Bone filling cement

Abstract

The present invention relates to an injectable bone cement for filling bones with mechanical properties equivalent to those of vertebral spongy bone comprising 70 to 99 wt. % of an acrylic polymer combined with an inorganic type radiopaque compound and 1 to 30 wt. % of calibrated hydrophilic flexible solid particles, said calibrated hydrophilic flexible solid particles being chosen from gelatin, poly(glycerol sebacate) or a mixture thereof. A bone cement according to the invention is particularly intended for vertebroplasty, kyphoplasty or cementoplasty.

Claims

1. A binary composition for the preparation of a fluid, injectable bone cement for filling bones with mechanical properties equivalent to those of vertebral spongy bone, said fluid, injectable bone cement having a Young's modulus of less than 1500 megapascals, wherein said binary composition comprises: a liquid phase L comprising a methyl methacrylate monomer; and a powder phase P comprising 70 to 99% by weight of a poly(methyl methacrylate) prepolymer combined with an inorganic type radiopaque compound and 1 to 30% by weight of calibrated hydrophilic flexible solid particles having an average diameter between 300 and 1,000 m, wherein the P:L ratio in said binary composition is between 3 and 4.6 and wherein the weight ratio of (a) the poly(methyl methacrylate) prepolymer powder, the methyl methacrylate monomer, and the radiopaque component to (b) the hydrophilic flexible solid particles ranges from 2:1 to 100:1.

2. The binary composition according to claim 1, wherein the calibrated hydrophilic flexible solid particles are chosen from gelatin, poly(glycerol sebacate) or a mixture thereof.

3. The binary composition according to claim 1, comprising 10 to 20% by weight of calibrated hydrophilic flexible solid particles.

4. The binary composition according to claim 1, wherein the inorganic radiopaque compound is barium sulfate or zirconium dioxide.

5. The binary composition according to claim 1, wherein the inorganic radiopaque compound is combined with a calcium phosphate.

6. The binary composition according to claim 1, wherein the liquid phase L further comprises a chemical polymerization activator and a stabilizer and the powder phase P further comprises a polymerization initiator.

7. Binary composition according to claim 1, wherein the P/L ratio is between 3.4 and 4.

8. Binary composition according to claim 1, wherein the weight ratio of (a) the poly(methyl methacrylate) prepolymer powder, the methyl methacrylate monomer and the radiopaque composition to (b) the hydrophilic flexible solid particles ranges from 4:1 to 9:1.

9. A method for filling a bone defect by injection of an injectable fluid bone cement, which method comprises steps of: preparing a binary composition according to claim 1; preparing a bone cement by mixing said powder phase P with said liquid phase L to form a bone cement; and injecting the bone cement into said bone defect.

10. The binary composition according to claim 2, comprising 10 to 20% by weight of calibrated hydrophilic flexible solid particles.

11. The binary composition according to claim 6, comprising: dimethyl-para-toluidine as a chemical polymerization activator; benzoyl peroxide as a polymerization initiator; and hydroquinone as a stabilizer.

12. A composition comprising a liquid phase L and a powder phase P, said composition comprising: a liquid phase L comprising a methyl methacrylate, a chemical polymerization activator, and a stabilizer; and a powder phase P comprising 70 to 99% by weight of a poly(methyl methacrylate) polymer, a polymerization initiator, a barium sulfate and/or zirconium dioxide radiopaque compound, and 1 to 30% by weight of calibrated hydrophilic flexible solid gelatin and/or poly(glycerol sebacate) particles having an average diameter between 300 and 1000 m, wherein the P:L ratio in said binary composition is between 3 and 4.6 and wherein the weight ratio of (a) the poly(methyl methacrylate) prepolymer powder, the methyl methacrylate monomer, and the radiopaque component to (b) the hydrophilic flexible solid particles ranges from 2:1 to 100:1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention will be understood from the following description, considered with the accompanying drawing in which:

(2) The FIGURE is a graph illustrating the modulus of elasticity (Young's Modulus) as a function of time for examples of a bone cement prepared in accordance with the present invention.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

(3) The specification of the bone cement according to the invention is as follows: Injectability, Setting time greater than or equal to 15 minutes, Fluoroscopy opaque during and after injection, Low exothermicity (polymerization temperature below 60 C.), Young's modulus of compression less than 1,500 MPa.

