GB2594243A

GB2594243A - A bone cement

Info

Publication number: GB2594243A
Application number: GB2005488.8A
Authority: GB
Inventors: Al-Lamee Kadem; Balmer Will; Bullett Nial
Original assignee: Arterius Ltd
Current assignee: Arterius Ltd
Priority date: 2020-04-15
Filing date: 2020-04-15
Publication date: 2021-10-27
Also published as: GB202005488D0; WO2021209747A1

Abstract

A two part hardenable composition comprising a solid first part and a storage stable liquid second part is provided, wherein the solid first part and storage stable liquid are operable to form a resorbable and injectable bone cement which hardens to a solid mass upon mixing of the parts together, the solid first part comprising (i) a filler and/or polymer particles, wherein each of the filler and polymer particles, when present, have an average size of up to 200µm and wherein the polymer particles, when present, have a weight-average molecular weight (Mw) of at least 10,000 Da; and (ii) 0.01 to 15wt % of an initiator based on the total weight of the solid first part; and the storage stable liquid second part comprising: (I) a monomer component, wherein the monomer component is operable to undergo free radical polymerisation in the presence of the initiator to form a polymer upon mixing of the parts together; and (II) 0.5 to 50 wt% of a crosslinker material based on the total weight of the storage stable liquid part, wherein each of the polymer particles, when present, and the polymer formed from the free radical polymerisation of the monomer component are resorbable. Preferably, the filler comprises tricalcium phosphate, and preferably the polymer particles comprise polyvinyl alcohol. The initiator is preferably benzoyl peroxide and the monomer component preferably comprises N-vinyl pyrrolidone.

Description

A Bone Cement

Field

[1] The present invention relates to two part hardenable compositions comprising a solid first part and a storage stable liquid second part which are operable to form a resorbable and injectable bone cement which hardens to a solid mass upon mixing of the parts together. The present invention extends to the two part hardenable compositions for use in the treatment of human or animal bone, a method of producing a resorbable and injectable bone cement from the two part hardenable compositions, a solid bone cement produced from the two part hardenable compositions and a kit of parts comprising the two part hardenable compositions.

Background

[2] Distal radial fractures (DRFs) are among the most common of all fracture types observed by orthopaedic surgeons, accounting for 17% of all fractures in emergency departments. They are commonly referred to as fragility fractures and are more prevalent among osteoporotic elderly women. However, they are also commonly found in younger patients due to high impact trauma or fall (e.g. contact sports, skiing, horse riding etc.). The occurrence of DRFs is approximately 165 and 195 per 100,000 person per year in the US and UK, respectively.

[3] The treatment of DRFs commonly require complicated surgical procedures that can be painful for the patient and often have a risk of complications due to, for example, infections. This can lead to further surgical interventions being required. Common DRF treatments include a wide range of therapies, which cover invasive as well as non-invasive treatments, such as, for example, plaster casts, pins, Kirchner wires, fillers, bone cements, externally fixated stabilising frame, plates and screws. Less invasive treatments are typically preferred in order to allow a rapid patient recovery and to reduce the risk of complications from invasive surgery.

[4] An example of a less invasive treatment for DRFs involves the use of fillers and/or bone cements, which involves inserting material within the intramedullary canal of the bone to provide stiffness and stabilisation. However, typically fillers and bone cements are made of nonresorbable materials and are commonly not injectable. Furthermore, in addition to not being resorbable, fillers are often reported as being too brittle once fully cured leading to a higher risk of further fractures in the same, or a similar, location.

[5] For the treatment of DRFs, mechanical support is typically required for a period of 8 to 10 weeks, beyond which there is no need for a permanent implant (with its associated potential adverse reactions).

[6] It is an object of aspects of the present invention to provide one or more solutions to the above mentioned or other problems.

Summary

[07] According to a first aspect of the present invention there is provided a two part hardenable composition comprising a solid first part and a storage stable liquid second part, the solid first part and storage stable liquid part being operable to form a resorbable and injectable bone cement which hardens to a solid mass upon mixing of the parts together, the solid first part comprising: (i) a filler and/or polymer particles, wherein each of the filler and the polymer particles, when present, have an average particle size of up to 200 pm and wherein the polymer particles, when present, have a weight-average molecular weight (Mw) of at least 10,000 Da; and (ii) 0.01 to 15 wt% of an initiator based on the total weight of the solid first part; and the storage stable liquid second part comprising: (I) a monomer component, wherein the monomer component is operable to undergo free radical polymerisation in the presence of the initiator to form a polymer upon mixing of the parts together; and (II) 0.5 to 50 wt% of a crosslinker material based on the total weight of the storage stable liquid part, wherein each of the polymer particles, when present, and the polymer formed from the free radical polymerisation of the monomer component are resorbable.

[08] According to a second aspect of the present invention there is provided a method of producing a resorbable and injectable bone cement from a two part hardenable composition according to the first aspect of the present invention comprising the step of mixing the solid first part and the storage stable liquid second part.

[09] According to a third aspect of the present invention there is provided a solid bone cement produced from mixing the solid first part and the storage stable liquid second part of the two part hardenable composition according to the first aspect of the present invention, wherein the solid bone cement is resorbable.

[10] According to a fourth aspect of the present invention there is provided a two part hardenable composition according to the first aspect of the present invention for use in the treatment of human or animal bone.

[11] According to fifth aspect of the present invention there is provided a two part hardenable composition according to the first aspect of the present invention for use in the repair or partial repair of human or animal bone.

[12] According to a sixth aspect of the present invention there is provided a kit of parts comprising the two part hardenable composition according to the first aspect of the present invention and a syringe or caulking gun.

Detailed Description

[13] "Resorbable", and like terms as used herein, refers to materials that are capable of being completely degraded and/or eroded when installed in the body, and can be gradually resorbed, adsorbed and/or eliminated by the body. When used herein, this term can be used interchangeably with the terms "biodegradable", "bioerodable" and "bioabsorbable" [14] "Injectable", and like terms as used herein, refers to materials that are able to be injected and, in particular, which are able to be injected into a cavity using a syringe or caulking gun, for example. For the avoidance of doubt, the bone cements of the present invention are injectable upon and after mixing of the first and second parts and for the duration of the working time of said bone cements. The bone cements are not injectable once said bone cements have hardened to a solid mass (i.e. after the setting time of said cements).

[15] For the avoidance of doubt, in the context of the present invention, the two part hardenable compositions become a bone cement upon mixing of the first and second parts thereof together. Once the bone cement has hardened to a solid mass the bone cement may be referred to herein as a 'hardened bone cement'.

[16] Advantageously, not only are the hardened bone cements of the present invention resorbable and injectable but they are also load bearing. In other words, the hardened bone cements have sufficient mechanical strength to act in a load bearing capacity.

