Abstract:
A drug-eluting endocardial lead and method of manufacture. The silicone elastomer of the present invention is ideally suited to a manufacturing environment due to its extended pot life and decreased curing time. A preferred silicone elastomer is comprised of a multi-part mixture having at least a base portion and a curing portion. Additionally, since curing does not begin until the base and curing portions are combined, the mixing can be physically undertaken closer to the location of the endocardial lead and the curing “clock” does not start until the mixing occurs and external heat is applied. Since the silicone elastomer formed by base and curing components have improved the pot life and curing characteristics, the mixture is suitable for mixing with a steroid and then dispensing into an endocardial lead tip thus eliminating current design limitations imposed by current art while concomitantly minimizing manufacturing costs.

Description:
This application is a divisional of U.S. patent application Ser. No. 09/904,055, filed Jul. 11, 2001, titled “APPARATUS USING A SILICONE ELASTOMER AS A DRUG CARRIER IN A DRUG-ELUTING ENDOCARDIAL LEAD AND METHOD OF MANUFACTURE.” MANUFACTURE,” now abandoned. 

   FIELD OF THE INVENTION 
   The invention generally relates to implantable cardiac leads for use with devices such as pacemakers and implantable cardioverter/defibrillators (ICDs), and in particular, to such leads that controllably release a drug or steroid at the site of implantation of the lead&#39;s tip electrode. 
   BACKGROUND OF THE INVENTION 
   A dysrhythmia is an abnormal heart beat pattern. One example of a dysrhythmia is a bradycardia wherein the heart beats at an abnormally slow rate or where significant pauses occur between consecutive beats. Other examples of dysrhythmias include tachyarrhythmias where the heart beats at an abnormally fast rate, e.g., atrial tachycardia where one or more atria of the heart beat abnormally fast. It is well known to treat such dysrhythmias with a pacemaker, an implantable cardiac defibrillator (ICD), or the like which delivers electrical stimulation pulses through one or more electrodes proximate to the distal end of one or more leads implanted within a patient&#39;s heart, i.e., endocardial leads. Many types of endocardial leads are known but they generally fit into two broad categories, passive fixation leads that use tines or the like to affix to the traebaculae in the patient&#39;s heart and active fixation leads that typically have a screw-in helix that screws into the myocardium. In either case, the mechanical trauma of implanting the endocardial lead will generally result in some degree of inflammation due to, among other things, foreign body reaction that can adversely affect the primary purpose of the implantation, that being to cause the heart tissue to contract by applying electrical stimulating pulses to the heart tissue under the control of the pacemaker. The ability of a pacemaker/ICD to stimulate the heart tissue depends upon overcoming a cardiac pacing threshold. A threshold value is related to the minimum amount of energy contained in a stimulation pulse of known amplitude and duration that is capable of stimulating the heart tissue. Typically, the threshold energy value following implantation, i.e., the acute stimulation threshold, is generally higher and decreases during the first few weeks after implant to a more stable chronic stimulation threshold value. It is well known that an endocardial lead can be made to elute a steroid, e.g., dexamethansone sodium phosphate or glucocorticosteroid, to reduce the amount of inflammation resulting from the implant and thus improve the capability of the pacemaker to stimulate the cardiac tissue with a decreased amount of energy, a limited resource in an implanted device. Accordingly, the battery life and the time between implants of a pacemaker/ICD will normally be extended. 
   Typically, the steroid is eluted from an endocardial lead electrode that contains a monolithic controlled release device (MCRD), in the form of a plug that is made of a mixture of a steroid, e.g., dexamethansone sodium phosphate, or equivalent, and a medical adhesive as a carrier for the steroid. The currently known and used medical adhesive/steroid combinations have limitations that add to manufacturing costs. Typically, the pot life, i.e., the time before the viscosity of the combination makes it difficult to handle (e.g., dispense, inject or spread), is relatively short, e.g., only about 10 minutes. Thus, the pot life limits the capability to mass-produce leads by dispensing or injecting the mixture into a completed or partially completed lead. In contrast, the curing time is typically relatively long, e.g., up to 24 hours. Accordingly, to accommodate for these characteristics, monolithic controlled release device (MCRD) plugs are typically manufactured outside the lead and inserted into the lead as an additional manufacturing step. To manufacture these plugs, a mixture is formed