Patent Application
20100234815
The present invention generally relates to medical devices having antimicrobial properties. More particularly, the present invention pertains to melt processable medical devices having antimicrobial properties and method of production thereof.
Medical devices are commonly used to facilitate care and treatment of patients undergoing surgical procedures. Examples of such devices include catheters, grafts, stents, sutures, and the like. Unfortunately, organisms such as bacteria and fungi may infiltrate and/or form biofilms on these medical devices which may be difficult to treat. Such contamination may lead to infections and cause discomfort or illness.
It is generally known that in various medical procedures, the use of medical devices having antimicrobial properties may reduce the incidence of infection in the patient. Typically, the antimicrobial agent is applied as a coating on the conventional medical device or the antimicrobial agent is infused into the conventional medical device by soaking the device in a solution of the antimicrobial agent. In these and other conventional methods of introducing the antimicrobial agent to the medical device, this extra step of coating or soaking takes time and increases costs.
In addition to the added step and increased production time, soaking and coating may not achieve relatively high concentrations of antibiotic in the base material of the medical device. For relatively short procedures having a duration of a few hours, this relatively low antibiotic concentration may be sufficient. However, for longer procedures lasting several days, the antibiotic present in conventional devices may be insufficient. As such, these conventional devices must be replaced frequently as the antibiotic falls below effective levels.
Accordingly, it is desirable to provide an antimicrobial medical device and/or method of introducing an antimicrobial agent to a medical device that is capable of overcoming the disadvantages described herein at least to some extent.
The foregoing needs are met, to a great extent, by the present invention, wherein in one respect an antimicrobial medical device and method of introducing antimicrobial agent to the medical device is provided.
An embodiment of the present invention pertains to a medical device having an antimicrobial agent. The medical device includes a base material and an amount of chlorhexidine or a pharmaceutically acceptable salt thereof disposed in the base material sufficient to reduce microbial growth. The base material has a melt processable temperature below a temperature at which the chlorhexidine is destabilized.
Another embodiment of the present invention relates to a medical catheter including an elongated hollow tube, an exterior surface of the elongated hollow tube including a base material, and a chlorhexidine/fatty acid salt being disposed in the base material. The base material has a melt processable temperature below a temperature at which the chlorhexidine/fatty acid is destabilized.
Yet another embodiment of the present invention pertains to a medical catheter including an elongated hollow tube, an exterior surface of the elongated hollow tube including a polyvinylchloride base material, and a chlorhexidine/fatty acid salt being disposed in the polyvinylchloride base material in an amount sufficient to reduce microbial growth. The base material is melt processed at a temperature less than about 165° C. together with the chlorhexidine/fatty acid salt to form the medical catheter which is substantially free of destabilized chlorhexidine.
Yet another embodiment of the present invention related to a medical catheter including an elongated hollow tube, an exterior surface of the elongated hollow tube including a polyurethane base material, and a chlorhexidine/fatty acid salt being disposed in the polyvinylchloride base material in an amount sufficient to reduce microbial growth. The polyurethane base material is melt processed at a temperature less than about 138° C. together with the chlorhexidine/fatty acid salt to form the medical catheter which is substantially free of destabilized chlorhexidine.
Yet another embodiment of the present invention pertains to a method of fabricating a medical device having an antimicrobial agent. In this method, a base material is melted and the antimicrobial agent is added to the melted base material in an amount sufficient to reduce microbial growth. The antimicrobial agent includes chlorhexidine or a pharmaceutically acceptable salt thereof. The medical device is formed with the melted base material together with the chlorhexidine and is substantially free of destabilized chlorhexidine.
Yet another embodiment of the present invention related to a method of fabricating a medical device having an antimicrobial agent. In this method, a polyvinyl chloride base material is melted at less than about 165° C. and the antimicrobial agent is added to the melted polyvinyl chloride base material in an amount sufficient to reduce microbial growth. The antimicrobial agent includes chlorhexidine or a pharmaceutically acceptable salt thereof The medical device is formed with the melted polyvinyl chloride base material together with the chlorhexidine and is substantially free of destabilized chlorhexidine.
