Biopharmaceuticals – Andrew W. Hannaman, Robert M. Bernard, Stephen A. Morse, Oliver Ruck, Adam Hartman, Thomas David COX, Ichor Medical Systems Inc
Abstract for “Methods and apparatus for the delivery of therapeutic agents”
“Methods for the consistent, reliable and effective delivery of a therapeutic drug to a subject” The present disclosure includes an apparatus that allows controlled administration of the therapeutic drug through an orifice. It also includes a plurality penetrating electrodes that are arranged in a predetermined relationship to the orifice. An electrical signal generator is connected to the electrodes.
Background for “Methods and apparatus for the delivery of therapeutic agents”
“Prophylactic or therapeutic agents have been administered to patients for many years using a variety of routes, including topical, intravenous and parenteral. The route chosen for the administration of the agent is dependent on the tissue’s inherent physicochemical characteristics. However, certain components of the delivery composition, such as carriers, adjuvants or buffers, can facilitate the delivery to the tissue.
The local application of electric signals has been shown in studies to increase the uptake and distribution of macromolecules within living tissue. The application of these electrical signals to tissue can result in beneficial effects for the tissue and/or the drug being administered. Techniques such as electroporation or iontophoresis can be used to improve the distribution and/or absorption of various agents in tissues. These agents can include pharmaceuticals, proteins and peptides as well as nucleic acid sequences. These techniques could be used in clinical settings to deliver chemotherapeutic drugs to tumors, nucleic acids sequences for prophylactic or therapeutic immunization and nucleic acids sequences encoding therapeutic protein sequences or peptides.
“Many devices have been developed for the application and enhancement of agent delivery by electrical signals to tissue. Most of them have been focused on the application of electrical signals in a targeted area of tissue. For generating desired electrophysiological effects, a variety of penetrating and surface electrode systems has been created.
These procedures involve the administration of an agent to a target site and the application of sufficient electrical fields for the desired effects on delivery, distribution and/or potential of the agent. Two or more electrodes are used to transmit the electrical fields to the tissue. These electrode configurations are suitable for use with tissue penetrating, surface contact, and air gap electrodes. You can choose from a variety of electrode configurations including elongate or rod electrodes as well as point, meander, planar, and combination thereof. Based on the type of target tissue and the purpose of the procedure, the specific type and arrangement for electrodes are chosen.
“An important consideration when using these techniques is that enhancement agent activity is dependent on spatial and temporal co-localization. The best outcome can be achieved when the agent of interest is present in the target tissue and the electrical fields are generated within it.
“A wide range of devices and methods have been described to allow the application of electric fields in tissue when an agent of interest is present. This allows for enhanced agent delivery in skin or muscle tissue. These devices can be used with both tissue- and surface penetrating electrodes, as well as combinations thereof. Despite the promise of electrically-mediated agent delivery and potential clinical applications, there is still much to be done. However, the lack of an efficient way to deliver these agents efficiently and reliably has hampered progress. The inability to apply the agent consistently from one subject to another is one of the major flaws of current systems. Variability in technique and skill levels of operators are significant causes. Current systems do not address other sources of variability, such as differences in the physiologic characteristics of patients that could affect the application of the procedure. The ease of use of the devices and their ability to reduce the impact of possible user errors are other considerations.
The development of better application systems is highly recommended, as it is important to ensure that clinical therapies are safe, reliable and accurate. This development should address operator-associated variability and accommodate patient differences. Specific areas of improvement include the ability to maintain consistent performance across diverse recipient populations, and the reduction in training and skill requirements for the user. The device must be designed to minimize the impact of any user- or device-related errors, and prevent them from ever happening.
This Background provides a context for the Summary & Detailed Description. This Background is not meant to help determine the claimed subject matter. It should also not be considered to limit the claims subject matter to those implementations that address all or some of the problems or disadvantages listed above.
The present disclosure provides methods for the consistent, reproducible, and efficient delivery of therapeutic agents to patients or subjects using Electrically Mediated Therapeutic Agent Deliver (EMTAD). A subject is also referred to as a patient in this document. The term “patient” is used. Does not imply that the subject is under the care of a doctor, even though they might be.”
“One aspect of an apparatus for administering therapeutic agents to patients or subjects consists of an assembly that allows for controlled administration of the agent to the subject. It includes a reservoir, at most one orifice, and a controlled source energy sufficient to transfer a predetermined amount from the reservoir through the orifice at the predetermined rate to the site. The apparatus may also include a number of penetrating electrodes that are arranged in a predetermined space relation to the orifice and means to generate an electrical signal.
“Other aspects include Therapeutic Agent Administration (TEA), in controlled spatial-temporal relation with Electric Signal Administration, (ESA).
There are many benefits and advantages to certain implementations based on current principles. Some implements allow for the adjustment of the depth of the needle and electrode insertion. This allows for insertion in various types of tissue (e.g. dermis, muscle, etc.). It can be used to treat heterogeneous populations with varying body masses and body compositions. These implementations allow for the adaptation of methods to specific target populations. For example, pregnant women who are vaccinated or treated with Zika virus vaccines or treatments, men for prostate cancer therapeutic drugs, men for vaccines and/or treatments, as well as individuals for vaccinations and/or treatment. Small children can also be used for vaccines for their pediatrics. Systems and methods described herein include design features that render them resistant to accidental discharge and misuse, such as dropping, jarring, or falling. Devices may be configured to allow multiple injection depths in some embodiments. Many safety interlocks are available in systems and methods that follow the present principles to reduce the risk of human error. These features include the ability to properly prepare and configure the dose, ensure that the device is applied with the required force to the recipient’s tissue, and remove any safety caps. These systems, apparatus, and methods can be used to deliver a consistent therapy regardless of the recipient’s type or administrator. These systems, apparatus, and methods can enable, for example, the creation of a consistent force profile prior to and during delivery. This allows recipients with different skin and muscle characteristics to receive consistent doses.
“Provided is an apparatus for controlled delivery of therapeutic agent to a tissue site in a subject. It comprises: an outer cartridge, an inner cart, and a needle hub. An applicator, which includes a receiver for the cartridge assembly and an insertion detector. A vessel interlock is a device that locks out the apparatus until it is properly loaded in the vessel receiver.
“In some embodiments, an additional needle is included in the apparatus. Some emdociments have multiple elongate electrodes. Another embodiment of the vessel interlock prevents accidental actuation or a malfunction in cartridge function. A mechanical interlock could be used as the vessel interlock. The apparatus may include a second interlock that includes a light emitter/collector and a cartridge breech. A force interlock, a cartridge interlock, an alignment shield, a force interlock and a force interlock. The mechanical interlock may include tabs that can be moved by the vessel from a first to a second position when it is properly loaded. When the tabs are in their second position, the device can be actuated. Another embodiment of the vessel interlock includes at least one vessel locking hole. Another embodiment provides an optical line through the vessel lockout hole via the cartridge breech. In another embodiment, a vessel detector cap can be used to engage the cartridge breech via a vessel detection spring. The vessel detection spring may be configured to push the reservoir into contact with the needle hub in some embodiments. The vessel interlock may also include a tab that extends from the cartridge surface. In these embodiments, the tab interacts with the detent feature in the applicator so that the cartridge is not physically loaded into the applicator unless the tab has been deflected by properly loaded vessels.
