GB2544261A

GB2544261A - Method

Info

Publication number: GB2544261A
Application number: GB1518465.8A
Authority: GB
Inventors: Mcneill Andrew; Sharp Duncan; Robert De Beauchamp Lucie
Original assignee: Taragenyx Ltd
Current assignee: Taragenyx Ltd
Priority date: 2015-10-19
Filing date: 2015-10-19
Publication date: 2017-05-17
Also published as: WO2017068492A1; GB201518465D0

Abstract

A method for producing a medical device or a medical device component comprising the steps of: coating bioactive particles with a bioactive material to form bioactive composite particles; mixing a polymer binder and the bioactive composite particles and melting the polymer binder using a screw extruder; and manufacturing a medical device or a medical device component from the mixture produced in the previous step by moulding. Preferably the bioactive composite particles are powdered ceramic or silicon-based comprising a phosphate and/or sulphate & a metal. The polymer binder may be selected from the group consisting of polyetheretherketone (PEEK), polyaryletherketone (PAEK), poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL). The medical device is an orthopaedic or dental medical device.

Description

METHOD

Field of the Invention

The present invention relates to methods for producing a medical device or a medical device component.

Background to the Invention A range of materials has been used for the construction of medical implants. These include titanium (Ti) and its alloys, cobalt and its alloys, chromium and its alloys and polyether ether ketone (PEEK). These materials have been chosen for their biocompatibility, mechanical properties and resistance to corrosion. However, clinical applications require a broader range of benefits than just these properties. Additional benefits may include enhanced osseointegrative properties and resistance to infection.

To give one example, PEEK as a material can be constructed into medical implants and requires the addition of bioactive particles in order to address wider clinical properties such as osseoconduction and anti-microbial effects. These particles can be introduced to the PEEK via processes such as compounding (WO 2012/110803). Once these particles are introduced homogenously throughout the bulk plastic, machining of the plastic into an implant will expose some of these particles on the surface of the implant, thereby imparting bio-active properties to an otherwise bio-inert surface. However, the amount and composition of the particles may compromise the mechanical properties of the final implant. Alternatively, if the desired mechanical properties are to be preserved, the proportion of particles in the final implant is limited. Furthermore, ensuring the correct ratio of bioactive materials in the final implants manufactured from compounded materials is difficult if more than one bioactive material is included.

The treatment of microbial infections represents a serious challenge in the field of orthopaedic surgery. For example, infection has been found to be the most common reason for revision of total knee arthroplasty in the USA, accounting for approximately 25% of revision procedures, each with an average cost of $49,360.

In recent decades, the number of orthopaedic patients with antibiotic-resistant bacterial infections has become significant. This problem has been compounded by the difficulty in discovering new effective antibiotics, which has led to declining rates of new antibiotics being approved by the USFDA.

Several promising alternatives to antibiotics have recently emerged, but very few are available to orthopaedic surgeons to prevent implant-associated infections.

One promising alternative, or complement, to the use of antibiotics is the use of gallium (Ga). Bacterial infections are often limited by the availability of iron (Fe). Indeed it has previously been found that the innate immune system reduces in vivo biofilm formation by chelating free Fe, which is important to normal bacterial metabolism.

Coatings of silver (Ag) on implanted medical devices have also been used to reduce the incidence of post-operative infections (Wafa et al. (2015), The Bone & Joint Journal, 97-B (2) 252-257).

Ceramics such as calcium phosphates have previously been included in PEEK using compounding techniques (WO 2012/110803). This has successfully increased the osteoconductive properties of the implants manufactured using these compounded materials. As discussed above, it is however difficult to conventionally introduce an additional bioactive material along with the ceramics.

Previous attempts have been made to substitute strontium into hydroxyapatite before inclusion into PEEK (Wong et al. (2009), Mechanical properties and in vitro response of strontium-containing hydroxyapatite/polyetheretherketone composites, Biomaterials, 30, 3810-3817). This substitution approach changes the properties of both the ceramic and bioactive metal. The t/vet chemical’ approach taken is also a lengthy process, taking several days to perform. Furthermore this method may limit the ratio of bioactive metal to ceramic achievable.

There is therefore a need in the art for medical devices that overcome these problems.

Summary of the Invention

The present inventors have developed a method for compounding composite bioactive particles with polymer binder materials such that additional properties may be imparted to the implant. These additional properties may include increased osseointegrative or antimicrobial properties.

Accordingly, the present invention provides a method for the manufacture of a medical device or a medical device component that comprises: A) coating bioactive particles with a bioactive material to form bioactive composite particles; B) mixing a polymer binder and the bioactive composite particles produced in step A) and melting the polymer binder using a screw extruder; C) manufacturing a medical device or a medical device component from the mixture produced in step B) by moulding.

