FR2805747A1 - Injectable calcium phosphate paste for dental and surgical fillings, contains a polyethylene glycol in addition to tricalcium and tetracalcium phosphate, glycerophosphate, phosphoric acid and calcium hydroxide - Google Patents

Abstract

A process of preparing an injectable calcium phosphate paste capable of hardening after injection to form a hydroxyapatite by mixing water and calcium phosphates, adding to the phosphates or to the mixture 0.20-20.0 wt.% of a polyethylene glycol An Independent claim is included for a surgical or dental set containing a dose of the powder cement and a dose of the aqueous solution containing polyethylene glycol at 0.5-3.5 wt.% of the dose..

Description

 PROCESS FOR THE PREPARATION OF INJECTABLE PHOSPHOCALCIUM PASTE MATERIAL FOR FORMING APATITIC BIOMATERIAL AND SURGICAL OR DENTAL APPLICATION

The invention relates to a process for preparing injectable pasty material from a mixture of water and calcium phosphates, able to evolve, harden forming a hydroxyapatite constituting a biomaterial usable especially in orthopedics or dentistry. By pasty material "injectable" means the ability of the pasty material to circulate in a conduit adapted to the application envisaged under a non-destructive pressure of said material and compatible with this application and the equipment used. By "biomaterial" is meant in the present description the solid material obtained after curing, the material having biocompatibility properties and being intended to replace or treat in humans or animals an organ or function.

Phosphocalcic hydroxyapatites are well known materials increasingly used in the surgical or dental field because of their biocompatibility and osteoconductive properties. They can be used in dentistry for periodontal filling, restoration of bone ridges, filling of cysts or alveoli after tooth extraction ... and, in bone surgery for bone defect filling, interstitial filling between prosthesis and cortical , the injection into the vertebral bodies, the treatment of osteoporosis ... The biomaterial thus put in place may optionally contain active substances which, after hardening in situ, are slowly diffused.

These apatitic biomaterials are in particular obtained by curing pasty mixture prepared by mixing a mixture of calcium phosphates with water; in the above applications, setting and curing of the pasty mixture is carried out at the application site. Currently, pasty mixtures of this type are either set up on open sites where they are applied manually or spatula, or pushed for very short distances under heavy pressure on directly accessible sites. These pasty mixtures are ineffective to circulate under moderate pressure over distances greater than a few centimeters because of their viscosity characteristics.

This non-injectable nature limits the scope of these materials to directly accessible on-site interventions that do not represent the general or require open, traumatic and heavy surgery.

The present invention proposes to provide a process for preparing a novel injectable phosphocalcic pasty material, that is to say capable of being circulated under moderate pressures and over significant distances (a few tens of centimeters), said material having setting and curing times similar to those of existing phosphocalcic materials and leading, after curing, to an apatitic biomaterial of mechanical characteristics comparable to those of apatitic biomaterials obtained from these existing materials.

The process for preparing the injectable pasty material of the invention is of the type in which a pasty mixture capable of evolving, hardening and forming a hydroxyapatite is produced from water and calcium phosphates. According to the present invention, this process is characterized in that a polyethylene glycol (PEG) is added to the pasty mixture of calcium phosphates in a proportion by weight with respect to the mixture of greater than 0%, and preferably less than 0%. , 3% and 1.5%.

Experiments have shown that the material thus obtained is injectable and can be transported in pasty form in catheter type conduits, in particular flexible conduits, under moderate pressures (relative pressure less than 1 bar) which are compatible with the intervention conditions. surgical or dental and the equipment used. This pasty material is set even in a moist environment and hardens similarly to the mixture not containing polyethylene glycol; however, in the absence of polyethylene glycol, the mixture is impossible to inject as is known to those skilled in the art.

