Source: http://www.google.com/patents/US7190997?dq=3798359
Timestamp: 2016-09-27 09:31:53
Document Index: 790326373

Matched Legal Cases: ['art.\n24', 'art.\n25', 'art.\n26', 'art.\n32', 'application No. 60', 'art 102']

Patent US7190997 - Drug delivery device - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsElectrical treatment apparatus (100) for use with an associated molecule source, comprising: at least one electrode (106); a power source (120) for electrifying said at least one electrode; and a controller, which is programmed to activate the power source (120) to selectively electrify said at least...http://www.google.com/patents/US7190997?utm_source=gb-gplus-sharePatent US7190997 - Drug delivery deviceAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS7190997 B1Publication typeGrantApplication numberUS 09/980,908PCT numberPCT/IL2000/000319Publication dateMar 13, 2007Filing dateJun 4, 2000Priority dateJun 4, 1999Fee statusPaidPublication number09980908, 980908, PCT/2000/319, PCT/IL/0/000319, PCT/IL/0/00319, PCT/IL/2000/000319, PCT/IL/2000/00319, PCT/IL0/000319, PCT/IL0/00319, PCT/IL0000319, PCT/IL000319, PCT/IL2000/000319, PCT/IL2000/00319, PCT/IL2000000319, PCT/IL200000319, US 7190997 B1, US 7190997B1, US-B1-7190997, US7190997 B1, US7190997B1InventorsNissim Darvish, Itzhak (Itrik) ShemerOriginal AssigneeImpulse Dynamics NvExport CitationBiBTeX, EndNote, RefManPatent Citations (40), Non-Patent Citations (8), Referenced by (46), Classifications (7), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetDrug delivery device
US 7190997 B1Abstract
Electrical treatment apparatus (100) for use with an associated molecule source, comprising: at least one electrode (106); a power source (120) for electrifying said at least one electrode; and a controller, which is programmed to activate the power source (120) to selectively electrify said at least one electrode (106) to apply at least one electric field including a transport effect for transporting a molecule in a desired manner and a non-excitatory control effect for controlling the activity of at least apart of a heart, said programming selected to achieve a desired provision of said molecule into at least a portion of a patient's heart or associated vasculature.
a controller, which is programmed to activate the power source to selectively electrify said at least one electrode to apply at least one electric field which has a transport effect for transporting a molecule in a desired manner and has a non-excitatory control effect, which does not induce a propagating action potential in the heart, independent of the transport effect, adapted to electrically control an activity of at least a part of a heart,
said programming selected to achieve a desired provision of said molecule into tissue including at least a portion of a patient's heart or associated vasculature.
5. Apparatus according to claim 1, wherein said programming comprises programming adapted for said patient.
7. Apparatus according to claim 1, wherein said programming comprises a selection of at least one operational protocol from a set of available protocols in said apparatus.
9. Apparatus according to claim 1, comprising a synchronization connection to a molecule source containing said molecule.
13. Apparatus according to claim 12, wherein said synchronization connection is comprised in said at least one electrode.
16. Apparatus according to claim 1, wherein said molecule source is integral with said at least one electrode.
19. Apparatus according to claim 1, wherein said molecule source comprises a catheter, coupled to said apparatus outside said patient.
22. Apparatus according to claim 1, comprising at least one sensor that senses a cardiac parameter and provides said sensed parameter to said controller.
23. Apparatus according to claim 22, wherein said sensor measures a cardiac parameter relating to the entire heart.
24. Apparatus according to claim 22, wherein said sensor measures a cardiac parameter relating to a portion of the heart.
25. Apparatus according to claim 22, wherein said controller analyses said sensed parameter to detect an effect of said molecule on said heart.
26. Apparatus according to claim 22, wherein said controller is configured to analysze said sensed parameter to detect an activity of the heart and wherein said controller is configured to synchronize said provision to said sensed activity.
27. Apparatus according to claim 22, wherein said controller is configured to analyze said sensed parameter to detect an effect of said field on said heart.
