Hardenable multi-part acrylic composition

Abstract

The invention relates to a hardenable multi-part acrylic composition. The composition has at least two parts which react with each other upon being mixed together to progressively harden to form a solid cement, such as a bone cement. The beads in the first part comprise an acrylic bead polymer core produced by suspension polymerisation and having a Tg of >70° C. and emulsion polymerised acrylic microparticles at least partially coating the surface of the acrylic bead polymer core. The microparticles may form a porous coalesced network. The bone cement composition comprises the first part and a liquid second part and optionally, further parts. The parts are operable to form a cement which hardens to a solid mass upon mixing of the parts together. The composition further comprises an acrylic monomer component in the second part and an initiator component. A method of production of coated beads for the hardenable multipart composition and a solid cement is also described.

Claims

1. A composition comprising coated acrylic polymer beads comprising: a) an acrylic bead polymer core produced by suspension polymerisation and having a Tg of >70° C.; and b) emulsion polymerised acrylic microparticles at least partially coating the surface of the said acrylic bead polymer core; wherein the emulsion polymerized acrylic microparticles (b) reduce the dough time of the acrylic bead polymer core (a) when the polymer beads are combined with an acrylic monomer and an initiator; wherein at least 5% of the bead polymer core surface is coated with the said microparticles wherein the Z-average particle size range for the emulsion polymerized microparticles is between 0.02-1_μm, and wherein the mean particle size of the bead polymer cores is in the range 2-150 μm.

2. A composition comprising coated acrylic polymer beads comprising: a) an acrylic bead polymer core produced by suspension polymerisation; and b) emulsion polymerised acrylic microparticles at least partially coating the surface of the said acrylic bead polymer core wherein the microparticles form a porous coalesced network; wherein the emulsion polymerized acrylic microparticles (b) reduce the dough time of the acrylic bead polymer core (a) when the polymer beads are combined with an acrylic monomer and an initiator; wherein at least 5% of the bead polymer core surface is coated with the said microparticles wherein the Z-average particle size range for the emulsion polymerized microparticles is between 0.02-1_μm, and wherein the mean particle size of the bead polymer cores is in the range 2-150 μm.

3. The composition according to claim 1, wherein the microparticles form a porous coalesced network.

4. The composition according to claim 2, wherein the acrylic bead polymer core produced by suspension polymerisation has a Tg of >70° C.

5. The composition according to claim 1, wherein at least 10% of the bead polymer core surface is coated with the said microparticles.

6. The composition according to claim 1, wherein the composition is a multi-part composition and further comprises an acrylic monomer and an initiator wherein the acrylic monomer component and the initiator component are located in separate parts of the multi-part composition so that the monomer component is storage stable to polymerization; and wherein, upon mixing the coated acrylic polymer beads with both the liquid acrylic monomer and initiator, the composition hardens to a solid mass and forms a cement.

7. The composition according to claim 6, wherein the coated microparticles form a porous coalesced network of microparticles on the surface of the core.

8. The composition according to claim 1, wherein the coated acrylic polymer beads are solid.

9. The composition according to claim 1, wherein the ratio of emulsion polymerized microparticles (b) to suspension polymerized beads (a) is between 1:99 to 50:50 w/w.

10. The composition according to claim 1, wherein the acrylic polymer bead (a) or emulsion polymerized microparticle (b) are independently homopolymers of a polyalkyl(alk)acrylate, homopolymers or (alk)acrylic acid, or copolymers of an alkyl(alk)acrylate or (alk)acrylic acid with one or more other vinyl monomers in which at least 50% of the monomer residues are acrylic monomer residues.

11. The composition according to claim 1, wherein independently the acrylic polymer bead (a) or the emulsion polymerized microparticle is made of a homopolymer of methyl methacrylate or a copolymer of methyl methacrylate with one or more other vinyl monomers.

12. The composition according to claim 6, wherein the acrylic monomer is liquid and is an alkyl(alk)acrylate or an (alk)acrylic acid, optionally further comprising one or more additional comonomers.

13. The composition according to claim 6, wherein the multi-part composition is a bone cement forming composition, a dental composition or a composition for medical implantation.

14. The composition according to claim 13, wherein the composition is a bone cement forming composition.

15. The composition according to claim 11, wherein the one or more other vinyl monomers are present and are styrene or methyl acrylate.

16. The composition according to claim 12, wherein the comonomers are styrene and methyl acrylate.

17. The composition according to claim 6, further comprising an additive selected from the group consisting of a catalyst, a radiopacifying filler, a dyestuff, and a filler.