Detailed Description of the Invention

The present invention relates to the manufacture of medical devices and medical device components.

Herein the term “medical device” is defined as an instrument, apparatus, implant, or similar or related article that is used to prevent, treat disease or other conditions, and may achieve at least part of its purpose by the inclusion of a bioactive material.

The medical device may be any type of device that is suitable for implantation into the human or animal body, for example for the purposes of bone grafting (a surgical procedure that allows for the replacement of missing bone, for example due to complex fractures). The medical device is typically an orthopaedic (including spinal and maxillofacial) or dental implant. For example, the medical device may be a spinal cage, hip or knee (femoral, tibial, patellar component) replacement/implant, femoral stem, acetabular cup, intramedullary nail or an internal and/or external fixator that is used in surgery, for example trauma surgery.

Herein the term “medical device component” is defined as a component from which a medical device may be manufactured directly, for example by melting and moulding. The manufacture of medical device components is an intermediate step in the manufacture of complete medical devices.

As used herein, the term “bioactive material” means a chemical, protein or cellular material which has an effect on cells, for example an antimicrobial (for example antibacterial, antifungal or antiviral), osteoinductive, osteoconductive, angiogenic, antithrombotic, analgesic, pro-proliferative, anti-inflammatory, anti-rejection, anti-carcinogenic effect.

As used herein, the term “bioactive particle” means a particle that includes at least one bioactive material, as defined herein.

The present invention provides a method for the manufacture of a medical device or a medical device component that comprises: A) coating bioactive particles with a bioactive material to form bioactive composite particles; B) mixing a polymer binder and the bioactive composite particles produced in step A) and melting the polymer binder using a screw extruder; C) manufacturing a medical device or a medical device component from the mixture produced in step B) by moulding.

The bioactive composite particles produced in the method of the invention comprise bioactive particles coated with a bioactive material. Generally the bioactive particles are completely covered in the bioactive coat material. The bioactive composite particles typically have a core of at least one material, including at least one bioactive material, which is encapsulated in the coat, which comprises another bioactive material. Typically, the bioactive material used to coat the bioactive particles is different from the bioactive material that is present in the bioactive particle. In some embodiments, both the core bioactive particles and the bioactive material coat may comprise more than one material and there may be more than one coat of bioactive material applied to each bioactive particle.

Methods of particle coating that can be used to provide the bioactive composite particles for the method include but are not limited to chemical or physical vapour deposition (PVD), electroplating, dip coating, sputtering or molecular beam epitaxy (MBE) although other coating processes are possible.

Vapour deposition (PVD) is particularly useful in many cases, for example in coating ceramic particles with a metal where the technique can provide metal coated or encapsulated particles with an even layer of the metal of a controlled thickness.

For example titanium coated hydroxyapatite bioactive composite particles can be made by vapour deposition of titanium on hydroxyapatite, as described in the applicant’s own earlier application published as WO 2010/136777, which is incorporated herein by reference.

It has been found that hydroxyapatite particles can be individually coated with titanium or titanium alloy by using vapour deposition techniques that include means to prevent aggregation of the particles during processing. For example a vibrating table, rotating cup or tumble drier, each of which agitates the particles during the deposition process.

The particle core material may comprise materials selected from the group consisting of ceramics, silicon-based compounds, polymers, metals, metal alloys and combinations thereof. The particle coat material may also comprise materials selected from the group consisting of ceramics, silicon-based compounds, polymers, metals, metal alloys and combinations thereof. Other materials may be included in a particle core or a particle coat, such as inorganic salts, minerals, or organic compounds. In some cases particle cores or coats may consist of a chosen inorganic salt, mineral, or organic compound.

It will be appreciated that to obtain the benefits of using coated particles the coat and the core will be of different compositions, although they may contain components common to both. The use of a metal as core or coating has the advantage of providing a degree of ductility to the particles when they impact on the surface of the article or with each other in the coating layer as it forms.

In some embodiments, a powdered ceramic or silicon-based compound is included in the bioactive composite particles produced in step A). In some embodiments, the powdered ceramic or silicon-based compound comprises a phosphate and/or sulphate. In some embodiments, the ceramic or silicon-based compound comprises at least one compound selected from the group consisting of calcium phosphate, calcium carbonate, calcium sulfate, substituted-calcium phosphate, silicon oxide, silicon dioxide, silicon phosphate, silicon carbonate and composites and crystalline forms thereof. Typically the ceramic compound comprises an apatite, for example hydroxyapatite (HA). In another embodiment, the ceramic compound comprises tricalcium phosphate.