32. Apparatus according to claim 1, comprising a user input for receiving an indication of an effect of said apparatus from said patient.
33. Apparatus according to claim 1, wherein the controller is adapted to apply a single electric field which has both of said transport effect and said control effect.
34. Apparatus according to claim 1, wherein the controller is adapted to apply at least one transport field which has a transport effect but not a control effect and at least one control field which has a non-excitatory control effect.
35. Apparatus according to claim 34, wherein the controller is adapted to apply the transport field and control field simultaneously.
36. Apparatus according to claim 34, wherein the controller is adapted to apply the transport field and control field sequentially.
37. Apparatus according to claim 34, wherein the controller is configured to apply during a single heart treatment session a transport field which is accompanied by the control field only during part of the application of the transport field.
42. Apparatus according to claim 1, comprising an output port for generating an output to said patient.
51. Apparatus according to claim 50, wherein said at least one control electrode is spatially displaced from said at least one transport electrode.
52. Apparatus according to claim 1, wherein said transport effect and said control effect of said at least one electric field are applied using at least one common electrode of said at least one electrode.
57. Apparatus according to claim 56, wherein said controller selectively electrifies said independent contacts to achieve a desired, non-uniform, volumetric dispersion of said molecule, relative to said electrode.
66. Apparatus according to claim 1, wherein said apparatus is comprised in a cylindrical body adapted for implantation inside a blood vessel.
70. Apparatus according to claim 1, wherein the controller is not configured to apply excitatory electrical fields.
71. Apparatus according to claim 1, wherein the transport effect comprises releasing the molecule from a reservoir into tissue.
72. Apparatus according to claim 1, wherein the transport effect comprises transporting the molecule within tissue.
73. Apparatus according to claim 1, wherein the transport effect comprises transporting the molecule into tissue cells.
74. A method of selectively delivering a molecule, comprising:
providing a molecule adjacent a heart; and
applying at least one electric field having a transport effect for transporting a molecule in a desired manner into at least a portion of said heart or a vasculature associated with the heart and having a non-excitatory electrical control effect, which does not induce a propagating action potential in the heart, for controlling the activity of at least a part of said heart.
This application is a U.S. national filing of PCT Application No. PCT/IL00/00319, filed Jun. 4, 2000. This application also claims the benefit under 119(e) of U.S. Provisional application No. 60/137,553, filed Jun. 4, 1999, the disclosure of which is incorporated herein by reference.
One aspect of some exemplary embodiments of the invention relates to using a non-excitatory pulse to control molecule availability at or near the heart which might be activated in an undesirable manner by an applied electric field. The exerted control may include, for example, one or more of causing a molecule to exit a reservoir, iontophoresis of the molecule into cardiac tissue and/or electroporation of the molecule into individual cardiac cells. An optional second non-excitatory pulse may be provided to interact with the first pulse and/or the molecule. In some embodiments of the invention, the molecule availability pulse is excitatory and adverse effects of the pulse are prevented by the second pulse.
As used herein the term “non-excitatory pulse” means an applied electric field which does not induce a propagating action potential in the heart, for example due to its frequency, polarity, waveform, duration, amplitude and/or its being applied at a time in the cardiac cycle when the local heart tissue does not respond to the pulse.
As used herein the term molecule means any type of molecule, including, especially, genetic material, such as DNA and RNA, genetic vectors, such as viruses and plasmids, polypeptides, hormones and small molecule drugs. In addition, the molecules may include ATP, cAMP and/or particles having the molecule adsorbed thereto or located inside a volume of a hollow particle, such as a liposome, which can be transported into the tissue or trapped in a matrix, such as a hydrogel matrix reservoir on the electrode. Exemplary pharmaceuticals include: β-Blockers, anti-cancer drugs, SERCA, VEGF and Nitro components such as Nitroglycerine.
