FR2684003A1 - Biodegradable, implantable, malleable formulation with calcium phosphate - Google Patents

Abstract

The invention relates to formulations based on implantable products for obtaining materials formed in situ or extemporaneously from a mixture of ingredients which can be resorbed at varying rates. The materials obtained are malleable or pass through a malleable stage and are mainly intended for dental or orthopaedic use for filling bones. A mixture of hydroxyapatite or apatite containing other calcium phosphates or lime with lactic acid and water gives a malleable paste which later sets. A gelatine/apatite/glycerol/water mixture gives, by low-pressure treatment, a bony sponge of variable density and hardness. These materials are used for manufacturing femoral obturators or for filling defects for the purpose of promoting bone regeneration.

Description

IMPLANTABLE BIODEGRADABLE FORMULATION WITH
CALCIUM PHOSPHATE
Pure and stoichiometric hydroxylapatite (PAH) corresponds to the formula Ca5 (P04) 30H.

PAH is used as a bone filling material, and as a coating on metal prostheses to accelerate bone regrowth. Its chemical composition, close to that of the mineral phase of calcified tissue, gives it privileged properties which are highly prized in dentistry and orthopedic surgery. PAH can be used pure or mixed with other absorbable mineral phases, such as for example tricalcium phosphate, calcium carbonate or other calcium oxides or phosphates. The surgical technique varies according to the indications and PAH, pure or not, is used in the form of powder, porous granules, dense granules, cut blocks, sintered preformed pieces or pieces with variable porosity.

 PAH gives its best results in the presence of bone cells which colonize the surface of the material, deposit there an extracellular matrix which calcifies thereafter. Thus, one of the most widespread uses of PAH is as a complementary material for increasing the volume of bone grafts, by simple mixing of PAH and crushed bone fragments.

The drawback comes from the difficulty of handling such a mixture without intrinsic adhesion properties and from the observed dispersion of the implanted granules due in part to the blood pressure.

 The absorbable or porous products partly meet the need to have a homogeneous structured shape but oblige to achieve a preliminary shape by cutting a larger piece. All this has led users to look for compositions which can be implanted with PAH and which would be malleable. Among the existing products include the PAH-colagen composite which becomes soft when soaked with water, the "apatitic hydraulic cements" which are complex mixtures of calcium phosphates which when hydrated pass the composition from the liquid stage in a pasty or solid state, and the plaster of Paris-PAH mixture which makes it possible to introduce dense PAH fragments into an absorbable calcium sulphate matrix. Finally, recent work relates to PAH-charged thermoplastics in which the polymer is biodegradable and made up of polylactic, polyglycolic, polyhydroxybutyric acid or copolymers. One of the major drawbacks of all the aforementioned compounds is their high cost price, the origin of which is explained by the cost of the raw materials (in particular biodegradable polymers) or the complexity of the mixtures (case of "hydraulic cements"). Another factor limiting the use of malleable PAH as a composite with collagen is the instability of the product at temperature and humidity during storage. We now describe formulations with PAH intended for the manufacture of implantable biodegradable objects and which can go through a malleable phase during their implementation.

 It is known that dental caries is caused by a slow attack of the PAH of the enamel by the lactic acid present in dental calculus or adsorbed on the teeth. Lactic acid is a normal product of metabolism which is why it is used to form biodegradable polymers, homo or copolymers of lactic acid, which constitute preferred materials in that their hydrolysis in a physiological aqueous medium leads to the production of monomers, lactic acid or homologs which are then eliminated from the body by natural physiological mechanisms. We have found how to use these natural chemicals in combination with PAH to make a biocompatible material.