“In some embodiments, a first interlock is a splay-shield, wherein said outer cartridge cap comprises an inner face proximal said splayshield, and said inner surface further contains at least one hook that can engage a wall on said splayshield. In some cases, the apparatus may also include a third interlock. Another example is the force interlock. Another example is the force interlock. It senses force against a predetermined site on the tissue of the subject, and prevents the administration of the therapeutic drug to that site if the force is insufficient. The force interlock may also form an electrical lock within the applicator in some embodiments. A minimum of one contact for a cartridge force sensor may be included in the force interlock.”
“In some cases, the apparatus described herein also includes a key to a vessel. The key is designed to slide over the barrel of the vessel in order to ensure proper mating within the cartridge assembly. The first interlock may include a splay guard that has a rib and an edges designed to engage with predetermined tissue sites of the subject. It is configured to put the apparatus in tension perpendicularly to the direction of needle deployment to administer the therapeutic agent. A splay shield that includes a force contact pick-up may be the first interlock in the apparatus described herein. A force contact pick-up may include at least one pad, at most one second pad, as well as a flexible circuit. In some embodiments, the first contact spring is mechanically biased to create a splay cover.
The cartridge assembly of an apparatus described herein may also include a stick shield. The stick shield may also include a stick nub, stick shield hole and stick shield spring in some embodiments. In some embodiments, this first interlock is the splay-shield that has at least one hole to allow for the sliding of the stick shield. The apparatus described herein may also include at least one stick support to interface with an outer cartridge. The stick shield support in an exemplary embodiment is a support arm made of stamped metal. Another exemplary embodiment has the stick shield supports moving over at least one of the retaining walls in a sequential manner. The apparatus described herein may include a first retaining walls that can stop proximal movement in the case of discharge at a selected depth. A second retaining wall can also prevent proximal movements of the stick guard after discharge at a selected depth. Some embodiments integrate the stick shield support as an injection-molded plastic feature in an outer cartridge cap.
“Another embodiment of the stick support prevents the stick from moving in the proximal direction by preventing it from being ratcheted in a ratcheting manner. Another embodiment of the apparatus includes a gear rack that is attached to the stick shield in order to limit proximal movement. The stick shield support can be used to stop the stick shield supporting from moving in the proximal direction if at least 5 N is applied. Another case is that the stick support stops the stick shield moving in the proximal direction if at least 15 N force is applied. The stick shield support can be integrated into the alignment guide or splay shield as an injection-molded plastic component. Some embodiments allow the cartridge to be loaded into the applicator and the vessel will move forward to mate the needle hub. The cartridge then contacts the needle during administration of the therapeutic drug. Another embodiment of the inner cartridge is slidable relative to the outer cartridge along the same longitudinal axis. Sometimes, the inner cart engages with the inner cap at the distal end. This locks the electrodes in position and provides a bearing surface to the stick shield.
“The apparatus described herein may also include a sensor. The sensor may be selected from the following: a cartridge loading sensor; a cartridge loaded sensor; a cartridge force sensor; an insertion mechanism position sensor; an optical detector; and an electrical sensor. A loading drive subassembly may include a cartridge loading sensor or a loaded sensor. The loading drive subassembly may also include a cartridge guide rail and a motor. The loading drive subassembly may also include a connection to the pinion gear assembly that pulls the cartridge assembly into the receiver. This rack is located on the base of the outer cartridge. The pinion gear assembly may engage the rack on an outer cartridge in some embodiments. Some embodiments include at least one rack tooth. The first tooth of the rack provides a tactile sensation as the cartridge assembly is inserted into its receiving volume. The first tooth may provide torsional stability in some embodiments. Some embodiments detect a cartridge loading sensor that is attached to the cartridge assembly and initiates loading. Some embodiments detect a cartridge loaded sensor to stop loading. The apparatus may also include a continuing flag to allow the cartridge loading process to continue. The apparatus may also include an insertion detector, which is a light emitter/collector of IR sensors. The sensor can detect a vessel label to verify that the therapeutic agent is being administered.
“Provided is an apparatus for controlled delivery of therapeutic agent to a tissue site in a subject. It comprises: A cartridge assembly comprising an housing, a needle receiver, and a vessel to hold the therapeutic drug. An applicator consisting of a cartridge receiver and an applicator. The receiver is designed to detect the loading of the vessel. An electrode support comprising an array of apertures that correspond to the predetermined special relationship between the electrodes.
“In some embodiments, an apparatus also includes a needle. In some embodiments, an electrode insertion spring is included or a needle insert spring. An electrode shoulder or electrode bend can be used to separate the electrode’s proximal and distal portions. The electrode support can be used to provide an operative connection between the conductive contact area on the electrodes’ distal end and the controlled source energy for when the electrodes are placed into the patient’s predetermined tissue site. The electrode support may include a needle hole that allows for the passage of an injection needle. The electrode support may include a planar structure that is perpendicular to the electrodes’ elongate orientation. The planar structure may also include an aperture, which is a hole or slot that allows the electrode to pass through to the predetermined tissue site. The aperture may include at least one tubular structure that is perpendicular to the planar structure in some embodiments. The planar structure may be perpendicularly to the longitudinal axes for the electrodes in some embodiments. The electrode support may be an adaptive electrode support in some embodiments. The adaptive electrode support may be a compression spring in some instances. The compression spring can be made from metal, polymer, or an elastic material. The electrode support may include at least one telescoping tub in some embodiments. The electrode support may also include a stick shield spring in some cases. The electrode support may also include at least one lateral support member attached with the electrodes and at least one optional hinge feature. The electrode support may be made of a metal, a plastic, a ceramic, or a compressible material. The compressible matrix material can be selected from any of the following: a cellulose, a polymer, a rubber, a foamed, or a foamed resin, a microcellular, foamed, foamed silicon, polychloroprene, carbon-foam matrix, and a foamed cellulose. The electrode support may be made of an unconducive material in some embodiments. The electrode support may be made from a thermoplastic material in some embodiments. Some embodiments use a thermoplastic material, which can be a polycarbonate or polystyrene, a plastic propylene, acrylic, or polyethylene.
“In some embodiments, an electrode support supports transcutaneous electrode deployment and maintains tissue depths up 60mm. An electrode proximal part of each electrode is connected to or contacts an electro contact in some embodiments. Each electrode is placed on the outer cartridge of the cartridge assembly. The electrode contact is designed for power communication with the applicator. In some embodiments, an outer cartridge contact is added to the electrode contact. The electrode contact may provide an electrically conductive interface to the corresponding electrodes without interfering with the forward travel of the inner cartridge’s electrodes. The cartridge assembly may also include a port for loading a vessel. An outer cartridge is included in some embodiments. This outer cartridge contains an inner cartridge containment quantity. The applicator may also include an injection drive assembly. In these cases, the injection drive assembly is paired with the cartridge assembly. The applicator may also include an applicator cartridge assembly receiving point. The applicator may also include a procedure activation trigger in some embodiments. The applicator may also include a connector to connect to the controller, a top and side housings, as well as an inner protective shell. The vessel may also include a cap. In some embodiments, an egress port is added to the apparatus. The apparatus may also include a plunger stopper. The apparatus may also include a multiconductor cable. The exterior cartridge cap chamfer surface may also be included in some embodiments. The apparatus may also include an exterior cap hook. The apparatus may also include a main power port. The apparatus may also include a main power switch and a power button in some embodiments. The apparatus may also include at least one connector to allow for a switch in some embodiments.
