts the porosity characteristics of the part independently of the value of the pore volume, while obtaining good mechanical characteristics.

According to the invention, this method comprises the following successive steps:
a) densification by hot isostatic pressing, at a pressure of 20 to 1SOMPa, at a temperature T1 of 900 to 12000 C, a calcium phosphate powder having an atomic ratio
Ca / P from 1.600 to 1.666, more particularly from 1.640 to 1.665 for medical applications; and
b) subject the densified part to a thermal treatment carried out at a temperature
T2 from 9000C to 14000C.

 In the process of the invention, the fact of densifying the hydroxylapatite powder by hot isostatic compression, followed by a heat treatment, makes it possible, on the one hand, to create a homogeneous microporosity of 10 to 20% in volume with pores of 0.5 to 5 * um whose shape is close to a spherical geometry and, on the other hand, to give the porous edifice a good mechanical stability, by adjusting moreover the ratio of the open microporosity to total microporosity independently of the latter.

 Indeed, hot isostatic compression of the hydroxylapatite produces water and oxyapatite according to the Ca10 (PO4) 6 (OH) 2 -> CalO (PO4) 60 + H2O reaction.

 The water vapor is held under pressure in the closed microporosities which have dimensions less than 1 μm.

 During the heat treatment which follows at the temperature T2, under a pressure lower than the compression pressure, for example at atmospheric pressure, the water vapor enclosed in the pores exerts a pressure which deforms the matrix. A micron pores network is thus formed with a proportion of open microporosity relative to the total microporosity which depends on the T2 temperature used.

 In this process, the microporosity (total microporous volume and pore size) of the part is thus controlled by choosing the temperature T1 and the pressure used for the hot isostatic pressing, and the ratio between the open microporosity and the closed microporosity is adjusted. by choosing the temperature T2 of the heat treatment.

 The durations used for the isostatic compression and the heat treatment also make it possible to act on the characteristics of microporosity of the part. Generally, isostatic compression is carried out for 10min to 2h. The heat treatment can be carried out for periods ranging from 3 hours to 24 hours, generally at atmospheric pressure, under air.

 According to the invention, it is also possible to create a macroporosity in the room, by adding a pyrogenic agent in the form of granules to the calcium phosphate powder itself granulated, before carrying out the isostatic compression. In this case, after the isostatic compression step, the pore-forming agent is removed, for example by dissolution, in order to create a macroporosity in the part before carrying out step b).

 The blowing agents used are inorganic or organic products which can then be removed by volatilization or dissolution.

 By way of example, the pore-forming agent may be magnesia. The amount of blowing agent added can represent from 2 to 3% of the volume of the calcium phosphate powder. When the blowing agent is magnesia, it can then be dissolved by a slightly acidic solution, for example in an acetic buffer.

A powder dispersing agent can also be used to prepare microporous calcium phosphate granules; in this case, the dispersing agent which has been pre-used is preferably removed.
the granules to be treated after step b), and the process advantageously comprises the following successive steps:
a) densification by hot isostatic pressing, at a pressure of 20 to 1SOMPa, at a temperature T1 of 900 to 1200 C, granules of calcium phosphate having an atomic ratio
Ca / P from 1.640 to 1.665 dispersed in the dispersing agent;
b) subject the densified part to a thermal treatment carried out at a temperature
T2 from 900 to 14000C; and
c) disintegrate the densified piece thus obtained by removing the dispersing agent to obtain microporous granules.

 The dispersing agents used are mineral products which can then be eliminated.

 As an example of dispersing agent that may be used, mention may be made of magnesia.

 The amount of dispersing agent used can represent from 10 to 50% of the volume of the calcium phosphate granules. When the dispersing agent is magnesia, it can then be dissolved by a slightly acidic solution, for example in an acetic buffer.

 The process of the invention can be used for producing calcium phosphate microporous granules comprising biologically active compounds in the open microporosity of the workpiece. In this case, the process consists in preparing microporous calcium phosphate granules according to the invention and then including in the open microporosity granules thus obtained a biologically active compound by infiltration into the micropores.

