JPH07509735A - System for controlled release of antiarrhythmic drugs - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to controlled release dosage forms for site-specific release of therapeutic agents, and more particularly, to controlled release dosage forms for site-specific release of therapeutic agents. or administer antiarrhythmic drugs directly through the myocardium, either alone or in combination with cardiac rhythm control devices. and its preparation and use. Description of the Prior Art Life-threatening cardiac arrhythmias are a medical problem faced by millions of people every day. Irregularity Pulse is the leading cause of death from myocardial infarction in hundreds of thousands of other people. In addition, cardiac arrhythmias Pulse disease complicates 173 to 1/2 of the more than 300,000 open heart surgeries performed in the United States each year. The term "cardiac arrhythmia" is used in this field in -a, and here refers to abnormal heart rhythm conditions, specifically ventricular arrhythmia, ventricular fibrillation, supraventricular arrhythmia, such as atrial fibrillation, atrial flutter, supraventricular tachycardia, multifocal atrial tachycardia, junction tachycardia, etc. include. Hundreds of people suffering from abnormal heart rhythms are currently being treated with oral medications. Examples of frequently prescribed oral antiarrhythmic medications are digitalis, digitoxin, and procainamide. Lidocaine, or other antiarrhythmic drugs such as amiodarone, are given intravenously. Traditional drug treatment is limited to where and/or where the drug is needed. Because of inadequate drug concentrations when needed and the adverse side effects of drugs, they are often ineffective in preventing or treating life-threatening ventricular arrhythmias. In addition to drug treatment, many patients each year now receive intracardiac electronic pacemakers such as automatic defibrillators/cardiodefibrillators or implantable devices for severe cardiac dysfunction. I have a countershock device.However, I do not have an electronic pacemaker or There are several important issues with the surgical implantation and subsequent maintenance of countershock and implantable countershock devices. In particular, the required current is lower and the epitome used is It would be desirable to increase the functionality of the above device so that the number of swords can be reduced. What courage do you need? ! ! Lowering the current increases battery life and facilitates miniaturization. -H, patients with implanted countershock devices also receive antiarrhythmic drug therapy to prevent arrhythmias. However, most of the drugs administered systemically with these devices have no real effect on lowering the ventricular defibrillation threshold. Recently, open surgery and catheterization techniques have been developed to destroy sensitive myocardial tissue. However, this was not particularly effective. Therefore, drug treatment, pace Manufacturer implants, surgeries may be used to prevent and/or suppress cardiac arrhythmias. It has only a partial effect. A sustained, site-specific cardiac drug release system provides bioprotein therapy to prevent bacterial endocarditis. It has been developed to prevent heart valve calcium deposition and fibrous tissue formation. Thyroid and adrenal medullary myocardial autografts are recognized as “endocrinological cardiac pacemakers” was studied. Myocardial implantation of silastic reservoirs containing a variety of compounds, including digoxin, isoproterenol, and thyroid hormones, allows for the release of chronotropic drugs. Drug delivery is also underway. All of the above drugs can effectively promote heart rate when delivered directly to the myocardium. Although these methods have been used to stimulate and control heart rate through transmyocardial drug administration, there are no examples in the prior art of treating ventricular or atrial arrhythmias through transmyocardial administration of antiarrhythmic drugs. do not have. There is no disclosure in the prior art of lowering the defibrillation threshold in the event of life-threatening fibrillation or increasing resistance to the development of this condition by intramyocardial administration of antiarrhythmic drugs. Additionally, none of the above polymeric devices can be manufactured with specific dosage release characteristics. stomach. In the treatment of certain medical conditions, such as acute arrhythmias, rapid release of antiarrhythmic drugs immediately after implantation followed by slow sustained release is clearly advantageous. It is therefore an object of the present invention to provide bio-based or artificial polymeric materials that are compatible with body tissues and that incorporate therapeutic agents, such as antiarrhythmic drugs, for the treatment of heart rhythm disorders. It is to serve. It is a further object of the present invention to provide a biocompatible polymeric matrix containing an antiarrhythmic agent that can be applied directly to the heart muscle via the epicardium, endocardium, or pericardium. The present invention provides a method for making a biocompatible polymeric matrix containing an antiarrhythmic drug that can selectively alter the release properties of the antiarrhythmic drug. A further object of the invention is that it can be applied directly to the heart muscle in conjunction with a cardiac rhythm control device to increase the effectiveness of the rhythm control device and/or to suppress the occurrence of dysrhythmias. The present invention provides a biocompatible polymeric matrix containing anti-arrhythmic straw. SUMMARY OF THE INVENTION The above and other objects are achieved by the present invention which provides a combination for controlling heart rhythm in a patient. According to the present invention, the device includes electrodes for transmitting electrical signals to and from the patient's heart. In one embodiment of the present invention, the implantable controlled release dosage form delivers a therapeutically effective amount of an antiarrhythmic agent to the heart of a patient, the substrate formed from a biocompatible polymeric material has at least one Incorporating various antiarrhythmic drugs I'm reading. In a preferred embodiment, the biocompatible polymeric material is polyurethane, polyurethane, Lydimethylsiloxane, ethylene/vinyl acetate copolymer, polymethacrylate methacrylate polyamide, polycarbonate, polyester, polyethylene, polypropylene polystyrene, polyvinyl chloride, polytetrafluoroethylene, or vinegar synthetic non-biodegradable polymers such as acid cellulose. Of course, the polymeric matrix material can be a mixture or copolymer of two or more biocompatible polymers. In another embodiment, the biocompatible polymeric material is collagen, polylactic acid-polyglyceride, Cholic acid, or a biodegradable polymeric material such as a polymeric anhydride. The incorporated antiarrhythmic drug can be a therapeutic agent or a combination thereof that has an effect on heart rhythm disorders. In certain embodiments, the antiarrhythmic agent is a cardiac stimulant such as isoproterenol, dopamine or norepinephrine, or docaine. In another advantageous embodiment, the antiarrhythmic drug can be a cardiac depressant such as Can be a lucium channel blocker, verapamil, or diltiazem Ru. In an advantageous embodiment of the pond, and especially in an embodiment for use with a cardiac rhythm control device, The antiarrhythmic drugs include amiodarone, altilide, ibutilide, sotalol or or a time-extending agent such as cloylium. fruit of desire In embodiments, the antiarrhythmic agent comprises about 5-40% by weight of the substrate. In some embodiments, pharmacologically inert fillers or cocipients, such as antiarrhythmia Dosage release characteristics can be adjusted by adding polyethylene glycol, inulin or dimethyl tartrate, which have a water solubility different from that of the pulse drug. Wear. Anionic tartrates form cation-anion pairs with cationic antiarrhythmic drugs. Pharmacologically inert fillers are useful for slowing down the rate of release. selected from the group consisting of Nurin, polyethylene glycol, and dimethyl tartrate. In order to deliver antiarrhythmic drugs via the myocardium, the substrate is placed directly into the patient's heart. suitable for direct application. The term "transmyocardial delivery" refers to delivery to the heart muscle and specifically includes contact with the epicardium, endocardium, and 6 membranes. An implantable device can be any form that can be attached to the heart muscle in some manner, such as a film patch, coated electrode wire, or a fixable catheter tip. In some implementations, the tt pole is equipped with tissue fixation means for fixation to live heart tissue, such as a conical tip. In some embodiments of the invention, the electrode further comprises a pacing electrode. In still other embodiments, the electrodes are used to detect predetermined conditions in the patient's heart. It has a sensor at the end. The electrodes include multiple defibrillator/cardioverter defibrillator m poles. You can Like the top sheet, the substrate may be in the form of a film, and in some embodiments the substrate It may be fixed to the pole. This membrane has a thickness of the order of 20 Hm-1 cm, preferably about 200 rtm. Alternatively, the membrane may be a multilayer membrane. In other embodiments, the substrate is a heart-contacting molded member attached to an electrode means. drug release properties can be achieved. Treatment of biological heart rhythm disorders is based on polymeric matrices containing the desired antiarrhythmic drug. It consists of controlled-release delivery of an antiarrhythmic drug directly to the epicardium or endocardium using an implantable device consisting of a gasket. According to further aspects of the invention, a cardiac rhythm control device includes a cardiac contact for transmitting electrical signals to the heart, and a controlled