Yet another embodiment of the present invention pertains to a method of fabricating a medical device having an antimicrobial agent. In this method, a polyurethane base material is melted at less than about 138° C. and the antimicrobial agent is added to the melted polyvinyl chloride base material in an amount sufficient to reduce microbial growth. The antimicrobial agent includes chlorhexidine or a pharmaceutically acceptable salt thereof. The medical device is formed with the melted polyvinyl chloride base material together with the chlorhexidine and is substantially free of destabilized chlorhexidine.
There has thus been outlined, rather broadly, certain embodiments of the invention in order that the detailed description thereof herein may be better understood, and in order that the present contribution to the art may be better appreciated. There are, of course, additional embodiments of the invention that will be described below and which will form the subject matter of the claims appended hereto.
In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of embodiments in addition to those described and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein, as well as the abstract, are for the purpose of description and should not be regarded as limiting.
As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.
Embodiments of the invention provide infection resistant medical devices and methods of melt processing a base material with a chlorhexidine to generate the medical device. In various embodiments, the base material is selected and/or modified to include a melt processable temperature that is below a degradation temperature of the chlorhexidine. More particularly, a chlorhexidine and/or a pharmaceutically acceptable salt thereof may be uniformly incorporated into medical devices by directly melt processing it with polymers without degrading the chlorhexidine. In this regard, chlorhexidine degradation products may cause irritation or other such negative reactions in patients. By avoiding the production of these irritants, relatively high concentrations of chlorhexidine such as, for example up to about 30% (wt. chlorhexidine/wt. polymer), may be incorporated into a bulk material of the medical device. In addition, it is within the purview of this and other embodiments of the invention that other suitable agents may be incorporated into the bulk material. Examples of suitable agents includes other antibiotics, antiseptics, chemotherapeutics, antimicrobial peptides, mimetics, antithrombogenic, fibrinolytic, anticoagulants, anti-inflammatory, anti-pain, antinausea, vasodilators, antiproliferatives, antifibrotics, growth factors, cytokines, antibodies, peptide and peptide mimetics, nucleic acids, and/or the like.
Medical devices suitable for use with various embodiments of the invention may include catheters, tubes, sutures, non-wovens, meshes, drains, shunts, stents, foams etc. Other devices suitable for use with embodiments of the invention include those that would benefit from having a broad spectrum of antimicrobial and antifungal activity. Suitable methods of processing chlorhexidine and its salts in accordance with various embodiments of the invention may include compounding, extrusion, co-extrusion, injection molding, blow molding, compression molding, or other such ‘hot melt’ process. Benefits of one or more embodiments of this invention are the ability to form a device and at the same time incorporate high loadings of chlorhexidine without destabilizing or creating chlorhexidine degradation products. In this regard, as used herein, the term, ‘destabilized’ chlorhexidine refers to degraded, inactivated, or otherwise compromised chlorhexidine.