 The biologically active compounds used can be of any type, generally they are organic compounds.

 The method of the invention can also be implemented to include a biologically active compound in the closed microporosity of calcium phosphate granules.

 In this case, is added to the calcium phosphate granules subjected to isostatic compression a stable biologically active compound at the temperatures T1 and T2 used for the isostatic compression and the heat treatment, then the steps of isostatic compression and thermal treatment are carried out as previously, by removing the dispersing agent which has been added to the calcium phosphate powder subjected to isostatic compression.

 Thus, the method of the invention is very interesting, because it allows for parts or granules of calcium phosphate suitable for the intended applications. Moreover, the choice of starting calcium phosphate, that is to say The choice of the atomic ratio Ca / P is also carried out according to the applications envisaged.

 Thus, for bone reconstitution, nonabsorbable substitution parts, reshabitable and resorbable parts and resorbable granules supporting releasable biologically active compounds can be produced.

 In the case of non-absorbable substitution parts, a calcium phosphate having a Ca / P atomic ratio close to that of hydroxylapatite, that is to say a ratio close to 1.666, is used. In addition, the temperature of the heat treatment T2 is chosen to obtain an almost zero open porosity so as to adjust the density of the part by creating a closed microporosity without, however, appearing an open microporosity. Such parts can be used, for example as ossicles of the inner ear or as nonabsorbable granules for the hardening of muscle tissue. Thus, a room substituting a ossicle of the inner ear can be adjusted to the same density as neighboring ossicles.

 For the production of bone replacement parts, resealable and resorbable, used for example for volume-to-volume bone reconstitution and the filling of bone cavities with granules, a calcium phosphate having a Ca / P atomic ratio of 1.653 to 1.665 is chosen. or a mixture of hydroxylapatite and tricalcium phosphate with proportions of tricalcium phosphate of 2 to 20 mol%. In this case, it is preferable that the open microporosity be maximum to facilitate the resorption of the part and the temperature T2 of the heat treatment is chosen to obtain this result.

 For the production of resorbable granules supporting releasable biologically active compounds, the choice of starting calcium phosphate and the conditions for preparation of the granules depends on the treatment for which they will be intended.

Thus, for treatments spread over time, the active compound is included in the closed microporosity of the granules and a calcium phosphate having a Ca / P atomic ratio close to that of the hydroxylapatite is used in order to make the granules poorly soluble, for example a Ca / P ratio of 1.665 to 1666, which corresponds in the case of mixtures of hydroxylapatite and tricalcium phosphate at 1 mol% at most of tricalcium phosphate. In this case, the release of the biologically active compound which is enclosed in the closed microporosity is done as the dissolution of the granule is very slow, and thus obtained a treatment spread over time.

 In the case where it is desired to carry out a treatment of short duration, the biologically active compound is immobilized in the open microporosity of the granules; the release rate of the compound will thus depend on the size and the interconnection of the micropores. Furthermore, a calcium phosphate consisting of a mixture of hydroxylapatite and tricalcium phosphate containing 2 to 20 mol% of tricalcium phosphate is preferably used, ie a calcium phosphate having a Ca / P ratio of 1.653 to 1.665, to facilitate the resorption of the granules.

 The biologically active compounds that may be included in the granules are, in the first case, compounds resistant to the T1 and T2 temperatures used for isostatic compression and heat treatment, for example inorganic compounds such as calcium fluoride.

 In the second case, that is to say when the compound is included in the open microporosity of the granule, this compound can be included after the heat treatment and it is therefore possible to use organic compounds capable of stimulating the metabolism of bone synthesis. .

 The subject of the invention is also microporous calcium phosphate particles or granules obtained by the process of the invention, characterized by a Ca / P atomic ratio of 1.640 to 1.665, a total microporosity of 10 to 30% by volume and a open microporosity less than 2%, optionally containing a biologically active compound.

