WO2004103420A1

WO2004103420A1 - Injectable bioactive acrylic formulations for use in minimally invasive surgery

Info

Publication number: WO2004103420A1
Application number: PCT/ES2004/070036
Authority: WO
Inventors: José Alberto MENDEZ GONZÁLEZ; Blanca VÁZQUEZ LASA; Julio SAN ROMÁN DEL BARRIO
Original assignee: Consejo Superior De Investigaciones Científicas
Priority date: 2003-05-23
Filing date: 2004-05-24
Publication date: 2004-12-02
Also published as: ES2220216A1; ES2220216B1

Abstract

The invention relates to the preparation of acrylic formulations containing: a bioactive component; bioactive glass or silica nanoparticles having different sizes and morphologies, such as aerosil; and an anti-inflammatory drug comprising phosphate groups, which can be injected and cured in situ. Said type of formulations are intended for percutaneous vertebroplasties, bone defects produced following the recession of tumours or hypertrophies and biomechanical stabilisation in the field of osteoporosis with loss of bone mass. At present, the formulations used for said purpose comprise commercial acrylic bone cement formulations which do not have suitable fluidity and radiopacity properties.

Description

Title

INJECTABLE BIOACTIVE ACRYLIC FORMULATIONS FOR APPLICATION IN MINIMALLY INVASIVE SURGERY

Technical sector

This invention is framed within the polymeric bone cements used as filler systems in percutaneous vertebroplasties or for fixation of osteoporotic fractures within minimally invasive surgery

State of the art

The bone cements used in orthopedic surgery are predominantly based on polι (methyl methacpilate), PMMΛ They are obtained by cold curing of the precursor compositions that generally comprise two phases, a solid phase and a liquid phase The solid phase usually comprises particles in the form of pre-polymerized PMMΛ beads or their copolymers, together with one or more radical initiators and, optionally, one or more radiopaque agents A radical-type initiator is a compound, for example a peroxide, that is capable of producing free radicals A radiopaque agent is a compound as its name suggests is substantially opaque to radiation, in particular to radiation used in medical diagnostics, such as X-rays. The liquid phase comprises a pohmeπzable monomer, usually methyl methacrylate, MMΛ, together with one or more activators Activator is a compound, such as an aromatic tertiary amine, that causes the decomposition initiator ion at room temperature to lead to the formation of free radicals. The liquid phase may also comprise one or more inhibitors and / or stabilizers that are added in order to avoid polymerization of the monomer during storage. Bone cement precursor composition are mixed, the monomer polymerization reaction occurs, obtaining a bone cement consisting of solid powder particles embedded in an interstitial matrix of polymer formed

This type of systems have also been used as self-healing composites for dental fillings and fillings, adding finely divided quartz or vine particles and pharmacologically active compounds such as antibiotics. The same methodology is applied in all cases, which consists of hardening pastes of greater or lesser viscosity by radical polymerization, from the moment the two components of the cement are mixed.

Currently there is great interest in the application of low-viscous bone cement formulations in percutaneous vertebroplasty (PVP) (Cortón Λ, Boutry N, Cortet B, Λssaker R, Demondion X, Leblond D, Chastanet P, Duquesnoy B, Deramond H . "Percutaneous vertebroplasty: State of the art", Radiographics 1998, 18, 31 1-323). This technique was first introduced for the treatment of vertebral angiomas by Galibert and Deramond in 1987 (Galibert P, Deramond R. "Preliminary note on the treatment of vertebral angioma by percutaneous acrylic vertebroplasty", Neurochirurgie 1987, 33, 166-168; Galibert P, Deramond R. "Percutaneous acrylic vertebroplasty as a treatment of vertebral angioma as well as painful and debilitating disease", Chirurgie 1990, 116, 326-334). The clinical results were very promising since the technique provided pain relief, and its application has extended to other cases such as the treatment of osteolytic bone metastases (Weill A, Chiras J, Simón JM, Rose M, Sola-Martínez T , Enkaoua E. "Spinal metastases: Indications for and results of percutaneous injection of acrylic surgical cement", Radiology 1996, 199, 241-247), myelomas and, more recently, it is applied in the biomechanical fixation of osteoporotic fractures. The antalgic effect of PMMA is probably based on its mechanical effect by increasing the bone density of the trabecular bone at the fracture site, leading to a stabilization of the affected vertebrae with respect to compressive forces, but it is also related to the induction of tumor necrosis and the thermal or chemical destruction of nerve endings, as a consequence of the heat release produced during the MMΛ polymerization reaction.