“Provided are embodiments in which an apparatus described herein includes a hybrid motor/spring mechanism to contact at least one said injection orifice, or said plurality electrodes with said tissue site.”
“In some embodiments, at least one connector is included in the apparatus for switching. The apparatus may also include a USB port in some embodiments. The apparatus may also include a reminder tab in some embodiments. The apparatus may also include a battery indicator in some embodiments. The apparatus may also include a mute switch in some embodiments. In some embodiments, at least one menu navigation button is included in the apparatus. In some embodiments, an eject button is added to the apparatus. The apparatus may also include a display screen in some embodiments. The apparatus may also include a tray in some embodiments. The apparatus may also include an applicator connector port. The apparatus may also include an applicator tray. The apparatus may also include a cradle in some embodiments. The apparatus may also include a storage bin. The apparatus may also include a handle in some embodiments. The apparatus may also include abutment walls in some instances. In some embodiments, at least one electrode contact for the applicator electroporation is included in the apparatus. In some embodiments, at least one electrical connector is included in the apparatus. In some embodiments, an additional cartridge loading subassembly is included. The apparatus may also include a motor drive and at most one electrical contact to drive the motor. The apparatus may also include a loading drive motor. In some embodiments, the apparatus also includes a motor trigger connector. In some embodiments, the apparatus also includes a motor drive shaft. In some embodiments, at least one electromechanical component is included in the apparatus. The apparatus may also include at least one cartridge loading, electrode insert, and injection subassembly. The apparatus may also include at least one injection level selection button and an indicator. The apparatus may also include a procedure countdown clock. The apparatus may also include at least one bracket for mounting and a gear cover bracket.
“In some embodiments, an additional system trigger switch is included in the apparatus. In some embodiments, an additional system trigger switch is included in the apparatus. In some embodiments, an indicator for procedure fault and a complete indicator are included in the apparatus. The apparatus may also include a depth selection button. The depth selection button can be selected from a group that includes a toggle, switch, or sliding switch. The apparatus may also include a plurality channel and a plurality retaining posts in some embodiments. In some embodiments, an insertion mechanism gear drive and ring are included in the apparatus. Rotation of the insertion mechanism ring can rotate the retaining pin into the channel in some embodiments.
“In some embodiments, a insertion mechanism flag, a insertion motor drive motor, an insert mechanism position sensor, an insertion drive plunger, or an inject drive motor are all included in the apparatus. The apparatus may also include a cartridge lock rings in some instances. The retaining posts can be rotated by the rotation of the cartridge lock rings in some embodiments. The cartridge assembly may only be used once in some cases. The applicator can be used for multiple purposes in some embodiments. The applicator may also include a top housing and a side housing. An inner protective shell is included. A front cap and an end cap are optional. The applicator may also include a user interface and a procedure activation trigger. The apparatus may also include a controller in some embodiments. The controller may also include a controller assembly in some embodiments. The applicator may also include a connector to connect to the controller in some embodiments. The controller may also include an electrical field controller in some embodiments.
“In some embodiments, penetrating electrodes or the injection needle contact the predetermined tissue site at a velocity of at most 50 mm/second. In some embodiments the penetrating needle and/or the injecting needle contact the predetermined tissue site at a velocity of at most 500 mm/second. Some embodiments use a nucleic acids as the therapeutic agent. In some cases, the nucleic acids is DNA. Some embodiments place the predetermined tissue site in the subject’s skeletal muscle. In some embodiments, the subject’s skeletal muscle is the medial deltoid or vastus lateralis muscles. Some embodiments allow for injection depths of 19-30mm at the medial deltoid muscles. Some embodiments allow for injection depths of 25-38mm at the vastus lateralis muscles.
“In some embodiments, an apparatus is provided that comprises a motor/spring mechanism to contact at least one said injection site or said plurality electrodes. The apparatus may also include a measurement circuit and logic circuit that monitors the motor’s usage during injection strokes and compares it to a predetermined standard.
“Provided herein is an apparatus that includes a controller and a force circuit. A feedback loop between said controller, said force contact circuit and said controller detects a change in applied force and prompts the initiation of a check to ensure that the electrodes are properly placed in the predetermined tissue location.
“In certain cases, the apparatus described herein allows for the deployment of a plurality or more electrodes/needles by rotational motion.”
“Provided are methods of providing therapeutic agents to predetermined tissue sites in subjects in need. This includes contacting the subject with the apparatus described herein. Systems for administering a therapeutic agent to a predetermined site of tissue in a subject who is in need thereof are provided, which include an apparatus described herein.
This Summary is intended to provide a summary of selected concepts in a simplified format. Further details are provided in the Detailed Description section. It is possible to include elements or steps that are not described in the Summary. However, no step or element is required. This Summary does not identify the key features or essential features in the claimed subject material. It is also not intended to be used as an aid in determining its scope. The claimed subject matter does not include implementations that eliminate all or some of the disadvantages described in this disclosure.
“The following descriptions and examples show embodiments of the invention in depth. This invention is not limited by the specific embodiments listed herein. It is possible to vary. The scope of the invention includes many modifications and variations, as will those skilled in the art.
“All terms are meant to be understood in the same way that they would be understood by someone skilled in the art. All technical and scientific terms are understood as they would be by someone of ordinary skill in art.
“The section headings in this document are used for organizational purposes only. They should not be construed to limit the subject matter.
“Various features of the invention can be described in the context a single embodiment. However, they may also be provided separately or in any combination. The invention can also be described in the contexts of different embodiments to increase clarity. However, the invention could be implemented in one embodiment.
The following definitions are intended to supplement the art and to the current application. They are not to be attributed to any other case or related matter, e.g. to any patent or application that is commonly owned. While any method or material similar to the ones described herein may be used for the practice of testing the present disclosure, the preferred methods and materials are described herein. The terminology used in this document is intended to describe particular embodiments and not be considered limiting.
“Unless otherwise stated, the singular is used in this application. The specification uses the singular forms?a and?an. ?an? ?an? If the context requires otherwise, plural referents should be used unless they are clearly defined. The use of the?or? in this application is not permitted. means ?and/or? Except where stated otherwise. Additionally, the term “including” is allowed. As well as other forms such as ‘include’,?includes?, and?includes? as well as other forms such as?include?,?includes?? It is not restrictive.”
“Refer to the specification for?some embodiments? ?an embodiment,? ?one embodiment? Or?other embodiments? This means that at least some embodiments of the inventions include a specific feature, structure, or characteristic. However, not all embodiments.
“As used herein, the words ‘comprising? are used in this specification. (and any other form of including, such as ‘comprise? ?comprises? ), ?having? (and any other form of having, like?have? (and any form of having, such as?have? ), ?including? (and any other form of including, such?includes? (and any form of including, such as?includes? or?containing? (and any other form of containing, like?contains?) (and any form of containing, such as?contains? These terms are inclusive or unrestricted and don’t exclude any additional elements or steps. Any embodiment described in this specification may be used with any method or composition according to the invention. You can also use compositions of invention to realize methods of the invention.