Other features and advantages of the invention will appear better on reading the description which follows given of course by way of illustration and not limitation with reference to the accompanying drawing in which
FIG. 1, already described, is a graph showing the evolution of the open microporosity and of the total microporosity of a hydroxylapatite as a function of the relative density of this hydroxylapatite in the case of hydroxylapatite parts prepared by the process of the invention. prior art.

 FIG. 2 is a diagram showing the influence of the Ca / P atomic ratio on the flexural strength of calcium phosphate parts.

 - Figures 3 and 4 are micrographs showing the microporosity of calcium phosphate parts obtained by the method of the invention.

 FIG. 5 represents, by way of comparison, the microporosity of a calcium phosphate part obtained by a process according to the prior art.

 FIG. 6 is a schematic representation for the direct production of injectable granules of hydroxylapatite by the process of the invention.

 To carry out the process of the invention, starting from a calcium phosphate powder having a Ca / P ratio of 1,600 to 1,666.

 The choice of such a ratio makes it possible to obtain good characteristics as shown in FIG.

 This FIG. 2 is a diagram illustrating the evolution of the bending strength of solid pieces of calcium phosphate produced by sintering at a temperature of 1 2000 ° C. for 5 hours, as a function of the Ca / P atomic ratio of the starting phosphate powder.

 In this figure, it can be seen that the flexural strength varies considerably according to the Ca / P ratio and that the best resistances are obtained in the Ca / P interval ranging from 1.600 to 1.666, ie for the hydroxylapatite mixtures. and tricalcium phosphate having molar ratios of tricalcium phosphate to hydroxylapatite of up to 66%.

 Calcium phosphate powders corresponding to these Ca / P atomic ratios of 1.600 to 1.666 can be prepared by conventional methods, for example by precipitation of calcium phosphate in an aqueous medium. To carry out this precipitation, one can slowly add a solution of diammonium phosphate (NH4) 2HPO4 containing NH40H to a boiling solution of calcium nitrate also containing NH 4 OH. The Ca / P ratio of precipitated calcium phosphate depends on the amount of calcium nitrate used.

 After precipitation, the precipitate is filtered and heat treated for example at 8000c for 5h. A calcium phosphate powder is thus obtained.

 To prepare microporous parts from this powder in accordance with the process of the invention, the powder is first compressed in a mold to give it the desired shape by adding a pore-forming agent if necessary and then the steps are carried out. a) isostatic compression and b) heat treatment of the process of the invention.

 The following examples illustrate the preparation of calcium phosphate parts by the method of the invention.

Example 1: Preparation of a massive piece with controlled micro-roughness.

 Starting from a hydroxylapatite powder containing 20% by mole of tricalcium phosphate (Ca / P ratio of 1.653) and having a particle size of 50 μm and put in the desired form by cold pressing in a mold under a pressure of 200 MPa.

 The compressed part is introduced into a steel casing in which the vacuum is evacuated, and the envelope is then closed under vacuum by electron bombardment. The envelope containing the compressed part is then introduced into a hot isostatic compression chamber, using argon as a compression fluid, and the isostatic compression is carried out under a pressure of 100 MPa, at 10,000 ° C., for 1 hour.

During this step, the hydroxylapatite produces water and the water vapor is held under pressure in closed microporosities of dimensions less than one micrometer
The piece is removed from the envelope and then subjected to a heat treatment carried out under atmospheric pressure at a temperature of 10000 ° C. for 5 hours.

 The total microporosity (Pt) of the part, its closed microporosity (Pf) and its open microporosity (PO) are then determined.

 The results obtained are given in Table 1 which follows.