release dosing device for controlled release of an antiarrhythmic drug. shift the position. According to the method of the present invention for treating cardiac rhythm disorders in a living body, a polymeric matrix containing a therapeutically effective amount of at least one antiarrhythmic drug is used to treat cardiac rhythm disorders. A step of placing the control device in direct contact with the epicardium or endocardium of a living heart is provided. According to this method of the invention, the cardiac rhythm control device is an implantable cardioverter-defibrillator device. In certain embodiments, the cardiac rhythm control device is an implantable pacemaker. Further, according to the method of the present invention, the drug contains a therapeutically effective amount of at least one antiarrhythmic drug, which is desired as a time-extending agent, to treat or prevent ventricular or atrial fibrillation or ventricular tachycardia in a living body. A method is provided that includes placing a polymeric matrix containing a cardiac rhythm control device in direct contact with the epicardium of a living heart. BRIEF DESCRIPTION OF THE DRAWINGS The purpose, features, and advantages of these and other features are illustrated in the accompanying drawings and in FIG. Expressed as cumulative % release over time (minutes). T22 is a graph illustrating the long-term release characteristics of docaine-polyurethane matrices prepared according to the present invention, expressed as % cumulative release versus time (days). FIG. 3 is a graph showing the long-term release characteristics of glue docaine-polyurethane prepared according to the present invention at various drug content ratios (lidocaine weight; polymer precursor storage weight) as cumulative % released versus time (days). It represents. FIG. 4 is a graph illustrating the short-term release characteristics of a docaine-polyurethane matrix prepared in accordance with another embodiment of the present invention in which the matrix mixture is compression molded, expressed as cumulative % release versus time (minutes). FIG. 5 is a graph showing the long-term release characteristics of a docaine-polyurethane matrix manufactured by another method of the present invention in which the matrix mixture is compression molded. Expressed as cumulative % free over time (days). Figure 6 shows the present invention in which the matrix mixture is solvent cast from a dimethylacetamide solution. 1 is a graph showing the long-term release characteristics of a lidocaine-polyurethane matrix prepared according to another embodiment of the present invention, expressed as cumulative % free versus time (days); Figure 7 shows tachycardia induced with ouabain followed by docaine prepared according to the present invention. - Shows an electrocardiogram of a dog in which a polyurethane batch was applied directly to the epicardial left ventricular myocardium. FIG. 8 is a graph showing the relationship between tested lidocaine plasma levels and time when transmyocardial delivery is performed via a lidocaine-polyurethane patch according to the present invention. FIG. 9 is a graph showing the relationship between the test-type transcardiac plasma level and time in the case of intravenous porous administration of transcardiacine corresponding to the transcardiac dosage shown in FIG. 8. Figure 10 shows the controlled release lidocaine-polyurethane matrix (28% weight) of the present invention. Weight: 44 mg, 5 mm x 5 mm (epicardial batch) 2 is a graph showing the difference between the coronary venous blood level and the systemic blood level of an antiarrhythmic drug when revalidation is performed. Figure 11 shows that ibutilide polyurethane releases about 30% of the antiarrhythmic drug from the polyurethane matrix at once and at a reduced rate in the first 15 minutes. It is a graph showing a rhethane matrix. FIG. 12 shows a polyurethane polyurethane containing an inert cocibient dimethyl tartrate. Figure 2 is a graph showing the in vitro release of anti-arrhythmic drugs from Tan Matrix. FIG. 13 is a graph showing VERP in lns as measured by epicardial and ventricular III electrodes placed near the ibutilide-containing matrix. Figure 14 shows Ibuchirai measured by an extracardiac mus placed near the matrix. Figure 15, which is a graph showing the effect of a doped polyurethane matrix on the activation time (in milliseconds), shows the effect of a 2-2-2O monophasic pulse of energy measured in Joules. 3 is a graph showing the success fl rate of defibrillation by an implantable cardiac defibrillator when the implantable cardiac defibrillator is used. FIG. 16 is a graph showing the defibrillation threshold when a monophasic pulse is applied to the i sound before administration of 0.025 mg/kg of ibutilide. FIG. 17 is a graph showing the defibrillation threshold when 0.0025 mg/g of ibutilide is applied with a pre-projection biphasic pulse. FIG. 18 shows an ibutilide polyurethane matrix containing an inert cosibilant. FIG. 3 is a diagram showing the relationship between the applied biphasic pulse (joules) and the fibrillation conversion % when a box is used on the epicardium. Figure 19 shows the croylium-polymers when a biphasic pulse is applied from a cardiac defibrillator. It is a graph showing defibrillation of urethane batch. Figure 20 shows that a matrix containing sotalol or ibutilide (<0.025 mg/kg) was placed in the outer thigh as shown in the figure, and then the activation was measured from electrodes placed at various distances. 21 is a graph showing the variation in time (in milliseconds). FIG. 21 schematically depicts an embodiment of an atrial pacing electrode of the present invention having a multilayer butyride-containing polyurethane coating. FIG. Demonstrates the long-term in vitro release characteristics of dip-coated wire. This graph is expressed as cumulative % free versus time (days). FIG. 23 is a bar graph showing the reduction in atrial flutter induction by the ibutilide polyurethane coated atrial electrode of the present invention. FIG. 24 is a schematic illustration of a pacing transvenous defibrillator catheter having a shaped annular conical tip made in accordance with the present invention. Figure 25 shows the in vitro release rate of molded annular conical tips of the type shown in Figure 24. This graph is expressed as cumulative % free versus time (days). FIG. 26 shows defibrillation performed using a pacing transvenous defibrillator catheter manufactured in accordance with the present invention. This is a graph showing success probability. DETAILED DESCRIPTION A novel controlled release dosage form for the treatment of cardiac arrhythmias is described below. In this case, at least A substrate consisting of a polymeric matrix containing a therapeutic agent is placed in direct contact with the heart muscle. Is the tachycardia a normal sinus? 1 to quickly convert Directly to the area where it is needed

[: To elute or diffuse. Direct contact of the dosage form with the cardiac muscle at the epicardium or endocardium, or in some cases through the heart, is hereby referred to as is called “peak myocardial release.” A particular advantage of the new dosage form is that the transmyocardial release is local or This is because the dosage of antiarrhythmic drugs used for local or local treatment is small, and when administered systemically in sufficient dosage to produce a therapeutic effect. Polymer matrix materials that can reduce common side effects include, for example, Synthetic products such as urethane or dimethylpolysiloxane (Silastic). Controlled-release dosage forms for transmyocardial delivery are designed to withstand the strong mechanical effects of the heart. As such, the synthetic polymeric matrix material is preferably flexible, elastomeric, and of high tensile strength. In this regard, polyurethane and Chylpolysiloxane is ideal. High molecular weight polyurethanes (e.g. 40° o oo-so, ooo daltons) may have some desirable properties such as an overall negative surface charge. For sustained release with favorable surface properties, negative surface charges are advantageous as they bind well to cationic antiarrhythmic drugs (see Figure 2). In particular embodiments, hydrophilic polymers such as polyurethane are preferred when rapid release of the antiarrhythmic drug is desired, converting life-threatening arrhythmias to normal rhythms as quickly as possible. Other examples include, but are not limited to, ethylene/vinyl acetate copolymers, polymetallic Methyl acrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene hydrophilic or hydrophobic biocompatible polymers such as cellulose acetate or cellulose acetate. In another example, protein-rich collagen, polylactic-polyglycolic acid, or Biobased polymers such as synthetic anhydrides are suitable polymeric matrix materials. In certain situations, such as short-term arrhythmias associated with cardiac surgery, biodegradable polymer matrices Ricks has the advantage. This is a sustained drug delivery – over a period of time, the drug is reabsorbed by the body. This is because On the other hand, for chronic recurrent arrhythmias, non-degradable and/or refillable or renewable systems, such as hollow polymeric reservoirs, may be more appropriate. currently widely used for heart rhythm disorders and suitable for inclusion in the controlled release dosage forms of the present invention. Two commonly used treatments are lidocaine and amiodarone. lidoka In, a highly effective antiarrhythmic drug typically administered intravenously, this drug It is used at different times due to the adverse side effects that occur. Amiodarone is administered orally. However, more than 70% of patients who receive it experience severe side effects. The controlled release dosage forms of the present invention were formulated to contain antiarrhythmic drugs from the four recognized classes of antiarrhythmic drugs (Vaughan-Williams classification). Some examples are shown below. Class I