MXPA06010202A - Improved apparatus for electrically mediated deliveryof therapeutic agents - Google Patents

Abstract

Apparatus for the delivery of an electrical field which facilitates the intracellular delivery of a therapeutic agent to a predetermined site within the tissue of a patient. The apparatus will comprise a plurality of penetrating electrodes arranged in a predetermined spatial relationship, each electrode with a cross sectional area contributing to the total cross sectional area of all electrodes, and structural means incorporating an inanimate source of energy operatively connected to the plurality of electrodes for deploying the electrodes, wherein the source of energy is sufficient to impart a force of at least 1000 pounds per square inch (0.7 kilogram per square millimeter) of total cross sectional area of all electrodes at the initiation of the deployment of the electrodes. The apparatus will also comprise means for generating an electrical field which facilitates the intracellular delivery of a therapeutic agent, which means is operatively connected to said electrodes at least in their deployed state.

Description

- i - IMPROVED APPARATUS FOR ELECTRICALLY MEASURED SUPPLY OF THERAPEUTIC AGENTS TECHNICAL FIELD The present invention relates to an apparatus for the delivery of prophylactic and therapeutic agents to patients, and more particularly to an apparatus that uses electric fields to deliver said agents intracellularly in a safe, reproducible, effective and cost-effective manner.

BACKGROUND OF THE INVENTION Prophylactic and therapeutic agents have long been administered to patients using various conventional routes of administration such as topical, oral, intravenous, parenteral and the like. Once administered to the patient by the selected route, the delivery of the agent to the tissue of interest and its beneficial interaction with the tissue depends to a large extent on its inherent physicochemical factors, but can be facilitated, for example, by selected components of the delivery composition. such as carriers, adjuvants, buffers and excipients, and the like. More recently, it has been shown that the application of electric fields improves the movement and uptake of macromolecules in living tissue. The application of said electrical fields in tissue in relation to the administration of a prophylactic or therapeutic agent may have desirable effects on the tissue or agent to be delivered. Specifically, techniques such as electroporation and iontophoresis have been used to improve the supply or uptake of a variety of agents in tissues. Such agents include pharmaceutical substances, proteins, antibodies and nucleic acid. Potential clinical applications of such techniques include the provision of chemotherapeutic drugs and therapeutic genes in tumors, the provision of DNA vaccines for prophylactic and therapeutic immunization and the delivery of nucleic acid sequences encoding therapeutic proteins. Many devices for the application of electric fields in tissue have been described for the purpose of improving the supply of agents. The vast majority of these have focused on a means for the efficient application of electric fields within a target tissue region. A variety of surface electrode and penetration systems have been developed to generate the desired electrophysiological effects. Despite the promise associated with the provision of an electrically mediated agent and the potential clinical applications of these techniques, this advancement has been held back by the lack of an effective means to achieve the general objective of an efficient and reliable supply of agents using these techniques. Significant drawbacks of current systems include a complex application procedure, a device design that is not comprehensive, potential dangers for the user and the patient, and the inability to provide a cost-effective means of administration. Since a safe, effective, consistent and cost-effective means of administering therapeutic agents would be highly desirable, the development of improved application systems is well guaranteed. Such development should include a means to minimize the variability associated with the operator and ensure the safety of the user and the patient and at the same time provide the ability to adapt to the differences in patient characteristics that are likely to be encountered during a widely disseminated clinical application. of a supply of an electrically mediated agent.

DESCRIPTION OF THE INVENTION The present invention provides an integrated apparatus that allows administration of an electrically mediated therapeutic agent (EMTAD) which is carried out in a safe, consistent and cost-effective manner. The present invention provides intramuscular, intradermal or subcutaneous administration of therapeutic or prophylactic agents such as nucleic acids, drugs, antibodies and proteins. In one aspect, the present invention provides an apparatus for the delivery of an electric field which facilitates the intracellular administration of a therapeutic agent at a predetermined site within the tissue of a patient. In this regard, the apparatus will comprise a plurality of penetration electrodes distributed in a predetermined spatial relationship, each electrode with a cross-sectional area contributes to the total cross-sectional area of all the electrodes and a structural medium incorporating an inanimate source of energy operatively connected to the plurality of electrodes for deploying the electrodes, wherein the energy source is sufficient to impart a force of at least 0.7 kg / mm2 (1,000 pounds per square inch) of total cross-sectional area of all the electrodes in the start of the deployment of the electrodes. The apparatus will also comprise a means for generating an electric field which facilitates the intracellular administration of a therapeutic agent, which means is operatively connected to the electrodes at least in their deployed state. Another aspect of the invention provides the apparatus with a structural means configured to accept a fluid reservoir for containing a therapeutic agent or with the fluid reservoir itself, wherein the reservoir is operatively connected to at least one injection port and one medium of actuation configured to transmit the therapeutic agent through the orifice to a predetermined site within the tissue of the patient. Other aspects of the invention include said apparatus configured to accept substitutable therapeutic agent fluid reservoir sub-assemblies, electrode sub-assemblies and a combination thereof. An inclusion means is also included for priming the automated mechanisms incorporated in the applicator before inserting the cartridge, identifying the model or type of cartridge that has been inserted and protecting the user and the patient from accidental damage associated with the use of the device. . Additional aspects of the invention include such apparatus configured to improve the functionality and ergonomics of the applicator (i.e., interconnection with the user) in numerous ways. The inanimate energy source can be placed along the fluid reservoir so that the overall length of the device is reduced to improve its ease of use. The deployment of the electrodes and the administration of the therapeutic agent as well as the creation of the electric field can be implemented with a single activation trigger. In addition, safety guards and covers that are included can be included to reduce the risk of accidental discharge and inadvertent contact with the electrodes and fluid port. Additional improvements may be included in the design of the fluid reservoir such as the use of a bottle, such as a glass jar, polycarbonate, polyethylene, etc., as a means of using a dry therapeutic agent, for example lyophilisate and a supply of fluid and allow separate components to mix just before use.