[17] Advantageously, the use of the bone cements of the present invention comprising resorbable materials provides mechanical support for a relatively short period of time, such as for up to 20 weeks, such as for up to 18 weeks, such as for up to 16 weeks, such as for up to 14 weeks, such as for up to 12 weeks, or even for up to 10 weeks, before natural healing occurs. After this time, the bone cement may be resorbed by the body.

[18] The solid first part comprises a filler and/or polymer particles.

[19] The filler may be any suitable filler. Suitable fillers will be known to a person skilled in the art. The filler may be organic or inorganic. Examples of suitable fillers include, but are not limited to, calcium phosphate, strontium-doped calcium phosphate compounds, bioglass, calcium carbonate, barium sulphate, hydroxyapatite, tetracalcium phosphate, octocalcium phosphate, monocalcium phosphate, heptacalcium phosphate, fiuoroapatite, wollastonite, calcium pyrophosphate, oxyapatite, dicalcium phosphate, tricalcium phosphate such as, for example, a-, a'-or 6-tricalcium phosphate, zirconium dioxide or combinations thereof.

[20] Suitably, the filler may comprise tricalcium phosphate, such as 3-tricalcium phosphate, hydroxyapatite or combinations thereof.

[21] Suitably, the filler may comprise tricalcium phosphate. More suitably, the filler may comprise 6-tricalcium phosphate.

[22] Suitably, the filler may be osteoinducfive.

[23] The filler, when present, has an average particle size of up to 200 micron (pm). Suitably, the filler may have an average particle size of up to 175 pm, such as up to 150 pm, such as up to pm, or even up to 100 pm. The filler may have an average particle size of at least 0.25 pm, such as at least 0.5 pm, such as at least 1 pm, such as at least 5 pm, such as at least 10 pm, such as at least 15 pm, such as at least 20 pm, such as at least 30 pm, such as at least 40 pm, or even at least 50 pm.

[24] The filler may have an average particle size from 0.25 to 200 pm, such as from 0.5 to 200 pm, such as from Ito 200 pm, such as from 5 to 200 pm, such as from 10 to 200 pm, such as from 15 to 200 pm, such as from 20 to 200 pm, such as from 30 to 200 pm, such as from 40 to 200 pm, or even from 50 to 200 pm. The filler may have an average particle size from 0.25 to 175 pm, such as from 0.5 to 175 pm, such as from Ito 175 pm, such as from 5 to 175 pm, such as from 10 to 175 pm, such as from 15 to 175 pm, such as from 20 to 175 pm, such as from 30 to 175 pm, such as from 40 to 175 pm, or even from 50 to 175 pm. The filler may have an average particle size from 0.25 to 150 pm, such as from 0.5 to 150 pm, such as from 1 to 150 pm, such as from 5 to 150 pm, such as from 10 to 150 pm, such as from 15 to 150 pm, such as from 20 to 150 pm, such as from 30 to 150 pm, such as from 40 to 150 pm, or even from 50 to 150 pm. The filler may have an average particle size from 0.25 to 125 pm, such as from 0.5 to 125 pm, such as from Ito 125 pm, such as from 5 to 125 pm, such as from 10 to 125 pm, such as from 15 to 125 pm, such as from 20 to 125 pm, such as from 30 to 125 pm, such as from 40 to 125 pm, or even from 50 to 125 pm. The filler may have an average particle size from 0.25 to 100 pm, such as from 0.5 to 100 pm, such as from 1 to 100 pm, such as from 5 to 100 pm, such as from 10 to 100 pm, such as from 15 to 100 pm, such as from 20 to 100 pm, such as from 30 to 100 pm, such as from 40 to 100 pm, or even from 50 to 100 pm.

[25] Suitably, the filler may have an average particle size from 50 to 200 pm.

[26] Suitably, the filler may have an average particle size from 50 to 150 pm.

[27] Suitably, the filler may have an average particle size up to 100 pm.

[28] Suitably, the filler may have an average particle size from 50 to 100 pm.

[29] Advantageously, the use of a filler having an average particle size of less than 200 pm means that the composition may be injectable, i.e. is able to be injected via a syringe or caulking gun, for example.

[30] The solid first part may comprise any suitable amount of filler, when present. The solid first part may comprise up to 99.99 wt%, such as up to 99 wt%, such as up to 95 wt%, such as up to 90 wt%, such as up to 80 wt%, such as up to 70 wt%, such as up to 60 wt%, such as up to 50 wt%, such as up to 40 wt%, or even up to 30 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise at least 0.5 wt%, such as at least 1 wt%, such as at least 1.5 wt%, such as at least 2 wt%, such as at least 2.5 wt%, such as at least 5 wt%, such as at least 7 wt%, such as at least 10 wt%, such as at least 15 wt%, or even at least 20 wt% filler based on the total solid weight of the solid first part.

[31] The solid first part may comprise from 0.5 to 99.99 wt%, such as from Ito 99.99 wt%, such as from 1.5 to 99.99 wt%, such as from 2 to 99.99 wt%, such as from 2.5 to 99.99 wt%, such as from 5 to 99.99 wt%, such as from 7 to 99.99 wt%, such as from 10 to 99.99 wt%, such as from to 99.99 wt%, or even from 20 to 99.99 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 99 wt%, such as from 1 to 99 wt%, such as from 1.5 to 99 wt%, such as from 2 to 99 wt%, such as from 2.5 to 99 wt%, such as from 5 to 99 wt%, such as from 7 to 99 wt%, such as from 10 to 99 wt%, such as from 15 to 99 wt%, or even from 20 to 99 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 95 wt%, such as from 1 to 95 wt%, such as from 1.5 to 95 wt%, such as from 2 to 95 wt%, such as from 2.5 to 95 wt%, such as from 5 to 95 wt%, such as from 7 to 95 wt%, such as from 10 to 95 wt%, such as from 15 to 95 wt%, or even from 20 to 95 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 90 wt%, such as from 1 to 90 wt%, such as from 1.5 to 90 wt%, such as from 2 to 90 wt%, such as from 2.5 to 90 wt%, such as from 5 to 90 wt%, such as from 7 to 90 wt%, such as from 10 to 90 wt%, such as from 15 to 90 wt%, or even from 20 to 90 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 80 wt%, such as from 1 to 80 wt%, such as from 1.5 to 80 wt%, such as from 2 to 80 wt%, such as from 2.5 to 80 wt%, such as from 5 to 80 wt%, such as from 7 to 80 wt%, such as from 10 to 80 wt%, such as from 15 to 80 wt%, or even from 20 to 80 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 70 wt%, such as from 1 to 70 wt%, such as from 1.5 to 70 wt%, such as from 2 to 70 wt%, such as from 2.5 to 70 wt%, such as from 5 to 70 wt%, such as from 7 to 70 wt%, such as from 10 to 70 wt%, such as from 15 to 70 wt%, or even from 20 to 70 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 60 wt%, such as from 1 to 60 wt%, such as from 1.5 to 60 wt%, such as from 2 to 60 wt%, such as from 2.5 to 60 wt%, such as from 5 to 60 wt%, such as from 7 to 60 wt%, such as from 10 to 60 wt%, such as from 15 to 60 wt%, or even from 20 to 60 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 50 wt%, such as from 1 to 50 wt%, such as from 1.5 to 50 wt%, such as from 2 to 50 wt%, such as from 2.5 to 50 wt%, such as from 5 to 50 wt%, such as from 7 to 50 wt%, such as from 10 to 50 wt%, such as from 15 to 50 wt%, or even from 20 to 50 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 40 wt%, such as from 1 to 40 wt%, such as from 1.5 to 40 wt%, such as from 2 to 40 wt%, such as from 2.5 to 40 wt%, such as from 5 to 40 wt%, such as from 7 to 40 wt%, such as from 10 to 40 wt%, such as from 15 to 40 wt%, or even from 20 to 40 wt% filler based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 30 wt%, such as from 1 to 30 wt%, such as from 1.5 to 30 wt%, such as from 2 to 30 wt%, such as from 2.5 to 30 wt%, such as from 5 to 30 wt%, such as from 7 to 30 wt%, such as from 10 to 30 wt%, such as from 15 to 30 wt%, or even from 20 to 30 wt% filler based on the total solid weight of the solid first part.

