WO2014152653A1 - Self sterilizing orthopedic implants - Google Patents

Abstract

Methods of post-charging ammonium ions into ceramic particles having antimicrobial metal cations are disclosed. In certain embodiments, the post-loaded particles are zeolites, wherein the zeolites have been incorporated into a resin and the combination is used as an implantable device. In certain embodiments, the polymer is a thermoplastic polymer such as polyaryletheretherketone (PEEK). In certain embodiments, the source of antimicrobial activity includes ion-exchangeable cations contained in a zeolite.

Description

SELF STERILIZING ORTHOPEDIC IMPLANTS

This application claims priority of U.S. Provisional Application Serial No. 61/782,719 filed March 14, 2013, the disclosure of which is incorporated herein by reference.

BACKGROUND

Incorporating silver zeolite, or other ceramic or glass carriers of antimicrobial ions, in PEEK or other thermoplastics is seen as a possible approach to fighting biofilm formation and infection in patients who require orthopedic or surgical implants. However, physiological fluids such as blood and interstitial fluids found in mammals inluding humans, contain about 0.8% sodium and potassium chlorides, which are dissociated in aqueous solution to Na⁺, K⁺ and CI^" ions. The presence of chloride ions in solution forces the formation of silver chloride which has very low solubility. Furthermore, since the chloride ion concentration in solution is much higher than the eluted silver concentration, by LeChatelier ' s Principle the solubility of silver chloride will be forced to much lower concentration than in aqueous media.

Since silver chloride has very low aqueous solubility, and since almost all the silver chloride is precipitated from solution and not available as Ag+ ions in solution, it will show much diminished antimicrobial activity. In such environments, 40 to 100 times more silver is required for antimicrobial efficacy. As a result, silver eluting implants, which are employed to reduce infection in orthopedic surgeries and similar applications, have shown disappointing efficacy in vivo compared to when the materials are evaluated in vitro. Although silver shows antimicrobial activity at as low as 20 ppb in aqueous media, the result is that the available Ag+ level will be too low to provide effective antimicrobial efficacy .

Furthermore, silver zeolite is a porous material and if silver chloride precipitates in the channels or pores in the zeolite, it can negatively impact any ion exchange reactions which are necessary for the release of Ag+ into solution.

Zeolite and silver zeolite are ion exchange media and can absorb ammonia for solution and gaseous media. Zeolite has been used as a scavenger for ammonia. It is considered useful to incorporate some ammonia into antimicrobial zeolites. However, in order to incorporate silver zeolite into thermoplastics such as PEEK for producing antimicrobial materials for applications such as spinal implants or other implantable orthopedic fixtures, it is necessary to heat the PEEK to its softening or melting point, which is about 350 to 400°C. At these temperatures and perhaps even as low as 200 °C, any ammonia which was present in the zeolite matrix will be driven off.

SUMMARY

The shortcomings of the prior art have been overcome by the embodiments disclosed herein, which relate to devices, such as surgical implants, having antimicrobial properties produced by an inorganic antimicrobial agent, and methods of post-loading ammonia into such devices. In certain embodiments, the devices are orthopedic implants. In certain embodiments, the antimicrobial agent is a ceramic species, preferably a metal zeolite. In certain embodiments, the device includes a polymer. In certain embodiments, the polymer is polyaryletheretherketone (PEEK) . In certain embodiments, the source of antimicrobial activity includes ion-exchangeable cations contained in a zeolite. In certain embodiments, disclosed are methods of imparting antimicrobial activity to devices by controlling the delivery of certain cations through ion-exchange via a zeolite incorporated in the device introduced in a patient. In certain embodiments, the metal cation is present at a level below the ion- exchange capacity in at least a portion of the zeolite particles.

Methods of post-charging ammonium ions into ceramic particles having antimicrobial metal cations are disclosed. In certain embodiments, the post-loaded particles are zeolites, wherein the zeolites have been incorporated into a resin and the combination is used as an implantable device. In certain embodiments, the polymer is a thermoplastic polymer such as polyaryletheretherketone (PEEK) . In certain embodiments, the source of antimicrobial activity includes ion-exchangeable cations contained in a zeolite.