18. The composition according to claim 6, further comprising an accelerator, activator, or stabilizer.

19. A method of making the composition of claim 1, comprising: a) providing acrylic polymer bead particles prepared by suspension polymerization; b) providing emulsion polymerized microparticles in the form of a dispersion, c) mixing the suspension of a) and dispersion of b) in the presence of an electrolyte to cause coagulation of the emulsion microparticles with the bead particles to form an acrylic bead polymer core at least partially coated with emulsion polymerised acrylic microparticles.

20. The method according to claim 19, wherein the ratio of emulsion polymerized microparticle dispersion to suspension polymerized bead particles is between 2:98 to 60:40 w/w thereof.

21. A method of producing an acrylic cement comprising: (a) providing coated acrylic polymer beads comprising (1) an acrylic bead polymer core produced by suspension polymerisation and having a Tg of >70° C.; and (2) emulsion polymerised acrylic microparticles at least partially coating the surface of the said acrylic bead polymer core; the coating being effective to reduce the dough time when the polymer beads are combined with an acrylic monomer and an initiator; and wherein at least 5% of the bead polymer core surface is coated with the said microparticles wherein the Z-average particle size range for the emulsion polymerized microparticles is between 0.02-1 μm, and wherein the mean particle size of the bead polymer cores is in the range 2-150 μm, (b) providing a liquid acrylic monomer, (c) providing an initiator d) mixing the coated polymer beads (a) the liquid monomer (b), and the initiator (c) to make a dough, e) optionally, placing the dough in a mould or body cavity or around an implant by hand manipulation or injection, and f) allowing the dough to set and harden to a solid mass.

Description

(1) Embodiments of the invention will now be described with reference to the accompanying examples and by reference to the drawings in which:

(2) FIG. 1 shows an SEM image of the surface of coated acrylic polymer beads according to the invention;

(3) FIG. 2 shows an SEM image of the emulsion polymerized microparticles on the surface of the coated acrylic polymer beads according to the invention at a higher magnification than the image of FIG. 1; and

(4) FIG. 3 shows an SEM view of the surface of acrylic polymer beads without an emulsion polymerized microparticle coating.

EXAMPLES

(5) Characterisation Techniques:

(6) The molecular weight was measured by gel permeation chromatography using poly(methyl methacrylate) standards for calibration. Tetrahydrofuran was used as the mobile phase. The weight average molecular weight (Mw), number average molecular weight (Mn) and the polydispersity (Mw/Mn) were measured.

(7) The Z average emulsion particle size was determined using a Malvern Zetasizer nano series S particle size analyser.

(8) The mean particle size of acrylic polymer beads was determined using a Coulter LS230 laser diffraction instrument.

(9) Reduced viscosity (RV, dl/g) was measured in chloroform (1 wt % solution) using an Ubbelohde viscometer type OB at 25° C.

(10) Wt % residual dibenzoyl peroxide content was determined by a titration method.

(11) Wt % water content was determined by a Karl Fischer method using a Metrohm 874 over sample processor with 831 coulometer.

(12) Brookfield viscosity (BV, centipoise (cPs)) of the acrylic emulsions was determined at 25° C. using a Brookfield viscometer model DV-E operating with spindle number 5 and speed 20.

(13) Scanning electron microscopy (SEM) imaging was carried out using a FEI Quanta FEG 250 Environmental SEM. Specimens were prepared for SEM imaging by gently sprinkling the dried polymer powder directly onto conductive carbon sticky tabs mounted on SEM stubs. Any loose material was carefully dislodged and a very thin two pass conductive metal coating (Au/Pd) applied to the samples prior to SEM imaging.

Preparative Example 1

(14) Preparation of 50.1% wt Solids Acrylic Polymer Dispersion (MMA/styrene 85/15 wt % Copolymer)

(15) 600 grams of deionised water was added to a five-litre round bottomed glass flask fitted with a nitrogen inlet, condenser and electrically operated stainless steel paddle stirrer. The water was heated to 80° C. by means of a water bath whilst stirring at 150 revolutions per minute (rpm). A flow of nitrogen was passed through the vapour space of the flask above the surface of the liquid.

(16) An emulsified monomer mixture was prepared consisting of 850 grams methyl methacrylate (MMA), 150 grams styrene, 5.0 grams of sodium lauryl sulfate and 300 grams of deionised water. This mixture was stirred for 60 minutes prior to and throughout addition to keep it emulsified.