In an exemplary embodiment of the invention, knowledge of what types of pulses will not cause a fatal arrhythmia and/or methods for controlling such arrhythmia should they occur are used to apply pulses having larger voltages, currents and/or durations than previously thought possible, to the heart, for the purpose of transporting drugs. In addition, a variety of waveforms becomes available. Optionally, apparatus designed for non-excitatory pulses is used (e.g., not a pacemaker), making possible various programmable pulse forms and larger amounts of power. However, in some embodiments of the invention, a modified pacemaker may be used, for example a pacemaker with modified programming, to provide a non-excitatory pulse.
Various types of electrodes may be used. In an exemplary embodiment of the invention the type of electrode used is a point electrode. Alternatively or additionally, a line electrode, a wide area electrode, a coronary electrode which is inserted into a coronary vessel and/or a one- or two-dimensional matrix electrode may be used.
In an exemplary embodiment of the invention, the molecules are provided by the electrode, for example using a drug-eluting electrode of one of various types as known in the art. Alternatively or additionally, the molecule is provided in other ways. For example the molecule is injected systemically or locally or applied using an implanted pump (possibly with output ports at the region to be treated or in a vascular bed thereof or adjacent thereto where the electrical pulse can transport it). Possibly, a decomposing or other matrix having the molecule embedded therein is used to supply the molecule. Alternatively, the molecule is ingested or inhaled. In some cases, a plurality of molecules and/or molecule provision methods are used simultaneously in a single patient, for example both systemic and local provision of two different molecules. Optionally, such two or more molecules may interact, for example the local molecule blocking the activity of the systemic one or enhancing it.
An aspect of some embodiments of the invention relates to an interaction between non-excitatory signals applied and the molecule transport. In some embodiments of the invention, the transport pulse and/or an optionally provided second non-excitatory pulse prevent and/or counteract adverse affects of the transport pulse and/or of the transported molecule, for example by preventing the propagation of undesirable action potentials. In some embodiments of the invention, the transport pulse is applied at a location spatially displaced from the location of the second non-excitatory pulse. In some embodiments of the invention, the adverse effect that is contracted by the second non-excitatory pulse is caused by a non-transport electrical signal, for example an electrical or optical signal used to stimulate cells in or near the heart to perform angiogenesis, as apparently suggested in the art.
In an exemplary embodiment of the invention the molecule and the non-excitatory signal cooperate to have a desired, synergistic effect on the heart, for example the molecule enhancing a contractility increasing effect of the signal or the signal enhancing a contractility increasing effect of the molecule. Alternatively, the signal may be selected to have a minimal effect on the heart.
Various types of molecules may be used in exemplary embodiments of the invention. In some particular embodiments of the invention, non-ionized/charged molecules are used for electrically mediated transport in the heart. Optionally, the effect of electroporation is achieved by the electric field of the non-excitatory signal momentarily opening pores in the cardiac cell membranes. Alternatively or additionally, dipole charges are formed on the molecules, for transport, by using suitable electric field frequencies. In some embodiments, required field intensities, waveforms or frequencies are provided by virtue of using non-excitatory fields.
An aspect of some exemplary embodiments of the invention relates to a method of treating a cardiac dysfunction. In an exemplary embodiment of the invention, a patient is temporarily connected to a device that electrically transports molecules into cardiac tissue. Possibly, the device also performs monitoring functions and/or provides other treatment, such as applying electrical fields that prevent fatal arrhythmia or pacing the heart.
An aspect of some exemplary embodiments of the invention relates to treating coronary blood vessels or other blood vessels that are near the heart, using electrically mediated molecule transport. In an exemplary embodiment of the invention, the timing and/or other parameters of application of electric fields for transporting the molecules are selected to not have a pro-arrhythmic effect on the heart. In an exemplary embodiment of the invention the molecule transported is one which causes breakdown of clots or other occlusions, one which causes angiogenesis and/or one which prevents stenosis or re-stenosis of the vessel. Alternatively or additionally to using a transport pulse, the therapy may be effected using a non-transport pulse, for example a vessel spasm relaxation pulse. It is noted that pacemaker lead placement usually avoids placing the lead over a coronary vessel, in order to provide better electrical contact with the heart.