Additional improvements can be included to make the device more easily adaptable to a wide range of patients, for example patients with body mass indexes that differ widely indicating a range of thicknesses of the subcutaneous fat layers of patients or the need to adjust the depth from the predetermined site in the patient. Such improvements may include, for example, a depth gauge for adjusting the penetration depth of the electrodes and orifice or the use of electrodes and orifice structures with different lengths or diameters, for example, different length and gauge of syringe needles.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates three components (applicator, cartridge and syringe) of an embodiment of the integrated apparatus of the present invention, in an exploded view; Figure 2 illustrates the cartridge of the embodiment of Figure 1 assembled with the applicator; Figure 3 is a cross-sectional view of the applicator / cartridge / syringe assembly of the embodiment of Figure 1 with the primed insertion and injection spring mechanisms; Fig. 4 is a cross-sectional view of an applicator of the embodiment of Fig. 1 with unintended insertion and injection spring mechanisms; and Figure 5 is a cross-sectional view of the cartridge of the embodiment of Figure 1 with the syringe inserted.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an integrated apparatus that allows administration of an electrically mediated therapeutic agent (EMTAD) to be carried out in a safe, consistent and cost-effective manner. The present invention allows an effective intramuscular, intradermal or subcutaneous administration of therapeutic or prophylactic agents such as nucleic acids, drugs, antibodies and proteins. In one aspect, the present invention provides an apparatus for the delivery of an electric field which facilitates the intracellular administration of a therapeutic agent at a predetermined site within the tissue of a patient. In this regard, the apparatus will comprise a plurality of penetration electrodes distributed in a predetermined spatial relationship, each electrode with a cross-sectional area contributes to the total cross-sectional area of all the electrodes and a structural medium incorporating an inanimate energy source. operatively connected to the plurality of electrodes for deploying the electrodes, wherein the energy source is sufficient to impart a force of at least 0.7 kg / mm2 (1,000 pounds per square inch) of the total cross-sectional area of all electrodes at start of the deployment of the electrodes. The apparatus will also comprise a means for generating an electric field which facilitates the intracellular administration of a therapeutic agent, which means is operatively connected to the electrodes at least in their deployed state. Another aspect of the invention provides the apparatus with a structural means configured to accept a fluid reservoir for containing a therapeutic agent or with the fluid reservoir itself, wherein the reservoir is operatively connected to at least one injection port and one medium of actuation configured to transmit the therapeutic agent through the orifice to the predetermined site within the patient's tissue. Other aspects of the invention include said apparatus configured to accept fluid reservoir sub-assemblies of substitutable therapeutic agents, electrode sub-assemblies and a combination thereof. Also included is an inclusion means for priming automated mechanisms incorporated in the applicator before inserting the cartridge, identifying the model or type of cartridge that has been inserted and protecting the user and the patient from accidental damage associated with the use of the device. Additional aspects of the invention include said apparatus configured to improve the functionality and ergonomics of the applicator (i.e., the interconnection with the user) in numerous ways. The inanimate energy source can be placed along the fluid reservoir so that the overall length of the device is reduced and its ease of use is improved. The deployment of the electrodes and the administration of the therapeutic agent as well as the creation of the electric field can be implemented with a single activation trigger. In addition, safety guards and covers can be included to reduce the risk of accidental discharge and inadvertent contact with the electrodes and fluid port. Additional improvements in the design of the fluid reservoir, such as the use of a bottle, such as a glass jar, polycarbonate, polyethylene, etc., can be included, as a means of using a dry therapeutic agent, for example lyophilized and a supply fluid and allow separate components to mix just before use. Additional improvements can be included to make the device more easily adaptable to a wide range of patients, for example patients with body mass indexes that differ widely indicating a range of thickness of subcutaneous adipose layers of the patient or the need to adjust the depth of a patient. Default site in the patient. Such improvements may include, for example, a depth gauge for adjusting the depth of penetration of the orifice electrodes or the use of electrodes and orifice structures of different length or diameter, for example, a different length and gauge of needles. of syringe. In general terms, the present invention preferably provides an apparatus for the administration of a therapeutic agent and electric fields to a predetermined site within the skin or skeletal muscle of a patient in a manner that is effective, reproducible and safe for both the operator and for the patient. One embodiment of the apparatus comprises a single-use "cartridge" sub-assembly and a portable "applicator". The single-use sub-assembly comprises a reservoir for containing the agent of interest, at least one orifice through which the agent is delivered to the patient and two or more electrodes capable of propagating the electric fields within the tissue. The manual applicator interconnects with the single use cartridge and incorporates automated mechanisms to: (1) deploy the electrodes to the target tissue site, (2) place the hole in relation to the target tissue site, (3) transfer the agent from the reservoir through the orifice and into the target tissue site, and (4) retransmitting electrical signals from a suitable pulse generator to the electrodes. Although some distinctions can be made between agents which are administered to patients for prophylactic purposes and agents which are administered for therapeutic purposes in the context of the present invention such agents are considered to be substantially equivalent and will be referred to herein as "agents" therapeutic, unless otherwise indicated.