[32] Suitably, the solid first part may comprise from 5 to 50 wt% filler based on the total solid weight of the solid first part.

[33] Suitably, the solid first part may comprise from 7 to 30 wt% based on the total solid weight of the solid first part.

[34] The polymer particles may be any suitable polymer particles with the proviso that the polymer particles are resorbable. Suitable polymer particles will be known to a person skilled in the art. Suitably, the polymer particles may be operable to undergo hydrolysis, i.e. the polymer particles may be water soluble. Examples of suitable polymer particles include, but are not limited to, polylactides, polyglycolides, polycaprolactones, polyvinyl alcohol, Dextran, poly p-dioxanone, poly hydroxybutyrate and polyacrylates.

[35] Suitably, the polymer particles may comprise polyvinyl alcohol.

[36] The polymer particles, when present, have an average particle size of up to 200 microns (pm). Suitably, the polymer particles may have an average particle size of up to 175 pm, such as up to 150 pm, such as up to 125 pm, or even up to 100 pm. The polymer particles may have an average particle size of at least 0.25 pm, such as at least 0.5 pm, such as at least 1 pm, such as at least 5 pm, such as at least 10 pm, such as at least 15 pm, such as at least 20 pm, such as at least 30 pm, such as at least 40 pm, or even at least 50 pm.

[37] The polymer particles may have an average particle size from 0.25 to 200 pm, such as from 0.5 to 200 pm, such as from 1 to 200 pm, such as from 5 to 200 pm, such as from 10 to 200 pm, such as from 15 to 200 pm, such as from 20 to 200 pm, such as from 30 to 200 pm, such as from 40 to 200 pm, or even from 50 to 200 pm. The polymer particles may have an average particle size from 0.25 to 175 pm, such as from 0.5 to 175 pm, such as from 1 to 175 pm, such as from 5 to 175 pm, such as from 10 to 175 pm, such as from 15 to 175 pm, such as from 20 to 175 pm, such as from 30 to 175 pm, such as from 40 to 175 pm, or even from 50 to 175 pm. The polymer particles may have an average particle size from 0.25 to 150 pm, such as from 0.5 to 150 pm, such as from 1 to 150 pm, such as from 5 to 150 pm, such as from 10 to 150 pm, such as from 15 to 150 pm, such as from 20 to 150 pm, such as from 30 to 150 pm, such as from 40 to 150 pm, or even from 50 to 150 pm. The polymer particles may have an average particle size from 0.25 to 125 pm, such as from 0.5 to 125 pm, such as from 1 to 125 pm, such as from 5 to 125 pm, such as from 10 to 125 pm, such as from 15 to 125 pm, such as from 20 to 125 pm, such as from 30 to 125 pm, such as from 40 to 125 pm, or even from 50 to 125 pm. The polymer particles may have an average particle size from 0.25 to 100 pm, such as from 0.5 to 100 pm, such as from 1 to 100 pm, such as from 5 to 100 pm, such as from 10 to 100 pm, such as from 15 to 100 pm, such as from 20 to 100 pm, such as from 30 to 100 pm, such as from 40 to 100 pm, or even from 50 to 100 pm.

[38] Suitably, the polymer particles may have an average particle size from 50 to 200 pm.

[39] Suitably, the polymer particles may have an average particle size from 50 to 150 pm.

[40] Suitably, the polymer particles may have an average particle size up to 100 pm.

[41] Suitably, the polymer particles may have an average particle size from 50 to 100 pm.

[42] Advantageously, the use of polymer particles having an average particle size of less than 200 pm means that the composition may be injectable, i.e. is able to be injected via a syringe or caulking gun, for example.

[43] The polymer particles, when present, have a weight-average molecular weight (Mw) of at least 10,000 Da!tons (Da = g/mole). The polymer particles may have an Mw of at least 20,000 Da, such as at least 30,000 Da, such as at least 40,000 Da, such as at least 50,000 Da, such as at least 60,000 Da, such as at least 70,000 Da, such as at least 80,000 Da, such as at least 90,000 Da, or even at least 100,000 Da. The polymer particles may have an Mw of up to 750,000 Da, such as up to 500,000 Da, or even up to 250,000 Da.

[44] The polymer particles may have an Mw from 10,000 to 750,000 Da, such as from 20,000 to 750,000 Da, such as from 30,000 to 750,000 Da, such as from 40,000 to 750,000 Da, such as from 50,000 to 750,000 Da, such as from 60,000 to 750,000 Da, such as from 70,000 to 750,000 Da, such as from 80,000 to 750,000 Da, such as from 90,000 to 750,000 Da, or even from 100,000 to 750,000 Da. The polymer particles may have an Mw from 10,000 to 500,000 Da, such as from 20,000 to 500,000 Da, such as from 30,000 to 500,000 Da, such as from 40,000 to 500,000 Da, such as from 50,000 to 500,000 Da, such as from 60,000 to 500,000 Da, such as from 70,000 to 500,000 Da, such as from 80,000 to 500,000 Da, such as from 90,000 to 500,000 Da, or even from 100,000 to 500,000 Da. The polymer particles may have an Mw from 10,000 to 250,000 Da, such as from 20,000 to 250,000 Da, such as from 30,000 to 250,000 Da, such as from 40,000 to 250,000 Da, such as from 50,000 to 250,000 Da, such as from 60,000 to 250,000 Da, such as from 70,000 to 250,000 Da, such as from 80,000 to 250,000 Da, such as from 90,000 to 250,000 Da, or even from 100,000 to 250,000 Da.

[45] Suitably, the polymer particles may have an Mw of at least 10,000 Da.

[46] Suitably, the polymer particles may have an Mw of at least 50,000 Da.