(4) The expression setting time refers to the time defined in the ISO 5833 Standard, Annex C.

(5) Such a cement must be compatible with medical use from the point of view of its toxicity and its biocompatibility.

(6) In the present invention, it has been found that it is possible to formulate a bone cement with stiffness equivalent to or slightly greater than that of human vertebral spongy bone from an acrylic cement based on poly(methyl methacrylate) and methyl methacrylate monomer meeting the above specifications, by introducing into said acrylic cement a homogeneous dispersion of zones of controlled dimensions and density less than the acrylic cement, while at the same time keeping the properties required in terms of biocompatibility, injectability, setting time, exothermicity, radiopacity in interventional surgery.

(7) In the cement of the present invention, the zones of controlled dimensions and of density less than the acrylic cement are constituted of calibrated hydrophilic flexible solid particles of gelatin, poly(glycerol sebacate) or a mixture thereof. Gelatin is a substance of animal origin used in the composition of medical devices available on the market, poly(glycerol sebacate), or PGS, is a synthetic, biocompatible, bioresorbable and hydrophilic elastomer having mechanical properties similar to medical devices containing gelatin such as the diaphyseal obturator CEMSTOP. PGS is a flexible elastomer at human physiological temperature. The particles of gelatin or PGS have the advantage of reducing the modulus of elasticity of cements without modifying the ease of injection and the radiopacity characteristics of acrylic cements in vertebroplasty. Indeed, the particles of gelatin and/or PGS dispersed in the cement allow to create a flexible composite material, the mechanical properties of which mimic those of vertebral spongy bone, contrary to the products currently on the market which allow much superior mechanical properties. The known biocompatibility of cements on the one hand, and gelatin or PGS on the other hand, imparts to their mixture a guaranteed biocompatibility.

(8) More specifically, the aim of the present invention is an injectable bone cement for filling bones with mechanical properties equivalent to those of vertebral spongy bone comprising 70 to 99% by weight of an acrylic polymer combined with an inorganic type radiopaque compound and 1 to 30% by weight of calibrated hydrophilic flexible solid particles. The bone cement according to the present invention is medical grade and finds particularly advantageous applications in vertebroplasty, kyphoplasty or cementoplasty.

(9) The hydrophilic flexible solid particles of gelatin and/or PGS are added in proportions ranging from 1 to 30% by total weight of cement. Preferably, a quantity between 10 and 20% by total weight of cement is chosen.

(10) Hydrophilic flexible solid particles particularly suited to the preparation of the bone cement according to the present invention are of substantially spherical shape, of average diameter between 50 and 1,000 m. Preferably, the average diameter of the particles is greater than 300 m. Indeed, the applicant of the present invention has demonstrated that, up to 300 m, the smaller the dimensions of the hydrophilic flexible solid particles (the higher the specific surface), the greater the quantity of liquid monomer adsorbed by said particles during preparation of the cement, the lower the quantity of monomer available for the partial dissolution of the beads of poly(methyl methacrylate) prepolymer and the more difficult it is to obtain a fluid cement. This difficulty could be overcome by a higher provision of liquid monomer but this would increase the residual content of monomer in the hardened cement, thus the release rate of monomer into the body and consequently the toxicity level of the cement. Needle-shaped or straw-shaped hydrophilic particles are further objects of the present invention.

(11) Unexpectedly, it has been found that the calibrated hydrophilic flexible solid particles fulfill another particularly interesting function in the cement according to the invention. Indeed, it has been observed that the presence of calibrated hydrophilic solid particles brings about a reduction in the maximum temperature reached during the polymerization of the cement. The smaller the dimensions of the hydrophilic solid particles and the higher their quantity by total weight of cement, the greater this effect. Without going into theoretical studies, it is assumed that the calibrated hydrophilic solid particles act as heat dissipators. The result of this reduction in polymerization temperature, which can reach several tens of degrees Celsius compared to acrylic cements known from the prior art, is a reduction or even an absence of necrosis of the biological tissues in contact with the cement.