An aspect of some exemplary embodiments of the invention relates to providing one or more types of molecules at a plurality of locations on the heart. In an exemplary embodiment of the invention, the amount of molecule transported and the type of molecule transported at each point is individually controllable. Alternatively or additionally, the application regimen of the molecule may be pre determined. Alternatively, the application regimen may be varied, for example in response to needs of the heart or in response to the effect of a previous application. Optionally, a non-excitatory pulse is used to transport the molecule.
An aspect of some exemplary embodiments of the invention relates to synchronizing the transport of a molecule with cardiac activity, for example the cardiac cycle or cardiac output variations caused by activity, to achieve desirable effects, for example transport effects. Three types of synchronization may be distinguished. First is synchronization with the activity of a single cell (or a region) from depolarization to depolarization. The synchronization may be with any part of the electrical cycle, including, for example, an onset of depolarization or a plateau. Second is synchronization with the activity of the heart within a beat. Third is synchronization with longer term activities, such as increase in heart rate due to exercise. It is noted that the non-excitatory device can also control the above cardiac activities, alternatively or additionally to synchronizing with them. In one example, the molecule is transported at a time when it will have the greatest effect on the heart. In another example, the molecule is transported when travel through the heart tissue is easiest, for example when the muscles of the heart are relaxed. Possibly, the non-excitatory pulse is used to extend the refractory time of all or part of the heart to allow the molecule to travel further in one cardiac cycle.
a controller, which is programmed to activate the power source to selectively electrify said at least one electrode to apply at least one electric field including a transport effect for transporting a molecule in a desired manner and a non-excitatory control effect for controlling the activity of at least a part of a heart, said programming selected to achieve a desired provision of said molecule into at least a portion of a patient's heart or associated vasculature. Optionally, said controller is hardware programmable. Alternatively, said controller is software programmable.
In an exemplary embodiment of the invention, said apparatus comprises at least one sensor that senses a cardiac parameter and provides said sensed parameter to said controller. Optionally, said sensor measures a cardiac parameter relating to the entire heart. Alternatively or additionally, said sensor measures a cardiac parameter relating to a portion of the heart. Alternatively or additionally, said controller analyses said sensed parameter to detect an effect of said molecule on said heart. Alternatively or additionally, said controller analyses said sensed parameter to detect an activity of the heart and wherein said controller synchronizes said provision to said sensed activity. Alternatively or additionally, said controller analyses said sensed parameter to detect an effect of said transport field on said heart. Alternatively or additionally, said controller modifies said at least one electric field to modify said transport effect responsive to said sensed parameter. Alternatively or additionally, said controller modifies said at least one electric field to modify said control effect responsive to said sensed parameter. Alternatively or additionally, said apparatus comprises a watchdog that detects an abnormal effect of said applied fields. Alternatively or additionally, said apparatus comprises a watchdog that detects an abnormal effect of said molecule.
In an exemplary embodiment of the invention, said apparatus is comp rises in a cylindrical body adapted for implantation inside a blood vessel.
FIG. 1 is a schematic illustration of a heart connected to a non-excitatory signal providing device, in accordance with an exemplary embodiment of the invention;
DETAILED DESCRIPTION OF SOME EMBODIMENTS OF THE INVENTION GENERAL DESCRIPTION OF EXEMPLARY DEVICE
FIG. 1 is a schematic illustration of a heart 102 connected to a non-excitatory signal providing device 100 and showing various optional features of such a connection, in accordance with an exemplary embodiment of the invention.
Various suitable structures and electrical fields are described in a series of PCT applications field by Impulse Dynamics (previously NTC), now U.S. patent applications Ser. Nos. 09/254,900, 09/254,902, 09/254,993 and 09/254,994, the disclosures of which are incorporated herein by reference.