Apparatus Modalities The present invention provides an improved apparatus for safe, effective and reproducible transcutaneous intramuscular (IM) delivery of therapeutic agents with delivery of an electrically mediated therapeutic agent (EMTAD). A specific modality of an integrated unit for transcutaneous IM applications is illustrated in Figures 1-5. The apparatus consists of a main unit (applicator) 100 and a single-use sub-assembly (cartridge) 200 separable. The cartridge is configured to include a reservoir containing the agent to be administered prior to delivery. The deposit will be designed and constructed to keep the agent in a stable environment and avoid contamination. The reservoir is operatively connected to an orifice through which an agent is administered to the interior of the patient. More commonly, the reservoir and the orifice are comprised of a syringe connected to a hollow injection needle 300. The cartridge encloses the electrode array and includes an integral automatic protection against unwanted contact with the electrodes or the orifice / injection needle (ie, a "bar protection"). The applicator 100 incorporates a spring mechanism for automatic insertion of the electrode array into the injection needle within the target tissue. The applicator also includes a separate spring mechanism for automated injection of the therapeutic agent controlled through the built-in syringe. The applicator incorporates a means for enabling electrical communication with an appropriate pulse generating device capable of controlling the treatment application sequence. Most commonly, electrical communication is obtained through a conductor cable and a connector. A trigger 101 on the applicator is used to start the treatment. Finally, a system to identify the inserted cartridge and set the treatment parameters based on the cartridge is provided in the applicator.

Integration of the agent / syringe with the cartridge In previously described devices of this nature, a means for administration of the therapeutic agent comprising a reservoir and at least one orifice through which the agent is administered has been described. In the clinical practice of the invention described previously it is desirable to integrate the medium for administration of the therapeutic agent (reservoir and orifice) with the cartridge. The integration of the administration means with the cartridge can simplify the procedure by reducing the handling of the apparatus. Reducing the handling of the device can also improve safety for the operator and the patient by eliminating the hazards of an applicator with a needle and dosing errors. The integration also improves the accuracy of the predetermined spatial relationship between the agent supply port and the electrode array. There are several suitable ways of integrating the agent administration means with a single use cartridge. The cartridge can be configured to accept a syringe and a needle as the reservoir and orifice. It is desirable that once the syringe has been integrated with the cartridge, such integration is permanent. The permanent integration will prevent dissociation of the syringe and cartridge and reduce the possibility of damage by needle sticks. The syringe may be a general-purpose syringe that is loaded with the agent prior to the agent administration procedure. The use of a general purpose syringe allows a cartridge configuration to supply numerous agents and dosage combinations. Additionally, general use syringes are readily available and cost-effective. Alternatively, the syringe can be pre-filled with an agent and packed with the cartridge. The use of a prefilled syringe reduces the possibility of dosage errors. Additionally, a prefilled syringe does not require a plunger extend from the proximal end of the syringe to manually load the agent. The elimination of the plunger extension allows a smaller device that uses less material and is more ergonomic. Another way of integrating the reservoir and orifice with the cartridge is to incorporate the reservoir into the cartridge design and thus eliminate the need for a separate syringe. It is preferable that the cartridge be constructed of an inert material to avoid reaction with the agent. Suitable materials include, but are not limited to glass, polycarbonate and polyethylene. It is desirable to store certain agents in a lyophilized state to improve their shelf life. Such agents are mixed with a diluent before administration. A double chamber tank in which the lyophilized agent and the diluent are stored in separate chambers can also be used for such agents. Before the treatment the separation between the chambers is removed or broken to allow the mixing of the agent and the diluent. A suitable separation between the chambers is a shut-off valve that is manually opened. Another suitable separation is a thin film or a check valve that can be opened when adequate pressure is applied to the diluent chamber. Said double chamber tank can be incorporated in the cartridge. A specific embodiment for integrating the agent administration means with the cartridge is described herein. The specific modality uses an off-the-shelf syringe and a 300 needle for the administration reservoir and orifice. The cartridge 200 is configured to accept the syringe and place the hole of the needle in a predetermined spatial relationship with the electrode array. In addition, the cartridge is configured with snap-fit tabs 224 that lock the syringe in place once it is inserted into the cartridge.

Impulse mechanisms There are several mechanisms that are suitable as inanimate energy sources for inserting the electrodes and the injection needle through the skin and into the target treatment tissue and also for injecting the agent through the needle. A mechanism driven by compressed gas is the one used in said apparatus. Electromechanical mechanisms such as solenoids, linear motors and electrode screws are also acceptable. However, the preferred solution for the transcutaneous insertion of an electrode and an insertion needle is a spring-based mechanism. The electrode insertion mechanisms require sufficient force to quickly penetrate the skin and implant the electrodes inside the muscle. A rapid insertion can reduce the tension in the skin at the insertion site and in this way the deflection of the electrode or the needle is reduced. The deflection of the electrode can distort the distribution of the electrode and affect the effectiveness of the treatment and the safety of the patient. The distortion of the needle can lead to a colocalization of the agent and electric fields. In this way it is desirable to insert the electrodes and the needle rapidly to minimize deflection. Additionally, a rapid electrode / needle insertion reduces discomfort in the patient. Energy storage and discharge characteristics of spring-based mechanisms are adequate to allow rapid deployment of electrodes and injection needles into the tissue, with minimal distortion. The insertion and injection mechanisms for transcutaneous applications also require sufficient linear movement (throwing) to implant the electrodes at the target treatment depth to inject the prescribed volume / dose of the agent. Spring mechanisms are preferred since they can achieve adequate linear movement in a small, lightweight package. Additionally, the spring mechanisms do not require electrical or gas connections, do not require consumable equipment such as compressed gas cans and are ultimately cost effective.