Sodium channel blocker Class II β-adrenergic blocker Drug properties Class III Prolonger of action Class IV Calcium channel blocker Withdrawal of nickel chloride For example, lidocaine is a heart depressant. Other visceral stimulants, such as i-noproterenol, dopamine, and norepinephrine, can also be included in the polymeric polymer class in accordance with the principles of the present invention, and in some cases (secondary, i. [This is an example of a combination of one or more myocardial agents.] - The zycoquine/quinidine family used in the treatment of atrial fibrillation. However, antiarrhythmic agents, or drugs suitable for administration with antiarrhythmic agents, and It is to be understood that any combination of agents falls within the concept of the present invention. Therefore, as used herein, "antiarrhythmic agents" are defined as drugs whose mechanism of action follows one or more of the four pairs of Vaughan-Willia + ns, or which have therapeutic effects on cardiac arrhythmias in other ways. List drugs or combinations of drugs that can be used to treat or control cardiac arrhythmias. To facilitate elution from polymeric matrix materials in the presence of body fluids, Preferably, the arrhythmic drug is provided in an aqueous form, such as lidocaine hydrochloride. Controlled release dosage forms can be placed by a cardiac catheter with a removable tip, by 6-membrane puncture, or directly onto the heart muscle during open heart surgery. Three forms of substrates for cardiac use are: epicardial designs for direct application to the heart surface in the form of polymeric films/patch (see Figure 7);5 polymer-coated wires (see Figure 21). or hard, threaded polymeric structures. For intravascular placement with a cardiac catheter, a removable threaded catheter tip or a fixed, pointed tip may be used. An umbrella system (see Figure 24) is cited as an example of the many possible configurations that can be devised by those skilled in the art. A separate configuration for placement into the myocardium through a wound made with a sharp trocar can also be devised. Techniques such as film casting and compression molding can It can be applied to the production of discrete substrate forms of controlled release dosage forms. The form is chosen depending on the type of arrhythmia condition being treated; batch dosage forms are To avoid post-operative arrhythmia, it is best to place the heart epicardially or endocardially during open heart surgery. A dosage form in the form of a well-fitting, removable, threaded catheter tip can be used to prevent cardiac arrhythmias secondary to myocardial infarction. Additionally, as one skilled in the art will appreciate, anti-arrhythmia Certain pulse medications are more suitable for chronic arrhythmias than acute arrhythmias; Drugs such as Mido or Sotalol are the drugs of choice for inclusion in controlled free dosage forms for use in chronic arrhythmia conditions. The dosage form can be a unitary drug/polymer matrix, such as a true or implantable device in which laM occurs by diffusion. In another embodiment, a reservoir drug release system can be devised. For example, a polymeric matrix material is shaped to form a hollow core reservoir with an inlet for refilling (see Example 17). Regardless of the shape, the dosage forms of the present invention should preferably have a smooth surface that is non-porous and virtually free of pinholes to prevent thrombus formation and cellular ingrowth. Ru. In particular, fibrotic or endothelial cell ingrowth interferes with the efficient release and metabolism of antiarrhythmic drugs. Inclusion of anticoagulants such as heparin in the polymer matrix can minimize thrombus formation. This new dosage form can replace or replace existing oral or intravenous antiarrhythmic treatments. provides an important aid. Additionally, the dosage form can be used as part of procedures such as coronary angiography, angioplasty, routine cardiac surgery, catheterization, and clinical electrophysiology studies. In addition, dosage forms such as those described here may be used to prevent pacemaker implantation. It can also provide additional drug therapy or increase the efficiency of an implanted automatic cardiac defibrillator/cardioverter defibrillator. There are various techniques for incorporating therapeutic agents into the polymeric material matrix of the controlled release dosage forms of the present invention. Common methods include: 1. The therapeutic agent is mixed with the polymer precursor prior to solid state polymerization so that the therapeutic agent is incorporated as a member of the polymerizable mixture. Examples 1 and 2 are examples of this method. 2. Dissolve the polymerized matrix material in an organic solvent. Dissolve the therapeutic agent in the desired weight ratio. The therapeutic agent must also be soluble in the same organic solvent so that it can be added directly to the dissolved polymeric matrix material. The mixture is then poured into a mold or as a film (solvent casting) and the solvent is allowed to evaporate. Examples 3 and 4 are examples of this method. 3. Grind or mix the fully polymerized matrix material with the therapeutic agent and A blend is formed, then a catalyst is added and polymerized. Examples 5 and 6 are examples of this technique. An advantageous feature of the present invention is that the rate and duration of drug release is controlled by process variables. This means that it can be adjusted accordingly. Depending on the formulation of the polymer matrix, duration can vary from minutes to years. Parameters that can be varied to control release rate include particle size of the therapeutic agent, interruption of the polymerization process by agitation, compression molding, and polymerization temperature. The individual examples below demonstrate the effect of varying some of these variations. The results are shown graphically in Figure 1-6. In other embodiments, a pharmacologically inert cocivient is added, as described in Example 14, Formulation 14b, and illustrated graphically in FIG. The release rate is changed by In yet another embodiment, the morphology that confers voluptuousness can affect the rate of drug release, as shown graphically in FIG. 22. The release profile of the drug-polymer combination can also be made to respond to feedback signals. For example, electroresponsive acrylamide containing cation exchange resins By creating polymers or silicone rubber, they can deliver more medication when an arrhythmia is detected and adjust it downward when the abnormal rhythm stops. The electrically responsive embodiments described above are particularly useful in combination with cardiac rhythm control devices. It is for use. Some specific examples of biocompatible controlled release dosage forms and methods of making the same according to the present invention are provided below. Experiments demonstrating the effectiveness and advantageous characteristics of the dosage form in vitro and in vivo conditions. Also include test results. Although Examples 1-5 primarily relate to the production of polymer matrices incorporating the antiarrhythmic drug lidocaine, the techniques described herein are applicable to the creation of a wide variety of other drug/polymer combinations and devices constructed therefrom. Applicable. Additional examples (Examples 6-17) demonstrate that controlled release dosage forms in accordance with the principles of the present invention were prepared incorporating antiarrhythmic drugs from all four classes of antiarrhythmic drugs. ``One voice''. T ecofl ex 2-80A (Thersedic Inc.) consisting of about 1 to 4 parts of docaine hydrochloride (particle size 75 to 150 μm), 0.21 parts of diisocyanate monomer and 0.79 parts of polyether monomer. , 10 parts of polyurethane prepolymer available from Woburn, MA) to form lidocaine-polyurethane. A rethane matrix was produced. In the lidocaine/polyurethane example, the prepolymerized polyurethane component is In the presence of about 20% by weight or more of the lythmic drug, it will not react to form a polymer. However, FeCl, catalyst and slow curing at low temperatures result in the formation of stable polymers. one Generally from 0.1 μM to 1.0 μM per g of polyether monomer. O/JM FeCl3 is effective in providing practical polymer structures with drug contents up to 4o% w/w. Advantageously, the resulting antiarrhythmic drug-polymer matrix exhibits an accelerated initial rate. The antiarrhythmic drug is released at a slow rate and then at a sustained, slow, diffusion-limited rate. accelerated In the specific embodiment of Example 1, which is particularly advantageous for the treatment of acute arrhythmia disorders, 1,0174 μM FeCl/g polyether monomer was added as a catalyst. The mixture was then cast as a film approximately 200 μm thick and cured at 55° C. for 48 hours. Of course, the film thickness can vary; in practice, the film thickness ranges from about 20 μm to 1 cm; the degree of polymerization and time also range from about 24 hours to 3 days at about 50-60°C, respectively. be able to. a) 28% W/W lidocaine-containing polyurethane manufactured by the technology of LILI & fN1 Cumulative in vitro drug release of the matrix was monitored spectrophotometrically by absorbance at 260 nm. Redundant sink 11 fluid samples were taken over time and data were expressed as the average of two measurements. The complete sink sanitation solution consisted of 0.54 M K2PO, aqueous elutriate, at a pH of 7.4 and a temperature of 37°C. Figures 1 and 2 show the results of certain process variations to the method of Example 1 that affect lidocaine release. The process variations were (1) polymerization at 55°C as described in Example 1, and (2) an additional step in reaction time of 2 hours of agitation of the polymerization mixture (long chain polymerization and prior to crosslinking). ), and (3) polymerization at room temperature (see Figure 1). and short-term release characteristics are shown graphically as a plot