“The term “about” is defined as: “About” can be used in reference to a reference number value or its grammatical equivalents, as it is used herein. It can also include the numerical value and any range plus or minus 10% of that numerical value. The amount of 10 is an example. The amount?about 10? includes 10, and any amount between 9 and 11. The term “about” can be used to refer to the term. In relation to a reference number value, the term?about? can also be used. It can include a range plus or minus 10% 9%, 88%, 76%, 66%, 5% or 4% from that value.
“The present disclosure provides an improved system, methods, and apparatus for the consistent, reproducible, and efficacious delivery therapeutic agents such as drugs, peptides and proteins, together with combinations thereof using Electrically Mediated Therapeutic Agent Deliver (EMTAD)”
“In one embodiment, the present disclosure provides an apparatus to deliver a therapeutic drug to a predetermined location within a subject. It includes an administrator to control the administration of the therapy agent to the subject. The administrator has a reservoir or vessel that holds the therapeutic agent and an orifice through which it is administered. A controlled source of energy can be used to transfer the prescribed amount of therapeutic agent from the reservoir or vessel to the site. The apparatus also includes a number of penetrating electrodes that are arranged in a predetermined relationship to the orifice and an electrical signal generator. In the specification, the terms reservoir and vessel can be interchanged to mean a container for the therapeutic agents.
EMTAD is defined as the administration of a therapeutic drug to a biological tissue and subsequent, concurrent, or earlier application of electrical signals to that tissue in order to increase movement and/or uptake. The EMTAD process consists of two components: 1) Therapeutic Agent Administration, and 2) an Electrical Signal Application. These elements are sufficient to produce the desired EMTAD effect. The present disclosure reveals that therapeutic agent administration can be done in a controlled manner, called Controlled Therapeutic Agent Administration. This term CTAA refers to apparatus and methods that allow for spatial and/or time-controlled administration of therapeutic agents relative to inducing an EMTAD effect. Variations on the traditional needle-syringe can be used to control administration (e.g. Automatic injection device) or other needleless methods (e.g. jet injector, transdermal/transcutaneous patch, oral, gel, cream, or inhaled administration). ESA refers to the use of electrical signals to enhance or facilitate the delivery of therapeutic agent by increasing movement and/or uptake within tissues. This is known as an EMTAD effect. When used to facilitate or enhance delivery of a therapeutic agent, ESA processes such as electroporation, iontophoresis, electroosmosis, electropermeabilization, electrostimulation, electromigration, and electroconvection all represent various modes of EMTAD.”
“Specific uses for apparatus and systems described in this document include the delivery of vaccines and therapeutic proteins as well as chemotherapeutic drug. EMTAD is traditionally initiated using a needle-syringe to inject the therapeutic agent. Once the agent has been administered, an ESA device is used to apply the drug to the patient at the designated site. An appropriate ESA protocol is used to facilitate or enhance therapeutic agent delivery. Traditional EMTAD may not allow for the desired spatial and/or temporal relationship between agent administrations and ESA.
“Spatial Parameters”
“Some embodiments of the methods, apparatus, and systems described herein allow therapeutic agent administration to be performed with a standard needle syringe. TAA is complicated because certain agents must be delivered with EMTAD. FIG. FIG. 1 shows that in conventional needle-syringe injections, the needle 5 is inserted into tissue at a depth of 1 and angle 2 respectively. This can make it difficult to control the depth and angle. The needle’s point of penetration at the tissue surface may not correspond to the site of the agent administration 7 and the orifice 6. A transcutaneous intramuscular injectable may not be the same as the point of needle penetration on the skin. These tissues are often in close proximity and can move in different directions.
This conventional approach can be used to deliver many therapeutics, but it is not suitable for EMTAD. Variables in the distribution of therapeutic agents after injection can cause inconsistent or indeterminate distributions. This can hinder effective EMTAD. The best use of EMTAD is based on a predetermined relationship between the therapeutic agent in the subject and the ESA. In other words, if there is no spatial control of TAA in target tissue, a conventional needle-syringe may result in less effective EMTAD applications than an apparatus, method, or system that does so. This concept can be illustrated by electroporation, which facilitates the delivery of therapeutic agents. When TAA and ESA co-localize within the tissue target, electroporation is most effective in increasing therapeutic agent delivery. If the agent to deliver and the induced electroporation effect do not co-locate within the tissue target area, delivery is often suboptimal.
Iontophoresis is another example of the need to have adequate spatial control over TAA in EMTAD. EMTAD in this mode uses electric fields to move charged molecules. To achieve the desired agent movement, it is necessary to establish the correct spatial relationship between electrodes and therapeutic agent. A negatively charged agent placed close to a positive electrode would result in little or no movement through the tissue. However, if the negatively charged agent is placed near the negative electrode, it will cause significant movement through the tissue in the opposite direction.
“As shown by the examples above, it is crucial to control TAA’s exact location relative to ESA in order to achieve the desired effect. The apparatus and methods described herein allow for precise control over the location of TAA relative the application of ESA. They are therefore useful in achieving consistent, reproducible, and well-characterized distributions of one or more therapeutic drugs.
“Temporal Parameters”
“The problem with conventional needle-syringe injection is that the rate at which the agent is injected may differ from one operator to the next. This can lead to inconsistent distribution of the agent in the tissue. Multiple device placements can introduce additional temporal variability to the EMTAD process. For example, one application of EMTAD calls for the administration of plasmid DNA encoding for a therapeutic protein, followed by generation of an electroporation-inducing electrical field. The traditional EMTAD method involves injecting the plasmid with a needle-syringe. Next, place and activate the electroporation devices. This procedure requires two separate device placements: the initial needle syringe and the ESA device. This can lead to intersubject variability due to inconsistent temporal application by the operator. The clinician must place each device twice, which creates an inexorable time delay between activation and placement. Multiple application sites may be required to deliver the agent to the desired area of target tissue.
These issues are particularly important for agents such as nucleic acid, which can be inactivated or degraded in the extracellular environment. The therapy’s efficacy can be affected by the agent’s degradation. The inter-subject rate for therapeutic agent degradation is variable, which can lead to therapeutic inconsistency when combined with ESA and, more specifically, electroporation therapy.
Due to the spatial and temporal variability inherent in conventional needle-syringe combination with ESA, it is difficult to know the exact location and timing of TAA relative ESA. EMTAD can make it difficult to administer and dose therapeutic agents effectively. Although conventional needle-syringe injection can sometimes be sufficient for therapeutic agent administration. However, consistent and reproducible agent delivery can be significantly improved by controlling the spatial/temporal relationship between the administration of the therapeutic drug and the induction of the desired EMTAD effect.
“Thus, although the traditional EMTAD procedure is suitable for some applications, it is not ideal for clinical applications that require high levels of consistency and reproducibility. Contrary to the traditional EMTAD approach described above, the embodiments of systems, methods, and apparatus described herein enable CTAA and ESA, which provide more beneficial methods and apparatus for clinical application of EMTAD. In order to deliver therapeutic agent consistently, efficiently, and reproducibly, the present disclosure uses various aspects of CTAA with ESA. This disclosure describes apparatus and methods for spatial and temporal control of administration of a therapeutic drug relative to electrical signals. This improves the uptake and movement of the agent in target tissues.