According to our invention, the lactic acid is dissolved in a minimum of water in order to obtain a concentrated solution of lactic acid which has the consistency of a syrup, that is to say that one can obtain a single homogeneous phase. with a viscosity of the order of 1000 mPa.s. The solution thus obtained is mixed with a solid phase containing PAH in order to produce a paste. The solid phase contains PAH in fine powder (particle size less than 50 microns) and may also contain PAH powder (particle size greater than 50 microns) or PAH in granules (small pieces of a few millimeters in diameter ). A slow reaction occurs between the lactic acid and the surface of the PAH. This partial dissolution reaction of the PAH can be diagrammed according to the equation
2 CH3CH (OH) COOH +2 Ca5 (P04) 3 (0H) ~ Ca (CH3CH (OH) C00) 2 + 3Ca3 (PO4) 2 + 2H20
Thus, the acidic protons of lactic acid combine with the hydroxyl groups of PAH to form water, and a calcium cation forms a salt with two lactate functions.

PAH is degraded into calcium phosphate with a Ca / P ratio lower than the initial ratio of 1.667. Of course, the mixing need not be done stoichiometrically for the reaction to occur. The overall reaction can produce calcium monolactates mixed with bilactates and tricalcium phosphate mixed with other lower phosphates, mono and bicalcium. All calcium phosphates with an Ca / P atomic ratio lower than 1.667 crystallize with water molecules to give hydrated solids, in a similar way to plaster of Paris. Hence their use in "hydraulic cements". In our case, PAH serves as an anhydrous source of calcium phosphate which is transformed during the reaction into calcium phosphates which will hydrate and absorb water . it follows a progressive solidification of the dough which passes through a malleable stage to give a solid final product. In certain cases of incomplete reaction, a final product which remains pasty can be obtained.

The speed of the transformation depends on the basicity of the solid phase, its particle size, its temperature as well as its proportion relative to the liquid phase containing lactic acid. The preparation according to our invention can contain only lactic acid
or its counterparts and PAH or, instead of PAH, a mixture containing PAH and another calcium phosphate, oxide or carbonate to accelerate the reaction. The particle size mixtures are advantageous when it is desired to obtain sintered PAH included in a bioresorbable matrix. Lactic acid reacts faster with fine powder with a large specific surface than with dense, non-porous granules. Calcium oxide accelerates the setting of the material while leading to the same reaction products.

 We have seen that PAH can be replaced by calcium oxide or other calcium phosphates. Lactic acid can also be replaced by glycolic acid, hydroxybutyric acid, diglycolic, levulinic or succinic acid or more generally by any weak organic acid of formula RCOOH where R represents an aliphatic chain preferably substituted with a hydroxyl group in the alpha position.

In order to control the consistency of the implantable material it is possible to include in the formulation of additives which have no reactive function but which modify the viscosity and facilitate the implementation, for example pharmaceutical glycerol, polyethylene glycol polyol or any another hydrophilic molecule added in order to prevent dehydration of the dough. PAH can be used in the form of a suspension in pharmaceutical glycerol to obtain a paste of viscosity compatible with lactic acid syrup. In addition, the addition of gelatin makes it possible to obtain a more or less elastic final composite. Gelatin can be introduced into the PAH dispersion in which case it will dissolve when mixed with lactic acid. Gelatin may also be present in the organic phase, in which case the mixture will soften at a higher temperature. The components, pastes or final products can advantageously be sterilized by treatment with ionizing radiation. The products described in our formulations can be mixed to provide so-called single-component systems implemented at a temperature equal to or higher than 37 "C. The following example, illustrative but not limiting, allows to understand the progress of the stages of use of the preparation according to the invention:
To 50 ml of solution containing 40 g of lactic acid and 10 g of distilled water are added 50 ml of solid powder containing 50% of PAH of particle size less than 50 microns and 50% of PAH of particle size greater than 50 microns .On mixing to obtain a fluid and homogeneous paste. The paste is heated to around 40 ° C. to accelerate the reaction and after 15 minutes a malleable paste is obtained which can be used directly for bone filling or for the manufacture of implantable objects by molding, casting, injection, centrifugation, overmolding or any other production technique. By waiting longer or by simple cooling, the preparation becomes solid. The plasticity of the malleable phase can be improved by adding 1% of glycerol or 1% of gelatin. The material obtained according to this formulation contains lactates absorbable, resorbable calcium seIs and PAH.