of cumulative % release versus time (minutes). Line 1 is the release of the matrix formed by the method described in Example 1. Line 2 shows the process variation (2) above, and line 31 shows the process variation (3) above. FIG. 2 is a graph showing the long-term release characteristics as a percentage of cumulative release versus 1vl (B). Lines 1-3 show the release characteristics of the matrices formed according to processes (1)-(3), respectively. In vitro results show that variations in process parameters influence the drug release characteristics of drug/polymer matrices. In contrast to the polyurethane system of Example 1, the use of a higher molecular weight polyurethane with polymeric segments resulted in a product that was more linear and therefore more capable of retaining drug over time. In other experiments, the effects of various drug content ratios were tested in vitro. Figure 3 shows the lidoka 1 is a graph showing the long-term release properties of the Douin/Polyurethane Mado I7 class with different weight ratios of Ine to polyurethane. The data were obtained by spectrophotometric absorbance measurements and are expressed as % cumulative release versus time (days). The specific specific gravity tested was 2:10.3:10.4; The release rate profile consisted of an initial rate that was higher than the long-term diffusion tube rate. Furthermore, as the drug concentration increases, the initial rate increases, but the diffusion-limited delivery rate remains the same. Built. However, after about 2 hours, when the long chain polymerization was essentially complete, but before crosslinking, in this particular example, the reaction mixture was briefly agitated for 5 minutes. This mixture was then compression molded under 8-10 tons/in². The in vitro long-term and short-term release characteristics of the resulting dosage forms are shown in Figures 4 and 5 as a function of cumulative % release over minutes and days, respectively. Compression molding significantly improves release rates due to solvent casting techniques. A lidocaine-polyurethane matrix combination was prepared. The fully polymerized polyurethane was dissolved in an organic solvent to form a clear solution. Desired amount of glue Caine was added to this solution. The solution was then cast as a 2-4 mm thick film. FIG. 6 is a graph showing the long-term release characteristics of the solvent cast dosage form made according to this example. It is f. This in vitro experiment was conducted at pH 7.4 as described in Example 1. Comparing the results in Figure 2 with the results in Figure 6, it can be seen that the solvent-based technology allows for greater sustained release of therapeutic agents. Using the pear polymer matrix, which has been found to cause threshold lengthening, effective transcardial administration of lidocaine was demonstrated by placing the matrix batch directly onto the epicardium of the canine heart. The following experiment was carried out using the control fabricated by fNl. Uabai by myocardial implantation of controlled-release lidocaine-polyurethane matrix system Details of suppression of ventricular tachycardia induced by ventricular tachycardia. b) Ventricular tachycardia was induced by ouabain administration according to the method described in the article by Kniffen et al., C1rculation, Vol. 49, p. 264, 1974. uttered. Ouabain is used in therapy for its rapid digitalis saturation effect. It is a visceral glycoside. The experiment involved 14 male mongrel dogs, each weighing between 12 and 14 kg. I was reading. Sig+++a Inc,,St. Ouabain, obtained from Louis, Mo., was administered at an initial dosage of 40 μg/kg at a rate of 40 LLg/min, then in three equal doses until sustained ventricular tachycardia was demonstrated on the electrocardiogram. The left thoracotomy of each patient was performed to induce ventricular tachycardia with ouabain administration. See Figure 7. Then, a polymer batch 30 having dimensions of 3 cm x 3 cm x 2 cm is attached to the epicardial left ventricular myocardium of the heart 31, approximately 1 to 2 cm to the left of the anterior descending coronary artery and approximately 1 to 2 cm below the circumflex coronary artery. Ta. FIG. 7 is an example of an electrocardiogram obtained as a result of this experiment. The electrocardiographic tube is single with standard surface limb leads, and atrial and ventricular leads. Recordings from limb leads are shown in 11 and 12, and atrial and ventricular movements are shown in 13 and 14, respectively. Normal regulation of ventricular tachycardia after placement of lidocaine-polyurethane matrix The conversion to law is indicated by arrow 10. For each person, lidocaine-polyurethane TrixBatch 30 was placed on the left ventricular myocardium for the time necessary to convert the ventricular tachycardia to normal sinus rhythm. Once normal rhythm is restored, the wandering bar will be released after 1 minute. Experiments were continued to remove the trigger and detect the return of the induced arrhythmia. Some dogs received only the polyurethane patch as a control. As shown in Table 1, controlled release drug delivery of docaine from a polymeric matrix applied directly to the ventricular myocardium was performed. Lee converted ouabain-induced ventricular tachycardia to normal rhythm in all experiments. In the tables, times are indicated by standard error of the mean. Table 1 Middle]-Ko-1ll IT! −−−Le・−寥一町−暉−−−轡一控〜−Time (minutes) – Initial Final stage Polyurethane 4/4 4/4 >60 Lido'b-in/piece 0 Li 6/6 0/6 1.5 ± 0.77 urethane lithocain / ho1no O / 6 3 / 8 15.0 ± 25.0 urethane Removal of polyurethane and docaine-polyurethane matrices, as well as for cases of ventricular tachycardia. Results for the time range shown are for three animals. The remaining three animals remained in normal rhythm for more than 60 minutes. In control batch animals, ventricular tachycardia persisted for more than 60 minutes without recovery of normal rhythm. The lidocaine-polyurethane patch was 1.5±0. Ventricular tachycardia was converted to normal tachycardia in 77 minutes. Studies analyzing plasma levels of lidocaine in dogs have shown that myocardial application of lidocaine-polyurethane patches can be administered intravenously in porous doses and as rapidly as docaine. Although the therapeutic effect was rapid, lidocaine levels were lower when compared to plasma levels as measured by high-performance liquid chromatography (see Figure 8). Plasma levels are shown as the average of two experiments of plasma levels in 6 dogs and A time-dependent attenuation of lidocaine after muscle lidocaine-polyurethane treatment has been shown. For comparison, Figure 9 shows the plasma levels of two dogs after intravenous administration of lidocaine at dosages of 24 mg/kg and 45 mg/kg. Silence The intravenous dosing level was chosen to correspond to approximately the same dosing level as the myocardial delivery achieved with the polymeric patch as determined by the following method. That is, the residual drug remaining in the polymer matrix after in vivo use is extracted with Soxhlet methanol, and then filled. Prepacked C18 column (particle size 5 μm), A Itex ultrasphere - OD S 25 cm X 4. 6mm T,D, (Beckman Inc, San Ramon, CA), 0.7% v/v triethylamine/acetic acid. pl with tonitrile (50:50)! 3.0 of 0.1M sodium phosphate i? was determined by high performance liquid chromatography utilizing a Waters, Model 16000A system (Waters, Bedford, Mass.) with an isocratic mobile phase. Absorbance was monitored at 210 nm. The above experimental results demonstrate that transmyocardial site-specific drug release is an effective route for antiarrhythmic therapy. Direct placement of lidocaine-polyurethane release matrices into the myocardium rapidly converted induced arrhythmias to normal rhythms in all experimental animals in approximately 1.5 minutes, whereas controls did not induce two consecutive ventricular tachycardias within 60 minutes. I did it. Site-specific treatment was as rapid as intravenous projection, but with lower risk for comparable dosages. produced plasma levels of docaine. In studies involving epicardial and transmyocardial delivery of docaine-containing polyurethane batches in dogs, net dosages of between 19 mg/kg and 45 mg/kg of lidocaine were delivered. However, plasma levels of lidocaine were 8.75-25A1g/ml for the controlled release dosage form of the present invention, compared to 36.7-1012μg/ml for intravenous administration of comparable dosages. So Therefore, placing the dosage forms described herein directly into the myocardium is a Alleviates the bad side effects of anti-arrhythmic drugs. Example 4 Using various solvents including chloroform, methylene chloride, and ethyl acetate, Lidocaine was incorporated into the ethylcellulose matrix by surgery. , Ridokai The content ratio was 2]0. Completely polymerized Silastic 382 (trademark of Dow-Corning, Maryland, MI) was blended with docaine to form Silastic I made lidocaine in Kumatrix. This blend was polymerized by addition of tin(II) octoate catalyst. Example 6 An isoproterenol-polydimethylsiloxane matrix dosage form was prepared and It was found that it gave effective results. Prepolymerized polydimethylsiloxane (PDMS) is mixed with powdered isoproterenol (5-20% by weight based on the weight of PDMS). Knead to form a blend. This blend was then catalytically polymerized by heat or by the addition of chemicals such as tin(II) octoate or platinum oxide. Antiarrhythmics from the four Vaughan-Williams classifications of antiarrhythmic drugs Controlled release matrices with pulse drugs were formulated with various polymeric matrices. A specific example follows. lidocaine, pro-inamide, encainide, fluoride Common sodium channel blockers, such as Recanide, are shown in Examples 1-5 above. Example 7 According to the method of Example 3, a class II (β-adrenergic blocker) antiarrhythmic drug, propranolol, was added to various polymeric matrix materials, especially M 1 tralthane MPU-, in amounts up to 