[47] The weight average molecular weight (Mw) may be determined by gel permeation chromatography (GPC).

[48] The solid first part comprises an initiator. The initiator is suitably able to initiate free-radical polymerisation of the monomer component of the storage stable liquid second part.

[49] The initiator may be any suitable initiator. Suitable initiators will be known to a person skilled in the art. Examples of suitable initiators include, but are not limited to: peroxides such as, for example, t-butyl hydroperoxide, dicumylperoxide, di-tert-butyl peroxide, benzoyl peroxide, tertamylhydroperoxide, di-(2-ethylhexylperoxydicarbonate and lauroyl peroxide; persulphates such as, for example, potassium persulphate, sodium persulphate and ammonium persulphate; azo initiators such as, for example, 4,4'-azobis(4-cyanovaleric acid); and combinations thereof [50] Suitably, the initiator may comprise benzoyl peroxide.

[51] The initiator is present in the solid first part an amount of 0.01 to 15 wt% based on the total weight of the solid first part. The solid first part may comprise at least 0.05 wt%, such as at least 0.1 wt%, such as at least 0.15 wt%, such as at least 0.25 wt%, such as at least 0.5 wt%, such as at least 0.7 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise up to 14 wt%, such as up to 13 wt%, such as up to 12 wt%, such as up to 11 wt%, such as up to 10 wt%, such as up to 9 wt%, or even up to 8 wt% initiator based on the total solid weight of the solid first part.

[52] The solid first part may comprise from 0.01 to 15 wt%, such as from 0.01 to 14 wt%, such as from 0.01 to 13 wt%, such as from 0.01 to 12 wt%, such as from 0.01 to 11 wt%, such as from 0.01 to 10 wt%, such as from 0.01 to 9 wt%, or even from 0.01 to 8 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise from 0.05 to 15 wt%, such as from 0.05 to 14 wt%, such as from 0.05 to 13 wt%, such as from 0.05 to 12 wt%, such as from 0.05 to 11 wt%, such as from 0.05 to 10 wt%, such as from 0.05 to 9 wt%, or even from 0.05 to 8 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise from 0.1 to 15 wt%, such as from 0.1 to 14 wt%, such as from 0.1 to 13 wt%, such as from 0.1 to 12 wt%, such as from 0.1 to 11 wt%, such as from 0.1 to 10 wt%, such as from 0.1 to 9 wt%, or even from 0.1 to 8 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise from 0.15 to 15 wt%, such as from 0.15 to 14 vvt%, such as from 0.15 to 13 wt%, such as from 0.15 to 12 wt%, such as from 0.15 toll wt%, such as from 0.15 to vvt%, such as from 0.15 to 9 wt%, or even from 0.15 to 8 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise from 0.25 to 15 wt%, such as from 0.25 to 14 wt%, such as from 0.25 to 13 wt%, such as from 0.25 to 12 wt%, such as from 0.25 to 11 wt%, such as from 0.25 to 10 wt%, such as from 0.25 to 9 wt%, or even from 0.25 to 8 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise from 0.5 to 15 wt%, such as from 0.5 to 14 wt%, such as from 0.5 to 13 wt%, such as from 0.5 to 12 wt%, such as from 0.5 to 11 wt%, such as from 0.5 to 10 wt%, such as from 0.5 to 9 wt%, or even from 0.5 to 8 wt% initiator based on the total solid weight of the solid first part. The solid first part may comprise from 0.7 to 15 wt%, such as from 0.7 to 14 wt%, such as from 0.7 to 13 wt%, such as from 0.7 to 12 wt%, such as from 0.7 to 11 wt%, such as from 0.7 to 10 wt%, such as from 0.7 to 9 wt%, or even from 0.7 to 8 wt% initiator based on the total solid weight of the solid first part.

[53] Suitably, the solid first part may comprise from 0.01 to 10 wt% initiator based on the total solid weight of the solid first part.

[54] Suitably, the solid first part may comprise from 0.25 to 10 wt% initiator based on the total solid weight of the solid first part.

[55] Suitably, the solid first part may comprise from 0.5 to 10 wt% initiator based on the total solid weight of the solid first part.

[56] Advantageously, the use of the initiator in an amount of 0.01 to 15 wt% based on the total weight of the solid first part results in a hardened bone cement having increased working times than would typically be expected when using more than 15 wt% of the initiator based on the total weight of the solid first part.

[57] Advantageously, the use of the initiator in an amount of 0.01 to 15 wt% based on the total weight of the solid first part results in a hardened bone cement having improved mechanical properties than would typically be expected when using more than 15 wt% of the initiator based on the total weight of the solid first part.

[58] The initiator is suitably present at a level which will affect polymerisation of the monomer component that is at least 90% polymerisation, such as at least 93% polymerisaton, or even at least 95% polymerisation.

[59] The storage stable liquid second part comprises a monomer component, wherein the monomer component is operable to undergo free radical polymerisation in the presence of the initiator to form a polymer upon mixing of the parts together.

[60] The monomer component suitably comprises one or more monomer(s). The monomer component may comprise any suitable monomer(s) with the proviso that the polymer formed from the free radical polymerisation of the monomer component is resorbable.

[61] Suitably, the monomer(s) may have ethylenic unsaturafion. Thus, suitably, the monomer(s) may comprise one or more ethylenically unsaturated monomers(s). It will be appreciated by a person skilled in the art that ethylenically unsaturated monomers may suitably be chosen such that they are able to undergo free radical polymerisation.

[62] Suitably, the monomers may comprise one or more hydrolysable group(s), such as, for example, ester groups. Thus, suitably, the polymer formed from the free-radical polymerisation of the monomer component may comprise one or more ester group-containing side chains. Advantageously, the use of one or more monomer(s) having one or more hydrolysable group(s), such as ester group(s), means that the resultant polymer, formed from the free-radical polymerisation of said monomer(s), are resorbable.

[63] Suitable monomers will be known to a person skilled in the art. Suitably, the monomers are operable to form polymers that are able to undergo hydrolysis, i.e. the monomers are operable to form polymers that are water soluble. Examples of suitable monomers include, but are not limited to, polyethylene glycol methyl ether acrylate, polyethylene glycol methyl ether methacrylate, N-vinyl pyrrolidone, polyhexamethylene adipate, polyethylene glycol diacrylate, polypropylene fumarate, polypropylene glycol fumarate, acrylic acid, methacrylic acid, N-vinylformamide and combinations thereof.

[64] Suitably, the monomer component may comprise N-vinyl pyrrolidone.

[65] The monomer component may be present in the storage stable liquid second part in any suitable amount. The storage stable liquid first part may comprise at least 2.5 wt%, such as at least 3 wt%, such as at least 4 wt%, or even at least 5 wt% of the monomer component based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise up to 25 wt%, such as up to 20 wt%, such as up to 15 wt%, or even up to 10 wt% of the monomer component based on the total weight of the storage stable liquid second part.