 According to another mode of use of the invention, a bone sponge is produced which will subsequently be used to fill bone defects. This bone sponge can be spongy or more rigid depending on the formulation of the starting mixture but has interesting characteristics compared to what already exists in the art. In fact, porous calcium phosphates are produced either from a hydrothermal transformation of natural calcium carbonate in the form of coral into calcium phosphate, which limits the production range, or from synthetic calcium phosphates containing hydroxylapatite or tricalcium phosphate or both, these phosphates being shaped in several ways: by granulation, fine powder is agglomerated with a binder dissolved in water and then blocks of aggregates are made; by mixing with a solid such as camphor or naphthalene, a porous block is obtained by heating which causes the sublimation of the organic phase; by pouring a slip in a mold containing an organic foam, blocks are obtained traversed by a network of porosities left by high temperature calcination which leads to the combustion of the organic phase.

The disadvantage of these methods lies in the possible addition of impurities in the mineral phase during the elimination of the organic part.

 In one embodiment of malleable implantable objects according to our invention, the organic and inorganic phases are kept intact and the increase in the volume of the material is obtained by creating porosities by partial evaporation of the water of composition. Obtaining a foam is carried out by lowering the pressure by means of a vacuum pump, water pump or other means of suction, on a sample of mixture when it is pasty. Part of the water turns into water vapor which forms holes which remain in the solidified matrix.

 One of the ways to better control the density of the foam is to use a mixture heated to an adequate temperature, to introduce it into a bell which is gradually put under vacuum and when the desired volume is reached, to cool the mixture quickly in order to freeze the bubbles in the pasty material. A practical method of cooling is provided by the enthalpy of evaporation of the water of constitution which allows, by rapid increase in vacuum, to cause a drop in temperature sufficient to block the expansion of the foam. This process produces a bone sponge which contains an intact organic phase, calcium phosphates and water.

The following example, illustrative but not limiting, illustrates the preparation of a malleable biodegradable implantable foam
In a one-liter beaker, 150 g of powdered apatite, 50 g of gelatin, 40 g of water and 10 g of glycerol are mixed. Adding a small amount of lactic acid lowers the jelly strength of the mixture. It is heated in a water bath until a smooth paste is obtained, the temperature of which is stabilized at 450C. The beaker is introduced into an enclosure which is gradually removed with a vacuum pump. When the level stabilizes above 900 ml, the pressure is suddenly dropped to cool the foam and the vacuum is maintained for a few minutes while waiting for the assembly to be completely frozen. The vacuum is broken by slow introduction of air and the foam is extracted by cutting into the beaker.

Claims (6)

1. Preparation for the development of an implantable malleable paste characterized by the presence of two reactive components. The first component contains water and lactic, glycolic or hydroxybutyric acid or any other weak carboxylic acid RCOOH in which R is an aliphatic chain preferably containing a hydroxyl group in the alpha position.The second component contains hydroxylapatite pure or substituted or even other mineral phases such as calcium oxide, calcium carbonate or calcium phosphates. The mixture of the two components gives a paste which can be introduced into cavities to be filled and becomes solid containing a biodegradable fraction and a calcium phosphate fraction which can be non-absorbable (hydroxylapatite) or absorbable (tricalcium phosphate). 2. Two-component formulation prepared according to claim 1 characterized by the presence of gelatin in one of the components in order to modify the elasticity of the dough. 3. Two-component formulation prepared according to claims 1 or 2 characterized by the presence of pharmaceutical glycerol, polyethylene glycol polyol or any other hydrophilic molecule added for the purpose of preventing dehydration of the paste. 4. Single-component formulation comprising the mixed products described in claims 1, 2 and 3 and characterized by an processing temperature equal to or greater than 370C. 5. Implantable objects manufactured by molding, casting, injection, centrifugation, overmolding or any other production technique with as material constituting the products of the formulations described in claims 1 to 4. 6. Foam obtained according to one of the preceding claims and produced by swelling under low pressure and evaporation of part of the water.