“In some embodiments, methods and apparatus are provided that allow for the controllable spatial relationship between the administration of therapeutic agents relative to the application electrical signals. The optimal location of TAA relative to ESA must be determined before treatment. The treatment parameters (e.g., the type of agent and properties of the target tissue) determine the spatial relationship between TAA/ESA. In one example, the electrical signals are preferred to be applied distal of the site of therapeutic agent administration. Other embodiments prefer to apply EMTAD-inducing electric signals proximal the agent administration site. Co-localization of TAA and ESA may be desirable in certain situations. This is usually the case when electroporation or iontophoresis is used to induce the desired EMTAD effect.
“Another aspect of the disclosure is that the apparatus described herein allows for a controlled temporal relationship between the timing and sequence of TAA relative ESA. The optimal sequence and timing of TAA/ESA combination is determined prior to treatment. The desired temporal relationship between TAA/ESA is determined in the same way as for the spatial relationship. This is determined by factors such as the type of agent and properties of the target tissues. The therapeutic agent may be adversely affected by exposure to ESA’s electrical fields in certain situations. CTAA is used to generate such electrical fields in the practice of such applications. The typical temporal relationship is CTAA and ESA.
“The present disclosure provides improved methods for the consistent, reliable, and effective delivery of therapeutic agents such as pharmaceutical compounds, drugs, nucleic acids, and proteins with EMTAD. This is achieved by controlling the timing and spatial distribution of therapeutic agents relative to electrical signals. EMTAD can be achieved by delivering vaccines, therapeutic proteins and chemotherapeutic medications. EMTAD can be initiated using a standard needle-syringe to inject the therapeutic agent. Once the agent has been administered, an ESA device is applied to the subject at the designated location. To provide therapeutic agent delivery enhancement or facilitation, an appropriate ESA protocol will be used. Electroporation is an excellent ESA technique that has been proven to work in almost all cell types. Other exemplary methods of electrically mediated delivery include, but not limited to, iontophoresis, electroosmosis, electropermeabilization, electrostimulation, electromigration, and electroconvection. These terms are intended to be used as examples only and should not be taken to mean that the disclosure is limited in any way.
Electroporation is a technique that uses electric fields to temporarily increase cell membrane permeability, and move charged particles. Electroporation improves intracellular uptake of exogenous drugs administered to target tissues by permeating cell membranes. Electroporation can increase cell membrane permeability, and molecular movement. This allows for the removal of cell membrane barriers that prevent therapeutic agent delivery. Electroporation can be used to induce EMTAD in many tissue types. The present disclosure discusses, but is not limited to, the use of electroporation in inducing EMTAD.
“Therapeutic Agents”
“The term “therapeutic agent” is used in a broad sense. “The term?therapeutic agent?” is used in this context to mean any agent that has the potential to have a beneficial or desired effect on living tissue. The term can be used to refer to both therapeutic and prophylactic agents. The scope of the disclosure is sufficient to allow controlled delivery of any agent regardless of its classification. The therapeutic agents covered by the present disclosure include pharmaceutical drugs and vaccines as well as nucleic acids sequences (such supercoiled, relaxed and linear plasmidDNA, RNA and antisense constructs artificial chromosomes or any other nucleic-based therapeutic), and any formulations thereof. These agents include, but not limited to, cationic, nonionic, cationic, and liposomes, liposomes and saline. They also contain nuclease inhibitors and anesthetics. Agents and additives that can control the viscosity or electrical impedance of the administered drug may also be used in other formulations.
“In the case nucleic acid, plasmid DNA would be a therapeutic agent. It would be dissolved in a phosphate-buffer sodium chloride solution and a competitive nuclease inhibitor like aurintricarboxylic acids (ATA) added. It may be beneficial to include a signaling protein onto a construct in some cases that use nucleic acid-based therapeutics. Some peptides that could be useful include nuclear localization signals and endosomal-lyric peptides. These signals can improve the delivery and/or processing the therapeutic agents delivered to cells via EMTAD. These signals can be achieved using methods described in U.S. Pat. No. No. 6,165,720 (the complete disclosure is included by reference herein). These techniques can be used with other delivery systems but the EMTAD’s ability to deliver nucleic acids constructs to target tissue makes them particularly well-suited to use with these signals.
“Target Tissues”
EMTAD is a technique that targets healthy or diseased tissues. These include the epidermis and dermis as well as connective and muscle tissue. This technique can be used to access healthy or diseased organs using minimally invasive surgical procedures or other surgical methods. These target tissues include the liver and lungs, heart, blood vessels. lymphatic, brain, liver, heart, kidneys, stomach, intestines. colon, bladder, reproductive organs. A method or apparatus described herein can deliver the desired therapeutic effect to cells that are normally found in target tissues. It may also be used to deliver additional agent to other cells not normally found within those tissues. “chemotherapeutic treatment for tumors.”
“As previously discussed and illustrated in FIG. 1. Traditional EMTAD has a problem with precision and reproducibility in the spatial-temporal relationship between the administration and reception of the therapeutic agent. The present disclosure, which describes the apparatus and methods for combined CTAA/ESA to offer a more beneficial clinical application of EMTAD, is a departure from the traditional EMTAD approach. To provide consistent, reliable, and efficient therapeutic agent delivery, the present disclosure uses various aspects of CTAA with ESA. These methods and apparatus provide spatial and time control of administration of therapeutic agents relative to electrical signals. This improves the movement and/or uptake in target tissues.
“Methods”
“In one aspect, this disclosure describes systems and apparatus that can be used in controlled administration of a therapeutic drug followed by ESA. The present disclosure describes systems and apparatus that can be used in controlled administration of therapeutic agents prior to ESA. The present disclosure describes systems and apparatus that can be used in controlled administration of therapeutic agents accompanied by ESA. These methods can be used to determine treatment parameters, subject preparation, CTAA, ESA and other measures.
“Determination Treatment Parameters”
“In some cases, the treatment parameters are determined by the amount and/or length of dosing of therapeutic agent. Dosing of therapeutic agent can be determined by the specific indication or treatment application, such as the type and position of the target tissue, as well as other subject parameters, like age and body weight. The parameters that govern the administration of the therapeutic agents and ESA can control the dosing of the agent. Examples of controllable parameters for CTAA include agent volume, agent viscosity and injection rate. ESA is a good example of controllable parameters. They include the characteristics and exposure to electrical signals as well as the format of the electrode array. Further control is possible by adjusting the relative timing and position of CTAA or ESA.
“Patient/Subject Preparation”
“In embodiments described herein, methods described herein may include a patient/subject preparation step. Subject preparation can include antiseptic cleaning and anesthetic administration. This may include local, regional, spinal, epidural, or general anesthesia. An example of intramuscular (IM), ESA may include protocols to reduce the effects of electrical stimulation on the muscle. This could include thermal control (e.g. The administration of anesthetics and/or other stimulation patterns that can be used to reduce discomfort may be included in cooling the muscle. If there are alternatives, it is important to understand that therapeutic efficacy does not suffer from the chosen subject preparation methods. It has been demonstrated that intramuscular administrations of amide-based anesthetics can sometimes have an adverse effect on intramuscular DNA-based therapies. This is likely due to mild myotoxicity, which can prevent the muscles from expressing the DNA sequence.
