Implantable medical device

Abstract

An implantable medical device, which comprises a device substrate, a coating on the substrate which includes a drug which is highly soluble in water, and a protective layer which overlies the coating. The protective layer comprises a polymer selected from the group consisting of polylactic acid, polyglycolic acid and a lactic acid/glycolic acid copolymer having a weight average molecular weight of not more than 40,000.

Claims

1. An implantable medical device comprising: an orthopedic device substrate having a surface; a coating on the surface of the substrate, wherein the coating consists essentially of a water soluble antibiotic drug, wherein the solubility of the drug, measured by making a saturated solution of the drug in deionised water at 25 C, is at least 40 g.Math.l.sup.−1; and wherein the water soluble antibiotic drug is present on the surface of the substrate in a dosage of at least about 250 μg.Math.cm.sup.−2; and, a protective layer which overlies the coating, the protective layer comprising a polymer having a weight average molecular weight of not more than 40,000 g/mol, wherein the polymer comprises polylactic acid, polyglycolic acid or a lactic acid/glycolic acid copolymer; wherein the thickness of the protective layer is not more than about 20 μm; wherein the device is configured to release at least 90% of the drug within 1 day; wherein the device is configured to contact bone; and, wherein the device is configured to control infection at an orthopedic surgical site.

2. The device of claim 1, wherein the weight average molecular weight of the polymer is less than 20,000 g/mol.

3. The device of claim 1, wherein the thickness of the protective layer is not more than about 15 μm.

4. The device of claim 1, wherein the thickness of the protective layer is not more than about 12 μm.

5. The device of claim 1, wherein the polymer is the lactic acid/glycolic acid copolymer wherein the molar ratio of lactic acid to glycolic acid is from 70:30 to 30:70.

6. The device of claim 1, wherein the water soluble antibiotic drug is present on the surface of the substrate in a dosage of at least about 400 μg.Math.cm.sup.−2.

7. The device of claim 1, wherein the water soluble antibiotic drug is present on the surface of the substrate in a dosage of at least about 1000 μg.Math.cm.sup.−2.

8. The device of claim 1, wherein the water soluble antibiotic drug comprises an aminoglycoside antibiotic.

9. The device of claim 8, wherein the water soluble antibiotic drug comprises gentamicin in the form of a salt with a strong acid.

10. The device of claim 1, which is a component of an orthopaedic joint prosthesis.

11. The device of claim 1, wherein the surface of the substrate on which the coating is provided is at least in part by a metal.

12. The device of claim 1, wherein the lactic acid/glycolic acid copolymer is a random copolymer of lactic acid and glycolic acid.

13. The device of claim 1, wherein the device is configured to release at least 90% of the drug within 16 hours.

14. The device of claim 1, wherein the device is configured to release at least 90% of the drug within 12 hours.

15. The device of claim 1, wherein an area of the surface of the device substrate covered by the coating is less than an area of the surface of the device substrate covered by the protective layer, and wherein at least a portion of the protective layer directly contacts the surface of the substrate.

16. The device of claim 1, wherein, the protective layer has a thickness in the range of about 5 μm to about 10 μm.

17. The device of claim 1, wherein the device is configured to release at least 90% of the drug within 8 hours.

18. The device of claim 1, wherein the device is configured to release at least 60% of the drug within 4 hours.

19. The device of claim 1, wherein the device is configured to release at least 60% of the drug within 3 hours.

20. An implantable medical device for controlling infection at an orthopedic surgical site and configured to contact bone comprising: an orthopedic device substrate having a metallic surface; a coating on the surface of the metallic substrate, wherein the coating consists essentially of gentamicin sulfate present on the surface of the metallic substrate in a dosage of at least about 400 μg.Math.cm.sup.−2 to not more than about 2000 μg.Math.cm.sup.−2; and, a protective layer having a thickness of less than 20 μm which overlies the coating, the protective layer comprising a lactic acid/glycolic acid copolymer having a weight average molecular weight of not more than 20,000 g/mol, and a molar ratio of lactic acid to glycolic acid of about 50:50; wherein the device is configured to release at least 60% of the drug within 3 hours; wherein the device is configured to release at least 90% of the drug within 24 hours; wherein the device is configured to contact bone; and, wherein the device is configured to control infection at an orthopedic surgical site.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is described below by way of example, with reference to the accompanying drawings, in which:

(2) FIG. 1 shows the amount of gentamicin sulphate that is released from coated titanium pins.