[66] The storage stable liquid second part may comprise from 2.5 to 25 wt%, such as from 3 to 25 wt%, such as from 4 to 25 wt%, or even from 5 to 25 wt% of the monomer component based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise from 2.5 to 20 wt%, such as from 3 to 20 wt%, such as from 4 to 20 wt%, or even from 5 to 20 wt% of the monomer component based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise from 2.5 to 15 wt%, such as from 3 to 15 wt%, such as from 4 to 15 wt%, or even from 5 to 15 wt% of the monomer component based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise from 2.5 to 10 wt%, such as from 3 to 10 wt%, such as from 4 to 10 wt%, or even from 5 to 10 wt% of the monomer component based on the total weight of the storage stable liquid second part.

[67] Suitably, the storage stable liquid second part may comprise from 2.5 to 20 wt% of the monomer component based on the total weight of the storage stable liquid second part.

[68] Suitably, the storage stable liquid second part may comprise from 5 to 20 wt% of the monomer component based on the total weight of the storage stable liquid second part.

[69] Suitably, the storage stable liquid second part may comprise from 10 to 15 wt% of the monomer component based on the total weight of the storage stable liquid second part.

[70] The monomer component and the initiator are located in separate parts of the said two part hardenable composition so that the liquid second part containing the monomer component is storage stable to polymerization.

[71] The storage stable liquid second part comprises 0.5 to 50 wt% of a crosslinker material based on the total weight of the storage stable liquid second part. Advantageously, the use of the crosslinker material may give the final cured bone cement sufficient stiffness for the desired application.

[72] The crosslinker material may comprise any suitable crosslinker material. Suitable crosslinkers will be known to a person skilled in the art. The crosslinker material may be at least di-functional, i.e. have at least two (2) functional groups that are able to participate in a crosslinking reaction. The crosslinker material may be di-, tri-, or tetra-functional, for example.

[73] Suitably, the crosslinker material may comprise one of more di-functional crosslinker material(s) and/or one or more tetra-functional crosslinker material(s).

[74] Examples of suitable di-functional crosslinker materials include, but are not limited to, glyoxal, polyethylene glycol diacrylate, polyethylene glycol diglycidyl ether, ethylene glycol dimethacrylate, ethylene glycol diacrylate, di(trimethylolpropane), di(triethylolpropane), di(trimethylolethane), di(triethylolethane) and combinations thereof [75] Suitably, the di-functional crosslinker material may comprise polyethylene glycol diacrylate, ethylene glycol dimethacrylate, ethylene glycol diacrylate and combinations thereof [76] Suitably, the di-functional crosslinker material may comprise ethylene glycol dimethacrylate and/or di(trimethylolpropane). More suitably, the di-functional crosslinker material may comprise ethylene glycol dimethacrylate.

[77] Examples of suitable tetra-functional crosslinker materials include, but are not limited to, di(trimethylolpropane) tetraacrylate, di(triethylolpropane) tetraacrylate, di(trimethylolethane) tetraacrylate, di(triethylolethane) tetraacrylate, 4-Arm PEG-acrylate and combinations thereof.

[78] Suitably, the tetra-functional crosslinker material may comprise di(trimethylolpropane) tetraacrylate.

[79] The crosslinker material may alternatively or additionally comprise one or more multifunctional crosslinker material(s), whereby where by 'multi-functional' is meant a crosslinker material which is other than di-or tetra-functional. Examples of suitable multi-functional crosslinker materials include, but are not limited to, 8-Arm PEG-acrylate.

[80] Suitably, the storage stable liquid second part may comprise one or more di-functional crosslinker material and one or more tetra-functional crosslinker material.

[81] Suitably, the storage stable liquid second part may comprise ethylene glycol dimethacrylate and/or di(trimethylolpropane) tetraacrylate. More suitably, the storage stable liquid second part may comprise ethylene glycol dimethacrylate and di(trimethylolpropane) tetraacrylate.

[82] Suitably, the crosslinker material may be resorbable. Suitably, the crosslinker material may comprise one or more hydrolysable group(s), such as ester group(s). Advantageously, the use of one or more crosslinker material(s) having one or more hydrolysable groups, such as ester group(s), means that said crosslinker material(s) are resorbable.

[83] The crosslinker material may be present in the storage stable liquid second part in any suitable amount. The storage stable liquid second part may comprise at least 2.5 wt%, such as at least 5 wt%, such as at least 7.5 wt%, such as at least 10 wt%, or even at least 12.5 wt% crosslinker material based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise up to 25 wt%, such as up to 20 wt%, or even up to 15 wt% crosslinker material based on the total weight of the storage stable liquid second part.

[84] The storage stable liquid second part may comprise from 2.5 to 25 wt%, such as from 5 to 25 wt%, such as from 7.5 to 25 wt%, such as from 10 to 25 wt%, or even from 12.5 to 25 wt% crosslinker material based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise from 2.5 to 20 wt%, such as from 5 to 20 wt%, such as from 7.5 to 20 wt%, such as from 10 to 20 wt%, or even from 12.5 to 20 wt% crosslinker material based on the total weight of the storage stable liquid second part. The storage stable liquid second part may comprise from 2.5 to 15 wt%, such as from 5 to 15 wt%, such as from 7.5 to 15 wt%, such as from 10 to 15 wt%, or even from 12.5 to 15 wt% crosslinker material based on the total weight of the storage stable liquid second part.

[85] Suitably, the storage stable liquid second part may comprise from 2.5 to 25 wt% crosslinker material based on the total weight of the storage stable liquid second part.

[86] Suitably, the storage stable liquid second part may comprise from 5 to 20 wt% crosslinker material based on the total weight of the storage stable liquid second part.

[87] Suitably, the storage stable liquid second part may comprise from 10 to 15 wt% crosslinker material based on the total weight of the storage stable liquid second part.

[88] It will be appreciated by a person skilled in the art that the amount of crosslinker material may vary depending on the functionality of said crosslinker material. For example, if a di-functional crosslinker material is used, more of said di-functional crosslinker material may be required compared to when, for example, a tetra-functional crosslinker material is used. Conversely, if a tetra-functional crosslinker material is used, less of said tetra-functional crosslinker material may be required compared to when, for example, a di-functional crosslinker material is used.

[89] The storage stable liquid second part may further comprise an activator. It will be known to a person skilled in the art that an activator in the context of the present invention is a compound that acts to lower the activation energy of the initiator(s) as defined herein. The storage stable liquid second part may further comprise any suitable activator. Suitable activators will be known to a person skilled in the art. Examples of suitable activators include, but are not limited to, N,Ndimethyl-p-toluidine (DMPT), 4-(dimethylamino) phenethyl alcohol, N,N-bis (2-hydroxyethyp-ptoluidine, N,N-bis (2-hydroxyethyl)-p-xylidine and combinations thereof [90] The presence of an activator depends upon the final application. Where "cold-cure" is necessary, for example in bone cements, an activator is typically necessary. However, for some applications the use of heat in "heat-cure" systems is also possible. In heat-cure systems an activator is typically not necessary.