Automatic / passive spring priming Although their functional characteristics and profitability make them preferable over others, spring mechanisms require priming. The energy is imparted and stored in the spring before triggering the treatment sequence. Previously described devices of this nature require the user to actively perform a separate step to prime the spring mechanism before use of the device. The described invention includes a means for automatically or passively priming the spring mechanism before the insertion of the cartridge 200 in the applicator 100. It is desirable that the priming of the spring mechanism ("spring priming") be carried out together with the insert of the cartridge 200 in the applicator 100. In addition, to simplify the procedure, the automated / passive spring priming also eliminates the problematic failure mode of non-priming of the spring. A variety of mechanisms energized in the apparatus can be used to carry out automated priming of the spring. These mechanisms comprise an energy source, a suitable trigger and a means for transferring energy from the energy source to one or more springs. The insertion of the cartridge in the applicator activates the trigger that leads to the transfer of energy from the power source to one or more springs. Power sources / mechanisms to obtain this function include but are not limited to compressed gas, solenoids and motor-based electrical mechanisms. A preferred method and apparatus is to use the insertion and attachment of the cartridge 200 to the applicator 100 as a means to passively prime the spring mechanisms during insertion of the cartridge into the applicator - "cartridge priming". Utilizing the cartridge priming method the benefits of the described invention are provided and at the same time the need for an additional priming mechanism required for automated spring priming is eliminated. This simplifies the device and reduces costs without sacrificing ease of use and security. In the modalities where the cartridge is used to prime spring drives, there will be a means for applying force to the injection drive mechanism through the cartridge without depressing the spring plunger and ejecting the agent from the syringe. Additionally, since the operator applies force to the cartridge to prime the spring mechanisms, it is desirable that the apparatus include a means to prevent accidental deployment of the electrodes or needles during the insertion of the cartridge into the applicator to prevent damage by pinholes. needle. In addition, it is desirable that the means to avoid pitting also avoid damage or contamination to the electrodes and the needle during priming.

Finally, in this mode there is a risk that the operator can release the cartridge before completing the priming. This can result in the stored spring energy ejecting the cartridge from the applicator causing damage or alteration to the appliance. Therefore, it is desirable to avoid accidental ejection of the cartridge. A specific embodiment is presented in Figures 1-5 to obtain the invention of cartridge priming. Those skilled in the art will appreciate that the specific mechanisms used to obtain cartridge priming are a matter of convenience and that the use of alternative mechanisms to obtain cartridge priming do not depart from the scope of the invention described. In the specific embodiment described herein, cartridge 200 and applicator 100 are configured such that cartridge 200 can only be inserted into applicator 100 in a specific priming orientation. In the priming orientation, at least one cantilevered extension 202 of the cartridge engages the injection drive mechanism 110 and imparts the priming force to the mechanism while preventing the mechanism from contacting the syringe plunger 302. This specific mode provides pinhole prevention and protects the electrodes / needle from damage / contamination during priming by keeping the electrodes / needle securely retracted securely and immobilized within the cartridge. Press fit tabs 222 incorporated in the cartridge prevent the electrode hub 220 from moving axially relative to the cartridge collar 210 and thereby keep the electrodes / needle safely retracted within the cartridge. Additional protection against pitting and contamination by a cover 230 is provided on the distal end of the cartridge. The lid 230 is separated before the treatment application. Preferably, the lid is constructed of a puncture-resistant material and the interconnection between the lid and the cartridge is designed to minimize the risk of contamination during handling. The electrode hub 220 engages the insert drive mechanism 120 and transfers the priming force applied to the cartridge collar 210 to the insertion mechanism. To prevent accidental ejection of the cartridge during priming, this specific embodiment incorporates one-way leaf spring locks 130 in the applicator that allow the cartridge to insert in priming orientation but prevent it from being removed or ejected in said orientation. A ratchet mechanism is another suitable means to prevent accidental ejection of the cartridge. When the cartridge is fully inserted into the applicator two latches 112, 122 spring-loaded actuator retain the insert and injection spring mechanisms and keep them in their primed and energized state until they are actuated during the treatment. A solenoid actuator 114, 124 is attached to each latch 112, 122 and when actuated displaces the latch and releases the spring mechanism 110, 120. Upon completion of the cartridge insertion and priming of the spring mechanism, the cartridge is rotated 1/4 turn to complete the union of the cartridge to the applicator. In this attached orientation the cantilevered extension 202 is decoupled from the injection drive mechanism 110 by releasing the mechanism to act on the syringe plunger 302 when the injection mechanism is released. Additionally, in this attached orientation, the applicator presses the tabs 222 and releases the electrode hub to move it axially relative to the cartridge, so that the insertion mechanism can advance the electrodes and the needle when the mechanism is released.

Designs that allow improved factors of interconnection with the user In the practice of the invention, ergonomic and human factors play a significant role in consistently providing safe and effective agent administration. The size and shape of the apparatus used for administration of the agent (the interconnection with the user) can alter the ability of the operator to effectively deliver the agent to the target tissue site. It is desirable that the design of the apparatus facilitate the precise positioning of the apparatus in the proper location and orientation. Improper placement of the device can alter both the safety and effectiveness of the treatment. In addition to the human factors associated with the user, the size and shape of the device can also influence patient acceptance. A device can be intimidating to patients, particularly if it is especially large, has a shape that suggests a gun or intimidates it in some other way. Therefore, it is desirable that the device has a form factor that is ergonomic and does not intimidate. In previously described devices of this nature, the driving mechanisms have been distributed collinearly and in series with the cartridge. This results in a long and stupid device. The invention described uses one or more driving mechanisms distributed in parallel with the cartridge and the line of action of the electrodes and the syringe. The parallel drives can be distributed collinearly or in a deviated manner. This parallel distribution provides a more compact, ergonomic and non-intimidating device. A specific embodiment using desired parallel spring mechanisms is described in Figures 1-5, however, the invention can be adapted to obtain a desirable shape factor using other spring mechanisms and impellers. For example, the spring may surround the electrode array or the syringe. Additionally, the mechanism can use the mechanical advantage of increasing linear movement or force. In the specific embodiment illustrated in Figures 1-5, the spring mechanisms for insertion and injection are placed inside the applicator, parallel and offset from the cartridge. The force and movement of the spring mechanisms are transferred to the cartridge through the arms 116, 126 impellers that extend through the applicator and interconnect with the cartridge.