Preferably, as known per se, a pasty mixture of calcium phosphates with a Ca / P atomic ratio of between 1.5 and 1.67 is produced. This gives, after curing, a biomaterial consisting of a pure phase of hydroxyapatite whose chemical composition is very close to that of the mineral part of the bone. Outside this domain, the biomaterial obtained is multiphase (which can be sought in certain applications).

It is possible to add to the pasty phosphocalcic material according to the invention additives, in particular known additives intended to increase the regularity of setting of the dough (good homogeneity, absence of lumps). For example, a water-soluble glycerophosphate, especially potassium sodium glycerophosphate, or calcium, may be added to the mixture so that the weight percentage of this compound relative to the final mixture is less than 10%. This compound contributes to an improvement in the regularity of setting slightly decreases the setting speed. It should be noted that polyethylene glycol already contributes to improving the consistency of the setting of the dough so that the amount of glycerophosphates may be lower than that provided for similar mixtures not containing polyethylene glycol. It should be emphasized that glycerophosphate in this type of cold reaction is not decomposed and participates as a chemical reagent in the apatite formation reaction; the atomic ratios Ca / P are thus given in all the text except glycerophosphate.

The process of the invention can be carried out with a single compound of the family of polyethylene glycols or with a mixture of several compounds. The two following compounds give particularly good results polyethylene glycol hydroxystearate, polyethylene glycol glycerol oleate. These compounds give the pasty material an injectable character, but also, they reduce the setting times moderately (from 20% to 30% approximately) which is a favorable factor in most applications (dental procedures in particular).

The conditions for covering the process of the invention may advantageously be those defined in French Patent Application No. 2,776,282. According to a preferred embodiment, the pasty mixture is in particular made using a powdered phosphate cement. tricalcium and tetracalcium phosphate, and an aqueous solution containing calcium and phosphate; the methods of covering are preferably the following: Preparation of the cement by mixing powders of tricalcium phosphate, tetracalcium phosphate and glycerophosphate, preparation of an aqueous solution of phosphoric acid and lime, mixture of said solution aqueous solution and said cement so that the overall liquid / solid weight ratio L / S is between 0.30 and 0.65, in order to obtain a homogeneous paste having an overall Ca / P atomic ratio of between 1.50 and 1, 67.

This covering leads to a good reproducibility of setting and hardening and to a more consistent biomaterial (homogeneity of the product, constant setting time, absence of disintegration).

The polyethylene glycol is preferably solubilized in the aqueous solution, which increases its homogeneity in the mixture; in addition, this compound is generally in pasty form and this protocol is very simple to put covers.

In practice, in the surgical or dental field, the pasty material can be made from a set made available to the practitioners, comprising, in two separate containers, on the one hand, a dose of pulverulent phosphate, tricalcium phosphate and phosphate cement. tetracalcique and glycerophosphate, on the other hand, a dose of aqueous solution of phosphoric acid and lime, the polyethylene glycol being solubilized in said aqueous solution, in particular in a weight proportion of between 0.5% and 3.5% (by Of course, the containers containing the cement dose and the solution dose are sterilized after sealing.

At the time of the intervention, the practitioner opens the containers, mixes the dose of pulverulent cement and the dose of aqueous solution, homogenizes the mixture until a paste is obtained and injects it into the implantation site by means of suitable equipment (catheter, pump, syringe ...).