[91] The activator, when present, is suitably present at a level that will effectively activate the polymerisation reaction in the presence of initiator.

[92] The storage stable liquid second part may further comprise water and/or other solvent(s) as additional liquid components. The water and/or other solvent(s), when present, may suitably be sufficient to provide a liquid carrier for the other components present in the storage stable liquid second part such as, the monomer component, crosslinker material and, optionally, activator.

[93] The storage stable liquid second part may further comprise an inhibitor. The storage stable liquid second part may comprise any suitable inhibitor. Suitable inhibitors will be known to a person skilled in the art. Examples of suitable inhibitors include, but are not limited to, hydroquinone (HQ), methyl hydroquinone (MeHQ), 2,6-di-tertiary-butyl-4-methoxyphenol (Topanol 0), 2,4-dimethy1-6-tertiary-butyl phenol (Topanol A) and combinations thereof. The inhibitor may suitably be present to prevent the monomer component from spontaneously polymerising. For example, a suitable inhibitor is 6Oppm of hydroquinone to ensure long shelf life at room temperature.

[94] The two part hardenable composition may comprise a radiopacifying agent.

[95] "Radiopacifying", and like terms, as used herein means the ability to render a material more distinguishable from surrounding material when subjected to X-rays.

[96] The two part hardenable composition may comprise any suitable radiopacifying agent. Suitable radiopacifying agents will be known to a person skilled in the art. Examples of suitable radiopacifying agents include, but are not limited to, zirconium dioxide, bismuth oxides, iodine compounds such as iohexal, iodixanol, strontium carbonate, powdered gold, powdered platinum, powdered iridium, powdered, powdered tantalum, powdered rhodium, powdered tungsten, barium sulphate and combinations thereof [97] Suitably, the radiopacifying agent may comprise barium sulphate.

[98] The radiopacifying agent, when present, may be present in the solid first part and/or the storage stable liquid second pad.

[99] Suitably, the radiopacifying agent may be present in the solid first part. Thus, suitably, the solid first part may further comprise a radiopacifying agent.

[100] The radiopacifying agent may be present in the solid first part in any suitable amount. The solid first part may comprise at least 5 wt%, such as at least 6 wt%, such as at least 7 wt%, such as at least 8 wt%, or even at least 9 wt% radiopacifying agent based on the total solid weight of the solid first part. The solid first part may comprise up to 30 wt%, such as up to 25 wt%, such as up to 20 wt%, such as up to 15 wt% radiopacifying agent based on the total solid weight of the solid first part.

[101] The solid first part may comprise from 5 to 30 wt%, such as from 6 to 30 wt%, such as from 7 to 30 wt%, such as from 8 to 30 wt%, such as from 9 to 30 wt% radiopacifying agent based on the total solid weight of the solid first part. The solid first part may comprise from 5 to 25 wt%, such as from 6 to 25 wt%, such as from 7 to 25 wt%, such as from 8 to 25 wt%, such as from 9 to 25 wt% radiopacifying agent based on the total solid weight of the solid first part. The solid first part may comprise from 5 to 20 wt%, such as from 6 to 20 wt%, such as from 7 to 20 wt%, such as from 8 to 20 wt%, such as from 9 to 20 wt% radiopacifying agent based on the total solid weight of the solid first part. The solid first part may comprise from 5 to 15 wt%, such as from 6 to 15 wt%, such as from 7 to 15 wt%, such as from 8 to 15 wt%, such as from 9 to 15 wt% radiopacifying agent based on the total solid weight of the solid first part.

[102] Suitably, the solid first part may comprise from 5 to 30 wt% radiopacifying agent based on the total solid weight of the solid first part.

[103] Suitably, the solid first part may comprise from 5 to 20 wt% radiopacifying agent based on the total solid weight of the solid first part.

[104] Suitably, the solid first part may comprise from 10 to 20 wt% radiopacifying agent based on the total solid weight of the solid first part.

[105] It will be appreciated by a person skilled in the art that in the hardened bone cement the radiopacifying agent, when present, is suitably distributed throughout the polymer matrix of said hardened bone cement.

[106] The solid first part and storage stable liquid part are operable to form a bone cement which hardens to a solid mass upon mixing of the parts together.

[107] Thus, according to a second aspect of the present invention there is provided a method of producing a bone cement from a two part hardenable composition according to the first aspect of the present invention comprising the step of mixing the solid first part and the storage stable liquid second part.

[108] Suitable features of the second aspect of the present invention are as defined herein in relation to the first aspect of the present invention.

[109] The bone cements may have any suitable working time. The working time is the time during which the viscosity of the bone cement is such that it may be injected and/or manipulated by an operator. The bone cements may have a working time from 3 to 20 minutes, such as from 4 to 15 minutes, such as from 4 to 10 minutes, such as from 4 to 7 minutes, or even from 4 to 5 minutes. It will be appreciated by a person skilled in the art that the working time is the time during which the bone cement is injectable. After the working time, i.e. once the bone cement has hardened to a solid mass, the bone cements are no longer injectable. The time in which is takes the bone cement to harden to a solid mass is known as the setting time. The bone cements may have any suitable setting time. The bone cements may have a setting time from 5 to 25 minutes, such as from 6 to 20 minutes, such as from 7 to 15 minutes, such as from 7 to 10 minutes, such as from 7 to 8 minutes, or even 7 minutes.

[110] Advantageously, the bone cements of the present invention have a working time that is at least sufficient to allow an operator to inject and/or manipulate the cement in the desired fashion.

[111] The mixing of the solid first part and storage stable liquid second part may be carried out by any suitable technique. For example, the mixing of the solid first part and storage stable liquid second part may be performed by a manual mixing process or by the use of an optionally adapted syringe or caulking gun.

[112] A general procedure for mixing the solid first part and the storage stable liquid second part of the hardenable composition of the invention is described as follows: before mixing, the two parts are equilibrated for a suitable period, such as 1 hour or more at a temperature of 5 to 40°C, such as 10 to 35°C, or even 15 to 30°C. The solid first part is mixed with a suitable amount of storage stable liquid second part according to the ratios defined herein. Mixing is then carried out at the equilibrated temperature for at least 5 seconds, such as at least 20 seconds, or even at least 30 seconds. When the bone cement has been suitably mixed, the material may be injected within a cavity, such as a bone cavity, and allowed to exotherm and harden. The bone cement is suitably injected into a cavity, such as a bone cavity, within the working time of the bone cement (as hereinbefore described).

[113] Alternatively, the solid first part and storage stable liquid second part may be mixed at the equilibrated temperature in a static mixer connected to twin compartments of a syringe or caulking gun, for example. When the material has been suitably mixed, the material may be injected into a cavity, such as a bone cavity, and allowed to exotherm and harden.