Identification of the cartridge In order to be suitable for use in clinical applications, the EMTAD device must adapt the range of doses that can be prescribed for a given agent. When EMTAD is used, the "dose" of the agent is determined by the volume and concentration administered, the configuration of the electrode array, and the electrical field parameters applied to the tissue (including waveform, voltage, duration, frequency, and number). of pulses). In order to ensure that the prescribed "dose" is applied to a given patient, the appropriate electrical parameters will be transported to the pulse generator. Although this can be accomplished through a user input, such a system may create a risk that a user error may result in a dangerous operating condition. Therefore, it is desirable to provide an automated means for dosage recognition that minimizes the risk of a dangerous operating condition. Although there are several automated means for dosage recognition, a preferable method is carried out in conjunction with the insertion of the cartridge into the applicator. In such an embodiment, the parameters of the electrical signal partially determine the dose and are determined by the cartridge that includes the other two dose parameters (agent and electrode distribution). It is also desirable that the processing sequence can not be started until the parameters of the electrical signal are established. This ensures a safe and proper connection of the cartridge to the applicator. In previously described devices of this nature, programmable integrated circuits and relatively expensive ones have been described. In order to be suitable for commercial application the means for cartridge identification / electrical signal parameter recognition must be cost-effective. In particular, the components of the identification system and the associated manufacturing processes that are part of the one-time use cartridge must be cost-effective. A person skilled in the art will recognize that there are several suitable means for cartridge identification / electrical signal recognition. Suitable means include identification, optical of a bar code and wireless radio frequency identification. In the case of barcode identification, the barcode can be fixed or printed on the cartridge and the reader can be integrated into the applicator. In the case of radio frequency identification the transponder can be integrated into the cartridge and the receiver can be included in the applicator. Preferably, the receiver will be tuned only to receive the radio frequency signal when the cartridge has been properly attached to the applicator. Another suitable method is to use a series of separate switches on the applicator that can be closed when the cartridge is inserted. The pattern of open and closed switches can determine the electrical signal parameters. The switches can be electromechanical, optoelectronic or any other suitable switch. For example, a modality using three pairs of open contacts in the applicator 100 is illustrated. A conductive tape is attached to the cartridge 200 to close the contact pairs when the cartridge is attached to the applicator. This three-octet system will identify seven electrical signal parameter settings plus three pairs of open contacts that will indicate when the cartridge is not attached. In addition to defining the dose of administration, the invention described may also facilitate the use of a single application system for the delivery of multiple classes of agents, which require different electrical conditions to obtain an effective supply.

Adjustable treatment depth An effective, consistent and safe application of EMTAD for intramuscular delivery is based, in part, on the treatment of a consistent volume of muscle tissue. However, there is significant variation between patients and treatment sites in the thickness of the subcutaneous fat pad that is penetrated to gain access to target muscle tissue. In one study (Poland GA, et al., JAMA, 1997 June 4; 277 (21): 1709-11) a thickness range of deltoid fat pad from 3.7 mm to 35.6 mm is reported. Thus, for a given electrode array size, the volume of affected muscle tissue will vary based on the thickness of the fat pad. Additionally, the thickness of the tissue between the skin and the bone also varies significantly between patients and between treatment sites. In this way, an appropriate length of electrode / needle to treat a large patient may collide with the bone during insertion in a small patient. Electrode contact with bone can cause harm to the patient or can distort the electrode array and alter the safety and efficacy of the treatment. Therefore, it is desirable to provide a means for adjusting the penetration depth of the electrode / needle based on the treatment site and the anatomy of the patient. In the present invention, an adjustable ring 240 on the distal tip of the present invention modifies the penetration depth of the electrode / needle. The ring can be adjusted axially relative to the cartridge tip 200 so that the length of the ring extending beyond its distal tip of the apparatus reduces the length of the electrode / needle penetrating the patient. The specific embodiment illustrated in Figures 1-5 uses a diamond-shaped ring that snaps in separate axial positions. To modify its position, the major axis of the diamond-shaped ring is compressed causing the minor axis to expand and free the cartridge ring. Another suitable embodiment is a ring which is threaded on the tip of the cartridge and which can be adjusted by threading the ring back and forth on the cartridge. This mode allows a continuous number of depth adjustment positions.

Automatic / passive release of trigger safety Inadvertent release of primed insertion and injection spring mechanisms may result in damage, loss of therapeutic agent or damage to the device. Therefore, it is desirable to provide a safety system that prevents accidental release of the spring mechanisms. It is preferable that such a safety system prevents accidental release of the spring mechanisms due to external forces such as vibration and impact. Additionally, the operator may inadvertently activate the processing sequence when handling the device, so that it is preferable for the security system to prevent activation of the treatment sequence unless the device is properly applied to the treatment site. Proper placement at the treatment site can also alter the effectiveness of treatment. For example, the device is desirably applied to the treatment site with adequate force to ensure that the electrodes / needle penetrate the tissue to the full prescribed depth. Preferably, the security system is automatically and passively deactivated when the device is applied to the treatment site with adequate force. The automatic and passive disabling of the security system does not require a separate operator stage. In addition to simplifying the procedure, disabling automated / passive security also eliminates the possible failure mode of not deactivating the security system. To ensure that the electrodes / needle penetrate the tissue to the full prescribed depth, the minimum force with which the device is applied to the treatment site (the "application force") will exceed the force required to insert the electrodes / needle (the "electrode insertion force"). The electrode insertion force depends on several variables, which are described in detail in the following. By way of example, a typical electrode insertion force may be 11.1 Newtons (2.5 pounds), and therefore the minimum application force may be 11.1 Newtons (2.5 pounds). Preferably, a safety margin can be added to the insertion force so that the application force is between 15.6 and 22.2 Newtons (3.5-5.0 pounds). Preferably, the required application force will not exceed the force that the operator can comfortably apply to the treatment site. A preferred embodiment of the described security system is described herein. Within the applicator 100 at least one mechanical stop 140 physically prevents the bolts 112, 122 from disengagement from the insertion spring 120 and injection 110 mechanisms. The connection between the applicator trigger and the pulse generator is kept open by a electronic switch 142 and in this way the accidental activation of the treatment sequence is prevented. The internal mechanisms of the applicator float axially within the outer housing 102 and are held in a position extended by a spring 144 acting between the inner applicator and the outer housing. The spring is equal to the preferred application force. When the apparatus is applied to the treatment site with adequate pressure to overcome the force of the spring, the internal applicator is repositioned within the outer housing 102. In this position, security systems are disabled. The stop 140 changes position in relation to the bolts and no longer prevents the bolts from uncoupling from the insertion and injection spring mechanisms. In addition, the electronic switch 142 contacts the outer housing and closes allowing the trigger to communicate with the pulse generator and initiate the processing sequence.