Commercial formulations of acrylic bone cements are not designed for application in vertebroplasias, their main deficiencies being fluidity and radiopacity. The solid-liquid ratio recommended by cement manufacturers is frequently altered in order to decrease the viscosity of the resulting mass and increase the working time. This modification in the formulation can lead to a reduction in elastic modulus and stress at break by up to 24% (Jasper LE, Deramond H, Mathis JM, Belkoff SM "The effect of monomer-to-powder ratw on the material properties of cramoplastic to the material properties of cramoplastic", Bone 1999, 25, 27S-29S) Regarding insufficient radiopacity, the surgeon usually adds a additional amount of a radiopaque agent at the time of application This resource has the drawback that it provides a change in the theological properties of the cement and shortens the available working time

Brief description of the invention

The present invention is related to the development of acrylic formulations with bioactive components and carriers of an anti-inflammatory and analgesic drug with phosphate groups, belonging to the family of the so-called non-steroidal anti-inflammatory agents, ΛINEs, which present adequate injectability for application in percutaneous vertebroplasties or for the biomechanical fixation of osteoporotic fractures. Commercial pohmenic bone cements have been used for the last decades in this type of application, however, it is necessary to alter the formulation to achieve the necessary characteristics that commercial formulations lack.

Detailed Description of the Invention The present invention is based on the formulation of a fluid and injectable acrylic bone cement precursor composition whose solid phase comprises particles of polι (methyl methacrylate), PMMΛ or copolymers of methyl ethacrylate with other monomers in an amount comprised between 20-80% -p, a radical-type initiator in an amount of up to 3% -p and a non-steroidal antnniaphoramatous drug carrying phosphate groups of general structure such as that presented in Formula (1), in a amount of up to 30% -p, usable in its acid form or as sodium salt of the phosphoric and carboxyl acid groups

where

Ri is a hydrogen or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical

R ₂ is a hydrogen or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical

R ₃ is a hydrogen or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical

R 'is a hydrogen or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical

The composition of the solid phase may also contain a certain amount of a bioactive compound such as bioactive glass in the Sιθ ₂ -CaO- system.

Na ₂ θ-PjOs, in amounts between 20-50% -p, preferably 40% -p and / or silica nanoparticles of different sizes and morphology of the aerosil type, in amounts between 5-20% -p, all of these quantities with respect to the total weight of the solid phase

The solid phase composition may contain a certain amount of a radiopaque compound such as barium sulfate, zircomo dioxide, tantalum oxide, strontium oxide or organic compounds, in amounts between 20-25% -p with respect to the weight total solid phase

The composition of the liquid phase comprises monomer methyl methacrylate (MMΛ) in an amount ranging from 95-99% -p and an aromatic tertiary amine as activator in an amount ranging from 0 5-2 5% -p, prcfcπblemcntc 1% - p, with respect to the total weight of the liquid phase In those cases where it is desirable to achieve local hypothermic effects (for example, bone tumor accessions) acrylic acid will be added to the liquid phase in an amount between 5-10% -p, leaving the MMΛ in a proportion between 85-90% -p

The composition of the liquid phase can include one or more inhibitors in an amount of 0.01% -p and / or one or more stabilizers in an amount of 0.01% -p, where these compounds belong to the family of what

By mixing the different phases, solid and liquid, of any of the formulations described above, and the subsequent radical polymerization of the liquid phase, a cement is obtained consisting of a fluid material capable of being injected and finally cured "in situ "This feature allows these formulations to be used as precursor bone cement compositions for use in minimally invasive surgery such as percutaneous vertebroplasty or osteoporotic fracture fixation. The cements thus obtained have some advantages over commercial formulations of acrylic bone cements when used for this application.

The bone cement precursor compositions comprising this invention have significantly longer setting times than commercial formulations, making them suitable for use as injectable systems in minimally invasive surgery.

The bone cement precursor compositions comprising this invention reach temperatures lower than those of commercial compositions in the curing or polymerization process. This reduction in temperature could potentially decrease the damage caused to adjacent tissues during the formation of bone cement "in situ "

The cements of the present invention provide beneficial effects in the bone tissue regeneration process, as a consequence of the dissolution of the bioactive component and of the drug, favoring the precipitation of a hydroxyapatite layer and providing intimate union with it.