30% w/w. 5 (a polyurethane available from Symbion, Denver. Co.) or Biomer (a polyurethane available from Ethicon, Somerville, NJ). Built into the tongue. Class III antiarrhythmic drugs that extend the duration of action are specified. A specific example is shown by Amiodan (available from Wyeth, Philadelphia, PA). Amiodarone was incorporated into a polyurethane matrix by the method of Example 3. More specifically, amiodarone was dissolved in dimethylacetamide to form a solution with a concentration of 100 mg/m of therapeutic agent. This solution was co-treated with 10% polyurethane (Thyomer, Therapeutics, Inc., Woburn, Mass.) with polyethylene glycol (PEG200, I), MD, MI) as a 10% co-cipient. Dissolved in solution. This solution was solvent cast into 0.2 mm membranes and used in the studies reported in Table 2. Polyethylene glycol is an amino acid from a polyurethane matrix. Facilitate the release of Daron. In addition to amiodarone, altylide was added to polyurethane by the solvent casting technique of Example 3. incorporated into a lethane matrix. Altilide is structurally sotalol and ibutira. It is a class III antiarrhythmia drug related to the immune system. Like ibutilide, alutilide does not block beta-adrenergic receptors and other drugs such as sotalol It has an ionic mechanism different from that of last-in-one drugs, which extends its action time and therapeutic properties. Another class III antiarrhythmic drug, d-sotalol (Bristol-Meyers Quibb, Wallingford, CT), was added to a polyurethane according to the procedure of Example 3. ) and used in the large study reported in Table 3. In another embodiment, d-sotalol was dispersed in a paste silicone rubber (Silastic Q 7-4840.1:1) to form a composite. In a specific example, the composite was pressed at 2000 pounds per square inch for one minute in a stainless steel slab. Shrunk. The compressed composite was cured at 37°C for 24 hours. Example IO Verapamil, diltiazem, nitric chloride were prepared according to the solvent casting technique described in Example 3. Class IV antiarrhythmic drugs, i.e. calcium channel blockers, have been incorporated into various polymeric matrix materials such as polyurethanes such as Mitralthane MPU-5 and silastics such as G7-4850. . Example 11 An antiarrhythmic drug was prepared using a high molecular weight polyanhydride, polysebacic acid-carboxyphenoxyp Lopan (Nova, Baltjmore, MD) was incorporated into biodegradable matrices such as purified rat tail collagen. The membrane can be cast by dissolving the polyhydrate in methylene chloride. Collagen can be cast from a 0.1M acetic acid solution. In a particular embodiment of the biodegradable matrix, sotalol is dried by an "in water" drying technique as reported in Ogawa et al. was formulated in a poly(dl-lactidocoglycoside) (PLGA) matrix. In a typical procedure, 800 mg of sotalol and 100 mg of gelatin were dissolved in 1 ml of water in a 60°C water bath. This drug solution was treated with the polymer solution by sonication (Model W-225R, Heat Systems, Inc., Armingdale, NY) for 15 minutes at 30 Hz in a water bath. It became IL. The polymer solution consisted of 8 g of PLGAl dissolved in 20 ml of methylene chloride. This emulsion was mixed with dibasic Adjust the pH to 9.0 with sodium chloride! 1% W/V polyvinyl alcohol (PVA) saturated with methylene chloride at 400 rpm. 7Si was removed with subsequent stirring (Stir-pak, Code Palmer Instruments Co., Ltd., Chicago, IL). After stirring for 1 hour, the emulsion was added to a 0.1% W/A PVA aqueous solution (pH = 9° 0) 21 and further stirred for 3 hours. The microspheres thus formed were passed through a #100 mesh sieve. Centrifuge both portions remaining on the #400 mesh sieve. The samples were collected, washed four times with distilled water, freeze-dried for 48 hours, and then air-dried for 48 hours. In a specific example of use, sotalol-PLGA microspheres can be suspended in saline and injected, for example, into a space created within the pericardium. Ventricular tachycardia was induced and maintained by subjecting the chest dog model to rapid ventricular pacing. Three sets of bipolar epicardial electrodes were placed at a distance of 2 cm from the left ventricular apex to the heart base. Grass Model 8 Stimulator WH (Grass Instruments, Quincy, MA) delivers continuous electrical stimulation as 2-m5 ec square wave pulses with a 50-m5 ec cycle length through a stimulus isolation device W (Broom Associates, Reading, PA). The stimulus isolator also has a pacing current threshold. The value was repeatedly monitored. After induction of ventricular tachycardia, a punch-shaped controlled release dosage form of the invention of drug-containing polymeric matrix material was placed adjacent to the stimulating electrode. The time required to convert ventricular tachycardia into rhythm and the time course of quantitative changes to maintain induction of ventricular tachycardia were measured. Conclusion The results are shown in Table 2. The effects of controlled g@ release were monitored for up to 4 hours after conversion to normal rhythm. It was. A lidocaine-Ding ecoflex batch was prepared according to Example 1. All other pitches The drug form was prepared by dissolving the therapeutic agent in dimethylacetamide at a concentration of 100 mg/ml. This solution was further dissolved in a 10% solution of '1' hyomer polyurethane and solvent cast into a Q, 2 mm membrane. Amiodaro The matrix was made of polyester as a 10% cohabitant as described in Example 8. Cast with tylene glycol. Is the control a patch of each polymer matrix material? It was becoming. Conversion of ventricular tachycardia (VT) induced by fast ventricular pacing by controlled release via myocardium. -1%---1st layer 7 16 Teco flex 2B2 0.86± 0.68 367.7± 183.17"Oh 7 Thyomer 30χ 4.05± 3.15 208.7± 1 72.6 Amio9 3 Thyoser 30χ 5.90± 5.45 36.1± 12.70* NiC54Thyomer 50χ 2.08± 1.71 122.6± 1 01.3 vs. M5 Tecoflex O,0 No effect No effect control 2 Thyo■er O,0 No effect No effect control I Thyo■er* 0.0 No effect No effect* 10% polyethylene glycol, with PEG200; data are presented as standard error of the mean. Referring to Table II, site-specific application was effective with a net dosage of only O.1 mg/kg of lidocaine-containing forms. In addition, it is useful in converting tachycardia to normal rhythm. Despite its efficacy, peripheral plasma levels of lidocaine were undetectable. Ike's research shows that docaine administered by this route has no significant effect on normal heart function. It produced no fruit. Protinamide was also effective in converting ventricular tachycardia in a model of ventricular pacing. Amiodarone is a highly effective antiarrhythmic drug that often has severe side effects. Its efficacy when used in the controlled-release dosage form of the invention indicates that the transmyocardial route of administration may be one of the safest and most effective delivery methods for this drug.Nickel chloride can be administered systemically. Although difficult, it is expected to be an antiarrhythmic drug. This is an example of a basic drug system. However, the results in Table II show that nickel chloride is We show that direct epicardial delivery in a controlled-release dosage form is effective in converting tachycardia to normal sinus rhythm. Pharmacokinetic studies performed with a controlled release lidocaine-polyurethane matrix (28% w/w; 44 mg, 5 mm x 5 mm epicardial patch) demonstrated the importance of site-specific application of the controlled release dosing of the present invention. 10 is a graph showing the difference in coronary venous blood level of antiarrhythmic drugs with respect to systemic blood level. A lidocaine-polyurethane matrix was placed on the canine left ventricular epicardium adjacent to the pacing electrode. Lidocaine plasma levels were measured by high performance liquid chromatography in samples obtained after 4 hours of epicardial matrix application. Referring to Figure 1O, a total dose of 920 μg/kg was delivered. Site of lidocaine Coronary artery levels ranged from 0.8 to 2.3 μg/m1, taken during unidirectional Peripheral blood levels in the samples taken were about 100 times lower, i.e. 5.4-20.3 ng/ml. The controlled release dosage form of the present invention successfully prevented honestly induced ventricular tachycardia in a large model. hemp Detach the left anterior descending coronary heart of the dog by exposing the dog's artery under anesthesia and isolating it. This resulted in ventricular obstruction. A snare with a sliding knot was placed around the artery. Ventricular tachycardia was induced by closing the snare for 10 minutes to cut off blood supply to the left ventricle. The snare was opened for 1 hour, then the snare was closed for 10 minutes. This operation can be repeated up to six times, stimulating a heart attack. Ventricular tachycardia (VT) was defined as the occurrence of three or more consecutive premature ventricular beats. The effectiveness of the various controlled release dosage forms of the invention was demonstrated by IE gas physiology testing on a Hewlett Packard Physiologic Record S and continuous recording on an 8-channel analog tape deck (Hewlett Packard, Philadelphia, PA). It was done. The results are shown in Table 3. Table III Results of an acute ventricular tachycardia (VT) study in two dogs treated with antiarrhythmic controlled release. 