WO2008117043A2

WO2008117043A2 - Magnesium oxide cement

Info

Publication number: WO2008117043A2
Application number: PCT/GB2008/001036
Authority: WO
Inventors: Wei-Jen Lo
Original assignee: Orthogem Limited
Priority date: 2007-03-26
Filing date: 2008-03-26
Publication date: 2008-10-02
Also published as: WO2008117043A3; GB0705792D0

Abstract

The invention discloses a bone cement composition or premix comprising: (i) magnesium oxide; (ii) magnesium chloride; and (iii) a polymer. The composition or premix additionally preferably comprises one or both of calcium sulphate and/or magnesium sulphate. The polymer is preferably polycaprolactone. The compositional premix is preferably used in dental implants or maxillofacial repair, or maybe used in surgery, bone or dental repair. The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Description

Magnesium Oxide Cement

The invention relates to bone cement compositions and premixes for bone cement compositions comprising magnesium oxide, magnesium chloride and a polymer and optionally calcium sulphate. The composition is suitable for use in the repair of bones and for use in, for example, orthopaedic surgery, including vertebrae repair, musculoskeletal reconstruction, fracture repair, hip and knee reconstruction, osseous augmentation procedures and oral/maxillofacial surgery.

Bone cements for repairing bone and, for example, joining bones or attaching prosthetics to bone are well known in the art. Use of bone cement is a standard feature of the orthopaedic surgeon's repertoire.

Many different types of bone cement are known in the art. These include both organic polymers, such as polymethylmethacrylate (PMMA) and other such acrylates, including polyacrylic acid (PAA), and inorganic ceramic materials based on, for example, calcium phosphate and calcium sulphate.

Historically, PMMA has been established as the most common tool for fixation in joint replacement surgery. Polymerisation of methylmethacrylate is a reaction that results in a doughy substance that self-cures in a short time. PMMA is made of a methylmethacrylate monomer precursor that polymerises to form PMMA. There are a number of commercially manufactured PMMA cements available, each cement kit comprising an individually packaged granules and a liquid. The package granules typically contains PMMA as its major constituent, together with a liquid vial which contains the monomer sub-unit, methylmethacrylate. Additionally, there are a number of other chemicals included to start and regulate the polymerisation process (such as benzoyl peroxide). Additionally, opacifiers or oligomers of PMMA may also be contained. Polyacrylic acid has also been used as a cement, for example together with aluminosilicate to produce a glass ionomer cement (see US 6,479,565).

There are many different types of calcium phosphate- and calcium sulphate-based cements known in the art. Typically, these involve the mixing of, for example, a calcium source with a phosphate source in water, and allowing the mixture to harden to form a solid ceramic material. Calcium phosphate bone cements offer a route of obtaining orthocalcium phosphates in a monolithic form at physiological conditions, without sintering process, by means of a cementitious reaction. The calcium and phosphate precipitate within the mixture to form crystallites. Varying the calcium and phosphate ratio of the final precipitate allows the chemical characteristics and physical characteristics of the material to be varied. Different starting materials may be used, including phosphoric acid, monocalcium phosphate, dicalcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate (alpha and beta forms), tetracalcium phosphate, calcium oxide or calcium hydroxide. The precipitates formed in the setting cement will vary depending on the nature of the reactants and aggregate ratio of calcium and phosphorous in the mix. These include dicalcium phosphate dihydrate (DCPD), octacalcium phosphate (OCP), amorphous calcium phosphate (ACP) and hydroxyapatite (HA). This is summarised in, for example, the article by Komath M. (Bull. Meter. Sci. (2000), Vol. 23(2), pages 135-140).

Problems with conventional bone cements includes the ability to produce bone cements which have sufficient structural resilience and strength to be used for long periods of time within the body of a patient. Furthermore, there is a need to allow the patient's own bone tissue to inhabit and replace the bone cement. A number of attempts to prove the physicochemico properties of such materials have been made, including: Santos L.A., et al. (Artificial Organs (2002), Vol. 27(5)) discloses a method of increasing the mechanical strength of α-tricalcium bone cement. The authors mixed the cement with acrylamide and ammonium polyacrylate to produce a polyacrylamide network within the cement. This was noted to reduce the porosity of the material.