The dose of cement and the dose of aqueous solution are advantageously carried out with the conditions defined below which lead to a particularly favorable compromise of the injectable pasty material for medical applications (composition of the hydroxyapatite obtained very close to that of the mineral part of the bone and the tooth, setting time well adapted 'the intervention - of the order of 30 minutes-, total absence of disintegration, good mechanical properties of the biomaterial obtained <B> ... </ B>) i # atomic ratio CaIP between 1.60 and 1.64, # proportion by weight of glycerophosphate between 5% and 8 # proportion by weight of polyethylene glycol included. between 0.3% and 8%, # overall liquid / solid weight ratio of between 0.40 and 0.50, (the above ratios and proportions referring to the final pasty mixture). The invention is illustrated; by way of nonlimiting example, by the following examples, with reference to the accompanying drawings, in which - Figure .1 is a diagram of a device for measuring an injection pressure of a pasty mixture to define its injectability, FIG. 2, obtained in example 1, represents the curve of evolution of the injection pressure as a function of time; FIG. 3 is a reproduction of X-ray diffraction patterns of the product obtained in the example; 1 during its evolution (50 minutes, 60 minutes, 24 hours after mixing), - Figure 4, obtained in Example 1, shows the evolution curve of the penetration resistance of the product as a function of time. evaluate the injectability of pasty mixtures prepared in the examples, using a system as shown in Figure 1 for exercising and measuring an injection pressure. This system consists of a bypass tee 1, a syringe 2, a catheter 3, a manometer 4 and a separate syringe 5 for placing pasty material in the catheter 3 (temporarily separated of the bypass tee).

Each series of tests is carried out using identical amounts of pasty material but at different times after the end of the mixing (3 min, 6 min, 10 min, 14 min, etc ...).

Each quantity of material is injected in the form of a column 8 cm pasty material in the catheter 3 and is measured for each test the pressure (called injection pressure) necessary to move this column.

 EXAMPLE <U> 1 </ U> -: Preparation of an injectable pasty material Ca / P = 1.634; L / S = 0.43; Sodium glycerophosphate (NaGP) = 7.3%; PEG A = 0.3%; PEG .B = <B> 0.6%. </ B>

a) A mixture of powders by exact weighing comprising the following constituents - tetracalcium phosphate = 25.24 g, - tricalcium phosphate a = 19.51 g, - sodium glycerophosphate = 5.249 g.

The calcium / phosphorus atomic ratio (CalP) of this mixture, excluding sodium glycerophosphate, is equal to 1.77. This mixture is homogenized first with a mortar and then with a powder mixer.

b) The aqueous phosphate and calcium solution is prepared in the following manner. 5.863 g of phosphoric acid (density = 1.69 g / cm 3) are introduced into a small amount of distilled water, and then 1.629 g of calcium hydroxide. A solution is prepared containing 0.5 g of A and 1 g of PEG B where PEG A is a glycerol polyethylene glycol oleate, obtained from a mixture of castor oil and polyoxyethylene triglyceride ("cremophor EL" trademark, manufactured by BASF), PEG B is a polyethylene glycol hydroxystearate of molecular weight equal to 660 ("Solutol HS 15" trademark, manufactured BASF).

The two solutions are mixed and then made up to 50 ml with distilled water. A clear solution with a stable Ca / P atomic ratio of 0.368 is obtained.

c) Pour into a small mortar a quantity of 7.00 g of the mixture of powders prepared in a. Then add an amount of 3.01 g of the solution prepared in b, stirring vigorously by means of a pestle or spatula. The mixture is pasty and homogeneous, the mixing time remains fixed and equal to 2 minutes.

The pasty material prepared according to this method has a global atomic ratio Ca / P = 1.634 and a liquid / solid ratio L / S = 0.43.

This material is characterized with regard to its injectability and its evolution.

 Injectability The results of the measurements carried out using the device of FIG. 1 are presented in the form of a graph in FIG. 2. It can be seen that the injection pressure remains substantially constant and low (0.7 bar) for approximately 17 minutes and that this pressure then increases rapidly. The material is therefore injectable for a period of 17 minutes (injectability time) without these injectability characteristics vary. It should be noted that a comparative test carried out under the same conditions with a similar product devoid of PEG leads to injection pressures much higher than 2 bars, located outside the injectability range, and this as soon as the tempering. Evolution <U> of the pasty material </ U> In the same manner as previously, quantities of pasty material are prepared for the following tests and measurements.