(12) The applicant has shown that the presence of calibrated hydrophilic flexible solid particles homogeneously dispersed in the acrylic cement progressively reduces the stiffness of the hardened mixture according to the invention. The progressive diffusion of physiological liquids within the polymerized acrylic cement and their consecutive absorption by the hydrophilic flexible solid particles leads to a progressive and controlled reduction, followed by a stabilization of its stiffness at a level identical to or slightly greater than that of the vertebral spongy bone into which it is injected. The evolution over time of the mechanical properties of the mixture according to the present invention is linked to the reduction in the density of the zones occupied by the solid particles having absorbed the physiological liquids and not to the progressive creation of a porosity. As opposed to the creation of an open and interconnected porosity as disclosed in patent EP1592463B1 ending up with a bone substitution structure, the stiffness of which is immediately stable over time after injection of the cement and washout of the fluid component, the use of hydrophilic flexible solid particles as disclosed according to the present invention makes it possible to reduce the stiffness of acrylic cements in a progressive and controlled manner. The stiffness of the cement just after its injection is identical to the bone cements currently known in vertebroplasty, ensuring a stabilization of the fracture and an immediate antalgic effect. The final stabilized stiffness is identical to that of human vertebral spongy bone and contributes to reducing the risk of fracture of vertebrae adjacent to the cemented vertebrae.

(13) Another advantage of the present invention is to impart the surgical cements a stiffness equivalent to that of vertebral spongy bone by using a lower volume fraction of calibrated hydrophilic flexible particles in comparison to the third liquid component claimed in patent EP1592463B1. Indeed, at identical volume fraction, the gelatin particles reduce the stiffness of acrylic cements more without creating open and interconnected porosity, which moreover increases the specific surface of acrylic implants and consequently the risks of generation and dissemination of debris from the implant or of release of cement components in toxic amounts in the body.

(14) Although the biocompatibility or the recognition of acrylic cements by bone cells have been improved by the introduction into formulations of osteoconducting particles such as calcium phosphates, a mechanical biointegration has never been observed. An advantageous characteristic of the invention is the creation of a porosity at the surface of the cement in contact with the bone. This surface porosity due to the biodegradation of calibrated hydrophilic flexible solid particles entering into contact with the physiological fluids and the calcified tissues would enable a bone regrowth in the pores thereby created and would ensure the mechanical biointegration of the cement within the vertebral body.

(15) The acrylic polymer according to the invention is composed of at least one poly(methyl methacrylate) (or PMMA) prepolymer and at least one methyl methacrylate (or MMA) monomer commonly used for the preparation of acrylic cements. Copolymers based on methyl methacrylatestyrene can also fall within the scope of the present invention. The prepolymer powders are provided as beads. The molar mass of these powders ranges between 150,000 and 1,500,000 g/mol. The average diameter of the particles ranges between 30 m and 150 m. The monomer is the methyl ester of methacrylic acid. Monomers and prepolymers such as MMA, PMMA and MMA-styrene copolymers for medical use are commercially available.

(16) According to a preferred characteristic of the present application, the inorganic radiopaque compound is present in the acrylic cement and thus present throughout the life of the implant. This allows to visually monitor the injection of the cement to prevent any risk of extra-osseous leakage, and makes it possible to conduct post-operative medical monitoring. The radiopaque compound may be chosen from known compounds compatible with medical use. Preferably, it is chosen from the group composed of barium sulfate and zirconium dioxide. Barium sulfate (BaSO.sub.4) is a radio-opacifier commonly used in cements for the fixation of implants, the innocuousness of which is recognized. It generally comes in powder form, in which the particles have an average diameter of 1 to 10 m. Zirconium dioxide (ZrO.sub.2) may be used as an alternative. It is introduced in powder form, in which the particles have an average diameter of 20 m.

(17) For applications in vertebroplasty or kyphoplasty, the radiopaque composition represents an important fraction of the cement. Its purpose is to inject the cement under continuous fluoroscopic control. It may be constituted of a radiopaque compound, pure or as a mixture with other ingredients. A calcium phosphate, in particular a phosphocalcic hydroxyapatite of formula Ca.sub.10(PO.sub.4).sub.6(OH).sub.2 may advantageously be used. The introduction of calcium phosphate into the composition provides a twofold beneficial effect, firstly by improving the homogeneity of the cement and later its malleability, and secondly by increasing its biocompatibility. Indeed, it is known that hydroxyapatite favors bone regrowth by stimulating the biological activity of osteoblasts and their proliferation. It has been studied in this respect, although without its mechanical properties being profitably employed. Alternatively, in the present invention, the hydroxyapatite may be replaced by a tricalcic phosphate (TCP). Advantageously, the radiopaque composition present in the cement according to the invention comprises a radiopaque compound and calcium phosphate.