US 6,479,565 discloses bone cements made from (a) microscopic pellets or anhydrous particles containing components of biological fluids, (b) bioactive glass or ceramic particles and (c) a resin such as bisphenol α-glycidyl methacrylate (BIS- GMA). The biological fluid components are dissolved in the body and act to corrode the surface of the bioactive glass or ceramic. They also provide voids into which bone cells migrate. The bioactive glass comprises silicon, oxygen, hydrogen and phosphorous atoms in predetermined proportions.

US 6,027,742 discloses a bone cement made of a cement made of amorphous calcium phosphate and water, which hardens to form poorly crystalline apatitic (PCA) calcium phosphate. A wide range of biodegradable polymers, such as collagen, poly(L-lactide) and polyglycolide (PGA) are suggested as additives to enhance the strength of the PCA. Calcium deficient apatitic calcium phosphate materials prepared from amorphous calcium phosphate with a promoter and the biodegradable polymers are shown in US 6,331,312. WO 03/024316 discloses bone cements with pore-forming agents, including collagen, other polymers and bioactive glass compositions. Soft matrix material mixed with non-ceramic hydroxyapatite cement is disclosed in US 6,703,038.

Attempts have been made to improve bone formation on bone cements by producing macropores made from bubbles in the cement (del Real R.P., et al., J. Biomed. Mater. Res. (2003, Apr. 1), Vol. 65A(I), pages 30-36). This improved bone formation compared with non-porous material but is expected to reduce the mechanical strength of the material. Furthermore, this requires the use of a complicated gas bubbling method to produce homogenous results. Alternative methods of producing macroporous cements are shown in WO 00/45867, This uses a calcium source, such as calcium sulphate hemihydrate or a calcium phosphate, water and a hydrophobic liquid such as an oil, to form a porous cement.

Another way of making porous bone cement is to mix a calcium source with a phosphate source, a carbonate and acid to form porous hydroxyapatite, as shown in US 6,547,866.

Flautre B., et al. (J. Biomed. Mater. Res. (2002), Vol. 63(4), pages 413-417) discloses injectable hydraulic cements in the presence of beta-tricalcium phosphate granules. This was stated to improve biomechanical function of the bone material.

US 6,458,375 discloses alternative malleable bone compositions comprising demineralised bone granules of 250 μm to 750 μm, bone chips of 0.1 to 10 mm diameter in a carrier selected from an aqueous sodium-based phosphate buffered solution and a hydrogel consisting of a mucopolysaccharide.

US2004/0173122 discloses a bone cement comprising microcrystalline magnesium ammonium phosphate and nanoapatite. The document indicates that gypsum (from calcium sulphate hemihydrate) is resorbed so rapidly that there is "always a gaping hole between the resorption front and the deposition front and these materials do not have adequate supporting function due to their low resistance to pressure". The document suggests making cements with improved properties out of magnesium ammonium phosphate. Discrete granular particles of a wide range of compounds may be provided, including sodium chloride, calcium sulphate, β-TCP, polylactides and/or polyglycolides, calcium carbonate and calcium hydrogen phosphate. WO2004/050131 discloses mixing calcium phosphate with a radio opaque material to form a bone cement. The radio opaque material may be barium or another metal or its salt.

Griffon DJ. (Academic Dissertation entitled "Evaluation of Osteoproductive Biomaterials : allograft, bone inducing agent, bioactive glass, and ceramics (Helsinki, 2002)) discusses osteoproductive biomaterials in general but does not disclose any advantages or disadvantages of bone cements. Further, the experiments disclosed by Griffon do not use a bone cement or a bone cement precursor.