In certain embodiments, the zeolite is incorporated into the device and surface exposed zeolite is charged with metal ions from one or more aqueous solutions as a source of one or more metal ions.

In certain embodiments, the zeolite is post-charged with ammonium ions. The device is introduced into the body surgically. The rate of release is governed by the extent of loading of the PEEK with zeolite and the extent to which the exposed zeolite is charged with metal ions. The electrolyte concentration in blood and body fluids is relatively constant and will cause ion exchange with ions such as silver, copper and zinc, etc. from the surface of the implant, which deactivate or kill gram positive and gram negative organisms, including E. coli and Staphylococcus aureus. Effective antimicrobial control (e.g., a six log reduction of microorganisms) is achieved even at low metal ion concentrations of 40 ppb .

In accordance with certain embodiments, a metal-containing zeolite in the exposed surface of a thermoplastic implant is charged with ammonium ions, such as from gaseous ammonia or solvent or aqueous media. Silver chloride is very soluble in ammonium hydroxide solution and ammonia acts as a complexant or carrier for silver ion in solution.

By post-loading the zeolite or ceramic carrier of metal ions such as silver with ammonia or ammonium ions, the solubility availability of Ag⁺ ions and the antimicrobial ions will be significantly increased. In contrast, were ammonia pre-loaded into the zeolite before processing into melted thermoplastics, it would be driven off at the high temperature necessary to melt the plastic.

DETAILED DESCRIPTION

One particular thermoplastic resin that has been found to be useful in an implant is polyetheretherketone (PEEK) . This thermoplastic polymer has an aromatic backbone, interconnected by ketone and ether functionality. PEEK is suitable for implants because its modulus closely matches that of bone, and is resistant to chemical and radiation damage. Grades of PEEK approved for implantation are very pure and inert and need to pass stringent cytotoxicity testing before being allowed to be implanted into mammals .

Other suitable resins include low density polyethylene, polypropylene, ultra high molecular weight polyethylene or polystyrene, polyvinyl chloride, ABS resins, silicones, rubber, and mixtures thereof, and reinforced resins, such as ceramic or carbon fiber-reinforced resins, particularly carbon fiber-reinforced PEEK.

The latter can be produced by dispersing the reinforcing material or materials (e.g., carbon fibers) in the polymer matrix, such as by twin screw compounding of implantable PEEK polymer with carbon fibers. The resulting carbon fiber-reinforced product can be used to direct injection mold final devices and near net shapes, or it can be extruded into stock shapes for machining. The incorporation of fibers or other suitable reinforcing material (s) provides high wear resistance, a Young's modulus of 12 GPa (matching the modulus of cortical bone) and providing sufficient strength to permit its use in very thin implant designs which distribute the stress more efficiently to the bone. The amount of reinforcing material such as carbon fiber incorporated into the resin such as PEEK can be varied, such as to modify the Young's modulus and flexural strength. One suitable amount is 30 wt% carbon fiber. The resins also can be made porous, such as porous PEEK, PAEK and PEKK, with suitable porosities including porosities between 50% and 85% by volume. Average pore size is generally greater than 180 microns in diameter, suitably between about 300 and about 700 microns. Porosity can be imparted using a pore forming agent such as sodium chloride, to create a porous polymer comprising a plurality of interconnected pores, by processes known in the art. Each of the foregoing can be formulated to contain suitable amounts of zeolite particles, usually about 20 wt %. An UHMWPE is preferred for the implant devices.

Metal zeolites can be used as an antimicrobial agent, such as by being mixed with the resins used as thermoplastic materials to make the implantable devices, or as coatings to be applied to the devices; see, for example, U.S. Patent No. 6,582,715, the disclosure of which is hereby incorporated by reference. The antimicrobial metal zeolites can be prepared by replacing all or part of the ion-exchangeable ions in zeolite with ammonium ions and antimicrobial metal ions. Preferably, not all of the ion-exchangeable ions are replaced. Suitable metal ions include silver, copper, zinc, mercury, tin, lead, gold, bismuth, cadmium, chromium and thallium ions, with silver, zinc and/or copper being preferred, and silver being especially preferred.