and rapidly (within the pot life limitation) spread over and into multiple cavities in a mold. Typically, the mixture is then cured in an oven at an elevated temperature, e.g., 50° C., for 2 hours and then air cured for an additional 8 hours. After curing is completed, e.g., 10 hours later, the cured plugs are extracted from the mold and subsequently inserted into the partially manufactured lead. This process typically results in a substantial waste of the steroid mixture (the portion that is not actually inserted into the mold cavities) as well as increasing manufacturing delays (due to the curing time), production steps, and the costs associated with each of these deficiencies. Therefore, it is very desirable to have a composition and process for forming a monolithic controlled release device (MCRD) that reduces these material and production costs. Accordingly, the present invention is directed to remedying the deficiencies of the prior art. 
   SUMMARY OF THE INVENTION 
   The present invention relates to a drug-eluting endocardial lead that includes a drug dispenser at the leads distal tip. The drug to be dispensed is intended to significantly reduce cardiac tissue inflammation at the distal tip&#39;s implant site. The drug includes a steroid and is mixed with a silicone elastomer to facilitate manufacture of the lead especially during application of the drug to the lead. The drug carriers of the prior art typically include a medical adhesive that begins to cure as soon as it is exposed to air and has a relatively short pot life and relatively long curing time. The silicone elastomer of the present invention is more ideally suited to a manufacturing environment due to its extended pot life and decreased curing time. A preferred silicone elastomer comprises a multi-part mixture having at least a base portion and a curing portion. Additionally, since curing does not begin until the base and curing portions are combined, i.e., mixed, the mixing can be physically undertaken at the location of final assembly of the lead and the curing time “clock” does not start until the mixing occurs. Since the silicone elastomer formed by the base and curing components has improved pot life and curing characteristics, this mixture is suitable for mixing with a steroid and insertion into an endocardial lead, with the advantage of minimizing manufacturing costs. 
   A preferred monolithic controlled release device (MCRD) mixture for use in a drug-eluting endocardial lead to facilitate the controlled release of a drug to cardiac tissue comprises a mixture of a drug component that reduces inflammation of cardiac tissue and a silicone elastomer for carrying the drug component, wherein the silicone elastomer is comprised of a base component and a curing component. 
   In a further aspect of the present invention, the drug component includes a steroid, e.g., dexamethansone sodium phosphate, or equivalent. In a still further aspect of the present invention, the drug component is formed by mixing the drug, such as, dexamethansone sodium phosphate, with a wetting fluid such as silicone fluid prior to mixing with the silicone elastomer to facilitate mixing. 
   A preferred method for forming a monolithic controlled release device (MCRD) mixture for use in a drug-eluting endocardial lead comprises the steps of (1) forming a mixture of a drug and a silicone elastomer for carrying the drug, wherein the mixture is comprised of at least three components, a base component and a curing component for forming the silicone elastomer and a third component containing the drug to be released to the cardiac tissue, (2) dispensing the mixture into a portion of the endocardial lead, and (3) allowing the mixture to cure in place in the endocardial lead. In a further aspect of the preferred method, the curing time of the mixture is decreased by elevating the temperature of the mixture to at least 55° C. In a still further aspect of the preferred method, the third component is formed by mixing the drug, e.g., dexamethansone sodium phosphate, with a silicone fluid to facilitate mixing with the base and curing components, which form the silicone elastomer. 
   Other aspects, features, and advantages of the invention will be apparent from the detailed description, which follows in combination with the attached drawings. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  shows a simplified diagram of the apparatus of the present invention for forming a mixture of a drug, e.g., a steroid, and a silicone elastomer and subsequently dispensing the mixture into a plurality of endocardial leads. 
       FIG. 2  shows a simplified flow chart of the process used in forming, dispensing and curing the drug-eluting mixture into an endocardial lead. 
       FIG. 3  shows a curing jig used for accepting beads of a mixture of the drug and the silicone elastomer and curing the mixture prior to slicing the cured monolithic controlled release device (MCRD) mixture into plugs for insertion in an endocardial lead. 
   