The bioactive composite materials are particles that consist of a bioactive particle core and a coating of a bioactive material. The core of the bioactive composite particles includes a bioactive material such as hydroxyapatite. In addition the core of the particles may include a non-bioactive material such as silica. The particles typically range in diameter from 1 pm to 500 pm, for example from 2 pm to 400 pm, from 3 pm to 300 pm, from 4 pm to 200 pm, from 5 pm to 100 pm or from 10 pm to 50 pm.

In some embodiments, a metal is included in the bioactive composite particles produced in step A). In some embodiments, the metal comprises at least one metal selected from the group consisting of titanium, vanadium, aluminium, chromium, cobalt, steel, iron, gallium, lithium, strontium, magnesium, copper, zinc, silver and a salt, mineral, or alloy of any of these metals. Typically the metal is silver.

In some embodiments, the metal component of the bioactive composite particles comprises the coating of the bioactive composite particles. Typically, the metal coating on these bioactive composite particles may be of a thickness that ranges from 1 pm to 50 pm, for example from 2 pm to 40 pm, from 3 pm to 30 pm, from 4 pm to 20 pm or from 5 pm to 10 pm.

In some embodiments, one of the bioactive materials in the bioactive composite particles is an antibiotic. The antibiotic may, for example be an aminoglycoside, β-lactam, macrolide, cephalosporin, lincosamide, fluoroquinolone, glycopeptide antibiotic and/or a lipopeptide antibiotic. Suitable antibiotics include gentamycin, erythromycin, tobramycin, vancomycin and daptomycin.

In some embodiments, one of the bioactive materials in the bioactive composite particles is a chelating agent, for example ethylenediaminetetraacetic acid (EDTA). Chelating agents are used, for example, to remove heavy metals from the body.

In some embodiments, one of the bioactive materials in the bioactive composite particles is a growth factor, for example a bone morphogenetic protein. For example, the growth factor may be bone morphogenetic protein- 2 (BMP-2), bone morphogenetic protein-7 (BMP-7), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), a protein from the transforming growth factor beta (TGF-β) superfamily or a combination of any thereof.

In some embodiments, one of the bioactive materials in the bioactive composite particles is a bioactive metal, typically an antimicrobial metal, for example, silver, strontium, magnesium, lithium, gallium, copper, iron or a salt or alloy of any of these metals.

Bioactive composite particles produced by the method of the invention typically comprise a ceramic or silicon-based core with a bioactive metal coating. This enables the two or more bioactive materials to be compounded with polymer binder materials without detrimental effects on the mechanical properties of the resulting medical devices manufactured from them. Further benefits include delivering the bioactive materials at clearly defined ratios and enabling synergistic co-localisation of different bioactive materials in the implant. This is difficult to achieve conventionally using two different powders with separate components. The co-localisation of materials with different mechanical properties may also improve cellular response to the resulting implant.

In one embodiment, the bioactive composite particles comprise a metal core with a ceramic or silicon-based coating. In another embodiment, the bioactive composite particles comprise a ceramic or silicon-based core with a coating of an antibiotic. For example, hydroxyapatite particles can be coated with gentamicin before being compounded with poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL).

The bioactive metals are useful in a number of therapeutic applications and are more chemically robust than growth factors or antibiotics. The ceramic or silicon-based compound promotes osteoconduction.

Typically the medical device has mechanical properties complying with the standards set for orthopaedic implants. This is achieved by the inclusion of a polymer binder in the medical device. Herein, the term “polymer binder” is defined as the use of a polymer to bind the other components of the medical device together, and play a predominantly structural role in the implant.

Typically, the polymer binder includes phenyl moieties, ketone moieties and/or ether moieties. The polymer binder may be at least one polymer selected from the group consisting of polyetheretherketone (PEEK), polyaryletherketone (PAEK), poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL). Typically the polymer binder is PEEK.

In some embodiments, the polymer binder comprises a biodegradable polymer derived from lactide (LA), glycolide (GA), caprolactone (CL) and/or polyethylene glycol) (PEG). For example, the LA can be D,L-lactide (DLLA), L-lactide (LLA), D-lactide (DLA), meso-lactide (mLA) or a combination thereof.

In the methods of the invention, the polymer binders described above act as a binder for the compounding process. Typically these binders form the majority of the resulting medical devices, for example at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of the implant.

In the present invention, the polymer binder and the bioactive composite particles are mixed together and the polymer binder melted using a screw extruder. In some embodiments, a twin screw extruder is used to mix the polymer binder with the bioactive composite particles, and to melt the polymer binder. The output of the screw extruder may be used to form a medical device directly, or may produce medical device components, for example discrete units of the compounded material. These discrete units may be in the form of pellets, which are subsequently used to form medical devices by melting and moulding. In preferred embodiments, the medical device is formed by injection moulding following melting of the compounded material. Herein the term “compounded material” is defined as a material comprising both polymer binder and bioactive composite particles.