TABLE 1 ---------

Step <SEP> a) <SEP> Step <SEP> b) <SEP> Porosity
<tb> Isostatic <SEP> Compression <SEP> Thermal SEP Processing
<tb> T1 (C) <SEP> Pressure <SEP> Time <SEP> T2 (C) <SEP> Pressure <SEP> Time <SEP> Po <SEP> Pf <SEP> Pt
<tb> (MPa) <SEP> (h) <SEP> (MPa) <SEP> (% <SEP> in <SEP> vol) <SEP> (% <SEP> in <SEP> vol) <SEP> ( % <SEP> in <SEP> flight)
<tb> Ex <SEP> 1 <SEP> 1000 <SEP> 100 <SEP> 1 <SEP> 1000 <SEP> 0.1 <SEP> 5 <SEP> 15 <SEP> 10 <SEP> 25
<tb> Ex <SEP> 2 <SEP> 1000 <SEP> 100 <SEP> 1 <SEP> 1300 <SEP> 0.1 <SEP> 5 <SEP> 1 <SEP> 23 <SEP> 24
<Tb>
EXAMPLE 2 Preparation of a Massive Part Having a Controlled Microporosity

In the same way as in Example 1, a piece of calcium phosphate is produced, but the heat treatment is carried out at a temperature
T2 of 13000C during 5h. The total microporosity (Pt), the open microporosity (PO) and the closed microporosity (Pf) of the piece thus obtained are then determined.

 The results are also given in Table 1.

 In view of these results, it is found that the total microporosity (Pt) is practically the same in both cases but that the closed microporosity (Pf) is much greater in Example 2 where the temperature T2 is 13000 C. Thus, the choice of a higher temperature had the effect of closing the microporosity and increasing the pore size, but the total pore volume remains unchanged.

 Moreover, it is noted that the total microporosity is high (greater than 10% by volume).

 Figures 3 and 4 are micrographs, obtained with a magnification of 5000, respectively illustrating the microporosity of the parts respectively obtained in Examples 1 and 2.

 In these figures, we see that the parts have rounded and stabilized pores, which limits the appearance of critical defects. This results in a better behavior vis-à-vis the mechanical stresses of any kind: flexion, compression, attrition etc. For an identical pore volume, the parts and granules prepared according to the invention are therefore mechanically stronger.

 FIG. 5 is a micrograph, obtained with a magnification of 2000, representing for comparative purposes the structure of a porous piece of hydroxylapatite obtained, according to the prior art, by sintering at a temperature of 10000C for 5 hours.

 In this figure, it can be seen that the pores have elongated shapes with acute angle wall intersections, comparable to critical defects.

Thus, the process of the invention makes it possible to improve the shape of the pores and thus to limit
The appearance of critical defects.

Moreover, with this process, it is possible to regulate
- the microporous volume by choosing
The temperature of hot isostatic compression (in the range of 900 to 12000C),
- the pore size by action on the compression pressure (in the range of 20 to 1SOMPa), and
- The nature of the microporosity (open or closed) by the choice of temperature T2 of the heat treatment (900 to 13500C).

Thus, a microporous volume of 25% can be obtained with an open microporosity of 15%, which corresponds to point A in FIG.
T2 = 10000C) and an open microporosity of 1% with a microporous volume of 24% which corresponds to the point B (for T2 = 13000C) on the diagram of FIG. 1. These points are very far from what one would have had to be obtained normally with the method of the prior art (curve 2).

 Moreover, it is noted that in the case of point B, more than 20% closed microporosity is obtained, which is a very interesting property for the manufacture of injectable granules loaded with biologically active compounds, because it can thus be locked in this microporosity a large amount of active compound which will be released slowly as the granule dissolves.

 The dissolution rate depends, in addition to the microporosity, on the composition of the starting calcium phosphate, that is to say on the Ca / P ratio, the dissolution rate decreasing when the Ca / P ratio increases, which makes it possible to set the speed at which the active compound will be released.

Thus, with such granules, one can consider local treatments very spread over time.

 For the production of granules, the process of the invention also makes it possible to generate by pickling or abrasion a surface of controlled roughness because of the shape and the mechanical stability of the pores. Indeed, by stripping, we obtain a granular surface with geometrically defined edges, which allows a better control of the distribution of granules injected into the bone tissue because the friction induced by the presence of the edges will have the effect of immobilizing the larger granules near the injection site while the smaller ones will be trained at greater distance. The presence of edges on the surface of injectable granules therefore appears to be a dispersing factor.