Plaster of Paris cements based on calcium sulphate have been used for a number of years for both external use to support broken or fractured bones, and internal support and repair. Indeed, injectable calcium sulphate is commercially available from for example, Wright Medical Technology Inc. (Arlington, TN, USA) where it is sold under the trade mark MUG™^'

One problem associated with calcium sulphate based bone repair cement is that they are rapidly re-absorbed within the body. This means that if a portion of bone to be repaired is large, or alternatively if bone repair is reduced due to illness of a patient or to the age of a patent, then the bone cement may be reabsorbed too rapidly, before the patient has had sufficient time to grow through or over the region of the repair.

A number of groups have tried to improve properties of calcium sulphates. US2003/0055512 discloses an injectable and mouldable bone cement putty containing both calcium sulphate and hydroxyapatite. A number of accelerators for encouraging cement formation are disclosed in the document, including citrate and sodium chloride. Bohner, M. and Schmid, H. disclose hydraulic cements based on alpha-tricalcium phosphate-calcium sulphate dihydrate mixtures (European Cells and Materials (2003), Vol. 5, pages 3-4). Calcium phosphate-calcium sulphate bone cements are also disclosed in the article by Gisep A. and Rahn B. (European Cells and Materials (2004), Vol. 7, pages 34-35).

Swaintek J.N. et al. ("Self-setting Orthopedic Cement Compositions based on CaHPO₄ Additions to Calcium Sulphate", in Advances in Bioceramics and Biocomposites, pp. 79-86, (Ed.) M. Mizuno, the American Ceramic Society, 2005, USA) discloses that pure calcium sulphate cements rapidly deteriorate in aqueous solutions and crumble into a powder. Calcium sulphate cements are also not able to maintain their dry strength when soaked in human blood plasma or synthetic body fluids at 37°C. The authors found that additions of calcium phosphate powders, such as anhydrous di-calcium phosphate were found to significantly increase the wet mechanical integrity of these new cements.

ES2,178,556 discloses modified calcium sulphate cements containing dried calcium phosphate with the additional of sulphates, phosphates or carbonates to improve the properties of the material.

The inventor has found an alternative way of modifying the properties of magnesium oxychloride cement. The inventor has found that the addition of magnesium oxide and magnesium chloride and optionally calcium sulphate will allow the production of rapidly setting bone cement, for example with setting times of typically 20 to 30 minutes, which have improved re-absorption properties. The bone cement may include magnesium sulphate (MgSO₄). The addition of a polymer, such as polycaprolactone (PCL), improves the strength and flexibility of the material. Such cement may be made to allow new bone growth within and between the bone cement material. The ability to have rapid setting, while still allowing sufficient time for the material to be used by a surgeon to repair a bone, means that, for example, two portions of a broken bone need not be held immobilised by the surgeon for too long whilst the material is setting.

Moreover, magnesium oxide and magnesium chloride without calcium sulphate may also be used alone (with the polymer), or in combination with other materials to form a bone cement.

Use of magnesium oxide in combination with phosphates, such as powdered di- calcium phosphate is known in the art. Such compositions are disclosed in US2004/0086573A1. Such compositions are used in combination with retarders such as sodium chloride, sodium fluorosilicate, sodium polyphosphate, borate, and boric acid ester.

A first aspect of the invention provides a bone cement composition or premix comprising:

i) magnesium oxide; ii) magnesium chloride, preferably anhydrous magnesium chloride; iii) a polymer, and optionally one or both of: iv) CaSO₄ and/or MgSO₄

Preferably the calcium sulphate is anhydrous calcium sulphate or CaSO₄-V₂H₂O.

The calcium sulphate and magnesium sulphate may be used to alter the strength and/or setting times of the composition. Calcium sulphate has been found to decrease the setting time compared to magnesium sulphate. Calcium sulphate anhydrate reacts faster than calcium sulphate semihydrate (CaSO₄. V₂H₂O). The semihydrate form is preferably used to reduce the rate of reaction. An aqueous solution such as water or an acidified or basic solution is added to the composition or premix to allow it to react.