Force / Electrode array insertion spring rate The electrode insertion mechanisms require sufficient force to quickly penetrate the skin and implant the electrodes in the muscle. Rapid insertion can reduce the tension of the skin at the insertion site and therefore reduce the deflection of the electrode or needle. The deflection of the electrode can distort the electrode array and alter the effectiveness of the treatment and patient safety. The distortion of needles can alter the colocalization of the agent and the electric fields. In this way, it is desirable to insert the electrodes and needle quickly to minimize deflection. Additionally, a rapid electrode / needle insertion reduces patient discomfort. The storage and energy discharge characteristics of the spring-based mechanisms are adequate to allow rapid deployment of electrodes and injection needles into the tissue, with minimal distortion.

Several variables influence the spring force necessary for a rapid intramuscular insertion of the electrode, including the diameter of the electrode, the number of the electrode, the separation between electrodes and the geometry of the tip of the electrode. For intramuscular EMTAD, common electrode diameters vary from 0.25 mm to 1.50 mm and typical electrode array configurations contain 2 to 7 electrodes. The force required to insert the electrode arrays within these ranges is proportional to both the electrode diameter and the number of electrodes. For example, increasing the electrode diameter or increasing the number of electrodes results in an increase in the minimum necessary insertion force. On the other hand, the separation of the electrodes is inversely provided to the separation between electrodes. Due to the interaction of tissue that moves as the electrode is inserted, a smaller separation of the electrodes results in a greater insertion force. A typical EMTAD apparatus, incorporating arrays of penetration electrodes that use an intraelectrode spacing at least 10 times larger than the diameter of the electrodes comprising the array and more commonly 15-20 times greater. Within this range there is little displaceable tissue interaction and therefore the separation of electrodes has a minimal effect on the insertion force. The geometry of the cutting tip of the electrode is preferred to minimize the insertion force. A blunt and dilating tip geometry requires an increased insertion force.

Experiments have been carried out to determine the force / minimum rate necessary for a rapid percutaneous implantation of intramuscular electrodes. An appropriate electrode array selection is evaluated for EMTAD intramuscular application and with cutting tip electrodes. Each electrode array is implanted in a porcine model and the minimum spring force necessary to quickly penetrate the skin tissue and implant the electrode array without significant distortion is determined. Due to the force exerted by a spring decreases as the spring energy is released two results are provided. The first is the force at the start of the spring stroke and represents the minimum force necessary to penetrate the skin tissue. The second is the force at the end of the spring stroke and represents the minimum force necessary to implant the electrode array through the subcutaneous and muscular tissue. Because the forces depend on the electrode diameter and the number of electrodes, the results are given as a force ratio to the cross-sectional area of the electrodes in the array. The results indicate that a minimum of 0.7 kg / mm2 (1000 pounds of force per square inch) of cross-sectional area of the electrodes at the start of the implant stroke and a minimum of? .35 kg / mm2 (500 pounds) is desirable. strength per square inch) of cross-sectional area of the electrodes at the end of the implant stroke, to implant the electrodes. To ensure a consistent and reliable deployment of the electrodes, an initial implant force of at least 1.4 kg / mm2 (2000 pounds per square inch) of cross-sectional area of the electrode and a terminal implant force of at least 0.5 is preferred. kg / mm (750 pounds of force per square inch) of cross-sectional area of the electrodes. By way of example, an array consisting of 4 electrodes, each with a diameter of 0.5 mm (0.02 inches) will have a total cross-sectional area of approximately 0.8 square millimeters (0.00125 square inches). Therefore, a mechanism for the deployment of the example arrangement requires a minimum force of 5.5 Newtons (1.25 pounds) to obtain the insertion and more preferably a force of at least 11 Newtons (2.50 pounds). In the modalities where the spring mechanisms are manually primed, it is preferable to limit the force of the springs so that the operator can comfortably prime the springs. A preferred limit for spring priming is less than 67 Newtons (15 pounds of force). For embodiments where the spring mechanism is primed separately, the maximum force for a spring is 67 Newtons (15 pounds). However, for those embodiments wherein the insertion and injection spring mechanisms are simultaneously primed, the combined spring force will preferably not exceed 67 Newtons (15 pounds).