EXAMPLE 3 Preparation of a Macroporous Massive Part Having a Controlled Microporosity

 Granules are formed by compression, crushing and sieving a calcium phosphate powder having a Ca / P ratio of 1.660 to obtain grains of about 500 ".

 500 m grains are prepared from magnesia powder in the same way and 20 volumes of magnesia grains are mixed with 80 volumes of calcium phosphate grains.

 A blank is formed from the compression mixture and this blank is machined to dimensions close to the final piece. The blank is then placed in a steel container which is sealed under vacuum and subjected to hot isostatic pressing at a temperature of 10,000 ° C. for one hour under an argon pressure of 100 MPa. The piece is then extracted from the container and placed in a slightly acidic pH solution constituted by an acetic buffer, to preferentially dissolve the magnesia and thus create the required macroporosity.

 The part is then subjected to heat treatment at a temperature of 10000C for 5 hours to create a connected open microporosity. Finally, the piece is subjected to machining at final dimensions.

 A piece of calcium phosphate having a total microporosity of 25% with an open microporosity of 15% is thus obtained, which exhibits satisfactory mechanical characteristics for an application in surgery of bone traumas.

EXAMPLE 4 Preparation of Injectable Granules

 A porous piece of hydroxylapatite is prepared as in Example 3, and then, after the heat treatment at 10000 ° C for 5 hours, subjected to crushing and then sieving to collect granules in the range of 500 to 800 m.

 The granules are then placed in a slightly acidic medium consisting of an acetic buffer to slowly dissolve the calcium phosphate and the suspension is stirred in a bed of alumina beads to round off and spheroidize the preceding grains by attrition.

 After rinsing with water, form sorting is carried out on a vibratory plate and then sieving to select the spherical granules having the required size.

 Example 5: Direct Preparation of Injectable Granules

 An installation for the preparation of such granules is shown schematically in FIG.

 For this preparation, starting from a calcium phosphate slip stored in a vessel (1), subjected to stirring by means of a stirrer (3), and introducing this slip in a hydrophobic solvent consisting of cyclohexane present in the container (5) which is provided with a device for fragmenting the aqueous phase consisting of either a rotating disc or a vibrating capillary. In the figure, there is shown a rotating disk (7) which allows to eject the drops produced by fragmentation of the aqueous phase in cyclohexane.

 The wet granules produced in the container (5) are then introduced into a heating zone (9) to be dehydrated by heating in cyclohexane at a temperature of 70-750C. Dry granules are thus collected in the container (11).

 The pipe (17) is used to recover the cyclohexane which is entrained by the water at the upper part of the zone (9), and it is brought into the vessel (13) where the water is separated by decantation so that recycling the cyclohexane through the pipe (15) provided with a pump (16) in the container (5).

The remaining dry cyclohexane is then removed via line (12). The dry granules collected in the vessel (11) are then mixed with powdered magnesia, and the mixture is compressed to form a blank which is placed in a vacuum-sealed steel container. The assembly is then subjected to a hot isostatic compression cycle at 10000 ° C. under an argon pressure of 100 MPa for one hour. The piece is then extracted from the container and subjected to a thermal treatment carried out at a temperature of 10000 ° C for 5 hours to obtain the desired microporosity.

 After this operation, the part is subjected to disintegration and treated in an acetic buffer to dissolve the magnesia.

 The granules are sieved and sorted on a vibrating tray to remove nonspherical particles. Granules having a diameter of 200 to 600mu are thus obtained which are placed in a carrier liquid and which are packaged in doses for injection.

 When it is desired to include in these granules a biologically active compound such as calcium fluoride, calcium fluoride is added to the calcium phosphate slip of the container (1).

 Thus, the method of the invention makes it easy to produce parts suitable for various applications, especially for bone reconstitution.