   DETAILED DESCRIPTION OF THE INVENTION 
   The following description is of the best mode presently contemplated for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be determined with reference to the claims. 
     FIG. 1  shows a simplified diagram of the apparatus  10  of the present invention for forming a mixture of a drug, e.g., a steroid, and a silicone elastomer and subsequently dispensing the mixture into a plurality of endocardial leads. Although not shown in detail, the leads  34  and  34 ′ illustrated in  FIG. 1  represent implantable cardiac pacing leads, such as endocardial leads well known in the art. As was previously mentioned and also known in the art, upon implant of the lead in the heart, the heart tissue in contact with the leads distal tip electrode may become inflamed. Heretofore, many attempts have been made to abate the inflammation at the implant site immediately upon implant. These attempts include placing a monolithic controlled release device (hereinafter just “MCRD”) mixture in the leads tip electrode that comes in contact with the cardiac tissue. The efficacy of such MCRD mixtures is of course dependent upon the constituent parts or ingredients comprising the MCRD. The present invention attempts to greatly improve the efficacy of inflammation-reducing drugs with a new compound and method of manufacture that is intended among other things to be used in conventional cardiac pacing leads. Each of the leads contemplated for use with the present invention includes a chamber for housing a drug dispensing means either in the form of a MCRD containing plug or a porous electrode at the leads distal tip. 
   The silicone elastomer contemplated for the present invention is formed by mixing and curing multiple components, including at least a base component  12  and a curing component  14 . This silicone elastomer is used as a carrier for a drug  16 , which is concurrently mixed with the base  12  and curing  14  components. Initially, the base component  12  is loaded into container A  18 , the curing component  14  is loaded into container B  20  and the drug  16  is loaded into container C  22 . The three components are fed, preferably with the assistance of pumps  24 ,  26 ,  28  to a first mixer  30 , e.g., a static mixer, where they are combined into a drug/carrier mixture  31 , i.e., a monolithic controlled release device (MCRD) mixture. (The mixing process can be further improved with the use of additional components, as discussed further below.) The MCRD mixture  31  (in a pourable form, e.g., 0–2000 poise, until the curing process completes) is then fed into a suitable dispenser  32 , such as a needle or equivalent, from which it is dispensed, either by injection or by forming droplets of the mixture into the distal end of an endocardial lead  34 . Due to the large pot life, e.g., 1 hour or more, the mixture may be dispensed into a plurality of such leads  34 . Accordingly, a plurality of leads  34  may be held by a curing jig  36  (described further below) and the dispenser  32  (or optionally the whole apparatus  10 ) may be repositioned so that the MCRD mixture  31  can be dispensed into a plurality of leads  34  within the pot life time. Alternatively, one of ordinary skill in the art will readily recognize that the curing jig  36  may be repositioned relative to the dispenser  32  to accomplish the same function. This repositioning can be done via computer numerical control (CNC) type means (not shown) well known in the art, e.g., servo motors, stepper motors, hydraulics, pneumatics, etc. 
   Once the MCRD mixture  31  has been formed and dispensed, the curing process begins. If left at room temperature, the curing process would take approximately 24 hours. However, elevating the temperature of the MCRD mixture  31  will significantly decrease the curing time and, accordingly, the manufacturing process time. Preferably, the temperature of the MCRD mixture  31  is elevated by heating at least the distal end of the leads  34  to a temperature between 40° C. and 75° C., preferably about 55° C. At the preferred temperature a curing time of approximately 2 hours is anticipated, while at 65° C., the curing time can be further decreased to approximately 1 hour. 
   To elevate the temperature, a heater controller  38  is used to heat the curing jig  36  (preferably metallic) via a heater  40  and preferably under feedback control of a temperature sensor  42 . The operation of such a heater controller  38 , e.g., a pulse interval derivative (PID) controller, is well known in the art. Depending upon the selected curing temperature, the MCRD mixture  31  is cured within the endocardial lead in approximately 1 to 2 hours. 
   In a preferred variation of the aforedescribed process, a wetting fluid  44 , placed in container D  46 , is premixed with drug  16  (typically in a powder form) by a second mixer  48  to form a premixed fluid drug component that will mix easier with the base  12  and curing  14  components in the first mixer  30 . Additionally, it is preferred that this premixed fluid drug component be fed via pump  28  to a third mixer  50 , e.g., a static mixer, where it is mixed with the base component  12  before the curing component  14  is mixed in at the first mixer  30 . 
   Apparatus  10  may be used with active fixation leads  34  or may be used with passive fixation leads lead  34 ′. In the case of the active fixation leads  34 , the dispenser  32  is repositioned relative to each lead  34  and the MCRD mixture  31  is either injected or droplets are dripped into the distal tip  52  of the lead  34  and cured in a chamber  54 . In the case of a passive fixation lead  34 ′, the MCRD mixture is preferably injected, e.g., via a syringe type nozzle at the end of the dispenser  32  into a chamber  54 ′ through the distal tip  52 ′ of each lead  34 ′. The MCRD mixture  31  is then cured in the chamber  54 ′. Alternatively, a plurality of electrode tip portions  56 , e.g., ones with sintered porous tips, may be positioned in the curing jig  36  and droplets  58  of the MCRD mixture can be dripped into the backside of the electrode tip  56  and cured. Following curing, the distal electrode tip  56  may be attached, e.g., welded, to the rest of the lead  34 ′ via conventional means. In each of these cases the MCRD mixture  31  cures into a plug  59  within the chamber  54 ′ and thus does not require a separate manufacturing insertion step as is typically found in the prior art. Furthermore, there is little waste and many such leads can be manufactured in a single operation. Accordingly, the material and manufacturing costs are reduced from that typically found in the prior art. 
   Various materials can be used in the above process. The currently preferred combinations (Drug  16  is dexamethasone sodium phosphate in each of these cases) are described below: 
   