(18) The cement according to the invention may finally contain a number of reagents favoring polymerization control. In particular, it may comprise, further to the ingredients cited above, an effective quantity of one or several of the following reagents: a chemical polymerization activator, a polymerization initiator, a stabilizer. Those skilled in the art know these reagents and how best to use them.

(19) A reaction initiator may advantageously be chosen from polymerization catalysts such as benzoyl peroxide (BPO). The polymerization reaction activator or accelerator is preferably N,N-dimethyl-para-toluidine (DMPT). The stabilizer, preferably hydroquinone, may be added to avoid the premature polymerization of the monomer due to exposure to heat or light. These reagents are efficient at very low concentrations, which those skilled in the art know how to adjust as a function of the required kinetics.

(20) The introduction of calibrated hydrophilic flexible solid particles into the cement has consequential effects on its physical and chemical characteristics, particularly its injectability, its polymerization kinetics, as well as its mechanical properties. The bone cement according to the invention has, in particular, a Young's modulus less than 1,500 MPa. To obtain optimal functional properties, the ingredient ratios as defined by the present application must be respected.

(21) The present invention thus disclosed is suitable for medical use within the context of filling bones in various parts of the human body. However, on account of its mechanical properties, it finds a particularly advantageous application in the case of percutaneous vertebroplasties or kyphoplasties where the cement is injected through a trocar into a fractured vertebral body.

(22) The cement according to the invention has good fluidity in the minutes after the ingredients have been brought into contact and may be worked for up to 15 minutes or even more after its preparation. The polymerization reaction between poly(methyl methacrylate) and the monomer brings about the solidification of the cement. The temperature in the vertebral body during polymerization is less than 60 C. In the present application, the term cement or fluid cement corresponds to the cement as it appears after mixing the ingredients. The composition of the cement will be considered as that of the ready to use fluid cement, prior to solidification.

(23) A bone cement according to the invention may be obtained by the preparation of a binary composition resulting from the mixture of a powder phase P mainly comprising poly(methyl methacrylate) with a liquid phase L mainly comprising methyl methacrylate monomer in a P/L ratio between 3 and 4.6. Preferably, P/L is between 3.4 and 4.

(24) The calibrated flexible solid particles are equally well incorporated in one or the other of the two phases P or L. Preferably, they are incorporated in the powder phase P.

(25) The poly(methyl methacrylate) prepolymer powder, the methyl methacrylate monomer and the radiopaque composition on the one hand, and the hydrophilic flexible solid particles on the other hand, are advantageously provided in a weight ratio between 2 and 100. Preferably said ratio is between 4 and 9. Thus, it has been determined that the optimal formulation is that in which the proportion of cement is least and for which the mechanical properties are the lowest, adapted to those of vertebral spongy bone.

(26) The binary composition according to the invention preferably comprises an effective quantity of one or several of the following reagents: in the liquid component L, a chemical polymerization activator and a stabilizer; in the powder component P, a polymerization initiator.

(27) For example, the liquid component L may comprise from 0.7% to 2.5% of DMPT and 20 ppm of hydroquinone. The powder component P may comprise from 0.2% to 2% of benzoyl peroxide. Preferably, the liquid component L contains 1% of DMPT, while the powder component P contains between 0.3% and 0.35% of benzoyl peroxide.

(28) When used in the operating theater, the two powder and liquid components are mixed together. At this moment, the powder phase partially dissolves in the liquid phase, thereby giving a mixture that has to be sufficiently fluid to be able to be injected into a vertebral body. During mixing, the activator and the initiator react to produce free radicals. These radicals initiate the polymerization reaction, leading to the progressive hardening of the cement, according to the required kinetics.

(29) Once ready, the cement according to the invention will react to form a solid mass in a relatively short lapse of time (from several minutes to several tens of minutes), the formulation claimed here setting in not less than 15 minutes. It is obvious that the ingredients reacting together have to be mixed only at the time of use. For this reason it is useful to avail of a binary composition constituted of two pre-mixes of ingredients that simply have to be combined to prepare the cement according to the invention. These pre-mixes, one in powder form P mainly containing the poly(methyl methacrylate) prepolymer, the other in liquid form L mainly containing the methyl methacrylate monomer, constitute the two components of said binary composition.