Magnesium oxide, magnesium chloride and calcium sulphate react on addition to water in an exothermic reaction. Preferably the polymer is melted by the exothermic reaction. Hence, preferably the polymer has a melting point below the temperature of the exothermic reaction of the reaction mixture, below 100 ⁰C, below 80 ⁰C, most preferably below 75 ⁰C. This advantageously produces the mixture without other heating. The reaction heats to typically 75 ⁰C. PCL, a polymer, melts at 60 °C.

Preferably the polymer is biodegradeable. Polycaprolactone (PCL) is especially preferred as this has been found to be made to melt by the exothermic reaction of the reaction mixture. It has a melting point of ca. 60 ⁰C. The PCL may be low density or high density. The latter is especially preferred as it produces a stronger material.

This produces a plastic-like injectable paste which may be applied to a part of the body or implant.

The composition is allowed to set to produce a composition with less brittleness compared with conventional magnesium oxide and magnesium chloride cements.

This also improves the tensile strength of the material and also improves the ability to be drilled or otherwise machined.

The term "bone cement composition" is intended to mean the composition in the form where the components are mixed together. However, the components may be provided as separate components in a premix or kit. The components (without water) may be provided as powdered material.

The term "comprising" is intended to mean, within the context of the current application, "including". That is other components may be provided in the bone cement composition or premix.

Bone cements are also known as orthopaedic cements or bone grafting compositions.

The calcium sulphate is normally provided as calcium sulphate hemihydrate (C_aSO₄.l/2 H₂O). Upon the addition of water this converts into calcium sulphate dihydrate (C_aSO₄.2H₂O) which is also known as gypsum.

Preferably the composition or dry premix comprises 50 to 60 % of total of the components, the remainder being ceramic granules and/or aqueous solution, such as water. The dry premix preferably consists of 5 g MgO, 2.375g MgCl₂, 1 g MgSO₄, 4 g CaSO₄V₄H₂O and 3 g PCL. Total components preferably consist of the dry premix plus 7 ml H₂O and 3 g Tripore saturated with 2.5 ml liquid.

The percentage of all components in the total bone cement mixture are as follows:

10 to 15 % MgCl₂

2 to 5 % MgSO₄

12 to 17 % CaSO₄V₂H₂O

15 to 20 % MgO 8 to 12 % PCL

8 to 12 % ceramic granules

30 to 40 % H₂O

Pure calcium sulphate or pure magnesium oxide/magnesium chloride do not have the property of osteoconductivity. Hence, preferably the composition comprises porous ceramic granules. Bio-compatible ceramics granules are known in the art. WO 02/11781 discloses preferred methods of producing artificial bone using biocompatible ceramic granules. These granules are known as "Tripore" and are available from Orthogem Ltd., Nottingham, United Kingdom. Methods of improving the distribution of micropores through bone material are also disclosed in WO 2004/101013.

Preferably the granules have a plurality of micropores of an average diameter of from 1 μm to 10 μm, preferably from 4 to 5μm.

That is, the individual granules preferably have micropores. Preferably, the micropores are interconnecting. They are preferably not confined to the surface of the granules but are found substantially throughout the cross-section of the granules. Preferably, the size of the granules is from 200 μm to 900 μm, preferably 250 μm to 850μm, especially 250 to 500 μm or 500 to 850 μm.

Preferably, at least two different sizes of granules, most preferably two, are used.

Preferably, small and/or large granules are used. The small granules may have a size range of 250 to 500 μm. Preferably the large granules have a diameter of 500 μm to 850 μm.

The granules may each be substantially of the same size or of two or more predetermined sizes. Alternatively, two or more distinct size ranges may be used with a variety of different sized particles within each range. Preferably two different sizes or ranges of sizes are used. The different sizes of the granules may vary the mechanical strength of the cement to allow the strength of the bone cement after setting to be varied. 'Preselected' means that the sizes are predetermined and/or selected, prior to adding to the bone substitute.