     
       
             
             
             
           
         
             
                 
             
             
               Base Component 12 
               Curing Component 14 
               Fluid 44 
             
             
                 
             
           
           
             
               1. From Dow Corning: 
                 
                 
             
             
               MDX4-4210 
               Platinum catalyst 
               360 Medical Fluid 
             
             
               (dimethylsiloxane 
               10:1 by weight 
               colorless and 
             
             
               polymer and a 
                 
               odorless 
             
             
               reinforcing silica) 
                 
               polydimethyxiloxane 
             
             
                 
                 
               fluid 
             
             
               2. From Nusil: 
             
             
               MED-4211 or 
               Platinum catalyst 
               MED 360 
             
             
               MED-4210 
               10:1 by weight 
               dimethylpolymer 
             
             
               3. From Applied 
             
             
               Silicone: 
             
             
               40072 or 
               Platinum catalyst 
               40047 or 
             
             
               40029 or 
               10:1 by weight 
               40073 or 
             
             
               40082 
                 
               40074 or 
             
             
                 
                 
               40104 or 
             
             
                 
                 
               40098 
             
             
                 
                 
               medical grade 
             
             
                 
                 
               MDM 
             
             
                 
                 
               silicone fluid 
             
             
                 
             
           
        
       
     
   
     FIG. 2  shows a simplified flow chart of the process used in forming, dispensing and curing the MCRD mixture into an endocardial lead  34 . Initially in steps  60 ,  62 ,  64  and  66 , containers  18 ,  20 ,  22  and  46  are filled with the base component  12 , the curing component  14 , the drug component  16 , and the fluid component  44 , respectively. Next, in step  68 , the drug and fluid, e.g., wetting fluid, are mixed using the second mixer  48 . This wetted drug mixture is then mixed in step  70  with the base  12  and curing  14  components using the first mixer  30  and dispensed in step  72  used the dispenser  32 . Optionally, the wetted drug mixture is first mixed with the base component  12  using the third mixer  50  before mixing with the curing component in the first mixer  30 . Finally, the temperature of the dispensed MCRD mixture  31  is elevated in step  74  to reduce the curing time. 
   While the invention has been described by means of specific embodiments and applications thereof, it is understood that numerous modifications and variations could be made thereto by those skilled in the art without departing from the sprit and scope of the invention. For example, while dexamethasone sodium phosphate is the preferred steroid drug to be used in forming the MCRD, other drugs and steroids could also be used, e.g., glucocorticosteroid. Furthermore, while the disclosed composition is particularly suitable for eliminating manufacturing steps, its improved curing properties can also be beneficially used to more quickly generate externally molded plugs for later insertion into endocardial leads. For example as shown in  FIG. 3 , the dispenser  32  may be used to dispense beads of uncured MCRD material  31  into one or more grooves  80  on a heated curing jig plate  82 . Once the beads are cured, the MCRD material may be sliced into plugs and inserted into endocardial leads as in the prior art. However, this process will still be completed in less time and with less waste. Alternatively, any curing jig having a plurality of curing cavities may be used. It is therefore to be understood that within the scope of the claims, the invention may be practiced otherwise than as specifically described herein.