“CTAA and ESA.”
“In some embodiments, CTAA and ESA can be combined to enable consistent and reproducible therapeutic agents delivery. There are some apparatus that can be used for CTAA. This includes apparatus with at least one automatic injection device and jet injectors.
The present disclosure relates to methods and apparatus that enable the transcutaneous deployment in safe and consistent fashion of a plurality elongate electrodes at a target depth to treat recipients with heterogeneous skin composition and thickness. This is done in support of the application of electric fields in tissue to increase intramuscular, subcutaneous, and/or intradermal administrations of therapeutic or prophylactic drugs such as nucleic acid, pharmaceuticals and antibodies, peptides and proteins or combinations thereof.
“Systems and methods based on the present principles allow the continuous transcutaneous deployment of a plurality elongate, tissue-penetrating electrodes to a predetermined target tissue site to propagate electric fields in the skin, subcutaneous tissue, and/or muscle. This disclosure is intended to allow a user to deploy electrodes at a desired depth and maintain the correct spatial relationships among the plurality, even when they are applied to sites with different skin characteristics. Variation in skin characteristics can occur at different locations within an individual, or between heterogeneous recipients. Systems and methods based on the present principles should permit consistent profiles regardless of who the administrator is or who the recipient is. Some embodiments allow for the deployment of electrodes with one or more injections needles. These are designed for administering therapeutic agents to target tissue regions and are arranged in a predetermined spatial relationship to the electrodes to be used to provide ESA. An exemplary embodiment of the electrodes is such that the electrical signals from the electrodes are preferredentially applied distal of the site for therapeutic agent administration through the insertion one or more injections needles. Another embodiment is to arrange the electrodes so that any electrical signals are preferredentially applied proximal the site for therapeutic agent administration through the insertion one or more injections needles.
“Aspects can be used alone or in combination with other aspects of the disclosure to support transcutaneous insertion electrodes for in vivo electrical field stimulation to increase intramuscular, subcutaneous, and/or intradermal administrations of nucleic acid, small molecule drugs and antibodies, peptides and proteins and combinations thereof. Some embodiments coordinate the deployment of electrodes and the subsequent propagation of electrical fields with the distribution of the agent to the target tissue site. An exemplary embodiment of the agent’s administration and application of an electrical field is controlled and monitored so that there is the best chance of co-localization of the agent’s distribution with the electric field application site.
The present disclosure describes methods and apparatus that enable transcutaneous deployments of electrodes at predetermined sites within the skin, subcutaneous tissue and/or muscle of a recipient. This is in addition to the administration of an agent and local application of electric fields to enhance the delivery, uptake and/or biological effects of the agent. The present disclosure is implemented in a way that users can set up and use the device quickly and easily. The present disclosure includes numerous interlocks and sensors that can be used to reduce errors made by users during set-up and usage. Referring to FIG. Referring to FIG. 2, one embodiment described in this article is a ‘cartridge assembly? 100 are detachably connected to an ‘applicator? 400 that can be detachably interfaced to an?applicator? A user interface, tray and holster are all provided by controller 700. FIG. 2. A reservoir 101 can be inserted into the cartridge assembly 100 to provide a method for use.
FIGS. 3A-12 and the corresponding cooperating parts of the applicator 400 are shown in FIGS. FIGS. FIGS. 19-20D. 19-20D.
“Referring to FIGS. “Referring in addition to FIGS. The electrode mounting structure must be designed and constructed so that the dielectric barrier is adequate between opposite polarities within the device to prevent unwanted propagation of electric currents. The electrodes’ distal regions 137 are connected to the mounting structure by using standard mechanical features or bonding agents that correspond with the material composition of both the electrode mount structure, and the electrodes.
“In one exemplary embodiment, the cartridge’s outer housing structure 102 can interface with a fluid reservoir 101 or vessel 101 that contains the agent of interest. The reservoir 101 or vessel 101 and the cartridge housing structure102 are designed to connect to at least one injection port (needle 105) through the which the agent is administered to the target tissue. This configuration allows for co-localization between the location of electrical field application and the distribution of the agent. This configuration allows for the establishment of a pre-determined spatial relationship among the apparatus for ESA/CTAA. Another example is where a syringe 101 can be inserted into a cartridge 100. Then, upon loading the cartridge into an application 400, the Syringe 101 will move forward to mate the needle hub 152, and connect the cartridge to it.”
“Some embodiments of this disclosure may include the use of vials, ampoules or cartridges for the storage of one or more therapeutic agent. The reservoir or vessel may be made of at least one type of plastic or glass, depending on the compatibility of the agent. The reservoir or vessel may have protective or lubricious coatings. The electrodes 122 can be hollow or equipped with injection ports that can be connected to fluid vessels. Alternately, the injection port can be constructed with one or more needle-free injection ports or hypodermic needles. The desired route of administration, tissue distribution and physical characteristics of your agent of interest will all play a role in the selection of the size and type of injection orifice. The cartridge structure in a particular embodiment is designed to establish a pre-determined spatial relationship among the injection orifice, electrodes and their deployed states so that the distribution of agent of interest occurs substantially within the tissue bordered by the plurality electrodes. A cartridge 100 is designed to accommodate hypodermic needles. It allows the needle to be mated directly to the cartridge, rather than being matched to the syringe during use. Certain embodiments of the present disclosure may include features in the cartridge or the needle that ensure needle retention during manufacturing, distribution, handling, and usage. These features can also be used to ensure proper mating of reservoir or vessel to needle before use. These features may reduce the risk of agent leakage from the reservoir, reservoir orifice interface or due to improper mating.
“In some embodiments, the cartridge may include a tissue interface at the distal end. The tissue contact interface can be a substantially planed structure perpendicularly to the elongate orientations of the electrodes. It may also have one or more apertures that allow the passage of the electrodes through it. The interface can also be used to allow needle-free injections or injections, if there is an integrated reservoir or vessel. In certain embodiments, the apertures for the injection needle and electrodes are sufficiently large to avoid accidental contact. This reduces the chance of needle-related injuries and contamination. The tissue contact interface is usually composed of one or more plastics that are suitable for contact with tissue, at most for a short time.
The cartridge assembly 100 can be set up for one-time use to avoid cross contamination of biological material among recipients. Sometimes, the cartridge may contain one or more identification, mechanical, and/or electrical elements that limit the use of the cartridge to one administration. This includes, but is not limited to, lockouts or detents that secure the stick shield and/or electrode mount structure in their deployed state. For example, fuses and links that are connected to one or more electrodes can be considered electrical elements. These elements are activated by the source for electrical energy after the cartridge is used. For example, identification elements could be serialized radio frequency identification devices or bar codes. These codes can also be used to identify the source of electricity and the applicator. To prevent the accidental or deliberate re-use by the applicator and/or source of energy of a particular cartridge, the identification information can be used. One or more redundant features may be incorporated in an embodiment to reduce the possibility of reusing the cartridges.