Either natural zeolites or synthetic zeolites can be used to make the zeolites used in the embodiments disclosed herein. "Zeolite" is an aluminosilicate having a three dimensional skeletal structure that is represented by the formula: ΧΜ2_/ηΟ·AI₂O₃ · YS1O₂ · Z¾0, wherein M represents an ion-exchangeable ion, generally a monovalent or divalent metal ion, n represents the atomic valency of the (metal) ion, X and Y represent coefficients of metal oxide and silica respectively, and Z represents the number of water of crystallization. Examples of such zeolites include A-type zeolites, X-type zeolites, Y-type zeolites, T-type zeolites, high-silica zeolites, sodalite, mordenite, analcite, clinoptilolite, chabazite and erionite.

Zeolites can be incorporated into masterbatches of a range of polymers. For final incorporation into PEEK, a masterbatch should be produced by incorporating typically about 20% zeolite. When provided in this form, the pellets of masterbatch PEEK containing the zeolite particles can be further reduced by mixing with more virgin PEEK at high temperature and under high shear. If metal were present in the zeolite, this would result in yet a second exposure to conditions which could cause deterioration of the product.

Typical amounts of zeolite particles incorporated in an implant resin range from 0.01 to 50 wt.%, more preferably 0.01 to 8.0 wt.%, most preferably 0.1 to 5.0 wt.%. If an implant is coated with a coating or resin which is loaded with zeolite, the coating needs to be applied and dried or cured before the infusion is carried out.

The method used to coat an implant is not particularly limited, and can include spraying, painting or dipping. When compounded into a

PEEK masterbatch, for example, the PEEK should be protected from sources of moisture and contamination prior to reduction with virgin resin. The compounding can be carried out by blending the molten masterbatch and let down resin under conditions of high temperature and high shear.

The masterbatch is a concentrated mixture of pigments and/or additives (e.g., zeolite powder) encapsulated during a heat process into a carrier resin which is then cooled and cut into a granular shape. Using a masterbatch allows the processor to introduce additives to raw polymer (let down resin) economically and simply during the plastics manufacturing process.

The amount of metal ions in the zeolite should be sufficient such that they are present in an antimicrobial effective amount. For example, suitable amounts can range from about 0.1 to about 20 or 30% of the exposed zeolite (w/w%) . These levels can be determined by complete extraction and determination of metal ion concentration in the extraction solution by atomic absorption.

Preferably the ion-exchanged antimicrobial metal cations are present at a level less than the ion-exchange capacity of the ceramic particles. The amount of ammonium ions is preferably limited to from about 0.5 to about 15 wt . %, more preferably 1.5 to 5 wt . %. For applications where strength is not of the utmost importance the loading of zeolite can be taken as high as 50%. At such loadings the permeation of metal ions can permeate well below the surface layer due to interparticle contact, and much greater loadings of metal ions are possible. The amount of zeolite incorporated into the resin should also be an amount effective for promoting antimicrobial activity; e.g., a sufficient amount so as to prevent or inhibit the growth of bacterial and/or fungal organisms or preferably to kill the same. Suitable amounts of zeolite in the resin range from about 0.01 to 50.0 wt.%, more preferably from about 0.01 to 8.0 wt.%, most preferably from about 0.1 to about 5.0 wt.%.

The absorption of metal ions into synthetic zeolites, or natural Zeolites, in an aqueous dispersion, or loaded in a polymer can be carried out from solutions of the metal salts. The rates of absorption will be proportional to the area of zeolite surface available, the concentration of metal ions in solution and the temperature. As the concentration of metal absorbed by the zeolite increases, the rate will be reduced. When the rate of absorption reaches the rate of release, equilibrium is reached at that solution concentration. A higher concentration in solution could drive the loading higher. Loaded zeolite can be rinsed with deionized water to completely remove adherent metal ion solution. The objective is to have only ion exchanged metal cations attached to the cage and these will only be removed by ion exchange, not by deionized water.