 It is also suitable for the preparation of parts such as granules, for chromatography and catalytic reactors where the adjustment of the microporosity is advantageous for regulating chemical exchanges.

Claims (17)

T2 from 9000C to 14000C.  b) subject the densified part to a thermal treatment carried out at a temperature  a) densifying by hot isostatic pressing, at a pressure of 20 at ISOMPa, at a temperature T1 of 900 to 1200 C, a calcium phosphate powder having a Ca / P atomic ratio of 1.600 to 1.666; and  Process for the preparation of a porous piece of calcium phosphate, characterized in that it comprises the following successive stages  2. Method according to claim 1, characterized in that a pore-forming agent in the form of granules is added to the calcium phosphate powder which is itself granulated before carrying out the isostatic compression, and in that the pore-forming agent after the isostatic pressing step to create a macroporosity in the part before performing step b).  3. Method according to any one of claims 1 and 2, characterized in that the Ca / P atomic ratio of calcium phosphate is from 1.640 to 1.665.  4. Process for the preparation of granules of microporous calcium phosphate, characterized in that it comprises the following successive steps:  a) densify by hot isostatic compression, under a pressure of 20 to 1SOMPa. at a temperature T1 of 900 to 1200 C, granules of calcium phosphate having an atomic ratio Ca / P from 1.640 to 1.666 dispersed in a dispersing agent;  b) subject the densified part to a thermal treatment carried out at a temperature T2 from 900 to 14000C; and  c) disintegrate the densified piece thus obtained by removing the dispersing agent to obtain microporous granules.  5. Method according to claim 4, characterized in that the amount of dispersing agent is from 10 to 50% by volume of calcium phosphate.  6. Process according to any one of claims 2 and 4, characterized in that the blowing agent or the dispersing agent is magnesia and in that the magnesia is removed by dissolution in an acetic buffer.  7. Process according to any one of Claims 1 to 6, characterized in that the microporosity of the part is controlled by choosing the temperature T1 and the pressure used for the hot isostatic pressing, and in that one adjusts the ratio between the open microporosity and the closed microporosity by choosing the temperature T2 of the heat treatment.  8. Method according to any one of claims 1 to 7 for the preparation of non-absorbable bone replacement parts, characterized in that the Ca / P atomic ratio of calcium phosphate is close to 1.666 and in that one chooses the temperature T2 of the heat treatment to obtain a microporosity open almost zero.  9. Method according to any one of claims 1 to 7 for the preparation of reshaping and resorbable bone replacement parts, characterized in that the Ca / P atomic ratio of calcium phosphate is from 1.653 to 1.665 and that the temperature T2 of the heat treatment is chosen to obtain a maximum open microporosity.  10. Process for the preparation of microporous calcium phosphate granules comprising biologically active compounds, characterized in that it consists in preparing microporous calcium phosphate granules according to any one of claims 4 to 7 and to be included in the microporosity Opened granules thus obtained a biologically active compound by infiltration into the micropores.  11. Process according to claim 10, characterized in that the calcium phosphate has a Ca / P ratio of 1.653 to 1.665.  12. Method according to any one of claims 10 and 11, characterized in that the biologically active compound is an organic compound.  13. Process for the preparation of microporous calcium phosphate granules containing a biologically active compound included in the closed microporosity of the part, characterized in that it consists in preparing microporous calcium phosphate granules according to any one of claims 4. to 7 by adding to the calcium phosphate granules subjected to isostatic compression a stable biologically active compound at the temperature T1 and T2 used for isostatic compression and heat treatment.  14. The method of claim 13, characterized in that the biologically active compound is calcium fluoride.  15. Process according to any one of claims 13 and 14, characterized in that the Ca / P atomic ratio of calcium phosphate is from 1.665 to 1.666.  16. Part or microporous granules of calcium phosphate, characterized by a Ca / P atomic ratio of 1.640 to 1.665, a total microporosity of 10 to 30% by volume and an open microporosity of less than 2%.  Granules according to claim 16, further comprising a biologically active compound.