Forms of chlorhexidine suitable for use with embodiments of the invention include chlorhexidine base, pharmaceutically acceptable chlorhexidine salts such as, for example, diacetate, laurate (dodecanoate), palmitate (hexadecanoate), myristate (tetradecanoate), stearate (octadecanoate) and/or the like. Other examples of suitable chlorhexidine salts are to be found in U.S. Pat. No. 6,706,024, entitled Triclosan-Containing Medical Devices, issued on Mar. 16, 2004, the disclosure of which is hereby incorporated in its entirety. In addition, while particular examples are made of chlorhexidine base, chlorhexidine diacetate, and chlorhexidine dodecanoate, embodiments of the invention are not limited to any one form. Instead, as used herein, the term, ‘chlorhexidine’ refers to any one or a mixture of chlorhexidine base, pharmaceutically acceptable chlorhexidine salts such as, for example, diacetate, dodecanoate, palmitate, myristate, stearate and/or the like. In general, suitable concentrations of chlorhexidine include a range from about 0.1% weight to weight (wt/wt) to about 30% wt/wt. More particularly, a suitable chlorhexidine range includes from about 3% wt/wt to about 20% wt/wt. Suitable base materials generally include pure and/orblended elastomers and/orpolymer materials having melt processable temperatures of less than about 165 degrees Celsius (° C.). More particularly, materials having a melt processable range of about 130° C. to about 165° are suitable. Specific examples of suitable base materials include polyurethanes, polyvinylchlorides, thermoplastics such as, for example, fluoropolymers, vinyl polymers, polyolephins, copolymers, and/or the like. In other examples, polymers that are typically processed at temperatures relatively greater than 165° C. may be modified to be melt processable at temperatures below 165° C. For example, the addition of plasticizing agents may suitably modify such polymers.
Polymer containing chlorhexidine may be layered upon other bulk material to fabricate the medical device. For example, a material having a melt processable temperature greater than 165° C. may be co-extruded with the polymer containing chlorhexidine.
As described herein, to validate some embodiments of the invention, we compounded several different polymers with various chlorhexidine salt combinations over a range of temperatures and allowed the blends to solidify. The chlorhexidine was then extracted using an organic solvent and analyzed for degradants by High Performance Liquid Chromatography (HPLC). Degradants were identified as new peaks in the chromatogram that were not present in a non-degraded control run under the same conditions. This method was used to identify upper processing temperature limits for stable melt processing of polymers such as polyurethanes and the like with chlorhexidine salts. We further performed our methods on a variety of commercially utilized polyurethanes and, surprisingly, observed that many of these commercial polyurethanes could not be melt processed below the upper processing limit. These unexpected results indicate that many commercially used polyurethanes were found to be unsuitable for stable melt processing with chlorhexidine.
In addition, our methods were utilized to define a processing temperature cut-off for vinyl polymers to enable stable melt processing with chlorhexidine. We found that many widely used vinyl polymers are not suitable for stable melt processing with chlorhexidine. Research performed according to embodiments of our invention further shows that, for the case of vinyl polymers, such as polyvinylchloride (PVC), the processing temperature can be lowered through the use of plasticizing agents to enable stable processing with chlorhexidine. The addition of plasticizing agents is generally associated with a corresponding reduction in mechanical properties. However, we found that by laminating relatively soft PVC with chlorhexidine over a more rigid polymer, via co-extrusion or co-molding for example, the material characteristics such as excessive softness or lack of structural rigidity of PVC with chlorhexidine may be overcome. Furthermore, in some medical devices, antimicrobial protection may be most beneficial when present at the surfaces of the device. Therefore, this laminated construction may be advantageously employed in medical devices where the soft, chlorhexidine containing layers are disposed at the surface or exterior and mechanically stronger or more rigid layers are disposed below or to the interior of the medical device.
Moreover, the methods of our invention were utilized to define a processing temperature cutoff for a thermoplastic polyolephin elastomer (TPE). Again, our unexpected results indicate that many TPEs are not suitable for stable melt processing with chlorhexidine. Surprisingly, the upper processing temperature limits for stable melt processing are different for each class of polymer evaluated. It is also possible that specific salts of chlorhexidine may have different upper stable processing temperature limits. Accordingly, utilizing the methods and algorithms described herein, the upper stable melt processing temperature for other chlorhexidines in combination with other polymer chemistries could be defined.