The most useful ions to incorporate, for the purposes of release into orthopedic implants, are silver, copper and zinc ions. All three have antimicrobial properties, silver being the most active.

There also may be synergies between the metals, in terms of antimicrobial activity. For instance, if a microorganism is developing resistance to one metal species, it may still be readily killed by one of the others. Copper and zinc ions also exert further functions in healing and wound repair and bone growth.

In accordance with certain embodiments, the metal zeolite containing resin is post-charged with ammonium ions. A suitable source of ammonium ions is ammonium nitrate (e.g., ammonium hydroxide added to nitric acid) . This type of solution can also carry silver ions as silver nitrate, copper ions as copper nitrate and zinc ions as zinc nitrate etc. Other suitable sources of ammonium ions include ammonium sulfate and ammonium acetate.

In certain embodiments, the step of adding ammonium ions can include the further addition of metal ions to the zeolite. For example, during the step of charging the zeolite with ammonium ions, the metal zeolite might lose some of the metal such as silver from the zeolite into the solution. Alternatively or in addition, a higher level of metal such as silver may be desired in the zeolite. In such situations, the addition of metal such as silver as silver nitrate can be added to the ammonium ion-containing solution. The solution can be adjusted to be in equilibrium with the silver eluting from the zeolite so that the loading remains constant. If the concentration in solution is increased further, then the level of metal such as silver in the plastic imbedded zeolite can actually be increased as the ammonium is being added, subject to their being free sites in the zeolite .

The post-charging can be carried out at ambient temperature, but temperatures up to 70°C are effective and may speed up the charging. Preferably it is carried out in a sealed container, as a sealed container is less likely to allow ammonia to evolve from the solution especially if the solution is heated. Agitation should enhance the adsorption rate as it will bring more cation in contact with the surface of the zeolite as it is being absorbed from solution. Agitation can be effected by any suitable means, such as by placing sealed jars on a shaker, preferably a heated tilting rocker table. Agitation can also be achieved by allowing jars to roll back and forth on a tilting rocker.

It is important not to go too high in solute concentration because of the danger of bridging the zeolite and blocking access to deeper sites in the zeolite.

It is also possible to have absorption of ammonia into zeolite from the gaseous phase. If the gas is under pressure, the rate of adsorption will be increased. Further, if the gas is heated and the pressure is maintained, the absorption rate will be increased. In such a process the system should be allowed to cool under pressure to minimize potential loss of ammonia from the zeolite matrix.

In accordance with certain embodiments, the zeolite-containing resin is brought into contact with an aqueous mixed solution containing ammonium ions and optionally containing metal ions such as silver, copper and/or zinc ions to cause ion-exchange between ion- exchangeable ions in the zeolite and the aforesaid ions. The contact between these ions may be carried out according to a batch technique or a continuous technique (such as a column method) at a temperature of from 10 to 70°C, preferably from 40 to 60°C, for 3 to 24 hours, preferably 10 to 24 hours. The pH of the aqueous mixed solution can be adjusted to 3 to 10, preferably 5 to 7. In certain embodiments, the pH of the ammonium solution is between about 5.5-6.7, and can be adjusted with nitric acid.

The content of the ions such as ammonium ions in the zeolite may properly be controlled by adjusting the concentration of each ion species (or salt) in the aforesaid aqueous mixed solution. For example, if the antibiotic zeolite of the invention comprises ammonium and silver ions, the zeolite having an ammonium ion content of 0.5 to 5% and a silver ion content of 0.1 to 5% can properly be obtained by bringing a zeolite into contact with an aqueous mixed solution having an ammonium ion concentration of 0.2 M/l to 2.5 M/l and a silver ion concentration of 0.002 M/l to 0.15 M/l. Moreover, if the zeolite further comprises copper ions and zinc ions, the zeolite having a copper ion content of 0.1 to 8% and a zinc ion content of 0.1 to 8% can properly be obtained by employing an aqueous mixed solution containing 0.1 M/l to 0.85 M/l of copper ions and 0.15 M/l to 1.2 M/l of zinc ions in addition to the aforementioned amounts of ammonium ions and silver ions.