(3) FIG. 2 shows the result of a zone of inhibition test on a grit-blasted titanium coupon coated with one-step coating of gentamicin sulphate and PLGA 50/50, challenged with staph epidermis.

(4) FIG. 3a is an SEM image of the surface of an uncoated grit-blasted titanium surface.

(5) FIG. 3b is an SEM image of the surface of a grit-blasted titanium coupon with gentamicin and PLGA coating. This coupon has not been subjected to a heating step. It can be seen that the exposed surface of the protective polymer layer is uneven, with the thickness of the layer being greater in some areas than in others.

(6) FIG. 4 shows SEM images of the surface of grit-blasted titanium coupons which were coated, incubated in PBS for 24 hours, rinsed and dried. The coupon in FIG. 4a was coated with gentamicin/PLGA using the two-step coating method and no polymer underlayer. The coupon in FIG. 4b was undercoated with a 30 second spray of PLGA before coating using two-step process. The coupon in FIG. 4c was undercoated with a 60 second spray of PLGA before coating using two step process.

(7) FIG. 5 illustrates the effect on drug release rate of a variation in the thickness of the protective polymer layer.

(8) FIG. 6 illustrates the effect on drug release rate of a variation in the molecular weight of the polymer of the protective layer.

DETAILED DESCRIPTION OF THE INVENTION

Examples

Example 1

(9) The antibiotic coating and the protective layer are applied in two steps. By using a two-step method of coating it is possible to deposit a high dose of gentamicin but minimal amounts of polymer. Minimising the amount of polymer that could serve as a barrier between the surface of the implant and the newly-formed bone is extremely important in the optimal fixation of the polymer.

(10) The first step of the two-step method is the deposition of gentamicin. Here, the gentamicin is dissolved in water at a high concentration (e.g. 200 to 400 mg.Math.ml.sup.−1). The solution is filtered using a filter of appropriate size (for example about 2.7 μm) to remove insoluble impurities. This solution is transferred to the reservoir of an atomisation nozzle (such as that which is sold under the trade mark Tridek). An air source (or an inert gas such as nitrogen, argon, helium) as propellant is connected by tubing to the nozzle. The propellant is used to break up the fluid jet into droplets. The device to be coated can be stationary or fixtured to a rotating fixturing device.

(11) The reservoir pressure is set to 34.5 kPa (5 psi) and the nozzle pressure is set to 551.6 kPa (80 psi), and the distance between the nozzle and the substrate is set at 16 to 18 cm. The substrate is sprayed with the solution for 4 seconds. The substrate is air dried until it appears dry. The coating and drying cycle is repeated three times to achieve a target dose of drug on the substrate of 1 mg.Math.cm.sup.−2.

(12) The drug coated substrate is then coated with a copolymer of lactide and glycolide, which are present in the polymer in a mole ratio of 50:50. The copolymer was supplied by Purac. The polymer was dissolved in acetone to a concentration of 10% w/w.

(13) Once the gentamicin layer is finished the substrate can now be coated with a poly(lactide co-glycolide) layer. The purpose of the polymer layer is to prevent any loss of the gentamicin coating during shipping, handling, insertion, etc. A solution of the polymer is prepared by dissolving the polymer pellets in acetone to a concentration of 10% w/w. The distance between the nozzle and the substrate is about 6 to 7 cm and the flow rate is 4 ml.Math.hour.sup.−1. The substrate is grounded, and a potential difference is maintained between the nozzle and the substrate of about 9 to 12 kV. Spraying is continued for 60 seconds.

(14) Following polymer deposition further drying might be required in a drying oven. Subsequent to drying the coated device would be packaged shipped to sterilization facility. Sterilization would be accomplished by an appropriate method for orthopaedic devices.

Example 2

(15) A set of titanium coupons, each having a surface area of 5 cm.sup.2, were initially coated with gentamicin sulphate to the target dose of 1 mg.Math.cm.sup.−2. A subset of the coupons were randomly selected from these gentamicin coated samples for coating with the PLGA topcoat. The coated coupons were sterilised using gamma radiation.

(16) Analysis of elution rate of gentamicin in de-ionised water from the two types of coupons indicated a significantly larger amount of gentamicin sulphate was present on coupons that contained the protective top layer relative to those with no polymer top coat. For example, the total amount of gentamicin sulphate that eluted from two sets of coupons containing a topcoat was 4.9 and 6.9 mg, respectively. However, the total amount of gentamicin sulphate that eluted from coupons without the topcoat was only 3.3 and 3.6 mg, respectively. Analysis of the coupon surface after elution using FTIR and XPS indicated that no gentamicin sulphate remained after elution on the surface of the coupons. This data suggests the importance of the presence of the polymer topcoat. Coupons containing only the gentamicin coating can be envisioned as a donut with powdered sugar coating that can be shaken off during shipping and handling. The addition of the polymer topcoat fixes the gentamicin on to the surface of the coupon.