The evolution in wet medium - in order to simulate a biological medium - pasty material crystallographic point of view is followed by X-ray diffraction. The gradual disappearance of the initial phases of the mixture and the formation after about 72 hours of a phase are observed. pure crystallized apatite. The diagrams in FIG. 3 are X-ray diffraction patterns (on the abscissa dhk1 is the inter-particle distance in Amgstrom) a) 5 minutes after tempering, b) 60 minutes, c) 24 hours. <U> Setting time </ U> Changes in plasticity are measured throughout the evolution of the mixture using a penetrometer: this measures the resistance to the penetration on the surface of the pasty material of a point mm2. The curve of FIG. 4 gives the variation of this resistance as a function of time. It can be considered that at a value close to 300g / mm2, the material has lost all malleability: it has totally taken hold. Of course, then, he continues his hardening.

In the case of the material described here, the setting value (300 g / mm) is reached after 41 minutes.

<U> Mechanical Properties </ U> We are also interested in the mechanical properties of biomaterials obtained from the natural material prepared in this example. defines compressive strength on a "Hounsfield S Series" type machine. For this, we prepare five test pieces of the same size (h = 13mm and = 10.6mm) that is allowed to evolve 7 days at 37 C in a 100% moist medium. The compressive strength in this example of Mpa. This resistance is very slightly lower than that of the same non-injectable product, without PEG (22 to 23 MPa). It should be noted that a strength greater than 15 is satisfactory for the products concerned.

<U> Porosity </ U> The porosity is determined from the ratio between the experimentally calculated density (mass of the test piece divided by the volume of the test specimen) and the theoretical density (density of the hydroxyapatite = 3 15 g / mm3).

The ratio of the densities is equal to 49% so the porosity is 51%.

 EXAMPLE <U> 2: </ U> Preparation of an injectable pasty material Ca / P = 1.634; L / S = 0.43; Sodium glycerophosphate (NaGP) = 7.3%; PEG B = 0.6%.

The same mixture of powders is prepared by exact weighing, as in Example 1 (Ca / P ratio = 1.77).

The aqueous solution of phosphate and calcium is prepared in the following manner. 5.863 g of phosphoric acid (density of 1.69 g / cm 3) are introduced into a small amount of distilled water, and then 1.629 g of hydroxide are slowly added. calcium. A solution containing 1 g of PEG B is prepared. The two liquid solutions are mixed and then made up to 50 ml with distilled water.

A clear, stable solution with a Ca / P atomic ratio of 0.368 is obtained.

The material prepared according to this method has an overall atomic ratio Ca / P = 1.634 and an L / S ratio = 0.43.

As in Example 1, the same amounts are used to determine the characteristics of the material.

The injection pressure measured in this example is 0.8 bar and the injection time is equal to 14 minutes. In the case of the material described here, the setting value (300 g / mm 2) is reached after 32 minutes. The compressive strength of the biomaterial is 20 MPa and the porosity is 48%.

 EXAMPLE <U> 3: </ U> Preparation of an injectable pasty material Ca / P = 1.634; L / S = 0.43; Sodium glycerophosphate (NaGP) = 7.3%; PEG A = 0.6%.

The same mixture of powders is prepared by exact weighing in Example 1 (CaJP ratio = 1.77).

the aqueous phosphate and calcium solution is prepared in the following manner. 5.863 g of phosphoric acid (density = 1.69 g / cm 3) are introduced into a small amount of distilled water, and then 1.629 g of calcium hydroxide are slowly added. . A solution containing 1 g of PEG A is prepared. The two liquid solutions are mixed and then it is made up to 50 ml with distilled water.

A clear, stable solution with a Ca / P atomic ratio of 0.368 is obtained.

The material prepared according to this method has an overall atomic ratio Ca / P = 1.634 and a ratio L / S = 0; 43.

As in Example 1, the same amounts are used to determine the characteristics of the material.

The injection pressure measured in this example is 0. -7 bar and the injection time is equal to 14 minutes.