Strength / Agent administration spring rate Various variables affect the force required to administer the therapeutic agent. These variables include the viscosity of the agent, the cross-sectional area of the syringe, the gauge of the needle, the cross-sectional area of 1 or more of the orifices and the tissue density. For typical parameters of intramuscular EMTAD, the minimum spring force required to administer the therapeutic agent is 1.1 Newtons (0.25 pounds). Preferably, the injection spring force is between 4.5 and 45 Newtons (1 and 10 pounds). Although the functional characteristics and cost-effectiveness of the injection spring mechanisms make them generally preferable, the impact of the drive on the syringe plunger can generate a "water hammer" effect. The force wave generated from the impact can travel through the agent inside the syringe which can cause damage to the syringe or needle. In particular, the buckets of a standard plastic needle may fracture or split causing the agent to leak before it is fully administered. Therefore, it is desirable to dampen the impact energy of the drive without altering the force / injection rate of the agent. There are several means to dampen the impact energy of the drive mechanism. One such means is to place a material 118 that absorbs energy between the plunger 302 of the syringe and the drive mechanism 116. Suitable materials that absorb energy include, but are not limited to, elastomers such as silicone and polyurethane as well as foam and closed cell. Another suitable means for absorbing the impact is a gas / fluid buffer to slow down the speed of the drive. Such an apparatus requires at least a portion of the injection drive mechanism to move a gas or fluid through a small leak hole in order to move forward. Preferably the air gas and the leak hole is adjusted so that the generated damping is less than the damping produced from the administration of the agent through the injection needle. In such a case, gas damping will only affect the speed of the drive until the syringe has contact point at which the damping produced from the administration of the agent through the injection needle will be the limiting factor that alters the administration of the agent .

Automatic / passive prevention of stings The subsequent treatment of the electrodes and the injection needle represents a danger of needle stings and transfer of pathogens transported by the blood. Therefore, it is desirable that the apparatus includes an integral protection against pitting. In addition, it is desirable that the protection against pitting be automatic and passive. An automatic protection against bites will eliminate possible damages when manually describing the protection of pitting and also eliminates the possible failure mode of not deploying the protection against pitting. Preferably, upon activation, the pinhole protection includes a means to immobilize it in place or to prevent anyone from possibly trying to remove the pinhole protection once it is deployed. A preferred embodiment of a sting protection by integral automatic immobilization is presented, however, a person skilled in the art will appreciate that other modalities can achieve the same objective. The specific embodiment described herein utilizes an integral bite cover 250 to the cartridge that automatically extends over the electrodes / water as they are removed from the patient. A compression spring 252 is placed within the cartridge proximate the pitting cover between the pit cover and the electrode hub 220. As the electrode hub advances virtually during insertion of the electrode / needle, the spring is compressed. When the electrodes / needle are removed after treatment to the patient, the spring extends and extends the pinhole protection distally over the electrodes and the needle. As the cover over the electrodes and the needle is fully extended, cantilevered tabs on the pit cover are snapped into corresponding grooves in the collar 210 and thus secure the cover in its extended position.

Single use Users can try to reuse the single use cartridge to save costs or to apply an expired agent. The reuse of the cartridge can impair the effective safety of a treatment. For example, the coatings on the electrodes are used to ensure biocompatibility and can not receive multiple uses so that the treatment can generate a toxic result in the patient. Additionally, the sterility of the reused device can not be ensured. Therefore it is desirable to include features in the apparatus that prevent its reuse. The apparatus described herein includes three features that prevent its reuse. The pitting cover 250 is fixed in an extended position preventing the electrodes and the needle from being inserted into the patient. The syringe is permanently attached to the cartridge when it is inserted so that the syringe can not be separated to be reloaded with the agent. Finally, after insertion of the electrode, the configuration of the cartridge hub / collar is fixed with the hub inserted in the collar. In this configuration the cartridge will not prime in the spring mechanisms for injection and insertion. Furthermore, in this configuration the cartridge identification makes contact in the applicator and will not communicate with the cartridge so that the control system will not recognize the cartridge and will avoid the treatment. Those skilled in the art will recognize that other suitable means exist to avoid reuse. One such method is to incorporate a fuse into the cartridge and apply a signal from the pulse generator that burns the fuse at the end of the treatment. One such means is to identify each cartridge with a unique serial number that is read by an applicator. The pulse generator will store the serial numbers and will not apply treatments through cartridges whose serial numbers have been read and stored.

Manufacturing Susceptibility In order to be well suited for commercial application, the manufacturing costs of a single use cartridge should be as low as possible. In addition, when EMTAD is applied, multiple electrode array configurations may be required to provide a range of prescribed doses for a given agent. One method to reduce manufacturing costs while producing multiple array configurations is to use many of the same components in multiple cartridge configurations. This solution will reduce costs including but not limited to tool handling costs, inventory costs, quality control costs and management costs. In the specific embodiment illustrated in Figure 5, the electrode array configuration is combined by changing the geometry of only the electrodes 260. A bend 262 near the distal end of the electrode changes the relative position of the penetration end of the electrodes inside the cartridge and therefore changes the array configuration. The cartridge components are designed to accept multiple electrode geometries and can therefore be used in multiple electrode array configurations. Additionally, the cartridge components are designed to press fit together and use the bend in the electrode to securely hold the electrodes between the cartridge components. This solution further reduces manufacturing costs by eliminating more expensive bonding techniques such as adhesive gaskets, solvent bonding, insertion molding and ultrasonic welding. All patents and patent applications mentioned in this specification are incorporated herein by reference and if they have been specifically and individually indicated to be incorporated by reference, although the above invention has been described in some detail by way of illustration and examples for purposes of clarity and understanding, it will be apparent to those ordinarily skilled in the art, in light of the description that certain changes and modifications may be made thereto without thereby departing from the spirit or scope of the appended claims.

Claims (30)

1. An apparatus for the supply of an electric field which facilitates the intracellular delivery of a therapeutic agent at a predetermined site within the tissue of a patient, characterized in that it comprises: a) a plurality of penetration electrodes distributed in a predetermined spatial relationship, each electrode with a cross-sectional area that contributes to the total cross-sectional area of all the electrodes; b) a structural means incorporating an inanimate energy source operatively connected to the plurality of electrodes for the deployment of the electrodes and wherein the energy source is sufficient to impart a force of at least 0.7 kg / mm2 (1000 pounds per square inch) to a total cross-sectional area of all the electrodes at the start of electrode deployment; and c) a means for generating an electric field which facilitates the intracellular delivery of a therapeutic agent, which means is operatively connected to the electrodes at least in their deployed state.