(17) With the temperature of the water at 80° C., a polymer seed (Stage 1) was prepared by adding 30 grams of the emulsified monomer mixture to the flask followed by 10 millilitres of a 2 wt % solution of potassium persulfate in deionised water. Following a slight exotherm, the reaction proceeded for thirty minutes until the temperature returned to 80° C.

(18) The core was then grown over the polymer seed particles (Stage 2) by firstly adding 10 millilitres of a 2 wt % solution of potassium persulfate in deionised water to the flask followed by continuous addition of 300 grams of the emulsified monomer mixture over approximately 25 minutes using a peristaltic pump. The reaction proceeded for a further 15 minutes after the completion of addition of the monomer mixture until the temperature returned to 80° C. This step was then repeated twice.

(19) 30.0 grams of 75% active dibenzoyl peroxide were dissolved in the remaining 370 grams of emulsified monomer mixture with stirring for 45 minutes.

(20) The BPO-containing shell was then grown over the core (Stage 3) by firstly adding 10 millilitres of a 2 wt % solution of potassium persulfate in deionised water to the flask followed by continuous addition of the emulsified monomer mixture containing added BPO over approximately 25 minutes using a peristaltic pump. The reaction proceeded for a further fifteen minutes after all the monomer mixture had been added until the temperature had returned to 80° C.

(21) The resultant acrylic polymer dispersion was then cooled to below 40° C. and filtered through a 150 micron screen.

(22) The acrylic polymer dispersion had a solids content of 50.1% wt, reduced viscosity of 2.72 dl/g, Brookfield viscosity of 130 cPs, residual dibenzoyl peroxide of 2.2 wt % and a z-average dispersion particle size of 254 nm.

Preparative Example 2

(23) Preparation of 25% wt Solids Acrylic Polymer Dispersion (PMMA Homopolymer)

(24) 1500 grams of deionised water was added to a five-litre round bottomed glass flask fitted with a nitrogen inlet, condenser and electrically operated stainless steel paddle stirrer. The water was heated to 80° C. by means of a water bath whilst stirring at 150 revolutions per minute (rpm). A flow of nitrogen was passed through the vapour space of the flask above the surface of the liquid.

(25) A monomer mixture was prepared consisting of 500 grams methyl methacrylate, 1.0 gram of 1-dodecanethiol and 5.0 grams of 75% active sodium dioctylsulfosuccinate emulsifier (trade name: Aerosol™ OT). These components were mixed before use.

(26) With the temperature of the water at 80° C., a polymer seed (Stage 1) was prepared by adding 50 grams of the monomer mixture to the flask followed by 10 millilitres of a 2 wt % solution of potassium persulfate in deionised water. Following a slight exotherm, the reaction proceeded for thirty minutes until the temperature returned to 80° C.

(27) The core was then grown over the polymer seed particles (Stage 2) by firstly adding 20 millilitres of a 2 wt % solution of potassium persulfate in deionised water to the flask followed by continuous addition of 350 grams of the monomer mixture over approximately 35 minutes using a peristaltic pump. The reaction proceeded for a further fifteen minutes after the completion of the monomer mixture addition until the temperature returns to 80° C.

(28) 14.0 grams of 75% active dibenzoyl peroxide were dissolved in the remaining 100 grams of monomer mixture. This produces a residual dibenzoyl peroxide (BPO) content of approximately 2 wt % in the polymer.

(29) The BPO-containing shell was then grown over the core (Stage 3) by firstly adding five millilitres of a 2 wt % solution of potassium persulfate in deionised water to the flask followed by continuous addition of the monomer mixture containing added BPO over approximately 10 minutes using a peristaltic pump. The reaction proceeded for a further fifteen minutes after all the monomer mixture had been added until the temperature has returned to 80° C.

(30) The resultant dispersion was then cooled to below 40° C. and filtered through a 150 micron screen.

(31) The acrylic polymer dispersion had a solids content of 25 wt %, reduced viscosity of 2.02 dl/g, Brookfield viscosity of 150 cPs, residual dibenzoyl peroxide of 1.90 wt % and a z-average dispersion particle size of 197 nm.

Example 1

(32) Preparation of Acrylic Polymer Beads and Addition of Emulsion Polymer Coating

(33) The aqueous phase of a suspension polymerization was prepared by adding 1750 millilitres of deionized water and 8 grams of hydroxyethyl cellulose powder (Natrosol HEC 250HR from Aqualon Ltd) to a 5 litre glass flask fitted with a stainless steel anchor-type stirrer. The flask contents were stirred at 400 rpm and heated to 40° C. to dissolve the hydroxyethyl cellulose. The organic phase containing 1,000 grams methyl methacrylate and 44.0 grams of 75% active dibenzoyl peroxide was then added, the stirrer speed adjusted to 650 rpm and the contents of the reactor flask heated to 77-80° C. using a water bath. The polymerization was continued at 77-80° C. until the reactor contents experienced an exotherm, typically to approximately 92-95° C. The reactor flask contents were then cooled to room temperature.