Preferably, the granules each comprise a plurality of microparticles, substantially each microparticle being partially fused to one or more adjacent microparticles to define a lattice defining the micropores. Each microparticle preferably has an average size of 1 μm to 10 μm, with an average of 4 to 5μm.

Preferably, the average size of the micropores is from 2 to 8 μm, most preferably 4 to 6 μm. The micropores may be irregular in shape. Accordingly, the size of the micropores, and indeed the midi-pores referred to below, are determined by adding the widest diameter of the pore to the narrowest diameter of the pore and dividing by 2.

Preferably, the ceramic material is evenly distributed throughout a cross-section of the hardened bone cement, that is substantially without clumps of ceramic material forming.

Preferably, the microparticles have an average size of at least 2 μm or 4 μm and/or less than 10 μm or less than 6 μm, most preferably 5 to 6 μm. This particle size range has been found to allow the controlled formation of the micropores.

The granules may also comprise a plurality of substantially spherical midi-pores having an average diameter of 10 to 100 μm. They substantially increase the total porosity of the ceramic material without compromising the mechanical strength of the materials. Furthermore, the midi-pores can be beneficially used to deliver drugs, cell growth factors or other biologically active agents.

The midi-pores are preferably interconnected via a plurality of micropores. That is, the midi-pores may be in fluid connection with each other via micropores. The average porosity of the ceramic material itself is preferably at least 50%, more preferably greater than 60%, most preferably 70 to 75% average porosity.

The ceramic material used to produce the granules may be any non-toxic ceramic known in the art, such as calcium phosphate and glass ceramics. Preferably the ceramic is not a silicate. Most preferably the ceramic material is a calcium phosphate, especially α- or β-tricalcium phosphate or hydroxyapatite, or mixtures thereof. Most preferably, the mixture is hydroxyapatite and β-tricalcium phosphate, especially more than 50 % w/w β-tricalcium, most preferably 85 % β-tricalcium phosphate and 15 % hydroxyapatite. Most preferably the material is 100 % hydroxyapatite.

Preferably the cement composition or dry premix comprises 15 to 30 % by weight of granules of the total dry weight of the composition or premix.

The composition or premix may be further improved by the additional of one or more additives.

For example, preferably carboxymethylcellulose, or a salt thereof such as a sodium salt, may be added. This compound may be added to decrease the re-absorption rate still further.

The magnesium chloride is preferably anhydrous magnesium chloride. Anhydrous magnesium chloride when mixed with a liquid, produces an exothermic reaction. This may be used to melt the PCL powder into the composition.

Liquid, such as water or a solution, is used with the composition to cause the various components to react together to form the final solidified composition. Compositions or premixes of the invention may be for use in surgery or bone or dental repair. The invention also provides the use of a composition or premix according to the invention in a dental implant or a maxillofacial repair material, for the repair of bone breaks, fractures, osteoporatic bone, intervertebral as a bone glue, or as a putty for a load bearing surface on a bone.

Bone implants, dental implants or ear, nose or throat (ENT) implants, comprising a composition or premix according to the invention are also provided.

A still further aspect of the invention provides a method of surgery, or bone or dental repair comprising applying a composition or a premix according to the invention to a bone or dental surface to be repaired.

The composition or premix may additionally comprise one or more pharmaceutically and/or biologically active compounds. For example growth factors, such as transforming growth factor (TGF-βl) bone morphogenetic protein (BMP -2) or osteogenic protein (OP-I) may be incorporated into the material. Further material such as enzymes, and vitamins (including Vitamin D) and trace materials such as zinc (for example in the form of a salt) may also be incorporated.

A still further aspect of the invention provides a method of producing a bone cement composition according to the invention comprising the steps of:

i) Creating a dry premix (MgO, MgCl₂, and biodegradable polymer and optionally, MgSO₄ and/or calcium sulphate); ii) Addition of a liquid to initiate an exothermic reaction which subsequently heats the mixture and melts the polymer; and iii) Addition of the mixture to ceramic granules, such as Tripore granules, to form a bone cement composition. The ceramic granules may be saturated with the liquid prior to mixing.