In the following experiments, the use of specific polymers Tecothane®-2095A (Lubrizol, Cleveland, Ohio), Tecoflex®-93A (Lubrizol, Cleveland, Ohio) thermoplastic polyurethane (TPU), polytetramethyleneoxide (PTMO) (INVISTA, Wichita, Kans.), Versaflex® CL30 (GLS Inc., McHenry, Ill.), and Polyvinyl chloride having a flexural modulus or hardness of about Shore 65A and about Shore 85A (Colorite Polymers, Ridgefield, N.J.) is specifically described. However, it is to be understood that any suitable polymer is within the scope of embodiments of this invention. Other suitable polymers include those manufactured by The Lubrizol Corp., Wickliffe, Ohio 44092, U.S.A., INVISTA S.à, r.l. Wichita, Kans. 67220, U.S.A., GLS Corp., McHenry, Ill. 60050, U.S.A., and Colorite Polymers, Ridgefield, N.J. 07657, U.S.A. These polymers may be utilized in pure forms or combined with any suitable copolymer. Examples of suitable copolymers include one or more of silicone, fluoropolymers, polyurea-urethane, polyether-urethane, and the like. In addition, the chlorhexidine diacetate (George Uhe, Garfield, N.J.), chlorhexidine dodecanoate (chlorhexidine laurate or chlorhexidine dilaurate) are specifically described. However, it is to be understood that any suitable chlorhexidine or salt thereof is within the scope of the embodiments of the invention. Other suitable chlorhexidine salts include chlorhexidine Myristate (chlorhexidine tetradecanoate), chlorhexidine palmitate (chlorhexidine hexadecanoate), chlorhexidine stearate (chlorhexidine octadecanoate), and various other chlorhexidines manufactured by the George Uhe Company Inc., Garfield, N.J. 07026 U.S.A.
Tecothane®-2095A was coated with 5% w/w polytetramethyleneoxide (PTMO) of molecular weight (MW)=1000 by mixing 45.1 gram (g) of PTMO with 900g Tecothane®-2095A. The PTMO coated resin and chlorhexidine diacetate were separately fed into an 18 millimeter (mm) Leistritz twin screw intermeshing extruder (Somerville, N.J.) from K-Tron feeders (Pitman, N.J.) at rates of 2.5 kilograms per hour (kg/hr) and 0.25 kg/hr, respectively. The extruder was set at 112 revolutions per minute (rpm) for screw speed and the barrel zone temperatures were set from 145° C. thru 178° C. The extrudate was pelletized into small pellets.
Low melting temperature Tecoflex-93A and chlorhexidine diacetate were separately fed into al 8 mm Leistritz twin screw intermeshing extruder from K-tron feeders at rates of 1 kg/hr and 0.1 kg/hr, respectively. The barrel zone temperatures were set at 121° C. for all zones. The extrudate was pelletized into small pellets.
15.1 g chlorhexidine base was slurried in 150 milliliters (ml) of isopropyl alcohol. 13.2 g of dodecanoic acid was added to the slurry (2.1 molar equivalents). The solution went clear initially and later precipitation occurred. Precipitate was rinsed with 100 ml isopropyl alcohol and filtered twice, after which it was vacuumed dried at 25° C. for 24 hrs. Yield was 88.7%.
Low melting temperature Tecoflex-93A and chlorhexidine dodecanoate were separately fed into an 18 mm Leistritz twin screw intermeshing extruder from K-tron feeders at rates of 1 kg/hr and 0.2 kg/hr, respectively. The barrel zone temperatures were set at 121° C. for all zones. The extrudate was pelletized into small pellets.
A three layer construct (chlorhexidine layer-gentian violet (GV) layer-chlorhexidine layer) 7 Fr single lumen tubing was co-extruded at temperature 121° C. Co-extruded tubing was also analyzed for chlorhexidine degradants.
Versaflex® CL30 and chlorhexidine diacetate were separately fed into an 18 mm Leistritz twin screw intermeshing extruder from K-tron feeders at rates of 2.5 kg/hr and 0.25 kg/hr, respectively. The barrel zone temperatures were set from 131° C. thru 148° C. The extrudate was pelletized into small pellets.