It is suggested in U.S. Pat. No. 5,865,787, an exemplary range for iontophoresis is between 200 Hz and 10 MHz, for example between 2 and 15 kHz. However, in some embodiments, DC waveforms are used. Wave from generators are described in U.S. patent applications Ser. Nos. 08/110,109 and 07/957,209, both abandoned, the disclosures of which are incorporated herein by reference. With regard to electroporation, frequencies between 0.017 and 10 Hz are suggested. Voltages between 100 and 10,000 volts are suggested, with electrodes between 0.5 and 10 cm apart. Pulse durations are suggested between 1 microsecond and 1 second, more typically 100 msec. It is noted, however, that by providing a non-excitatory field to counteract adverse affects, a wider range of fields and field parameters is available, so the above should be taken as only exemplary field parameters.
Additionally, exemplary pulses and/or apparatus which may be useful can be found in U.S. patent application Ser. No. 08/129,252, now abandoned, U.S. Pat. No. 5,634,899, U.S. Pat. No. 5,286,254, U.S. Pat. No. 5,087,243, U.S. Pat. No. 5,458,568, U.S. Pat. No. 5,282,785 and U.S. Pat. No. 5,236,413, the disclosures of which are incorporated herein by reference.
In a paper in Nature 1999, Sep. 23; 401 (6751) pp390–394, the disclosure of which is incorporated herein by reference, Mulligan RC, et al. describe a mechanism for targeting stem cells to where they are required in the body. It is believed such stem cells are targeted by a localized inflammation process, which process may be artificially and locally induced using a suitable molecule in accordance with an exemplary embodiment of the invention.
Apparatus suitable for performing the function of device 100 and generate non-excitatory signals are described, for example in PCT application PCT/IL97/00012, the disclosure of which is incorporated herein by reference.
In an exemplary embodiment of the invention, CPU 122 uses a state-machine model of the heart to assess if the heart is operating as expected and/or to determine the possible timing of non-excitatory pulses, especially for drug transport. Alternatively or additionally, other state-machine models may be used. Alternatively, a non-state machine model is used. Various types of models are described in “Design of Cardiac Pacemakers,”, ed. John G. Webster, 1995, by the Institute of Electrical and Electronics Engineers, Inc., New York, NY, the disclosure of which is incorporated herein by reference.
In an exemplary embodiment of the invention, device 100 includes one or more watchdogs 124. Two types of watchdogs may be utilized in an exemplary embodiment of the invention. A first type of watchdog watches over the device itself, to assure that it is working within the operational parameters defined for it. For example, two processors run concurrently, and if one is not responding, the other one generates an alert. A second type of watchdog watches over the heart, to assure that the heart does not, as a result of the treatment, exceed operational and/or functional parameters defined for the heart's activity. In one example, the watchdog checks to see if the heart is acting differently after the transport pulse. Alternatively or additionally, the watchdog searches for particular tattletale signals of damage more likely to be caused by the treatment, for example, a certain type of arrhythmia in an pro-arrhythmic drug treatment or VT caused by the transport pulse. The damage and/or danger may be immediate, for example the detection of an injury current or of VT. Alternatively or additionally, the damage or danger detected may be longer term, for example, if the treatment causes a forced relaxation of part of the heart, which relaxation may cause hypotrophy or an aneurysm. A separate feedback loop may be provided to detect if the treatment is having a desired effect, for example a desired remodeling of cardiac tissue. Optionally, the watchdog is implemented as a separate processor and/or sensor. Alternatively, the watchdog comprises separate software.
Interaction Between Device and Heart, Other Than Transport
Various device parameters may be programmable, including, for example, pulse parameters such as temporal, spatial, amplitude, polarity, envelope and/or frequency of the applied transport, transport related, pacing and/or non-excitatory fields. Alternatively or additionally, various molecule provision parameters may be controllable, for example the molecule type, timing of provision, amount provided and duration. In some devices, a complete script (e.g. a short program) may be selected or programmed. Alternatively or additionally, script parameters may be selected. A particular example of a script parameter is which sensor to use for monitoring and its associated threshold levels or other value-response function.