The liquid is preferably an aqueous liquid such as water or an acidified or basic solution.

The bone cement composition may then be used in surgery, bone or dental repair and allowed to set.

The dry mixture is preferably formed before the addition of water to ensure that the exothermic reaction reaches a temperature that will ensure the complete melting, and therefore incorporation, of the polymer into the bone cement mixture.

The polymer is preferably as PCL as defined above.

The individual components of the method are preferably as defined above.

The invention also provides a syringe comprising magnesium chloride, magnesium oxide, a polymer, magnesium sulphate (anhydrous) and semihydrous calcium sulphate. The components may be as defined above optionally with additional materials as defined above.

The components may be provided in a dry form, such as a powder. Liquid may then be added to the mixture in the syringe, mixed by agitation, and the resultant mixture then applied to the point where the cement is required. Application may be carried out using any suitable method or apparatus, for example a syringe may be used.

Another aspect of the invention provides a composition comprising an inorganic compound, a liquid, and a powdered polymer wherein the inorganic compound is one which on exposure to the liquid generates an exothermic reaction in which the exothermic reaction generates sufficient heat to melt the powdered polymer.

Preferably the inorganic compound is biocompatible. Preferably the inorganic compound is non-toxic in vivo. Preferably the inorganic compound is a magnesium or calcium compound. More preferably the inorganic compound is selected from magnesium chloride, magnesium oxide, magnesium sulphate and calcium sulphate.

Preferably the liquid is aqueous such as water or an aqueous solution such as an acidified or basic solution.

Preferably the exothermic reaction generates a temperature of from 60 ⁰C to 100 ⁰C, for example from 60, 75 or 80 to 100 ⁰C. Such a temperature is sufficient to melt polymers such as PCL. PCL melts at 60 ⁰C.

Preferably the polymer has a low melting point. Preferably the melting point of the polymer does not exceed the temperature generated by the exothermic reaction.

More preferably the polymer is selected from those described for the first aspect of the invention.

The composition may comprise any of the elements of the first and subsequent aspects of the invention.

A further aspect of the invention provides a composition as described herein for the repair or augmentation of a bone or dental surface. Preferably the bone or dental surface is mammalian, such as human.

Another aspect of the invention relates to the use of a composition as described herein in the manufacture of a bone cement for the repair or augmentation of a bone or dental surface. Preferably the bone is a mammalian, such as human. The invention will now be described way of example only:

Process for the preparation of ceramic granules

Hydroxyapatite granules (200 g) are mixed with water (120 ml), and a dispersing agent (4 ml).

Starch (32 g) or other coating agent is then blended into the mixture within a heatproof vessel. This produces a liquid suspension or slurry. The mixture is then placed within a oven and heated to approximately 100 to 180 ⁰C.

A mixture of white strong flour with a high gluten content (150 g) and yeast (28 g), such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Saccharomyces carlsbergiensis or another carbon dioxide producing micro-organism, is prepared. An additional source of carbohydrate, such as a sugar, may also be incorporated, however this is not essential. The mixture of flour and carbon dioxide producing microorganism, is mixed with the cooled dough of coated ceramic particles. The mixing may be carried out by hand or may also be mixed using, for example, a food mixer such as a spiral mixer. The mixture may then be compressed in order to exclude any large voids which have appeared within the mixture during mixing.

The final mixture again has a dough-like consistency. This may be placed within, for example, an elongated mould made of any suitable material, such as stainless steel or aluminium. By placing the dough within the mould with a space at each end of the elongated mould, the yeast produces carbon dioxide and causes the dough to expand along the length of the mould. The dough is prevented from expanding widthways in the mould by the walls of the mould. Depending on the micro-organism used, the generation of carbon dioxide is achieved by "proving" in a similar manner to bread. That is, the dough is maintained at a temperature of 30 to 55 °C for 35 minutes to allow the yeast to produce carbon dioxide. If another pore-forming agent, such as sodium bicarbonate is used, it may be advantageous to add an acid, such as citric acid, which reacts with the sodium bicarbonate to produce carbon dioxide.