“In the embodiment of an apparatus described in this invention, as shown at FIG. 2. The applicator 400 includes a support structure that interfaces with the cartridge assembly 100. A user interface 410-418 is also included (FIG. 13B), electrically conductive electrical connections that provide an operative connection between a conductive contact area on the distal end of the elongate electrodes and the source for electrical energy when the electrodes have been deployed in the recipient’s target tissue. In some cases, the user interface includes a handle and one or more display elements that convey information to the user. There may also be one or more features that can accept input from the user. The display features can be used to show the operating status of the device, as well as any warning/error messages. These displays may include mechanical features, electronic screens, or alphanumeric display screens. Some features that can accept user input may be configured to allow the user to, at the appropriate time during the procedure, deactivate safety features in the device to prevent accidental discharge. They also enable the user to make selections about particular parameters (e.g. the intended depth of injection) and initiate procedure administration. These features include buttons, triggers and mechanical slides as well as levers.
“In some embodiments, the applicator400 also contains actuation mechanisms that interface with the cartridge assembly. These are designed for transcutaneous deployment and positioning of electrodes relative to target tissues. The agent of interest is then released from the reservoir/vessel through the orifice into the target tissue site. Additionally, electrical signals can be transmitted from an electric field generator, such as a controller 700, to the cartridge 100. The applicator 400 may be designed so that energy is supplied by the user. More preferably, the apparatus can include one or more inanimate energy sources operatively connected with the actuation mechanism within the applicator. These inanimate energy sources include, for example, electromechanical devices (solenoids and motors, lead screws), mechanical parts (springs and similar devices), and compressed gas.
FIG. 3A shows an exemplary cartridge assembly 100. 3A shows a cartridge 100 that includes a reservoir/vessel loading port 140 and reservoir/vessel containment volume 142. These are used to hold and contain a medicine reservoir 101. An electric field generator, such as a controller 700, is needed to create an electrical field and use it in therapy. A cartridge 100 is necessary because the device that contains the electrodes is designed to contact the target tissues requires an electronic interface. The controller can be set up for multiple purposes, while the reservoir 101 or vessel 101 can only be used once. Therefore, the cartridge 100 can be used to store the electrodes 122, 101 and 101. This allows the cartridge 100 to be used for one-time use. The applicator 400 is a reusable part and the cartridge 100 can be set up for single-use. You can also make sure that the cartridge 100 is in good condition so that it cannot be used again in case of errors or tampering in the inserting of a reservoir 101 or any other defects.
“Reservoir or vessel 101” can be used to refer to a vial, syringe or other device that can contain a medication or therapeutic agent. It can also include a vial, syringe or other device that can interface with a device with an orifice such as a needle. FIG. 4. A needle 105 with a needle hub 152. For a particular type of cartridge assembly 100 the reservoir 101 has a generally common shape and size. Although there are many components in the cartridge assembly 100 that allow for some variation in sizing and/or manufacturing tolerances; generally, a common form and size is required to minimize the possibility of drugs not being labeled for cartridge 100 being incorrectly delivered. The cartridge assembly 100 could be inoperable if the user does not provide a sufficient-sized reservoir 101. If this happens, the system will be unusable until the proper-sized reservoir 101 has been inserted.
“As shown in FIG. “As seen in FIG. To maintain the integrity and sterility of the agent, a removable cap 158 may be added to the reservoir until it is inserted. The needle hub 152 can be located proximal to this port, while the plunger can be placed opposite it. An alternative to an open port for drug escape, some embodiments provide a septum component that covers and seals the end container. You can make the septum from silicone or butyl rubber. The specific formulation and coating will be determined to ensure compatibility with the agent within the container or reservoir. A crimp seal or another fastening mechanism holds the septum component in place. This septum seal configuration eliminates the need to use a removable cap. However, needle 105 must be equipped with a suitable needle, spike or other piercing members to access the fluid in the reservoir. This configuration can be used in two-sided needle configurations or spike vial adapters.
“The cartridge assembly 100 can be used to receive the reservoir or vessel 101, but it can also be received by an application 400 in an applicator assembly receiving port 41 (FIG. 2). The cartridge assembly 100 contains a device that allows the applicator 400 pull the cartridge and keep it within an interior volume. The device may be one or more racks located on the surface of the cartridge 100 that engage the corresponding motorized gear assembly in the applicator 405. Other implementations allow the applicator 400 to interface with the cartridge 100 without having to pull it into an interior volume. Other techniques can be used to get the cartridge 100 to engage the 400, such as motorized brackets or tracks, onto which the 100 cartridge assembly can interface.
“The applicator 400 also has interface elements that allow it to control certain actions in the cartridge assembly 100. The applicator 400 can be used to control various actions, including needle insertion, medicament delivery and electrode insertion. These steps can be linked in some cases so that one action of the applicator 400 triggers multiple of them. Some implementations allow all these steps to be initiated by one action. This includes the electrode activation and medicament delivery.
The applicator 400 can be used to activate the cartridge assembly 100 by using electrical or optical signals to the mechanical, electrical, and optical elements. This will ensure that all subsystems are functioning properly and are ready for electric field application. The applicator 400 can check for such things as whether the cartridge 100 has been used before, the location of the reservoir or vessel within the cartridge, the application force against the subject’s body through the alignment guide/splay shield (108), a test that the user has selected a depth and the removal of the exterior cartridge cap 110. The applicator 400 is also able to monitor the operation of the cartridges during the execution of the procedure. These subsystems can be used to test, for example, whether electrodes 122 have been properly deployed in a subject before administering the medicament. Also, the applicator 400 will check that the plunger or reservoir has been properly actuated prior the application of the electric fields. The user has applied the appropriate force against the subject’s body during administration.
The applicator 400 can operate subsystems. However, the cartridge 100 can also include appropriate subsystems. These subsystems may interact with the applicator400, but not all, to achieve the objectives of electric field application therapy and medicament delivery. They include a subsystem that causes needle and electrode insertion; a system for protecting users against sharps after therapy administration; a subsystem that provides different depths for needle/electrodes inserting; a system for ensuring adequate force is applied against tissue of the recipient before initiating the procedure and then during administration. Although deployable needles are often used, there is no requirement for them. Systems with fixed or non-deployable needles or electrodes can also benefit from the present principles.
“In an exemplary implementation as shown in FIG. The cartridge assembly 100 contains an outer cartridge 102. In some cases, it is called a housing. An outer cartridge cap (106) terminates the outer cartridge 102 at its distal end. The outer cartridge 101 includes an inner containment volume 150 for receiving an inner cart 103. This inner cartridge is received and can be moved in a sliding manner relative to the outer one 102. The inner cartridge103 contains a reservoir/vessel containment volume of 142, in which the reservoir 101 or vessel 101 might be located. An inner cartridge cap 104 is located at the distal end of inner cartridge 103. The inner cartridge cap104 serves a variety of functions. It locks electrodes 122 into place (the inner cart 103 has seams where the electrodes are placed into), and provides a bearing surface to a stick shield. The inner cartridge cap104 locks onto the inner cart 103.
“A cartridge breech 112 can be found in the reservoir or vessel containment volumes 142, 103 and 104. It is located in the area opposite the inner cartridge cap. The vessel detection cap 118 encloses the cartridge’s breech 112 via a vessel detection spring. The system is locked in place by a cartridge lock ring (114), which connects the cartridge breech 112 with the inner cartridge. The vessel detection spring 112 pushes the reservoir 101 into engagement with needle hub 152 and allows for tolerances in the reservoir 101’s size.