The presence of the drug carrying phosphate groups accelerates the precipitation processes of the hydroxyapatite layer, essential for binding with bone.

The cements of the present invention can be considered as sustained dosage systems of non-steroidal antnnflamatoπos drugs (ΛfNEs)

The incorporation of an ΛINE in the cements of the present invention provides a decrease in the inflammatory response at the local level as observed after intramuscular implantation of rods in rats.

EXAMPLE 1

Formulation of bone cements bearing bioactive glass and "phosphosal"

Bone cement precursor compositions were formulated using a liquid phase composed of the methyl methaclate monomer and as an activator the compound (4- N, N-dιmetιlamιnofenιl) -methanol (DMOH). The solid phase consisted of particles of polι (methyl methacrylate) ) (QL pearls), whose morphological characteristics are given in table I. QL pearls are commercial pearls and were supplied by Industrias Quirúrgicas de Levante

Table I. Morphological characteristics of QL pearls

In different experiments, a certain quantity of the QL beads was replaced by bioactive vine and "fosfosal" (sodium salt of 2-phosphonoxι-benzoιco acid) as an antnnflamatoπo drug. The composition of the bioaccrative vine used is presented in Table II

Table II Composition of the bioactive glasses used The liquid solid ratio was 1.7 1 in all cases Λ itself, a precursor composition of bone cement based on PMMA was tested under the same conditions as a comparative example The compositions of the experimental cement tested were shown in Table III where the following abbreviations are used

BPO = Benzoyl peroxide

PMMΛ = Polι (methyl methacrylate)

FOS = Tosfosal

BVCP = Bioactive glass with phosphorous content

BVSP = Bioactive vine without phosphorus content

MMΛ = Methyl Mctacπlate

DMOH = (4-N, N-Dιmctιlamιnofcnιl) -mctanol

S L = Liquid solid ratio

Table III Bone cement precursor compositions formulated with bioactive glass and the drug "phosphosal"

For each example, a total of 40 g of solid phase and 23.5 ml of the liquid phase were used. These bone cement precursor compositions were mixed to form the cement paste that sets in a few minutes to give rise to the cured cement

The peak or maximum temperature (T _mdx ) is defined as the maximum temperature reached during the polymerization reaction and was recorded in accordance with ISO 5833 The two components of the bone cement precursor composition were mixed and the resulting paste was placed in a teflon mold. A thermocouple was placed in the center of the mold at a height of 3 mm in the internal cavity. Time was taken from the beginning of the mixture of the two components and the temperature were recorded An average of two measurements was made for each formulation

The pasty state time (t _pasl0so ) represents the time in which the cement mass does not adhere to the surgical glove. At this moment the cement is implanted in the body, for example, in the femoral cavity

The setting time (t _f r _AGUATE ) was determined in accordance with ISO 5833 as the time in which the temperature of the cement mass is the ametic mean of the maximum temperature in "C and the ambient temperature, 23 ± 1 ° C

The curing parameter values for the formulations with compositions listed in Table III are shown in Table IV. The setting time values of the compositions prepared in the presence of bioactive and "phosphosal" glass were higher than those obtained with the formulation. control prepared with PMMΛ exclusively This increase in setting time offers the possibility of using these formulations as injectable systems. The peak temperatures of the precursor compositions containing "phosphosal" were approximately 10 ° C lower than those obtained with the control formulation of PMMA, while that those of the precursor compositions containing both "phosphosal" and 40% -p of any of the bioactive glasses were approximately 20 ° C lower than those of the control, representing a significant and significant benefit from a biological point of view

Table RV Values of the curing parameters obtained with the precursor compositions specified in Table III [d s] standard deviation

The residual monomer content (CMR) was determined by proton nuclear magnetic resonance spectroscopy (Η-NMR). The samples were stored at room temperature in air for seven days before being analyzed. Three samples of each composition were dissolved in deuterated chloroform and the spectra were recorded on a Vanan 300MIIz spectrophotometer

Measurements of glass transition temperature (T ₈ ) were made on a DSC7 differential calorimeter (Perkín Elmer) connected to a TΛC 7 DX thermal data analysis system. The dried samples were placed in the form of thin films (15-20 mg) in aluminum capsules and heated at a constant speed of 10 ° C x in 'in the temperature range 50-200 ° C The T _t was taken as the midpoint of the transition of the heat capacity observed in the thermogram corresponding to the second bard