The porous structure is set by heating, for example, from 100 to 180 ⁰C in a oven for approximately 35 minutes. This kills the yeast and also sets the organic binder, such as gluten. It also expands the dough to fit the mould, in a similar manner to bread dough which is expanded to fit a bread mould. Adjusting the size of the mould and ensuring that the mould is closed, rather than open-ended, allows the density of the product to be adjusted. The body with the fixed porous structure is then allowed to cool. At this stage it is possible to shape the material as it typically has a moist bread-like consistency and texture. It is therefore easily cut to a desired shape. Freezing or refrigerating the product at this stage improves the ability to shape the product. The shaped product is then sintered to a sufficiently high temperature to partially fuse the ceramic particles. This temperature will vary depending on the ceramic particles used. Typically, a mixture comprising hydroxyapatite is sintered at a temperature of 1350 °C, and a mixture comprising tricalcium phosphate is sintered at a temperature of 1250 °C.

Using a mixture of hydroxyapatite and tricalcium phosphate has been found by the inventors to improve the rate at which cells distribute themselves through the product.

The ceramic material is then cut, for example using a ball mill or other milling machinery. The size of the granules may be adjusted, for example, by sieving through a mesh of the desired size to regulate the size of the granules.

1. Cement 1: Magnesium Oxychloride Cement with porous granules (prepared as above) Magnesium oxide, Magnesium chloride (anhydrous), Magnesium Sulphate, Calcium sulphate (hemihydrate), PCL polymer, Tripore and water were mixed together in the following weights:

5.00 g MgO

4.00 g CaSO₄l/2H₂O

LOO g MgSO₄

2.375 g MgCl₂ 3.0O g PCL

3.00 g Tripore + 2.5g H₂O

7 g H₂O

This produces an injectable material which results in a hard, brittle material via an exothermic reaction.

2. Cement 2: Cement with Citric Acid Solution in the place of water.

As Cement 1, however a 0.5M Citric Acid Solution was used in the place of water. Cement 2 was prepared to investigate whether the addition of citric acid would increase the amount if time for which the bone cement remained injectable.

This produced a very fluid like mixture which did not harden or even appear to increase in viscosity for a minimum of 2 hours.

3. Cement 3: Cement with addition of different sized Porous granules (prepared as above).

Granules of different sizes added to the bone cement mixture as described above (Cement 1). Porous granules of 250 to 500 μm, 500 to 850 μm, 500 to 1000 μm and 1 to 2 mm were used in the same quantities as given above and incorporated in the same way.

This produced an injectable mixture which formed a hard, brittle material via an exothermic reaction. The granules bring varying strengths to the bone cement mixture.

4. Cement 4: Cement using sized porous granules in a mixed size ratio.

Cement as prepared as for Cement 1, however where the porous granules are added a mixture if the sizes, as demonstrated in Cement 3, for example 50 % of granules sized 250 to 500 μm combined with 50 % of granules sized 500 to 850 μm.

This produces an injectable material via an exothermic reaction, which is increased in strength when compared to the material in Cement 3.

5. Cement 5: Different quantities of PCL polymer.

The cement as described for Cements 1, 3 and 4 however the quantity of PCL as originally described (Cement 1) varied with increasing quantities. For example 4 g, 5 g, 6 g and 9 g.

The PCL was observed to melt with the exothermic reaction and the mixture formed an extrudable paste which then set.

The resulting solid was observed to be less brittle however decreased in strength as the quantity of the PCL increased.