7 Teco-280, 2350, 6± 0.2in Inner shield Cutting flex medicine 7°1711” B-blocking MPU-5300, 1461, 22±0.12 no Le New Drug D-n NM Re KPU-5300,2090,048±0.110-L Polarization To’5 Cafwn MPIJ-5300,3011O,10±0.031P Milner Blockade Drug Treatment Control - -91,10:t: 0.30 None Referring to Table III, the total dosage (mg/kg/2 h) of the various drug-containing matrices over 2 hours is determined by the in vivo release rate. Estimates were made from in vitro release data, which are known to correlate well with Data are expressed as the mean number of dogs per group, N. It is. Episodes of vT were set at 1 per minute. Table III shows the number of vT episodes per minute with the drug-containing matrix described above placed epicardially. The class II calcium channel blockers veravamil and class II drug sotalol were most effective against acute myocardial arrhythmias. Of interest, verapamil is contraindicated for arrhythmias when administered systemically. However, Table III shows that verapamil is effective in transmyocardial delivery. Example 14 In Vivo Electrophysiology and Defibrillation Threshold Studies In an Advantageous Application of the Principles of the Invention The antiarrhythmic drug-containing controlled release dosage forms of the present invention are used in conjunction with cardiac defibrillators. It was shown to lower the defibrillation threshold in patients. Cardiac Pac makers, Inc. Automated cardiac defibrillator commercially available from M.Inncapolis, M.N. Implantable cardiac defibrillators, such as those described in U.S. Pat. is well known about. An implantable cardiac defibrillator is a miniature power supply, a system of two bipolar leads, and an electrocardiogram sensing mechanism that emits single- or biphasic electrical pulses through short-duration (usually 2-20m5) electrode leads. It consists of a computer chip. In one embodiment, a lead is placed intravenously into the epicardium of the right ventricle by a catheter, and the second lead consists of an array of subcutaneously placed electrodes. normal heart rhythm Up to about 20-25 Joules are generally required for recovery. Other embodiments In some patients, both electrode leads are inserted into the epicardium or the right and left ventricles of the heart during open heart surgery. can be placed directly on the endocardium. In this embodiment, normal heart rhythm is It typically takes 5 joules of energy to recover. Implantable cardiac defibrillators have been used successfully, but require lower discharge IE currents, and it is desirable to increase their functionality to reduce discharge current requirements to reduce use episodes. This advantageously increases battery life and facilitates miniaturization. Class III drugs are agents that extend cardiac action time. Some newly developed potential Class III drugs are toxic when administered intravenously or by other known methods. These drugs include ibutilide, cloiri For example, ibutilide has been shown to be effective against atrial and ventricular arrhythmias in dogs and atrial arrhythmias in humans. to the dog Studies of available time of action (APD) have shown that ibutilide increases the time of action and increases the plateau height at very low doses. , when applied epicardially to the defibrillator, A study was conducted to evaluate pneumophysiological effects and defibrillation thresholds. Report below In the study reported, an integrated controlled-release matrix was implanted together with an implantable automatic cardiac defibrillator. However, it is difficult to connect electrode leads to drug-containing polymer matrices. It can be seen that the drug-containing matrix can be directly integrated into an automated implantable cardiac defibrillator by coating it with a Rix material (see Figure 21). For the following in vivo studies, drug-containing matrices were prepared as follows. 2: Antiarrhythmic drugs and Pellathane polyurethane (high molecular weight polyurethane sold by Dow Chemical Co*pany, M1dland, MI) (Rethane) was dissolved in THF and solvent cast in a Teflon-coated mold to form a film with a thickness of 50-60 μm. 20% weight/1! Sufficient amount of antiarrhythmic drug was used to yield a drug content of . In a particular embodiment, 100 mg of ibutilide fumarate and 400 mg of polyurethane were dissolved in THFloml and stirred in a sealed vial for 60-90 minutes. Following solvent casting, the cast membrane was placed in a fume hood and the solvent was allowed to evaporate for approximately 48 hours at room temperature. Formulation 14b = Obtained by replacing a proportion of the antiarrhythmic agent with an inert, i.e. non-physiologically active, co-cipient or filler with low water solubility, such as inulin or dimethyl tartrate. Drug matrix release behavior Changed the dynamics. The specific formulation used in this study contained 16% N/w tartrate. Methyl, 4% w/w ibutilide in Pellathane polyurethane matrix The ratio of filler to antiarrhythmic drug incorporated into Trix is determined to achieve the desired effect. We should understand that we can change in order to achieve our goals. Dimethyl tartrate is also an organic Soluble. In this particular embodiment, 20 mg of ibutilide fumarate, dimethytartrate 80 mg of polyurethane and 400 mg of polyurethane were dissolved in THFIO ml and solvent cast to form a matrix of similar weight and dimensions to the matrix obtained in Formulation 14a. I'm tired. In vitro release studies were performed in phosphate buffered saline (pH 7,4) at 37° C. in perfect 5 ink conditions. Mato Rix samples were placed in buffer on a rotary shaker (110 rpm) and drug levels were monitored spectrophotometrically at 227 nm. The matrix prepared according to formulation 14a had an initial swarm effect releasing about 30% of the antiarrhythmic drug in the first 15 minutes, then at a decreasing rate, releasing about 40% of the antiarrhythmic drug in 120 minutes, as shown in Figure 11. % was consumed. In contrast, the matrix prepared according to Formulation 14b released only about 9.6% of the antiarrhythmic drug in the first 15 minutes, followed by about 17.1% in 120 minutes, as shown in FIG. It was released at an almost linearly increasing rate until exhaustion. Thus, the dosage administered over a given period of time can be lowered by slowing the rate of release in this manner. Standard (14 cm2) defibrillation electrodes were placed over the left and right ventricles of the dog's heart. To induce fibrillation, an epicardial electrode (Bloom Stig+ulator, Bloom A 5sociates, Reading, PA) was sewn into the left ventricle. and sent an electrical impulse (T-+10m5). A pair of recording electrodes was placed in the right ventricle to measure electrophysiological changes. Test shocks were delivered in random order to determine the baseline defibrillation threshold ifJ (D F T ). m-containing matrix (1.5 cm x 1.5 cm batch, weight approximately 25-28 mg) was placed in the anterior left ventricle. A DFT study was performed for 2 hours after implantation. Ibutyride polyurethane matrix (formulation 14a) placed in the epicardium It had significant effects on air physiology parameters. The ventricular effective antigenic period (VERP) ranged from baseline to 151.9 m from 124.9 ± 3.3 to 138.0 ± 1.71 m with epicardial electrodes located near the matrix location. ．． It changed from 7±3.4 to 154.6±3.5ms. For endocardial electrodes located near the matrix location, The base line ranges from 129.1±2.2 to 137°3±2.1ms to 148.0±1. It changed from 7 to 152.0±4.7ms. See Figure 13, which is a graph showing the VERP (ms) measured by an epicardial electrode and a ventricular 11[pole located near the ibutilide-containing matrix. Center direction 1 11 placed at the end of the matrix position! At the poles, similar changes were recorded for VERP. The same butylide polyurethane matrix (formulation 14a) had a significant effect on activation time (AT). Referring to Figure 14, the matrix position With the epicardial electrode located near the pericardial electrode, the AT (ms) was 65, 1 ± 6.2 to 71° from the baseline of 27.1 ± 1.4 to 27.1 ± 1.7 ms. It changed to 9ms. For endocardial electrodes located near the matrix location, the baseline was 27.1±1. It changed from 4-27.1±1.7ms to 50.2±7.2-54.2±7.1ms. Changes in AT of the same magnitude were recorded with a centripetal I electrode placed distal to the matrix location. After application of the ibutilide matrix (formulation 14a), the defibrillation threshold (DFT) was significantly reduced. Referring to Figure 15, which is a graph showing the probability of successful defibrillation by a defibrillator, the control data shows defibrillation before administration of ibuteride. Ibutyraido' polyurethane matrix according to formulation 14a. After epicardial application of gas, the energy associated with 80% probability of successful defibrillation (DFT80) Ghee decreased from 15 joules at baseline to 3.9 joules. DFT 90 decreased from approximately greater than 20 Joules to 4.9 Joules. No changes were observed in cardiac velocity or arterial pressure. The Ibutyride polyurethane matrix was tested at a dosage of 0.025 mg/kg during the experimental period, p<o, ool, vs. Shiichi test). The estimated dosage of ibutilide released from the matrix during the 2 hour experimental period was 0.025 mg/kg. When this small dosage was applied to the epicardium, This resulted in a 4-fold decrease in DFT. A dose-response study was conducted (1) It was found that ibutilide was effective in reducing DFT in rats administered a dose of approximately 0.0025 mg/kg. It was. For comparison, defibrillation thresholds were measured after intravenous administration of ibutilide at equivalent doses (0°25mg/kg and o,oo25mg/kg). The results are shown in Figures 16 and 17. The figure is for the application of 2-2-2O pulses of energy (Joules). Figure 16 shows the DFT for monophasic pulses following administration of ibutilide 0.025 mg/kg. Figure 171, Ibuchira. The DFT for biphasic pulses before and after administration of 0.0025 mg/kg of Id is shown. Ibutyride polyurethane matte IJx according to % '7 GO 14b was applied to the canine epicardium along with standard implantable cardiac defibrillator electrodes. Figure 18 shows Another embodiment is a graph showing % conversion of fibrillation for common biphasic pulses in pulses. A chlorylium-containing polyurethane matrix was also prepared according to procedure 14aLf). This released a dosage of 2 mg/kg of Blackfish IJum during the 2 hour experimental period. See Figure 19! II, then Crophyllium-poly Urethane (Sochi) is implanted together with an implantable IG visceral defibrillator electrode, and