Separate samples of polyvinyl chloride (shore 65A and shore 85A respectively) and chlorhexidine diacetate were separately fed into an 18 mm Leistritz twin screw intermeshing extruder from K-tron feeders at rates of 2.0 kg/hr and 0.2 kg/hr, respectively. The barrel zone temperatures were set from 140° C. thru 155° C. The extrudate was pelletized into small pellets.
Chlorhexidine diacetate content of the prepared samples was extracted with 1:1 tetrahydrofuran (THF): H2O and analyzed on the Agilent Eclipse XDB-CN 5u 4.6×150 mm column with guard column. Briefly, 2 centimeter (cm) sample segments were extracted with 5 mL of THF and 5 mL of H2O, vortexed, and centrifuged. HPLC analysis was run on an Agilent Eclipse XDB-CN 5u 4.6×150 mm column and 4.6×12.5 mm Eclipse XDB-CN guard column, with a mixture of deionized water, acetonitrile, and trifluoroacetic acid as the mobile phase. Concentrations of the analytes were determined via calibration curves.
In the following Results section, a positive control showing high performance liquid chromatography analysis of non-degraded chlorhexidine is illustrated in
In addition to the experimental conditions described with reference to
As shown in Table 1, chlorhexidine extracted from the samples prepared as described in Example 1 was characterized by HPLC and summarized as percentages of each peak recovered. Three additional chlorhexidine degradants were detected at RRTs of 0.6, 1.3, and 1.6.
In addition to the experimental conditions described with reference to
As shown in Table 2, chlorhexidine extracted from the samples prepared as described in example 2 does not exhibit additional chlorhexidine degradation peaks for chlorhexidine diacetate in these samples. Accordingly, the stable processing temperature limit for chlorhexidine diacetate with polyurethanes appears to be about 137° C.
In addition to the experimental conditions described with reference to
As shown in Table 3, chlorhexidine extracted from the samples prepared as described in Example 3 does not exhibit additional chlorhexidine degradation peaks for chlorhexidine dodecanoate detected in these samples. Thus, the stable processing temperature limit for chlorhexidine dodecanoate with polyurethanes appears to be at least 136° C. to about 137° C.
In addition to the experimental conditions described with reference to
As shown in Table 4, chlorhexidine extracted from the samples prepared as described in Example 4 does not exhibit additional chlorhexidine degradation peaks for chlorhexidine diacetate in this sample. Thus, the stable processing temperature limit for chlorhexidine diacetate with polyurethanes appears to be at least about 135° C.
In addition to the experimental conditions described with reference to
As shown in Table 5, chlorhexidine extracted from the samples prepared as described in Example 5 did not degrade at a processing temperature up to 161° C. Versaflex CL30 is a mixture or alloy of polyolefins. These results show chlorhexidine is thermally stable at processing temperatures up to about 161° C. with polyolefin thermoplastic elastomers. These findings are unexpected and surprising in light of the relatively lower maximum processing temperature for polyurethanes. These finding indicate that the thermal stability of chlorhexidine is temperature and materials dependent.
In addition to the experimental conditions described with reference to
As shown in Table 6, chlorhexidine extracted from the samples prepared as described in example 6 did not degrade at processing temperatures up to approximately 165° C. PVC (60A & 85A) materials are mixtures or alloys of different polyvinyl chloride compositions. These results show chlorhexidine is thermally stable at processing temperatures up to approximately 165° C. with vinyl polymers. These findings are unexpected and surprising in light of the relatively lower maximum processing temperature for polyurethanes. These findings present further evidence that the thermal stability of chlorhexidine is temperature and materials dependent.
A significant benefit of various embodiments of the invention is the ability to fabricate a chlorhexidine laden polymer structure in a single step. That is, the subsequent processing to introduce antibiotic agents into the extruded or molded structure that is performed during the fabrication of conventional medical devices may be omitted. In so doing, time and money may be saved.
The many features and advantages of the invention are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the invention which fall within the true spirit and scope of the invention. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.