The values of the residual monomer content and the glass transition temperature of the cements prepared with the precursor compositions collected in the table of FIG 3 are shown in table V Fl The residual monomer content of the formulations containing "phosphosal" was the same order that that obtained in the PMMΛ formulations, while the formulations containing bioactive vine and "phosphosal" had slightly higher contents, but always less than 5% -p, indicating that the conversion of the pohmeπzacion reaction carried out in the presence of a bioactive component and the drug "phosphosal" is comparable to that achieved in PMMA formulations. Likewise, the glass transition temperature values of the precursor compositions did not undergo notable changes in relation to that of the PMMΛ control.

Table V Values of content in residual monomer and glass transition temperature of bone cements obtained with the precursor compositions shown in Table III

EXAMPLE 2

Injectability of bone cements bearing bioactive glass or silica nanoparticles and "phosphosal"

Bone cement precursor compositions were formulated under the same conditions as in Table III where the bioactive vine was replaced by silica nanoparticles of average particle size 0.2-0 3 µm (Cab-o-sil® TS-610). The compositions of these formulations are listed in Table VI

Table VT Bone cement precursor compositions formulated with silica nanoparticles and the drug "phosphosal"

The solid and liquid components of the precursor compositions were conditioned at room temperature for 2 h prior to testing. 5 g doses of cement were prepared and loaded into 2.5 ml disposable syringes (Plastipak, Becton Dickinson) .8 gauge needles were used. (BoneMarrow Biopsy / pispiration Needle, Surecut BMB) 150 m long and 2 mm in diameter, which were attached to the syringe and through which the cement was injected into a previously tared container. The percentage of injectability was determined from the relationship between the weight of the cement injected and the weight of the total cement loaded in the syringe Likewise, this same test was performed with PMM formulationsΛ The injectability results of the precursor formulations shown in tables III and VI appear in the table VII

It is made of bone cements that are listed in Tables III and VI The injectability values of the precursor compositions prepared in the presence of "phosphosal" were very high, of the order of 85%, as were the injectability values of the precursor compositions containing bioactive and "phosphosal" vine, or silica nanoparticles and " phosphosal ", of the order of 80% However, the performance of the trial with acrylic formulations of PMMΛ resulted in 0% injected cement mass, which shows the increased fluidity of the cement mass in its stages initials with the incorporation of "phosphosal" and bioactive vine or silica nanoparticles, which allows the injection of cement

EXAMPLE 3

Study of "fosfosal" release and "in vitro" behavior of bone cements bearing bioactive and "fosfosal" vine

For the study of the release of the drug "phosphosal", rectangular plates of dimensions 10 cm x 1 cm and 1 mm thick were prepared. The samples were immersed in 10 ml of a phosphate buffer solution (pH = 7.0) and were maintained at 37 ° C throughout the time of the sample. Samples of the medium were taken at different time intervals, replacing all of the saline solution at all times. The concentration of phosphosal released into the saline medium was determined by visible ultraviolet spectroscopy analyzing the signal at 275 nm corresponding to phosphosal

Figure FIG 1 shows the release profiles of "fosfosal" from cements prepared with PMMΛ-containing precursor compositions and "fosfosal" and from cements prepared with bioactive vine-containing precursor compositions and "fosfosal" They contain bioactive vine, they showed a sustained release of the drug, quasi-linear with time, reaching 80% -p of "phosphosal" in a period of 150 h. When the cements were prepared from precursor compositions that contain bioactive vine, there was a quick release during the first 24 hours of immersion The cements containing the BVCP bioactive glass presented total release after 30 hours of immersion, while for that same period of time the cements containing BVSP produced releases close to 80% -p The swelling of the cements in simulated physiological fluid (SBF) solution (pH = 7 4) was studied from discs 1 cm in diameter and 1 mm thick. The samples were immersed in SBF and kept at 37 ° C for all the time of the experiment Λ different time intervals, the corresponding cement sample was taken out, dried superficially and weighed Λ then it was placed in an oven at 50 ° C and kept until constant weighing The degree of hydration (H) was determined gravimetrically from the expression

% H = [(W _h -W _s ) / W _o ] x l00

where W _h is the weight of the hydrated sample at time t, W _s is the weight of the oven-dried sample at time t and W ₀ is the weight of the initial dry sample. The experiments were carried out in triplicate