A decrease in DFT80 from approximately 18.5 Joules to 14.7 Joules was observed when using biphasic motion to defibrillate defibrillation. In yet another embodiment, following the operation of Formulation 14a, 20% weight/1! amount of sota The roll was incorporated into a polyurethane matrix. This is a two-hour experimental period. Figure 20 produced a dosage of 0.8 mg/kg of sotalol during the administration of epicardial injections containing sotalol or ibutilide (0,025 mg/kg) as shown in the figure. Figure 3 shows the variation in activation time (ms) measured by electrodes placed at various distances from the matrix. In conclusion, Ibutylide polymer matrices and other formulations, especially Formulations containing sotalol and/or sotalol have been successfully produced and shown to have electrophysiological effects (i.e., antigenicity and prolongation of conduction velocity) that are beneficial in preventing ventricular arrhythmias. . The controlled release epicardial implant of the present invention provides both potent and long-lasting electrophysiological effects. It was shown to be superior to intravenous administration of the drug in patients. Ibutyride polyurethane matrices used as cardiac implants also produced unusual effects that lowered defibrillation energy threshold requirements. Therefore, by using an ibutilide polyurethane drug delivery system in combination with an implantable defibrillator, we were able to significantly increase the functionality of the implantable defibrillator. In contrast, intravenous ibutilide, used at the same dosage as cardiac implantation, had no significant effect on lowering defibrillation energy thresholds. Controlled release drug delivery containing ibutilide as a component part of an implantable defibrillator electrode or as an adjunct. Inclusion of the Barry system lowers the electrical energy requirements for defibrillating the heart. Additionally, although ibutilide is a class I11 antiarrhythmic drug, it reduces episodes of ventricular arrhythmia that can lead to ventricular fibrillation. Therefore, ibutilide controlled release drug The overall design of an implantable defibrillator with a defibrillation delivery system makes the electrical device smaller and requires fewer episodes of its activity for defibrillation. This makes it a significant improvement over competing systems. The following example is a further embodiment of the use of an antiarrhythmic drug-containing controlled release dosage form of the present invention in conjunction with a cardiac rhythm control device. As used herein, the term "cardiac arrhythmia" includes abnormal heart rhythm conditions, including ventricular arrhythmia, ventricular fibrillation, atrial fibrillation, atrial flutter, supraventricular tachycardia, multifocal atrial tachycardia, Including supraventricular arrhythmias such as tachycardia. subordinate Thus, the term "cardiac rhythm control device" means any device that has the function of controlling the heart rhythm by sending electrical pulses to the heart, including implantable cardioverter-defibrillators; countershock, antitachycardia pacemaker, overdrive pedal including, but not limited to, base manufacturers, etc. However, in these embodiments, the antiarrhythmic agent also functions to control defibrillation and/or tachycardia, so long as it does not have a deleterious effect on the effectiveness of the cardiac rhythm control device. It can be any drug. Selection of an appropriate arrhythmic drug is within the skill of those skilled in the art. Class III antiarrhythmic drugs, especially ibutilide, sotalol, Polymers containing rutilide have been shown to significantly lower defibrillation thresholds in ventricular arrhythmias, lower the risk of atrial flutter, and prolong the antigenicity and conduction time of extraventricular stimuli. It was. Example 1 In an even more particular embodiment of the invention, the atrial pacing electrode is coated with butyride polyurethane, as shown in FIG. 21, which schematically shows an atrial pacing electrode 20. The atrial pacing electrode 20 has a polyurethane multilayer coating 21 on the end 22 of the electrode body 23. In practice, the atrial pacing electrode 20 is implanted in the atrial epicardium of the open heart surgery center. For acute atrial arrhythmias, the tip 24 of the pacing electrode is connected to a lead (1ead) (not shown) passed through the chest wall with a needle hole punch. Match. The leads are electrically coupled to a means for applying electrical current to the patient's heart. Acute - When the subshoulder arrhythmia is no longer dangerous, typically within 10 days of surgery. The adjustment electrode can be removed by a simple pulling operation. Of course, the atrial pacing electrode 20 can be permanently attached for chronic atrial arrhythmia. In a preferred embodiment, the following technique is used to form multilayer coating 21. The coating surrounds the electrode body 23, a cross-sectional view of which is shown in the inset of FIG. L1-LA ibutilide and Pellathane polyurethane (Dow Chemical Company, Maryland, MI) were dissolved in THF to create a coating solution. In this particular embodiment, using a sufficient amount of ibutilide to obtain a drug content of 10% w/w, an atrial pacing electrode wire lead (approximately 100 μm in diameter) was swung 18 times in the coating solution to reduce the thickness. A well-adhered coating of approximately 85 μm was formed. The coated wire had a diameter of about 270 μm. Of course, the number of layers can be adjusted to obtain the desired thickness of the coating. Advantageously, dip coating techniques allow the polymer coating to better adhere to the wire. wear it. Additionally, the multilayer system slows the rate of release of butyride from the polymer matrix. Figure 22 shows a long-term test tube of dip-coated wire produced according to recipe 15a. Graph showing internal release characteristics, expressed as cumulative release % versus time (days). Ru. Antiarrhythmia and electromagnetic properties of the ibutilide polyurethane coated atrial pacing electrode of the present invention The pneumophysiological effects were studied in a large model of atrial flutter. Buchanan et al., J. Cardiovascular Pharmacology, Vol. 3 3. No. 1 O-14, 1933; Frale et al., C1rc, Res, Co1.5 8. pages 495-511 (1986) s Wu et al., Cardiovasc. Following a modification of the method of Res., Vol. 23, 400-409 (1991), an intracaval Y-shaped incision was made in the right atrium of the dog to induce atrial flutter. A Y-shaped incision creates a distant conduction area. For atrial pacing and atrial effective antigenic period (AERP) measurements, bipolar platinum pacing and recording electrodes were sutured 2 mm from the right atrium. The electrode lead was connected to a measuring device. The atrial bipolar signal was amplified with a differential AC coupled amplifier and displayed on an oscilloscope. Recording electrode signals were recorded by a polygraph (Grass Model 79-D, Quincy, Mass.) and displayed on an oscilloscope. Bloomm model DTU 110 stimulator (Bloo+e As5ociates, Reading, PA) and WP I Model A 385 constant current isolation device The antigenic and and atrial pacing to determine the ability to induce atrial flutter. AERP was determined by pacing with a cycle length of 300 m5 and intervening one rapid stimulus every eighth beat. Each drive cycle ends in minutes with a 2 second stop. I let go. The cycle length was reduced in 10 m5 increments until the effective antigenic period (ERPI) was reached. At ERP, the stimulus was not captured and did not produce a propagated response. Start with a cycle length of 150 m5 and reduce in 10 ms increments to the minimum cycle length. Atrial flutter was induced by pacing at 2-3 second intervals up to 50 m5. Dogs considered atrial flutter more inducible when the arrhythmia lasted a minimum of 5 minutes. Atrial flutter was considered uninducible if it could not be evoked by the atrial pulse.The cycle length of atrial flutter was determined by averaging the intervals of several atrial potential intervals.Atrial flutter was a measure of arrhythmia. If it does not end naturally during recording (approximately 2 minutes), the recording will continue. It was considered as something that could be done. Sustained atrial flutter was terminated by overdrive pacing with a rapid cycle length between 50 and 150 m5. FIG. 23 is a bar graph showing the reduction in atrial flutter induction with ibutilide polyurethane coated atrial electrodes. During the 2-hour study period, acute atrial failure occurred as described above. A rhythm was induced. After implantation of ibutilide polyurethane-coated atrial electrodes, the inducibility of atrial flutter was significantly reduced (P<0.001; paired T-test). During the 2-hour study period, the estimated dosage of ibutilide was approximately lug/kg. No adverse effects due to drug administration were observed. Referring to Z24, another specific embodiment of the present invention is schematically illustrated. FIG. A pacing-venous defibrillator catheter 40 is shown having an annular conical tip 41 made of a silicone rubber matrix containing 30% by weight of ibutilide fumarate. Figure 25 is a graph showing the release rate of ibutilide from the molded conical tip of Figure 24. It is f. Approximately one year's worth of medication can be released from the conical tip. Pacing-intravenous defibrillator catheter 4o consists of two defibrillator electrodes 42 and 43 located at opposite ends of catheter wire 44. The conical tip 41 is placed at the heart-contacting end of the pacing-venous defibrillator catheter 4o! 1llll [surrounding pole 45]. The catheter can be a commercially available model such as the Endotak catheter (Cardiac Pac-akers, Inc., Minneapolis, MN). For use Then, the pacing-venous defibrillator catheter 4o is prepared by cardiac catheterization so that the conical tip 41 is in contact with the epicardium and the electrodes 42 and 43 are in the ventricles. A