Preferred Bone Cement mixture. Dry mixture of premix, comprising of ;

5 g MgO

2.375 g MgCl₂

I g MgSO₄ 4 g CaSO₄V₂H₂O

3 g PCL Addition of water to the premix to produce an exothermic reaction

7 ml H₂O

This then mixed to form a paste, the heat from the exothermic reaction melts the polymer to form an elastic paste.

Porous granules may be added in the form of porous granules saturated with water to above mixture to form the complete bone cement product. The porous granules preferably have a granule size ratio of 1 :1, 250 to 500 μm: 500 to 850 μm and comprise 3 g Tripore + 2.5 ml H₂O. A 'granule size ratio of 1 :1' means that if granules of two different sizes (e.g. size A and size B) are used, equal volumes of granules of size A and size B are used. For example, size A may be 250 to 500 μm and size B may be 500 to 850 μm.

Claims

1. A bone cement composition or premix comprising:

i) magnesium oxide; ii) magnesium chloride; and iii) a polymer.

2. A composition or premix according to claim 1 additionally comprising one or both of:

iv) calcium sulphate and/or magnesium sulphate.

3. A composition or premix according to claim 1 or 2, wherein the polymer has a melting point below the temperature that the composition or premix reaches on reacting in the presence of water.

4. A bone cement composition or premix comprising an inorganic compound, a liquid, and a powdered polymer wherein the inorganic compound is one which on exposure to the liquid generates an exothermic reaction of sufficient magnitude to melt the powdered polymer.

5. A composition or premix according to claim 4 wherein the inorganic compound is a magnesium or calcium compound.

6. A composition or premix according to claim 4 or 5 wherein the inorganic compound is selected from magnesium chloride, magnesium oxide, magnesium sulphate and calcium sulphate.

7. A composition or premix according to any one of claims 4 to 6 in which the exothermic reaction generates a temperature of from 60 ⁰C to 100 ⁰C.

8. A composition or premix according to any one of claims 3 to 7, wherein the polymer is polycaprolactone (PCL).

9. A composition or dry premix according to any preceding claim comprising:

i) 25 to 35 % by weight of magnesium oxide; ii) 10 to 20 % by weight of magnesium chloride, and iii) 20 to 30 % by weight of calcium sulphate; iv) 3 to 9 % by weight of magnesium sulphate v) 16 to 25 % PCL

wherein the percentage weight is based on the total weight of calcium sulphate (semihydrous), magnesium oxide, magnesium chloride (anhydrous), magnesium sulphate and polymer (PCL), in the composition or dry premix.

10. A composition or premix according to any preceding claim additionally comprising porous ceramic granules.

11. A bone cement composition or premix according to claim 10, wherein the porous granules comprise a plurality of micropores of an average size of fronm 1 μm to 10 μm.

12. A bone cement composition or premix according to claim 10 or 11, wherein the porous granules have a diameter of from 200 μm to 900 μm, preferably from 250 μm to 850 μm.

13. A bone cement composition or premix according to any one of claims 10 to 12 comprising 12 to 20 % by weight of granules of the total dry weight of the composition or premix.

14. A composition or premix according to any preceding claim wherein the magnesium chloride is anhydrous magnesium chloride.

15. A premix according to any preceding claim, additionally comprising water.

16. A composition or premix according to any preceding claim for use in surgery or bone or dental repair.

17. Use of a composition or premix according to any one of claims 1 to 16 in a dental implant or maxillofacial repair material, for the repair of bone breaks, fractures, osteoporatic bone, intervertebral space, as a bone glue, or putty for a load bearing surface on a bone.

18. A bone implant, dental implant or an ear, nose or throat (ENT) implant comprising a composition or premix according to any one of claims 1 to 16.

19. A method of surgery, or bone, or dental repair comprising applying a composition or premix according to any one of claims 1 to 16 to a bone or dental surface to be repaired.

20. A syringe comprising a composition or premix according to any one of claims 1 to 16.

21. Use of a composition or pre-mix according to any one of claims 1 to 16 in the manufacture of a bone cement for the repair or augmentation of a bone or dental surface.