The variation of the degree of hydration over time that occurs when the cements prepared with bioactive glass and "phosphosal" are immersed in a hydrated medium are presented in Figures FIG 2Λ and 2B for cements containing the bioactive vines BVCP and BVSP respectively. Cements prepared with the bioactive glass and "phosphosal" glass containing precursor compositions exhibited degrees of hydration of the order of 12-16% -p, substantially higher than that of the PMMΛ control formulation, which oscillates around 2% w, as a consequence of the presence of hydrophilic components in the solid phase

The weight variation in simulated physiological fluid (SBF) solution (pH = 7.4) was studied from discs 1 cm in diameter and 1 mm thick. The samples were immersed and kept at 37 ° C throughout the time of the experiment c different time intervals, the corresponding cement sample was taken out and placed in an oven at 50 ° C, keeping it until constant weighing. The weight loss was determined from the expression% Weight loss = f (W ₀ -W _s ) / W „] x 100

where W „is the weight of the initial dry sample and W _s is the weight of the dry sample at a time t of immersion. The experiments were carried out by typing The results of the variation in weight experienced by the cements comprising the present invention are shown in Figures FIG 3A and 3B for the cements that contain BVCP and BVSP bioactive glasses, respectively. Regardless of the type of vine used, the cements of this invention presented a weight loss in hydrated medium of the order of 18-26% -p, due to the presence of soluble components in the medium such as bioactive vines and the drug "phosphosal" itself

The surface of the cements prepared from the bioactive and "phosphosal" vine-containing precursor compositions after immersion in SBF was studied through spectroscopic and microscopic techniques. In order to study the influence of "phosphosal" on the formation of the hydroxyapatite layer, cements were peeled from precursor compositions containing bioactive vine in the absence of the drug. The surface of the samples was analyzed by FTIR-ΛTR spectroscopy (Total Reflection Attenuated) (Perkín Elmer, Spectrum One) and by environmental scanning electron microscopy (ESEM XL30, Philips) mismothe HTI FTIR spectrum was recorded as reference

Figure FIG 4 shows the FTIR spectrum of hydroxyapatite, where the characteristic tension bands of phosphate groups can be seen at 1030 cm '

Cements prepared with the bioactive glass that does not contain phosphorus oxide (BVSP) and in the absence of "phosphosal" did not show surface growth as confirmed by analysis of the FTIR-ΛTR spectra of the cement surface at different time intervals (FIG 5) However, cements prepared under the same conditions but in the presence of "phosphosal" showed superficial modification after 4 days of immersion. The FTIR-ΛTR spectrum of the cement surface at this time of immersion shows the disappearance of the bands characteristic of the PMMΛ polymer and the appearance of a wide band centered at 1025 cm 'assigned to the normal mode of vibration of the phosphate groups of hydroxyapatite. (FIG. 6) This fact shows the participation of the "phosphosal" molecule through the phosphate groups, in the precipitation processes of the hydroxyapatite layer. Finally, the morphology of the deposited layer was analyzed through microscopy of environmental scanning ESEM images are shown in Figures FIG 7Λ and 7B and reflected the typical morphology of the hydroxyapatite crystals

The cements prepared with the bioactive glass containing phosphorus oxide (BVCP) and in the absence of "phosphosal" showed superficial growth 10 days after the immersion as confirmed by FTTR-ΛTR spectroscopy, obtaining a spectrum at this time similar to the one presented by hydroxyapatite Λ itself for this time interval the morphology of the surface analyzed by ESEM showed images similar to those presented in figure FIG 7 Cements prepared with BVCP glass in the presence of "phosphosal" showed superficial modification to 4 days after immersion, indicating that the "phosphosal" molecule accelerates the phosphate salt precipitation processes

FJFMPLO 4

Intramuscular implantation of cured cement rods from precursor compositions formulated with bioactive and "phosphosal" vine

Rods of cured cement were implanted from the precursor compositions shown in Table III. Rods of commercial CMW3 cement were implanted as a control.