The medical device manufactured according to the method of the invention typically has a tensile strength and/or compressive strength of at least or greater than 15 MPa, at least 20 MPa, at least 23 MPa, at least 25 MPa, at least 30 MPa, at least 35 MPa, at least 40 MPa, at least 45 MPa or at least 50 MPa.

Claims

1. A method for producing a medical device or a medical device component, comprising: A) coating bioactive particles with a bioactive material to form bioactive composite particles; B) mixing a polymer binder and the bioactive composite particles produced in step A) and melting the polymer binder using a screw extruder; C) manufacturing a medical device or a medical device component from the mixture produced in step B) by moulding.

2. A method according to claim 1, wherein a powdered ceramic or silicon-based compound is included in the bioactive composite particles produced in step A).

3. A method according to claim 2 where the powdered ceramic or silicon-based compound comprises a phosphate and/or sulphate.

4. A method according to any of the preceding claims, wherein a metal is included in the bioactive composite particles produced in step A).

5. A method according to any of the preceding claims, wherein the polymer binder includes phenyl moieties, ketone moieties and/or ether moieties.

6. A method according to any of the preceding claims, wherein the polymer binder comprises a biodegradable polymer derived from lactide (LA), glycolide (GA), caprolactone (CL) and/or polyethylene glycol) (PEG).

7. A method according to claim 6, wherein the LA is D,L-lactide (DLLA), L-lactide (LLA), D-lactide (DLA), meso-lactide (mLA) ora combination thereof.

8. A method according to any of the preceding claims, wherein the polymer binder comprises at least one polymer selected from the group consisting of polyetheretherketone (PEEK), polyaryletherketone (PAEK), poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL).

9. A method according to any one of claims 2 to 8, wherein the ceramic or silicon-based compound comprises at least one compound selected from the group consisting of calcium phosphate, calcium carbonate, calcium sulfate, substituted-calcium phosphate, silicon oxide, silicon dioxide, silicon phosphate, silicon carbonate and composites and crystalline forms thereof.

10. A method according to any one of claims 4 to 9, wherein the metal comprises at least one metal selected from the group consisting of titanium, gallium, lithium, strontium, magnesium, copper, zinc, silver and a salt, mineral, or alloy of any of these metals.

11. A method according to any of the preceding claims, wherein the bioactive composite particles produced in step A) are formed from ceramic or silicon-based particles and are coated with a metal or polymer as defined in any of the preceding claims.

12. A method according to any of the preceding claims, wherein the bioactive composite particles produced in step A) contain at least one antibiotic selected from the group consisting of aminoglycosides, β-lactams, macrolides, cephalosporins, lincosamides, fluoroquinolones, glycopeptide antibiotics and lipopeptide antibiotics.

13. A method according to claim 12, wherein the antibiotic is selected from the group consisting of gentamycin, erythromycin, tobramycin, vancomycin and daptomycin.

14. A method according to any of the preceding claims, wherein the bioactive composite particles produced in step A) contain at least one chelating agent.

15. A method according to any of the preceding claims, wherein the bioactive composite particles produced in step A) contain at least one growth factor.

16. A method according to claim 15 , wherein the growth factor is selected from the group consisting of bone morphogenetic protein-2 (BMP-2), bone morphogenetic protein-7 (BMP-7), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), a protein from the transforming growth factor beta (TGF-β) superfamily and combinations thereof.

17. A method according to any of the preceding claims, wherein the bioactive composite particles produced in step A) contain at least one bioactive metal.

18. A method according to claim 17, wherein the bioactive metal is selected from the group consisting of silver, strontium, magnesium, lithium, gallium, copper, iron and a salt or alloy of any of these metals.

19. A method according to any of the preceding claims, wherein the bioactive composite particles produced in step A) are formed from ceramic or silicon-based composite particles coated with a metal or polymer using chemical or physical vapour deposition (PVD), electroplating, or dip coating.

20. A method according to any of the preceding claims, wherein the medical device has a tensile strength of greater than 15 MPa.

21. A method according to any of the preceding claims, wherein the medical device has a compressive strength of greater than 15 MPa.

22. A method according to any of the preceding claims, wherein composite pellets are produced in step A) prior to melting of the pellets and formation of the medical devices by moulding.

23. A method according to any of the preceding claims, wherein step B) comprises using a twin screw extruder to mix the polymer binder with the bioactive composite particles and to melt the polymer binder.

24. A method according to any of the preceding claims, wherein the medical device components comprise discrete units of compounded material.

25. A method according to claim 24, wherein the discrete units of compounded material comprise pellets of the compounded material.

26. A method according to any of the preceding claims, wherein the medical device is an orthopaedic or dental medical device.

27. A method according to any of the preceding claims, wherein the moulding is injection moulding.