(17) Although many of the experiments that we have conducted on coated substrates have a concentration of gentamicin sulphate of 1 mg.Math.cm.sup.−2, this coating system is highly flexible providing doses as low as 0.01 mg.Math.cm.sup.−2 and doses that can exceed the mg.Math.cm.sup.−2 target. Providing the high dose of gentamicin sulphate in a discrete layer rather than dispersed within a polymer matrix results in a rapid burst release of the gentamicin. Ninety percent of the gentamicin sulphate is released within the first 24 hours after immersion into physiological media and another ten percent is released by 48 to 72 hours (see FIG. 1).

(18) In contrast, the release rate and bioefficacy of gentamicin sulphate was tested from coupons coated using a one-step coating where the gentamicin sulphate and the polymer are deposited together on the surface. Due to the incompatibility of gentamicin sulphate and PLGA only small concentrations of gentamicin can be made miscible with PLGA/organic solutions (ratio of gentamicin sulphate to PLGA is 1:10). Due to the inequality in ratio of drug to polymer a significant amount of polymer is deposited in order to achieve the target dose of gentamicin sulphate. This large polymer concentration results in a slow rate of release of the gentamicin sulphate, resulting in concentrations that are below the MIC. This is demonstrated during bioefficacy testing of the coupons in a zone of inhibition test. Within the first 24 hours of the test the release rate of gentamicin is so low that the bacteria can actually grow upon the surface of the coupon (FIG. 2).

(19) Another advantage of this two layer approach to the coating is that the polymer disappears quickly. This allows large areas of the specially engineered surface features to be exposed and available for osteoblast attachment. The length of time to achieve this virtually uncoated surface was tested. Titanium grit-blasted coupons were coated with gentamicin (1 mg.Math.cm.sup.−2) and top-coated with PLGA. The coupons were incubated in PBS overnight, rinsed and dried. After drying the surface of coupons was analysed with SEM. Over the 24 hours of incubation much of the coating was lost and large areas of the surface of the coupon were exposed. Data relating to the loss of the coating and exposure of the coupon surface are set out in FIGS. 3 and 4. Two other sets of coupons were prepared, one was first sprayed with low molecular weight PLGA for 30 seconds before applying the two-layer coat, the other was sprayed for 60 seconds before applying the two layer coat. Both sets of coupons were incubated in PBS, rinsed and dried as described above. SEM analysis indicates that increasing the amount of polymer that contacts the titanium surface results in much greater retention of the coating on the titanium surface after incubation (see FIG. 4).

(20) FTIR and XPS data confirm that no gentamicin remains on the surface following incubation and the patches of coating that remain on the surface are composed only of PLGA. Areas without patches were also analysed by FTIR and XPS and found to be titanium.

(21) The effect of the coating on osteoblasts was tested in vitro by plating MG63 (human osteosarcoma) cells on to the surface of uncoated titanium coupons, titanium coupons coated with polymer, and titanium coupons coated with the two step system. At specific time points the coupons were removed fixed and stained using Live/Dead assay. Samples were analysed using a confocal microscope. No significant difference in numbers of live cells was apparent between the uncoated, and two step system during the three days that the cells were tested.

Example 3

(22) The 2.54 cm diameter titanium coupons with a grit-blast finish were sonicated in isopropyl alcohol in a Branson ultrasonic bath for 60 minutes, then rinsed three times with de-ionised water and dried in an oven under 100° C. Coupons were weighed and recorded after drying. The rim area of the coupons were then masked using 1.9 cm O-rings with metal coupon holders.

(23) Gentamicin sulphate was dissolved in purified water to a concentration of 400 mg.Math.ml.sup.−1 and filtered through a 2.7 μm nylon syringe filter. The gentamicin solution was sprayed using a spray nozzle (as sold under the trade mark EFD 481). The processing parameters were: Needle stroke setting 4.9; Spray distance 17.78 cm; Propellant pressure 103 kPa (15 psi); Reservoir pressure 20.7 kPa (3 psi).