2. An apparatus for the intracellular delivery of a therapeutic agent to a predetermined site within the tissue of a patient, characterized in that it comprises: a) a plurality of penetrating electrodes distributed in a predetermined spatial relationship, each electrode having a cross-sectional area which contributes to the total cross-sectional area of all the electrodes; b) a structural means incorporating an inanimate energy source operatively connected to the plurality of electrodes for the deployment of the electrodes and wherein the energy source is sufficient to impart a force of at least 0.7 kg / mm (1000 pounds per square inch) to a total cross-sectional area of all the electrodes at the start of electrode deployment; c) a structural means configured to accept a reservoir of fluid to contain a therapeutic agent, the reservoir is operatively connected to at least one injection orifice; d) a drive means configured to transmit the therapeutic agent through the orifice to a predetermined site within the patient's tissue; and e) a means for generating an electric field which facilitates the intracellular delivery of a therapeutic agent, which means is operatively connected to the electrodes at least in their deployed state.

The apparatus according to claim 1 or 2, characterized in that the energy source for deploying the electrodes is at least one spring.

4. The apparatus according to claim 1 or 2, characterized in that the energy source for deploying the electrodes is at least one compressed gas.

The apparatus according to claim 1 or 2, characterized in that the power source for deploying the electrodes is a linear motor.

The apparatus according to claim 1 or 2, characterized in that the electrodes comprise a sub-assembly that can be separated from the energy source.

The apparatus according to claim 2, characterized in that the reservoir and orifice comprises a needle and a syringe.

The apparatus according to claim 7, characterized in that the syringe is provided pre-filled with the therapeutic agent.

The apparatus according to claim 2, characterized in that the reservoir comprises a glass bottle.

The apparatus according to claim 2, characterized in that the reservoir and the orifice comprise a sub-assembly that can be separated from the energy source.

The apparatus according to claim 2, characterized in that the electrodes, the reservoir and the orifice are housed within a single sub-assembly that can be separated from the energy source.

12. The apparatus according to claim 11, characterized in that the reservoir is provided pre-filled with the therapeutic agent.

13. The apparatus according to claim 1 or 2, characterized in that the electrodes comprise a conductive metal coated with an electrochemically stable conductive compound.

The aatus according to claim 1 or 2, characterized in that the electrochemically stable conductive compound is selected from the group consisting of: titanium nitride, platinum, platinum and iridium alloys and iridium oxide.

The aatus according to claim 1 or 2, characterized in that the means for generating an electric field is configured to induce an electric field from about 50 to about 300 V / cm between at least two of said electrodes.

The aatus according to claim 1 or 2, characterized in that the means for generating an electric field is configured to supply the field for a duration of about 1 microsecond to about 100 milliseconds and a frequency of about 0.1 Hertz to about 1 megahertz. to at least two of the electrodes.

17. An aatus for intracellularly delivering a therapeutic agent to a predetermined site within the tissue of a patient, characterized in that it comprises: a) a reservoir of fluid for containing a therapeutic agent, the reservoir is operatively connected to at least one injection port; b) a drive means configured to transmit the therapeutic agent through the orifice to a predetermined site within the patient's tissue; c) a plurality of penetration electrodes distributed in a predetermined spatial relationship; d) a structural means incorporating operative connections for the penetration electrodes, the fluid reservoir and the injection orifice, wherein the structural means is configured to allow the distribution of the plurality of electrodes and the injection orifice within the tissue of a patient, according to a predetermined spatial relationship; e) an inanimate energy source operatively connected to the driving means, wherein the power source is configured to apply a force of at least 1.1 Newtons (0.25 pounds) through the fluid reservoir to the therapeutic agent; and f) a means for generating an electric field which facilitates the intracellular delivery of the therapeutic agent, which means is operatively connected to the electrodes at least in their deployed state.

18. The apparatus according to claim 17, characterized in that the energy source for transferring the therapeutic agent from the reservoir through the orifice is at least one spring.

The apparatus according to claim 17, characterized in that the energy source for transferring the therapeutic agent from the reservoir through the orifice is at least one compressed gas.

The apparatus according to claim 17, characterized in that the energy source for transferring the therapeutic agent from the reservoir through the orifice is a linear motor.

The apparatus according to claim 17, characterized in that the reservoir and the orifice comprise a syringe and a hypodermic needle.

22. The apparatus according to claim 21, characterized in that the syringe is provided pre-filled with the therapeutic agent.

23. The apparatus according to claim 17, characterized in that the reservoir is a glass bottle.

24. The apparatus according to claim 17, characterized in that the electrodes comprise a sub-assembly that can be separated from the source of inanimate energy.

25. The apparatus according to claim 17, characterized in that the reservoir and the orifice comprise a sub-assembly that can be separated from the source of inanimate energy.

26. The apparatus according to claim 17, characterized in that the electrodes, the reservoir and the orifice are housed within a single sub-assembly that can be separated from the source of inanimate energy.

27. The apparatus according to claim 17, characterized in that the electrodes comprise a conductive metal coated with a conductive and electrochemically stable compound.

The apparatus according to claim 17, characterized in that the conductive and electrochemically stable compound is at least one material that is selected from the group consisting of: titanium nitride, platinum, platinum and iridium alloys and iridium oxide.

29. The apparatus according to claim 17, characterized in that the means for generating an electric field is configured to induce an electric field from about 50 to about 300 V / cm between at least two of said electrodes. The apparatus according to claim 17, characterized in that the means for generating an electric field is configured to supply the field for a duration from about 1 microsecond to about 100 milliseconds and at a frequency from about 0.1 Hertz to about 1 megahertz to at least two of said electrodes.