[114] Suitably, the mixing of the solid first part and storage stable liquid second part may be performed by the use of an optionally adapted syringe or caulking gun.

[115] The solid first part and storage stable liquid second part may be mixed together at any suitable ratio. The solid first part and storage stable liquid second part may be mixed at a ratio of 2:1 to 1:2 by mass, such as at a ratio of 2:1 to 1:1 by mass, or even at a ratio of 1:1 by mass.

[116] When the solid first part and storage stable liquid second part are mixed together, the filler and/or polymer particles are wetted with monomer, solvated and begin to dissolve. The initiator interacts with activator, if present, to produce free radicals that react with the monomer component and initiate room temperature addition polymerisation of the monomer component. The mixture starts out at a relatively low viscosity and progresses to a stiffer and stiffer system that eventually hardens completely to a hardened bone cement.

[117] Thus, according to a third aspect of the present invention there is provided a solid bone cement produced from mixing the solid first part and the storage stable liquid second part of the two part hardenable composition according to the first aspect of the present invention, wherein the solid bone cement is resorbable.

[118] Suitable features of the third aspect of the present invention are as defined herein in relation to the first and/or second aspects of the present invention.

[119] The hardened bone cement may have any suitable flexural strength. The hardened bone cement may have a flexural strength of at least 15 mega Pascals (MPa), such as at least 20 MPa, or even at least 25 MPa. Suitably, the flexural strength may be measured according to ISO-5833 with the exception that a cylindrical sample (diameter = 8.5 mm; length = 40 mm) is used instead of a sample having a rectangular cross section.

[120] The hardened bone cement may have any suitable flexural modulus. The hardened bone cement may have a flexural modulus of at least 200 mega Pascals (MPa), such as at least 400 MPa, such as at least 500 MPa, such as at least 1,000 MPa, such as at least 1,200 MPa, or even at least 1,400 MPa. Suitably, the flexural modulus may be measured according to ISO 5833 with the exception that a cylindrical sample (diameter = 8.5 mm; length = 40 mm) is used instead of a sample having a rectangular cross section.

[121] The hardened bone cement may have any suitable 'strain to break'. The hardened bone cement may have a strain to break of up to 10%, such as up to 7.5%, or even up to 5%. Suitably, the strain to break may be measured according to ISO 5833 with the exception that a cylindrical sample (diameter = 8.5 mm; length = 40 mm) is used instead of a sample having a rectangular cross section.

[122] There is no particular temperature limitation on the use of the present invention. Suitably, however, it is used at temperatures acceptable to the operator i.e. temperatures found during normal working conditions that may be encountered indoors or outdoors by the operator, for example 5-40°C and atmospheric pressure and/or applied syringe pressure.

[123] For medical applications such as bone cement, to which the compositions of the invention are mainly directed, the composition is biocompatible and in particular hardens to a solid cement that is biocompatible in situ. Thus, the composition of the invention finds particularly advantageous utility as a medical implant material such as a bone cement. Thus, the two part hardenable composition may suitably be a bone cement composition.

[124] Thus, according to a fourth aspect of the present invention there is provided a two part hardenable composition according to the first aspect of the present invention for use in the treatment of human or animal bone.

[125] According to a fifth aspect of the present invention there is provided a two part hardenable composition according to the first aspect of the present invention for use in the repair or partial repair of human or animal bone.

[126] Suitable features of the fourth and/or fifth aspects of the present invention are as defined herein in relation to the first, second and/or third aspects of the present invention.

[127] According to a sixth aspect of the present invention there is provided a kit of parts comprising the two part hardenable composition according to the first aspect of the present invention, a syringe or caulking gun and, optionally, a balloon.

[128] Suitable features of the fifth aspect of the present invention are as defined herein in relation to the first, second, third, fourth and/or fifth aspects of the present invention.

[129] The syringe and/or caulking gun may be any suitable syringe and/or caulking gun. Suitable syringes and/or caulking guns will be known to a person skilled in the art.

[130] The balloon, when present, may be any suitable balloon. Such balloons can easily be implanted within a cavity, such as a bone cavity, using an appropriate delivery system and, together with the bone cement, can provide sufficient support. Suitable balloons will be known to a person skilled in the art. Suitably, the balloon may be commercially available. It will be appreciated by a person skilled in the art that the bone cements of the present invention may suitably be injected into the balloon in situ. Advantageously, the use of a balloon enables the bone cement to be removed from the body, such as a human or animal body, if necessary.

[131] The term "liquid" herein does not require definition because it is well understood by the person skilled in the art. However, for the avoidance of doubt it also includes a flowable material having a liquid carrier such as a slurry, suspension, emulsion or paste that is thus susceptible of delivery through a syringe or caulking gun outlet by the application of pressure. Typically, the term liquid is applicable to the material or composition at least between 5 and 35°C, more typically, between 5 and 30°C.

[132] The term "solid part" means a non-liquid or non-gaseous part and is generally a free flowing dry particulate material usually made up of one or a mixture of powder(s) and not including a liquid carrier.

[133] By "storage stable" is meant that the monomer or liquid does not polymerize under normally acceptable storage conditions of temperature and time i.e. between 5 and 30°C and 1 to 250 days, such as 15 to 25°C and 1 to 170 days.

[134] As used herein, unless otherwise expressly specified, all numbers such as those expressing values, ranges, amounts or percentages may be read as if prefaced by the word "about", even if the term does not expressly appear. Also, the recitation of numerical ranges by endpoints includes all integer numbers and, where appropriate, fractions subsumed within that range (e.g. 1 to 5 can include 1,2, 3,4 when referring to, for example, a number of elements, and can also include 1.5, 2, 2.75 and 3.80, when referring to, for example, measurements). The recitation of end points also includes the end point values themselves (e.g. from 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[135] Singular encompasses plural and vice versa. For example, although reference is made herein to "a" filler, "a" crosslinker material, "an" initiator, and the like, one or more of each of these and any other components can be used. As used herein, the term "polymer" refers to oligomers and both homopolymers and copolymers, and the prefix "poly" refers to two or more. Including, for example and like terms means including for example but not limited to.

[136] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. Additionally, although the present invention has been described in terms of "comprising", the coating compositions detailed herein may also be described as "consisting essentially of" or "consisting of'.

[137] As used herein, the term "and/or," when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and/or C, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination. As used herein, the term "and combinations thereof' when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, C and combinations thereof, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination.

[138] All of the features contained herein may be combined with any of the above aspects in any combination.

[139] For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the following examples.

Examples Examples 1-5 [140] Two part hardenable compositions were prepared according to the formulations in Table 1. At least, the polymeric particles and the polymers formed from the free-radical polymerisation of the monomer component of each of examples 1-5 are able to undergo hydrolysis such that they are fully resorbable.