In certain embodiments, the zeolite also may be prepared by using separate aqueous solutions each containing single different ion species (or salt) and bringing the zeolite into contact with each solution one-by-one to cause ion-exchange therebetween. The concentration of each ion species in a specific solution can be determined in accordance with the concentrations of these ion species in the aforementioned aqueous mixed solution.

After completion of the ion-exchange, the zeolite is washed with water sufficiently to remove adherent non absorbed metal ions, followed by drying.

The process of post-loading ammonia to the zeolite after the orthopedic implants are produced is also feasible where the PEEK is loaded with pure zeolite which is post loaded with antimicrobial metals after the implants are machined or molded.

In accordance with certain embodiments, the procedure can be carried out with solid or cast objects, such as implants, but also with fibers; for sutures; fabrics such as for use in filters, filter masks and meshes such as hernea meshes; and powdered plastics containing zeolite.

In certain embodiments, the surface of the object can be acid etched to increase the rate of ion exchange.

Example 1 .

About 5 grams of silver nitrate are dissolved in 250 ml of water in a 500 ml beaker. One gram of ammonium nitrate is added to the silver nitrate solution. The pH of the solution is checked and adjusted to pH 5 to 6 with dilute nitric acid.

Coupons of PEEK/zelolte type 4A composite which contain about 10% by weight of zeolite are introduced into the silver nitrate ammonium nitrate solution. The solution is placed under sufficient agitation to keep the coupons suspended in the solution. A temperature range from 25 to 50 °C is appropriate.

After 24 hours of agitation, the samples are removed from the solution, dried and rinsed with multiple rinsing of distilled water. Elution efficiency can be determined by extraction into 1% sodium nitrate solution and analysis by ICP OES.

Example 2.

Rods of PEEK, silver zeolite (Type 4A) composite, 25 mm in diameter, containing about 8% silver zeolite are cut into fine discs with a band saw. The coupons are immersed in a solution of about 5 grams of ammonium nitrate are dissolved in 250 ml of water in a 500 ml beaker. The pH of the solution is checked and adjusted to pH 5 to 6 with dilute nitric acid.

The discs are placed in the solution and agitated as before for 24 hours.

Example 3.

Rods of PEEK, silver zeolite (Type 4A) composite, 25 mm in diameter, containing about 8% silver zeolite are cut into fine discs with a band saw. The coupons are immersed in a solution of about 5 grams of silver nitrate are dissolved in 250 ml of water in a 500 ml beaker. One gram of ammonium nitrate is added to the silver nitrate solution. The pH of the solution is checked and adjusted to pH 5 to 6 with dilute nitric acid.

The discs are placed in the solution and agitated as before for 24 hours.

The added silver nitrate helps reduce elution of silver from the composite as the ammonia is being absorbed and can be used to actually increase the over all silver loading. Release of ammonia with silver ions will result in stabilization of the eluting silver with consequent greater stabilization and activity of the silver in physiological solutions.

Claims

What is claimed is:

1. A method of post-charging with ammonium ions a resin having metal-containing ceramic particles therein, comprising charging into said metal-containing ceramic particles ammonium ions.

2. The method of claim 1, wherein said ceramic particles comprise a zeolite.

3. The method of claim 1 or 2, wherein said metal-containing ceramic particles comprising cations are selected from the group consisting of silver, zinc and copper.

4. The method of claims 1 or 2, wherein said resin comprises PEEK.

5. The method of claim 1, wherein said charging with ammonium ions comprises exposing said resin having metal-containing ceramic particles to an ammonium nitrate solution.

6. The method of claim 1, further comprising forming said post- charged resin having metal-containing ceramic particles into an implant having a surface which contacts body tissue or fluid when implanted, and wherein at least some of said ceramic particles are present at said surface and capable or releasing said metal as ions in an antimicrobially effective amount .