In the case of the material described here, the setting value (300 g / mm 2) is reached after 34 minutes. The compressive strength of the biomaterial is 22 MPa and the porosity is 47%.

<U> EXAMPLE 4: </ U> Preparation of an Injectable Paste Material <B> -1.60; </ B> L / S = 0.43; Sodium glycerophosphate (NaGP) = 7.3%; PEG B = 0.6 The same mixture of powders is prepared by exact weighing in Example 1 (Ca / P ratio = 1.77).

The aqueous phosphate and calcium solution is prepared as follows. 7.22 g of phosphoric acid (density = 1.69 g / cm 3) is introduced in a small amount of distilled water, and then <B> 1.629 </ B> g calcium hydroxide. A solution containing 1 g of PEG B is prepared. The two liquid solutions are mixed and then made up to 50 ml with distilled water.

gives a clear, stable solution with an atomic ratio Ca / P = 0.299.

The material prepared according to this method has an overall atomic ratio Ca / P = 1.60 and an L / S ratio = 0.43.

As in Example 1, the same amounts are used to determine the characteristics of the material.

The injection pressure measured in this example is 0.4 bar for a time of 4 minutes and 0.8 bar for a time of 6 minutes the injection time is less than 7 minutes.

In the case of the material described here, the setting value (300 g / mm 2) is reached after 30 minutes. The compressive strength of the biomaterial is 26 MPa and the porosity is 50%.

 EXAMPLE <U> 5: </ U> Preparation of an injectable pasty material Ca / P = 1.634; L / S = 0.43; Sodium glycerophosphate (NaGP) = 9.09%; PEG B = <B> 1.39 </ B>%.

a) A mixture of powders by exact weighing is prepared comprising the following constituents: tricalcium phosphate and PEG B (solubilized in distilled water) - tricalcium phosphate a = 18.58 g, - PEG B = 1 g .

let the water evaporate in the oven. The other 2 constituents are added - tetracalcium phosphate = 24.04 g, - sodium glycerophosphate = 6.38 g. The calcium / phosphorus atomic ratio of this mixture is 1.75. This mixture is homogenized first with a mortar and then with a powder mixer.

b) prepares the aqueous solution of phosphate and calcium in the following manner is introduced 5.754 g of phosphoric acid (density = 1.69 g / cm 3) in a small amount of distilled water, then slowly added 1.603 g of calcium hydroxide. Then it is made up to 50 ml with distilled water.

A clear, stable solution with a Ca / P = O atomic ratio is obtained. As in Example 1, the same amounts are used to determine the characteristics of the material.

The injection pressure measured in this example is 0.5 bar and the injection time is equal to 15 minutes.

The material prepared according to this method has an overall atomic ratio Ca / P = 1.634 and a ratio LIS = 0.43.

In the case of the material described here, the setting value (300 g / mm) is reached after 40 minutes. The compressive strength of the biomaterial is 11 MPa and porosity of%.

 EXAMPLE <U> 6: </ U> Preparation of an Injectable Paste Material = 1.634; = 0.43:; Sodium glycerophosphate (NaGP) = 0%; PEG B = 0.6%.

a) A mixture of powders by exact weighing comprising the following constituents: tetracalcium phosphate = 16.92 g, tricalcium phosphate a = 13.08 g.

The calcium / phosphorus atomic ratio (Ca / P) of this mixture is 1.77. This mixture is homogenized first with a mortar and then with a powder mixer.

a) The aqueous solution of phosphate and calcium is prepared in the following manner 6.749 g of phosphoric acid (density = 1.69 g / cm 3) are introduced into a small amount of distilled water, then 1.875 g is slowly added. of calcium hydroxide. A 1 g PEG B solution is prepared. The two solutions are mixed and then made up to 50 ml with distilled water.

A clear, stable solution with a Ca / P atomic ratio of 0.368 is obtained.

As in Example 1, the same amounts are used to determine the characteristics of the material.