(34) Application of an emulsion polymer coating to these beads was carried out as follows: 820 grams of the acrylic polymer bead slurry was added to a 5 litre glass flask fitted with a stainless steel anchor-type stirrer, followed by 200 gram of deionized water and 20 grams of aluminium sulfate. The mixture was then heated to 85° C. with stirring at 300 rpm. After the aluminium sulfate had dissolved, 84 grams of the final acrylic dispersion prepared in preparative example 1 were added dropwise over 20 minutes. The mixture was stirred at 300 rpm at 85° C. for a further 60 minutes before cooling the mixture to room temperature. The resultant polymer beads with coagulated emulsion polymer coating were then filtered, washed with deionized water, dried in an air circulating oven at 50° C. and screened through an 840 microns screen. The dried product was a free flowing polymer with mean particle size 95 microns

Example 2

(35) Example 1 was repeated except that 30 grams of aluminium sulfate and 167 grams of the acrylic polymer dispersion of preparative example 1 were used.

(36) The dried polymer beads with coagulated emulsion polymer coating had the consistency of a free flowing powder with mean particle size 110 microns.

Example 3

(37) Example 1 was repeated except that 30 grams of aluminium sulfate and 225 grams of the acrylic polymer dispersion of preparative example 1 were used.

(38) The dried polymer beads with coagulated emulsion polymer coating had the consistency of a free flowing powder with mean particle size 104 microns.

Example 4

(39) Example 1 was repeated except that 167 grams of the acrylic polymer dispersion of preparative example 2 were used. The dried polymer beads with coagulated emulsion polymer coating had the consistency of a free flowing powder with mean particle size 96 microns.

Comparative Example 1

(40) Preparation of Uncoated Polymer Bead

(41) The polymer beads were made in the same way as example 1, but the application of an emulsion polymer coating was omitted. Analysis of the uncoated polymer beads gave the following results: mean particle size 68 μm, residual benzoyl peroxide content 3.0 wt %, weight average molecular weight (Mw) of 250 daltons and reduced viscosity 2.00 dl/g.

Comparative Example 2 and Examples 5 to 8

(42) Preparation of Powder/Liquid Mixtures and Determination of Dough, Work and Set Times

(43) These examples involved the mixing of the powders from comparative example 1 and examples 1, 2, 3 and 4 with monomer liquid to determine the dough, work and set times of each powder/liquid mixture. The monomer liquid consisted of 99 parts by weight of MMA monomer containing 60ppm HQ inhibitor and 1 part by weight of N,N-dimethyl-p-toluidine (DMPT) accelerator. The mix ratio was 10.5 g polymer powder to 6 ml monomer liquid. The two components were firstly equilibrated in an incubator at 23° C. for at least 10 hours. The required amount of polymer powder was then placed into a polypropylene beaker, followed by the monomer liquid. Timing was started from the point of adding the powder to the liquid. Hand mixing was then carried out for 30 seconds using a metal spatula, whereupon the material was covered and left to stand. Periodically, the material was assessed and the dough, work and set times were recorded. Table 1 records the results.

(44) It can be seen that the effect of the emulsion polymer coating in examples 5 to 8 significantly shortens the dough time compared to comparative example 2, thereby allowing an appreciable increase in work time.

(45) TABLE-US-00001 TABLE 1 Example: Comparative example 2 Example 5 Example 6 Example 7 Example 8 Identity of powder component: Comparative Example 1 Example 2 Example 3 Example 4 example 1 (no emulsion polymer coating) Dough time (minutes:seconds) 15 7 1:30  1  1:30 Work time (minutes:seconds) 4 17 14 9:30 10:30 Set time (minutes:seconds) 22 28 18 13 18:30

Comparative Example 3 and Examples 9 and 10

(46) Blends of Uncoated and Emulsion Polymer Coated Polymer Beads

(47) To demonstrate how the dough, work and set times can be fine-tuned, powder blends of the uncoated beads of comparative example 1 with the emulsion polymer coated beads of example 3 were prepared in ratios 100:0, 50:50 and 25:75 wt % of comparative example 1: example 3. These blends were prepared by weighing out the relevant amount of each ingredient into a 150 gram capacity lab scale cone blender and then blending for 10 minutes. The resulting blends were then used to determine dough, work and set times as follows:

(48) A monomer liquid was prepared consisting of 99 parts by weight of MMA monomer containing 60 ppm HQ inhibitor and 1 part by weight of N,N-dimethyl-p-toluidine (DMPT) accelerator. This was mixed with each polymer powder in mix ratio was 10.5 g polymer powder to 6 ml monomer liquid. The two components were firstly equilibrated in an incubator at 23° C. for at least 10 hours. The required amount of polymer powder was then placed into a polypropylene beaker, followed by the monomer liquid. Timing was started from the point of adding the powder to the liquid. Hand mixing was then carried out for 30 seconds using a metal spatula, whereupon the material was covered and left to stand. Periodically, the material was assessed and the dough, work and set times were recorded. Table 2 records the results.

(49) It can be seen that the effect of incorporating the emulsion polymer coated polymer beads of example 3 into a powder blend (examples 9 and 10) is to significantly shorten the dough time compared to comparative example 3 that does not contain any emulsion polymer coated polymer beads, thereby allowing an appreciable increase in work time.

(50) TABLE-US-00002 TABLE 2 Comparative example 3 Example 9 Example 10 Blend composition 100:0 wt % 50:50 wt % 25:75 wt % Comparative Comparative Comparative example example example 1:Example 3 1:Example 3 1:Example 3 Dough time 15 8:00 1:30 (minutes:seconds) Work time 4 10 12 (minutes:seconds) Set time 22 21 16 (minutes:seconds)

Comparative Example 4 and Examples 11 and 12

(51) Blends of Uncoated and Emulsion Polymer Coated Polymer Beads with Radiopacifier (Zirconium Oxide)

(52) The effect of adding radiopacifier to the polymer powders was assessed. The radiopacifier selected was zirconium (IV) oxide (available from Sigma-Aldrich as 5 um powder, product code 230693) and this was blended with the uncoated beads of comparative example 1 and the emulsion polymer coated polymer beads of examples 3 or 4 in the ratio 20:80 wt % zirconium oxide:polymer powder. These blends were prepared by weighing out the relevant amount of each ingredient into a 150 gram capacity lab scale cone blender and then blending for 10 minutes. The resulting blends were then used to determine dough, work and set times as follows: A monomer liquid was prepared consisting of 99 parts by weight of MMA monomer containing 60 ppm HQ inhibitor and 1 part by weight of N,N-dimethyl-p-toluidine (DMPT) accelerator. This was mixed with each polymer powder in mix ratio was 10.5 g polymer powder to 6 ml monomer liquid. The two components were firstly equilibrated in an incubator at 23° C. for at least 10 hours. The required amount of polymer powder was then placed into a polypropylene beaker, followed by the monomer liquid. Timing was started from the point of adding the powder to the liquid. Hand mixing was then carried out for 30 seconds using a metal spatula, whereupon the material was covered and left to stand. Periodically, the material was assessed and the dough, work and set times were recorded. Table 3 records the results.

(53) It can be seen that, even in the presence of zirconium oxide radiopacifier, the effect of the emulsion polymer coating in examples 13 to 14 significantly shortens the dough time compared to comparative example 4, thereby allowing an appreciable increase in work time.

(54) TABLE-US-00003 TABLE 3 Comparative example 4 Example 11 Example 12 Blend composition 20:80 wt % 20:80 wt % 20:80 wt % zirconium zirconium zirconium oxide:com- oxide:ex- oxide:ex- parative ample 3 ample 4 example 1 Dough time 17  1  9 (minutes:seconds) Work time 6:30 10 13 (minutes:seconds) Set time 25 14:30 27:30 (minutes:seconds)

(55) Scanning Electron Microscopy (SEM) Examination of Emulsion Polymer Coated Polymer Beads

(56) The product of example 4 was examined by SEM imaging to show the morphology of the dried polymer beads with coagulated emulsion polymer coating.

(57) FIG. 1 (300 micron scale bar) shows that the coagulated emulsion polymer particles (ca. 0.2 micron diameter) are mainly coating the polymer beads.

(58) FIG. 2 (3 micron scale bar) shows that the emulsion polymer particles are coagulated together to form a microporous morphology.

(59) Scanning Electron Microscopy (SEM) Examination of Uncoated Polymer Beads

(60) The product of comparative example 1 was also examined by SEM imaging to show the morphology of the dried polymer beads without an emulsion polymer coating. FIG. 3 shows that the beads are devoid of structure and have a smooth surface.

(61) 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.

(62) 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.

(63) 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.

(64) 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.