(30) The device according to the invention may advantageously be used for the preparation of a fluid cement for medical use for filling the vertebral body.

(31) According to an advantageous alternative embodiment, the powder component P comprises 1% to 36% of flexible particles, preferably between 13% and 25% by weight relative to the weight of powder.

(32) The following examples will make it easier to understand the invention, without however limiting its scope.

(33) The following abbreviations are used: PMMA: poly(methyl methacrylate) MMA: methyl methacrylate BPO: benzoyl peroxide BaSO.sub.4: barium sulfate ZrO.sub.2: zirconium dioxide HAP: phosphocalcic hydroxyapatite DMTP: dimethyl-para-toluidine HQ: hydroquinone P/L: powder phase/liquid phase ratio, by weight.

Example 1: Binary Composition with 13% by Weight of Gelatin Relative to the Weight of Powder, (10% by Weight of Gelatin, Relative to the Weight of Cement)

(34) TABLE-US-00001 Powder phase (wt. %) PMMA 43 BPO 0.4 ZrO.sub.2 39.2 HAP 4.4 Gelatin 13 Liquid phase (wt. %) MMA 99 DMPT 1 HQ 20 ppm where P/L = 3.4 Final Young's modulus = 1,000 MPa

Example 2: Binary Composition with 25% by Weight of Gelatin Relative to the Weight of Powder, (20% by Weight of Gelatin, Relative to the Weight of Cement)

(35) TABLE-US-00002 Powder phase (wt. %) PMMA 37.1 BPO 0.4 ZrO.sub.2 33.7 HAP 3.8 Gelatin 25 Liquid phase (wt. %) MMA 99 DMPT 1 HQ 20 ppm where P/L = 4 Final Young's modulus = 500 MPa

Example 3: Method of Preparing a Bone Cement with Suitable Stiffness

(36) Powder Component:

(37) The powder phase is obtained by mixing the various ingredients.

(38) Liquid Component:

(39) The liquid phase is prepared by dissolving hydroquinone in the methyl methacrylate monomer. The stirring is maintained up to complete dissolution. DMPT is then added.

(40) The two phases are packaged separately in containers suited to their conservation. The instantaneous preparation kits comprise a container containing the liquid phase and a container containing the powder phase.

(41) Binary Composition

(42) During use in the operating theater, the containers are opened and their contents are mixed together. The powder dissolves rapidly in the liquid phase, giving a fluid mixture that is injected into the vertebral body of the patient through suitable tubing. The BPO initiator and the DMPT activator react to form free radicals that initiate the polymerization reaction of the cement. The surgeon then has at least fifteen or so minutes to operate, continuously controlling the procedure by fluoroscopy.

Example 4: Tests as per the ISO 5833 Standard

(43) The ISO 5833 Standard, entitled Implants for surgeryAcrylic resin cements defines the characteristics required by regulations and the standard tests enabling these characteristics to be quantified. The compositions described in the above mentioned examples 1 and 2 were tested to determine their setting time and the maximum temperature reached during polymerization.

(44) The results obtained for the two compositions of examples 1 and 2 as well as the gelatin-free control composition are shown in Table 1.

(45) All of the procedures are described in detail in the ISO 5833 Standard.

(46) TABLE-US-00003 TABLE 1 Maximum temperature Composition Setting time (min) ( C.) Example 1 20.26 0.44 52.0 3.2 Example 2 19.96 0.43 47.2 2.0 Control 18.24 0.24 69.3 2.1

(47) It should be noted that their characteristics meet the specifications defined previously for bone cements used in percutaneous vertebroplasty (setting time greater than 15 minutes, fluoroscopy opaque).

Example 5: Mechanical Properties

(48) A second series of tests relates to the mechanical properties of the installed cement, in other words its Young's modulus of compression. This parameter has been determined at regular intervals (4, 24 hours, 3, 8 and 14 days) on test specimens conditioned as per the ISO 5833 Standard and placed in distilled water at 37 C. under slow stirring. The results obtained with the compositions cited in example 1 and 2 and the gelatin-free control cement are shown in FIG. 1. For comparison, it will be recalled that the Young's modulus of compression of human vertebral spongy bone is between 100 and 800 Mpa.