The cement pads (3 mm diameter x 15 mm length) were inserted through a cannula into the dorsal muscle of medium weight 300 ± 10 g female Wistar rats. The hay was sutured with a 3/0 silk stitch and Betadine® was applied. Three groups corresponding to 2, 2 and 3 animals respectively were made, which were sacrificed at 2, 4 and 8 weeks after the operation

The samples were fixed in a 10% formalin buffered solution (phosphate buffer, pll = 7.6) and embedded in paraffin. Histological sections were prepared which were stained according to the hcmatoxihna-cosina technique. The samples were examined under a light microscope. Nikon Microphot FXΛ

FIG 8 shows the histological images of the response of the muscle to the control cement after 4 and 8 weeks after implantation. The cross section of surrounding tissue showed the formation of a fibrous membrane along with the presence of polymorphonuclear leukocytes, macrophages, and eosinophils. The thickness of the fibrous membrane increased with time of implantation. However, no signs of necrosis were detected as expected due to the implantation of an in vitro cured cement

Figures FIG 9Λ, 9B and 9C reflect the tissue response after 2, 4 and 8 weeks of implantation, respectively, to the cement stick prepared with PMMΛ and “fosfosal” Fl PMMΛ cement loaded with the drug “fosfosal” did not give place to the formation of a well differentiated fibrotic capsule during the implantation time, as it was found after implantation of vaπllas of the commercial cement CMW3 (FIG 8) Fstc phenomenon is due to the anti-inflammatory character of the "fosfosal" that, acting "in situ" gives As a result, the decrease in the inflammation and foreign body processes that take place in every implantation process. TI muscular tissue was not affected by the introduction of maleπal, with which it can be affirmed that the cement loaded with "fosfosal" is perfectly tolerated by the body

Figure FIG 10 shows the tissue response to cements prepared with bioactive and "phosphosal" glass at 2 weeks after implantation. The inflammatory response was independent of the type of bioactive glass used (FIG 10A and 10B). At this time period it was observed the appearance of a fibrotic capsule characterized by the existence of an area with high cell proliferation next to the implanted mateπal, consisting mainly of macrophages The area of the capsule furthest from the implant was looser, presenting a lower density, and increasing the amount of edema and vasculature In this first period of time, there was also the appearance of a reaction to a foreign body, characterized by the existence of giant polynucleated cells, macrophages, lymphocytes, and fibroblasts.

Four weeks after implantation, the loose area of the fibrotic capsule showed greater vascular proliferation, even though macrophages and characteristic lymphocytes of the inflammatory response still existed. This area of lower density than the area closest to the implant gave rise to the appearance of more edema Figure FIG 1 1 shows the response to a cement prepared with the bioactive glass BVCP and "fosfosal" A similar response was obtained when using the glass BVSP Eight weeks after implantation (FIG. 12), a higher content of fibroblasts and collagen fibers and a lower content of edema were detected, with abundant vascular proliferation. The fibrotic capsule was well constituted and the inflammatory elements decreased. As in the previous cases, the response was independent of the type of bioactive glass used. FIG FIG. 19 shows the response for this implantation time to a cement prepared with the BVSP bioactive glass.

Brief description of the figures FIG. 1. "Phosphosal" release profiles over time, from cements prepared with the precursor compositions detailed in Table III. FIG. 2. Variation of the degree of hydration over time of the cements prepared with the precursor compositions in Table III. FIG. 2A: Cements containing BVCP bioactive glass. FIG. 2B: Cements containing BVSP bioactive glass. FIG. 3. Weight loss experienced by the cements comprising the present invention formulated with bioactive glass and "phosphosal". FIG 3Λ: Cements containing BVCP bioactive glass. FIG. 3B: Cements containing BVSP bioactive glass. FIG. 4. FTIR spectrum of hydroxyapatite. FIG. 5. FTIR-ΛTR spectra of the surface of cements prepared with the BVSP bioactive glass in the absence of "phosphosal" at different times of immersion in SBF. FIG. 6. FTIR-ΛTR spectra of the surface of the cements prepared with the BVSP bioactive glass in the presence of "phosphosal" at different times of immersion in SBF. FIG. 7. ESEM micrographs of the surface of the cements repaired with the BVSP bioactive glass in the presence of "phosphosal" at 15 days of immersion in SBF. FIG. 7Λ: x 1000. FIG. 7B: x 8000.

FIG. 8. Micrographs showing the histological response to intramuscular implantation in CMW 3 commercial cement rod rats. FIG. 8Λ: Λ 4 weeks after implantation. FIG. 8B: Λ 8 weeks after implantation.