In an exemplary embodiment of the invention, feedback is provided with regard to the penetration of the molecules. By using local sensing electrodes, the arrival of the molecules at the desired tissue depth can be monitored by detecting the effect of the molecules. Alternatively or additionally, by transporting radioactive or other marker drugs, it is possible to image or otherwise view the tissue and determine which cells were affected. A marker drug may be the same as the one used for therapy or it may be a different one, specifically selected for ease of detection. Alternatively or additionally, the provision and/or effect of molecules may be detected by applying an electric field to the treated area and base don the response of the tissue estimate the molecule effect and/or arrival.
FIG. 6 illustrates a vascular treatment device 800, in accordance with an exemplary embodiment of the invention. In a coronary vessel application, iontophoresis and electroporation become possible in blood vessels which are near the heart. Example treatments include anti-clotting drugs, drugs to prevent re-stenosis, drugs to prevent stenosis and gene therapy to convert the blood vessel cells to those having a desired function, such as excretion of a desired anti-clotting factor. Such an the electric field may be applied using a dedicated suitable stent or to augment the behavior of a stent which needs to be implanted. Exemplary device 800 is stent-like, having a cylindrical body 802. A plurality of electrodes 804 and 806 are provided, which are electrified by a power supply 810. In one embodiment of the invention, the power supply is a battery. Alternatively or additionally, the power supply comprises an antenna 812 for receiving RF radiation and a converter for converting the received radiation in suitable voltages. Alternatively or additionally, power supply 810 include control logic and/or one or more sensors, for example for sensing a cardiac activity, for example for synchronization purposes or a sensor for sensing the blood vessel state. Optionally, electrodes 804 and 806 can serve as antenna 812. Alternatively, a wired external power source is provided and connected to device 800. In some embodiments, device 800 is used with blood vessels not adjacent to the heart.
In another exemplary embodiment, the salvage of ischemia-damaged tissue is enhanced by both reducing its oxygen requirements using a desensitizing electric field (or fences) and by locally providing work-reducing molecules, such as calcium blockers. In some embodiments, the calcium blockers are systemically provided in a form which has difficulty crossing blood vessel walls. By application of a local field, the calcium blockers affect substantially only the treated area. In some cases, the molecule and the electric field are applied simultaneously. In other cases, they are alternated, for example to allow the tissue to recuperate from adverse effects of one or the other, once the tissue has sufficiently recuperated, it may be trained back to shape and/or have angiogenesis enhancing methods applied to it.
The above application has focused on cardiac applications. It should be noted that similar devices may be used for non-cardiac applications, in excitable or in non-excitable tissues. It should be noted that the heart typically has two properties not found in other excitable tissue: synchronous operation and significant and immediate health risk due to adverse effects. The brain for example, as a whole, does not exhibit unitary synchronized behavior as does the heart. The stomach on the other hand, while it is synchronous, does not pose immediate life-threatening danger as a result of adverse effects.
One exemplary application is treatment of irritable bowel syndrome using locally transported anti-inflammatory drugs, possibly timed to the normal bowel electrical activity so as not to interfere with it. For bowel and other hollow organ applications, a device similar to that of FIG. 6 may be used.
In a urinary example, muscle relaxants to bladder are locally provided. A suitable implantable device may be, for example, a stent implanted inside the urethra.
It will be appreciated that the above-described methods of transporting molecules in the heart and nearby tissues may be varied in many ways. In addition, a multiplicity of various features, both of methods and of devices has been described. Where methods are described, devices for carrying out the methods are also contemplated. It should be appreciated that different features may be combined in different ways. In particular, not all the features shown above in a particular embodiment are necessary in every similar exemplary embodiment of the invention. Further, combinations of the above features are also considered to be within the scope of some exemplary embodiments of the invention. Also within the scope of the invention are devices and/or software for programming existing devices to make the device comply with the methods described herein. Section headings where they appear are meant for clarity of browsing only and should not be construed as limiting the contents of a section to that particular section. When used in the following claims, the terms “comprises”, “includes”, “have” and their conjugates mean “including but not limited to”.
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