(24) The spray cycle was 4 seconds for 4 times with 60 second intervals. The coupons were air dried for 60 minutes then stored in a nitrogen box overnight. Coupons were un-masked then weighed for obtaining the gentamicin sulphate coating weights.

(25) A 50:50 PLGA, 0.20 IV polymer (estimated viscosity average molecular weight 16,500) was dissolved in acetone to a concentration of 100 mg.Math.ml.sup.−1. The solution was sprayed using an electrostatic nozzle (as sold under the trade mark Terronics Dart) with small setback on to the gentamicin-coated coupons. The processing parameters were: Spray distance 6.5 cm; Flow rate 4 ml.Math.h.sup.−1, Voltage 9 kV.

(26) Spray time was set for desired thickness. For example, 90 and 180-second were set to obtain 5.8 and 11.6 mg coating weights that yielded about 5 and 10 μm thickness respectively on each coupon.

(27) Additional samples were made using other materials, as follows. 75:25 PLGA 0.73 IV (estimated viscosity average molecular weight 126,000), 75:25 PLGA 0.23 IV (estimated viscosity average molecular weight 19,000), 50:50 PLGA, 1.0 IV (estimated viscosity average molecular weight 200,000).

(28) These materials were applied using a solution having a concentration, 20 mg.Math.ml.sup.−1. The flow rate and spray time were adjusted accordingly to obtain the desired drug dose on the substrate surface.

(29) The coupons were exposed to heat under vacuum in an oven. The sample made using 50:50 PLGA 0.2 IV for the protective layer was exposed to a temperature of 85° C. for 90 minutes. The samples made using the other protective layer materials were exposed to a temperature of 110° C. for 90 minutes. A comparison between the coupons before and after the heating step showed that the protective layer changed from a pre-heating state in which its thickness is variable, with regions in which the layer was undesirably thin and other regions in which the layer was undesirably thick, and yet other regions in which the drug coating was exposed, to a post-heating state in which it is continuous with a generally uniform thickness across the surface of the device.

Example 4

(30) The thickness of the polymer topcoat was calculated using coated polymer weight, the polymer density, and the coating area adjusted by the surface area indices (SAI), measured using an optical profiler (as sold under the trade mark Veeco Wyko NT9100) of both the gentamicin drug coating and the polymer protective layer.

(31) The coupons which were coated with 50:50 PLGA 0.2 IV, prepared by the process of Example 3, were individually placed in suitable polypropylene containers with the protective polymer layer facing upwards. 25 ml de-ionised water was supplied to each of the containers. The containers were placed into a oven, pre-heated to 37° C. The containers were taken out at the desired time points. An aliquot of the elution media was transferred to auto sampler vials for HPLC-CAD analysis. The gentamicin contents in the elution media were obtained by HPLC-CAD. The release percentages of the coupons were calculated via original weight of the coated gentamicin with the adjustment of the pre-determined moisture and potency.

(32) The gentamicin release rates were calculated over the time periods of 2 hours, 6 hours, 24 hours and 72 hours. It was found that increasing the thickness of the protective layer results in a slower release rate. It was found that increasing the molecular weight of the polymer of the protective layer results in a slower release rate.

Example 5

(33) The samples under elution study were taken out from the elution media at the desired time points. The dried samples were sputter coated with a thin layer of gold. The SEM analysis was performed using a scanning electron microscope (JEOL JSM-5900LV). Three separate regions approximately 30 mm.sup.2 were evaluated across the surface of the coupon. The images were captured using the standard SEM secondary electron image (SEI) detector and the back scattered electron image (BEI) detector. The BEI images clearly show exposed regions of the coupon surface as white dots in contrast to the darker polymer background. The proportion of remaining polymer was analysed using three BEI images for each coupon sample using Image Pro 6.2 software from MediaCybernetics.

(34) The gradual erosion of the 50:50 PLGA 0.2 IV thin layer coating has occurred from the coupon surface over the course of the 7 day elution study. The analysis indicated a 99.0% polymer area for the 2 hour elution sample in contrast with a 93.1% polymer area for the 7 day sample.

(35) The effects of thickness, PLGA molecular weight, and polymer composition after exposure to the elution solution for 7 days are illustrated in FIG. 6. The thin coating of 50/50 PLGA 0.2 IV material degraded more quickly than others. The thicker coating with the same materials retained more polymer coverage. The coating layer of the 50/50 PLGA 1.05 IV appeared to be intact after 7 days. The 75/25 PLGA with the same low IV but with higher L/G ratio also showed slower degradation.