FIG. 9. Micrographs showing the histological response to the formulation prepared with PMMΛ and "fosfosal". FIG. 9Λ: After 2 weeks of implant (x 20). FIG. 9B: After 4 weeks of implantation (x 20). FIG. 9C: After 8 weeks of implantation (x 20). FIG 10 Micrographs showing tissue response to cements prepared with precursor compositions containing 40% -p of bioactive vine and 30% -p of "phosphosal", 2 weeks after implantation FIG 10A Cements containing BVCP bioactive glass ( x 20) FIG 10B Cements containing BVSP bioactive vine (x 10)

FIG 11 Tissue response to a cement prepared with precursor compositions containing 40% -p of BVCP bioactive vine and 30% -p of "phosphosal", 4 weeks after implantation (x 20)

FIG 12 Tissue response to cement prepared with precursor compositions containing 40% -p of BVSP bioactive glass and 30% -p of "phosphosal", 8 weeks after implantation (x 20)

Claims

1 A composition for use as a precursor composition of fluid and injectable acrylic bone cement characterized in that the solid phase comprises a non-csteroidic anti-inflammatory drug carrying phosphate groups, in an amount between 20-30% -p, preferably 20-25% -p with respect to the total weight of solid and structured phase

which can be used in its acid form or as a sodium salt of the phosphoric and carboxyl acid groups where

Ri may be hydrogen or a methyl, ethyl, propyl isopropyl, butyl, isobutyl or tert-butyl radical,

R? it can be hydrogen or a methyl, ethyl, propyl isopropyl, butyl, isobutyl or tert-butyl radical,

R ₃ may be hydrogen or a methyl, ethyl, propyl isopropyl, butyl, isobutyl or tert-butyl radical,

R4 can be hydrogen or a methyl, ethyl, propyl isopropyl, butyl, isobutyl or tert-butyl radical

2 A composition according to claim 1 characterized in that the solid phase also includes bioactive glass in the Sιθ ₂ -CaO-Na ₂ θ-P ₂ θ _{5 system} , in an amount between 20-50% -p, preferably 40% -p with respect to the total weight of the solid phase

A composition according to claim 1, characterized in that the solid phase also includes silica nanoparticles of different sizes and morphology of the aerosol type in an amount between 5-20% -p with respect to the total weight of the solid phase

A composition according to claim 1 characterized in that the solid phase also includes particles of prepolymethyl poh (methyl methacrylate), PMMA, or copolymers of MMΛ with other monomers, and because the particles are present in an amount between 20-80% -p with respect to the total weight of the solid phase 5

5. A bone cement precursor composition according to claims 1, 2, 3 or 4, characterized in that the solid phase comprises one or more initiators in an amount of up to 3% -py / or one or more radiopaque agents in an amount comprised between 10 20-25% -p with respect to the total weight of the solid phase

A bone cement precursor composition according to claim 5 characterized in that the initiator is benzoyl peroxide and / or the radiopaque agents are / are selected from baπo sulfate, zirconium dioxide or tantalum oxide, oxide

15 strontium and / organic compounds

A precursor composition according to claims 1 to 6 characterized in that the liquid phase comprises methyl methacrylate, MMA, in an amount of 95-99% -po MMΛ in an amount of 85-90% -pycrylic acid in an amount of 5 -10% -p

twenty

A precursor composition according to claim 7, characterized in that the liquid phase also includes an activator based on aromatic tertiary amines in amounts of 0.5-2.5% -p, preferably 1% -p, and one or more inhibitors in an amount of up to 0.01% -py / or one or more stabilizers in an amount of up to

25 0.01% -p

A precursor composition according to claim 8 characterized in that the inhibitor and / or the stabilizer is a compound of the quinone family

A composition for use as a precursor composition of injectable bone cement characterized in that it contains a solid phase and a liquid phase, wherein the solid phase comprises a composition according to any one of claims 1 to 6 and the liquid phase comprises a composition according to a any of the claims 7 to 9

11 A process for obtaining a cement from a composition according to claims 1 to 10 which comprises a solid phase and a liquid phase, the mixing of both phases and the consequent polymerization of the liquid phase to give rise to a fluid material capable of be injected and finally cured "in situ"

12 Use of bone cement obtained according to any one of claims 1 to 11, among others, in minimally invasive surgery for fixation of vertebrae in percutaneous vcrtcbroplasty or for biomechanical fixation of osteoporotic fractures