pacing-venous defibrillator catheter of the type shown in Figure 24 is attached to the dog's anterior left ventricle. I got it. To induce fibrillation, an epicardial electrode (Bloom stimulator, Bloom A 5sociates, Reading, PA) was sewn into the left ventricle and delivered electrical impulses (T=10 ms). A pair of notes to measure electrophysiological changes! An electrode was placed in the right ventricle. To determine the baseline defibrillation threshold (tl (D F T )), test shocks were delivered in a random order. At 2 hours of implantation, a DFT study was performed. Pacing of the Invention - Transvenous Defibrillation Defibrillation thresholds are significantly lower with the use of catheters. It decreased significantly. FIG. 26 is a graph showing the flI* of successful defibrillation with a pacing-venous defibrillator catheter for application of 2-20 tns monophasic pulses of energy measured in Joules. Referring to FIG. 26, the control data is Figure 3 shows defibrillation of an animal using a tip, i.e., a drug-free tip. Chaosing - Seizu I! The energy required for 90% successful implantation of the IV defibrillator catheter 4o was reduced from more than 10 joules before dosing to 3-5 joules. Similarly, 80% implantation success could be achieved with less than 3 Joules applied, whereas pre-dosing required more than 10 Joules. No changes were observed in cardiac velocity or arterial pressure. Over the course of the experiment, the ibutilide polyurethane matrix depleted a dosage of 3 μg/kg (Pro, 001, one pairwise test). FIG. 25 shows that the pacing-venous defibrillator catheter of the present invention successfully reduces the energy level required for ventricular defibrillation. It shows a little bit. Example 17 In another embodiment of the invention, an iontophoretic device for epicardial delivery of antiarrhythmic drugs is responsive to an electrical signal. In a particular embodiment, the rate limiting selection for a hollow reservoir iontophoretic device The permeable heterogeneous cation exchange member was made of dry conditioned polystyrene cation exchange resin (Dowex 50W, 2x, I ("shape, 200-400 mesh, Sigaa, ST, Louis, MO) and pharmaceutical grade silicone rubber, details was formulated from Silastic Q7-4840 (A and B 1:1N! ratio).The polystyrene cation exchange resin had a weight ratio of 42%.The resulting dispersion was placed in a mold to remove air bubbles. A vacuum was applied for 20 minutes.The mold was then compressed with approximately 1000 pounds of force and the present invention Although embodiments and applications have been described, this teaching will allow those skilled in the art to make many different embodiments based on these principles without departing from the spirit and scope of the invention. can be done. For example, physiologically inert cocivients are well known in the art, and one of skill in the art will be able to select one or more cocivients for use in the practice of the present invention. Wear. Therefore, the explanations disclosed herein are provided to facilitate understanding of the invention and should not be construed as limiting the scope of the invention. Time (minutes) Figure 2 Figure 3 Time (B) Time (minutes) Minutes DFT before and after intravenous injection of ibutilide (0,0025 mg/kg) Figure 17 Confucian translation Changes in activation time - ibutilide and sotalol Figure 20 % release of ibutilide over time (10% loading) Figure 22 Pre-dose Post-dose Figure 23 Ibnalide release time from 30% loading cap over time (days) Heart for DFT reduction Procedural amendment due to intimal catheter tip January 11, 1995

Claims (1)

[Claims] 1. electrode means for transmitting electrical signals to or from the patient's heart; and an implantable control device for releasing a therapeutically effective amount of an antiarrhythmic drug into a patient's heart a device for controlling the heart rhythm of a patient, comprising: 2. the implantable controlled release means incorporating the antiarrhythmic drug; a substrate formed from a biocompatible polymeric material, the substrate containing the antiarrhythmic drug; Claim 1 adapted for application directly to a patient's heart for transmyocardial delivery. equipment. 3. The therapeutically effective amount of the antiarrhythmic agent is about 5-40% by weight of the substrate. Equipment in the required range 2. 4. the substrate has water solubility properties different from those of the arrhythmic drug; 3. The device of claim 2, comprising at least one physiologically inert filler. 5. Physiologically inert fillers include inulin, polyethylene glycol, and alcohol. 5. The device of claim 4, wherein the device is selected from the group consisting of dimethyl phosphate. 6. The biocompatible polymeric material is non-biodegradable, polyurethane, polydimethyl Siloxane, ethylene/vinyl acetate, polymethyl methacrylate, polyamide, polyester Recarbonate, polyester, polyethylene, polypropylene, polystyrene , consisting of polyvinyl chloride, polytetrafluoroethylene, and cellulose acetate 3. The device of claim 2 selected from the group. 7. the electrode means comprises tissue fixation means for fixation to heart tissue of the patient; The apparatus of claim 1. 8. said fixing means being in the form of an annular conical tip disposed at the apex of said electrode means; The apparatus of claim 7, which is 9. The electrode means is further arranged on the electrode means. 2. The device of claim 1, comprising a base electrode. 10. The electrode means is adapted to detect a predetermined condition of the patient's heart. 2. The apparatus of claim 1, comprising detection means located at. 11. Claims wherein the electrode means comprises a plurality of defibrillator/cardioverter defibrillator electrodes. The device in Box 1. 12. The biocompatible polymer material is biodegradable and contains collagen, polylactic acid, and 3. The device of claim 2, wherein the device is selected from the group consisting of glycolic acid, and polyanhydrides. 13. The antiarrhythmic drug is a drug that extends the effective period of action, and selected from the group consisting of cilium, ibutilide, and sotalol. 1 device. 14. 2. The device of claim 1, wherein said substrate is membrane-shaped. 15. 15. The device of claim 14, wherein the membrane is a multilayer membrane. 16. Claim wherein said substrate is in the form of a shaped heart contacting component attached to said electrode means. Equipment in range 1. 17. a heart contact means for transmitting electrical signals to the heart of the living body, and comprising a controlled release dosing means for effecting controlled release of an antiarrhythmic drug; Heart rhythm control device. 18. the controlled release dosing means incorporates a therapeutically effective amount of an antiarrhythmic drug; 18. The cardiac rhythm control device of claim 17, comprising a substrate of biocompatible polymeric material. 19. Physiologically inert with an aqueous solubility different from that of the antiarrhythmic drug 18. The cardiac rhythm control device of claim 17, incorporating a filler. 20. The physiologically inert fillers include inulin polyethylene glycol and 20. The cardiac rhythm control device of claim 19, wherein the cardiac rhythm control device is selected from dimethyl bitartrate. 22. 18. The cardiac rhythm control device of claim 17, wherein said biocompatible polymeric material is non-biodegradable. control device. 23. The non-biodegradable biocompatible polymer material is polyurethane, polydimethylsiloxane, etc. xane, ethylene/vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate carbonate, polyester, polyethylene, polypropylene, polystyrene, polyester The group consisting of polyvinyl chloride, polytetrafluoroethylene, and cellulose acetate 23. The heart rhythm control device according to claim 22, selected from: 24. The cardiac rhythm according to claim 17, wherein the antiarrhythmic drug is an agent for extending the active period. dynamic control device. 25. The antiarrhythmic drugs include altilide, clofilium, ibutilide, sota 18. The cardiac rhythm control device of claim 17, wherein the cardiac rhythm control device is selected from the group consisting of: 26. The cardiac rhythm control device according to claim 17, wherein the antiarrhythmic drug is ibutilide. Place. 27. The cardiac rhythm control device according to claim 17, wherein the antiarrhythmic drug is altilide. Place. 30. The cardiac rhythm control device according to claim 17, wherein the antiarrhythmic drug is sotalol. . 31. Claim 1, wherein the substrate is in the form of a membrane adhered to the heart rhythm control device. 8 heart rhythm control device. 32. 32. The cardiac rhythm control device of claim 31, wherein the membrane is a multilayer membrane. 33. The cardiac rhythm according to claim 31, wherein the membrane has a thickness of about 23 μm to 1 cm. dynamic control device. 34. the substrate is in the form of a shaped heart-contacting component attached to a heart rhythm control device; The heart rhythm control device according to claim 18. 35. a therapeutically effective amount of at least one antiarrhythmic drug in conjunction with a cardiac rhythm control device; Place the incorporated polymer matrix in direct contact with the epicardium of a living heart A method for treating heart rhythm disorders in living organisms with a heart. 36. The cardiac rhythm control device is an implantable cardioverter-defibrillator device. , the method of claim 35. 37. Claim 3, wherein the heart rhythm control device is an implantable pacemaker. Method 5. 38. together with a cardiac rhythm control device, at least one of the types of duration-of-action prolonging agents; A polymeric matrix incorporating a therapeutically effective amount of an antiarrhythmic drug in a biological heart Ventricular cells in living organisms with a heart consist of a process in which they are placed in direct contact with the epicardium of the heart. treatment or prevention of atrial fibrillation.