The injection pressure measured in this example is 0.4 bar and injection time is equal to 5 minutes.

The material prepared according to this method has an overall atomic ratio CaIP = 1.634 and a ratio LIS = 0.43.

In the case of the material described here, the setting value (300 g / Z) is reached after 1 hour and 20 minutes. The compressive strength of the biomaterial is 9 MPa and the porosity 49%. This much lower resistance than in the other examples leads to prefer in practice the presence of glycerophosphate, associated as additive to polyethylene glycol.

Claims (1)

 1 / - A process for preparing an injectable phosphocalcic paste material called after curing to form an apatitic biomaterial, in which is made from water and calcium phosphates a pasty mixture able to evolve, harden and form a hydroxyapatite, characterized in that a polyethylene glycol is added to the pasty mixture of calcium phosphates in a proportion by weight relative to the mixture of greater than 0.20% and less than 20%. 2 / - Preparation process according to claim 1, wherein a pasty mixture of calcium phosphates with an atomic ratio CalP of between 1.5 and <B> 1.67 is produced. </ B> 3 / - Preparation process according to one of the claims or 2, wherein is added to the pasty mixture a water-soluble glycerophosphate in a proportion by weight relative to the mixture of less than 10%. 4 / - A method of preparation according to one of claims 2 or characterized in that polyethylene glycol glycol hydroxystearate is used as polyethylene glycol. 5 / - A method of preparation according to one of claims 2 or characterized in that as polyethylene glycol a polyethylene glycol glycerol oleate. 6 / - A method of preparation according to one of claims 2, 3 or 5, characterized in that a weight proportion of polyethylene glycol substantially between 0.3% and 1.5%. 7 / - A preparation process according to one of the preceding claims, wherein the pasty mixture is produced by means of a tricalcium phosphate and tetracalcium phosphate powder cement, and an aqueous solution containing calcium and phosphate. 8 / - A method of preparation according to claim 7, wherein the pasty mixture is made by preparing a cement by mixing powders of tricalcium phosphate, tetracalcium phosphate and glycerophosphate, by preparing an aqueous solution of phosphoric acid and lime, # and mixing said aqueous solution and said cement so that the overall liquid / solid weight ratio is between 0.30 and 0.65, in order to obtain a homogeneous paste of overall Ca / P atomic ratio between 1 , 50 and 1.67. 9 / - Preparation process according to one of claims 7 or 8, characterized in that solubilizes the polyethylene glycol in the aqueous solution. 10 / - A method according to claim 9 for the preparation of a pasty material to be injected during a surgical or dental procedure for curing in situ at its implantation site, characterized in that # a dose is prepared beforehand of pulverulent cement tricalcium phosphate, tetracalcium phosphate and glycerophosphate, # a pre-dose of aqueous solution of phosphoric acid, lime and polyethylene glycol, # at the time of the intervention, mixing said dose of cement and dose of solution aqueous, and the mixture is injected into a conduit, in particular flexible conduit type catheter. 11 / - Method according to claim 10, characterized in that the cement dose and the dose of aqueous solution are prepared so that the atomic ratio Ca / P of the final mixture is between 1.60 and 64, the proportion by weight of glycerophosphate relative to the final mixture is between 5% and 8%, the proportion by weight of polyethylene glycol relative to the final mixture is between 0.3% and 0.8%, and the overall liquid / solid weight ratio is included between 0.40 and 0.50. 12 / - Surgical or dental set comprising in two separate containers, on one hand, a dose of tricalcium phosphate powder, tetracalcium phosphate and glycerophosphate cement, on the other hand, a dose of aqueous solution of phosphoric acid and lime, characterized in the dose of aqueous solution contains polyethylene glycol. 13 / - Surgical or dental set according to claim 12, characterized in that the dose of aqueous solution contains polyethylene glycol in a weight proportion of between 0.5 and 3.5% relative to said dose.