Table 1 -Formulations of Examples 1-5 Component Example 1 Example 2 Example 3 Example 4 Example 5 SOLID BIRSTPARTIAy*Polyvinyl alcohol 10 g 10 g 10 g 10 g 10 g 13-tricalcium phosphate 6.66 g 6.66g 6.66g 5.06g 2.46g Zr02 1.6 g BaSO4 4.2g Benzoyl peroxide 0.166g 0.166g 0.166g 0.166g 0.166g STORAG E STABLE LIQUID BBC ONO PART (B) N-vinyl-2-pyrrolidone 2m1 2m1 2m1 2m1 Poly(ethylene glycol) 2m1 methyl ethyl acrylate Ethylene glycol dimethacrylate 10 ml 10 ml 10 ml 10 ml 10 ml Di(trimethylolpropane) tetraacrylate 2.5 ml 2.5 ml 2.5 ml 2.5 ml 2.5 ml 4-(dimethylamino) phenethyl alcohol 0.043 g 0.0439 0.0439 0.0439 0.0439 Polyethylene glycol 1 ml Comparative Example 1 [141] Comparative example 1 is a semi-resorbable cement which was prepared according to the formulation in Table 2. The polymer formed from the monomer component, methyl methacrylate, of comparative example 1 is not able to undergo hydrolysis such that it is not resorbable.

Table 2 -Formulation of Comparative Example 1 Comparative Example 1 Component 6.669 Polyvinyl alcohol Methyl methacrylate 17.5 ml 0.13 ml NN-dimethyl-p-toluidene g p-tricalcium phosphate 1 g Benzoyl peroxide

OS

EGON

E LIQU

PART 13)

STORAGE STAB 4 ml

Ethylene glycol dimethacrylate

SOLID FIRST PART

Poly(ethylene glycol) methyl ethyl acrylate 7.5 ml Comparative Example 2 [142] Comparative example 2 is Versabond (RTM), a non-resorbable commercially available cement from Smith and Nephew, containing in 19.87 g methyl methacrylate (stabilized with hydroquinone) and 0.13 g N,N-dimethyl-p-toluidine in Part (A) and 18.0 g methyl methacrylatemethacrylate copolymer, 20.0 g methyl methacrylate homopolymer, 0.5 g benzoyl peroxide (hydrous 75%), 3.8 g zirconium dioxide, in Part (B).

[143] The solid first part and storage stable liquid second part for each of examples 1-3 and comparative example 1 were mixed by hand for 30 seconds at room temperature until homogenous and drawn up into syringe barrels. The samples were left to sure until the bone cement had reached its heat spike (as measured according to an infrared temperature monitor) and then pushed out into sample trays. The samples were let to cure for a minimum of 16 hours. Comparative example 2 was prepared in the same way with the exception that the two parts were mixed according to the manufacturer's instructions. The maximum temperature, working time and setting time were recorded as well as the injectability of the cements (which was assessed visually). The physical properties of the resultant cements were tested according to the following test methods. The results are shown in Table 3.

[144] Flexural strength: the flexural strength of the cements was measured according to ISO-5833 with the exception that a cylindrical sample is used instead of a sample having a rectangular cross section. The cylindrical sample had a diameter of 8.5 mm and a length of 40 mm.

[145] Flexural modulus: the flexural modulus was measured according to ISO 5833 with the exception that a cylindrical sample is used instead of a sample having a rectangular cross section. The cylindrical sample had a diameter of 8.5 mm and a length of 40 mm.

[146] Strain at break: the strain at break was measured according to ISO 5833 with the exception that a cylindrical sample is used instead of a sample having a rectangular cross section. The cylindrical sample had a diameter of 8.5 mm and a length of 40 mm.

Table 3 -Results

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Flexural Strength (MPa) 39.2 37.8 35.8 37.5 29.2 38 39.8 Flexural Modulus (GPa) 1.7 1.7 1.5 1.8 1.6 1.1 1.2 Strain at Break (%) 3.51 3.41 3.52 3.24 3.03 5.21 6.16 Maximum 84.2 93.1 74.5 - - 120 120 temperature (°C) Working time (minutes) 3 >2 3.5 - - 5-6 >2 Setting time (minutes) 4-5 4-5 6 - - 10 10 lnjectability High High High - - Medium Required cooling [147] The results show that the cements according to the invention perform at least as well as, if not better than, those of the comparative examples.

[148] Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[149] All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

[150] Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[151] The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

CLAIMSA two part hardenable composition comprising a solid first part and a storage stable liquid second part, the solid first part and storage stable liquid part being operable to form a resorbable and injectable bone cement which hardens to a solid mass upon mixing of the parts together, the solid first part comprising: a filler and/or polymer particles, wherein each of the filler and the polymer particles, when present, have an average particle size of up to 200 pm and wherein the polymer particles, when present, have a weight-average molecular weight (Mw) of at least 10,000 Da; and (H) 0.01 to 15 wt% of an initiator based on the total weight of the solid first part; and the storage stable liquid second part comprising: (I) a monomer component, wherein the monomer component is operable to undergo free radical polymerisation in the presence of the initiator to form a polymer upon mixing of the parts together; and (II) 0.5 to 50 wt% of a crosslinker material based on the total weight of the storagestable liquid part,wherein each of the polymer particles, when present, and the polymer formed from the free radical polymerisation of the monomer component are resorbable.
2 A composition according to claim 1, wherein the filler comprises tricalcium phosphate.
3 A composition according to any one of claims 1 or 2, wherein the polymer particles comprise polyvinyl alcohol.
4 A composition according to any one of claims 1-3, wherein each of the filler and the polymer particles may have an average particle size up to 100 pm.
5. A composition according to any one of claims 1-4, wherein the polymer particles have a weight average molecular weight (Mw) of at least 50,000 Da.
6 A composition according to any one of claims 1-5, wherein the initiator comprises benzoyl peroxide.
7. A composition according to any one of claims 1-6, wherein the monomer component comprises N-vinyl pyrrolidone.
8. A composition according to any one of claims 1-7, wherein the crosslinker material comprises one of more di-functional crosslinker material(s) and/or one or more tetra-functional crosslinker material(s).
9. A composition according to any one of claims 1-8, wherein the crosslinker material is resorbable.
10. A composition according to any one of claims 1-9, wherein the storage stable liquid second part comprises di(trimethylolpropane) and/or di(trimethylolpropane) tetraacrylate.
11. A composition according to any one of claims 1-10, wherein the solid first part further comprises a radiopacifying agent.
12. A method of producing a resorbable and injectable bone cement from a two part hardenable composition according to any one of claims 1-11, comprising the step of mixing the solid first part and the storage stable liquid second part.
13. A solid bone cement produced from mixing the solid first part and the storage stable liquid second part of the two part hardenable composition according to any one of claims 1-11, wherein the solid bone cement is resorbable.
14. A two part hardenable composition according to any one of claims 1-11 for use in the treatment of human or animal bone.
15. A kit of parts comprising the two part hardenable composition according to any one of claims 1-11, a syringe or caulking gun and, optionally, a balloon.