“A vessel interlock 120 acts as a mechanical lock to prevent accidental or unintentional actuation of cartridge functions. The vessel interlock 120 is also known as a first cartridge insertion trigger and is located below the inner cartridge. It has fingers 121 that pass through the slots or holes in the inner cartridge. (see FIG. 5B). The fingers 121 stop the cartridge breech 112 slidably moving in relation to the inner cart 103. In particular, the cartridge breech 112 cannot move within the inner capsule 103 towards the cap 104.
“When a container 101 is correctly inserted into the reservoir/vessel containment volume 142, the reservoir/vessel interlock 120 is pushed to the bottom and the fingers 121 are pushed to the bottom, but not extending into the vessel containment volumes 142. The vessel interlock 120 can also be pushed down or depressed to produce an audible, tactile or haptic click. This can be used to inform the user that proper insertion has been done. After being depressed, the cartridge’s breech 112, which is no longer blocked by fingers 121 or vessel interlock 120 is allowed to move. In particular, it is permitted to move towards the inner cartridge cap.104
The spring cap/cartridge interface (470) causes the cartridge breech 112 to move in a manner described below. The cartridge breech 112 locks when it moves forward enough, secures the reservoir 101 or vessel 101 within the vessel containment volume 142, and ensures that the needle hub 152 is correctly positioned relative it to the needle hub 152. This allows for a fluid path from the reservoir 101 to the needle 105.
“For devices where the injection needle is integrated into the cartridge 100, standard ‘off-the-shelf? products are recommended. The device may use single-use hypodermic injections needles. The device’s reliability and operational characteristics may be enhanced by the addition of custom design elements. These elements are not found in conventional hypodermic needles for parenteral administration. The needle hub 152 may include the material it is made from, retention features that prevent the needle from being removed from the inner cartridge 103 during distribution or use, and orientation of any bevel elements in the needle relative the hub.
“Custom injection needles are used in embodiments. One or more mechanical features allow the device to be inserted into inner cart 103. These features could include snaps, tabs, or ridges that correspond to the mechanical features on inner cartridge.103 Some features are designed so that the hub matches the inner cartridge 103 with a consistent orientation. This is combined with a needle manufacturing process capable of consistently orienting any needle orifice features, ensuring that there are no biases in injector location or distribution of medicament due to the design and location of the orifice. A needle with an asymmetrical tip feature (e.g., bevel cut) may exhibit a bias in its deployment into tissue because of the interaction between the tissue layer and the needle’s asymmetrical penetration. The electrodes that have a symmetrical tip feature (e.g., trocar tip) will not show a bias in their deployment characteristics. To account for the expected deployment characteristics due to the asymmetrical needle bevel, the mounting feature for inner cartridge 103 for needle hub 152 can include an offset in needle 105’s injection orifice relative to electrodes 122. The exact dimension of the offset will depend on the nature and depth of the target tissue. However, certain embodiments offset the needle by 0.5-1mm for every 10 mm of penetration depth. These features are useful for ensuring co-localization of medicament distribution when using injection needles or electrodes with different tip profiles.
Summary for “Methods and apparatus for the delivery of therapeutic agents”
“Prophylactic or therapeutic agents have been administered to patients for many years using a variety of routes, including topical, intravenous and parenteral. The route chosen for the administration of the agent is dependent on the tissue’s inherent physicochemical characteristics. However, certain components of the delivery composition, such as carriers, adjuvants or buffers, can facilitate the delivery to the tissue.
The local application of electric signals has been shown in studies to increase the uptake and distribution of macromolecules within living tissue. The application of these electrical signals to tissue can result in beneficial effects for the tissue and/or the drug being administered. Techniques such as electroporation or iontophoresis can be used to improve the distribution and/or absorption of various agents in tissues. These agents can include pharmaceuticals, proteins and peptides as well as nucleic acid sequences. These techniques could be used in clinical settings to deliver chemotherapeutic drugs to tumors, nucleic acids sequences for prophylactic or therapeutic immunization and nucleic acids sequences encoding therapeutic protein sequences or peptides.
“Many devices have been developed for the application and enhancement of agent delivery by electrical signals to tissue. Most of them have been focused on the application of electrical signals in a targeted area of tissue. For generating desired electrophysiological effects, a variety of penetrating and surface electrode systems has been created.
These procedures involve the administration of an agent to a target site and the application of sufficient electrical fields for the desired effects on delivery, distribution and/or potential of the agent. Two or more electrodes are used to transmit the electrical fields to the tissue. These electrode configurations are suitable for use with tissue penetrating, surface contact, and air gap electrodes. You can choose from a variety of electrode configurations including elongate or rod electrodes as well as point, meander, planar, and combination thereof. Based on the type of target tissue and the purpose of the procedure, the specific type and arrangement for electrodes are chosen.
“An important consideration when using these techniques is that enhancement agent activity is dependent on spatial and temporal co-localization. The best outcome can be achieved when the agent of interest is present in the target tissue and the electrical fields are generated within it.
“A wide range of devices and methods have been described to allow the application of electric fields in tissue when an agent of interest is present. This allows for enhanced agent delivery in skin or muscle tissue. These devices can be used with both tissue- and surface penetrating electrodes, as well as combinations thereof. Despite the promise of electrically-mediated agent delivery and potential clinical applications, there is still much to be done. However, the lack of an efficient way to deliver these agents efficiently and reliably has hampered progress. The inability to apply the agent consistently from one subject to another is one of the major flaws of current systems. Variability in technique and skill levels of operators are significant causes. Current systems do not address other sources of variability, such as differences in the physiologic characteristics of patients that could affect the application of the procedure. The ease of use of the devices and their ability to reduce the impact of possible user errors are other considerations.
The development of better application systems is highly recommended, as it is important to ensure that clinical therapies are safe, reliable and accurate. This development should address operator-associated variability and accommodate patient differences. Specific areas of improvement include the ability to maintain consistent performance across diverse recipient populations, and the reduction in training and skill requirements for the user. The device must be designed to minimize the impact of any user- or device-related errors, and prevent them from ever happening.
This Background provides a context for the Summary & Detailed Description. This Background is not meant to help determine the claimed subject matter. It should also not be considered to limit the claims subject matter to those implementations that address all or some of the problems or disadvantages listed above.
The present disclosure provides methods for the consistent, reproducible, and efficient delivery of therapeutic agents to patients or subjects using Electrically Mediated Therapeutic Agent Deliver (EMTAD). A subject is also referred to as a patient in this document. The term “patient” is used. Does not imply that the subject is under the care of a doctor, even though they might be.”
“One aspect of an apparatus for administering therapeutic agents to patients or subjects consists of an assembly that allows for controlled administration of the agent to the subject. It includes a reservoir, at most one orifice, and a controlled source energy sufficient to transfer a predetermined amount from the reservoir through the orifice at the predetermined rate to the site. The apparatus may also include a number of penetrating electrodes that are arranged in a predetermined space relation to the orifice and means to generate an electrical signal.
“Other aspects include Therapeutic Agent Administration (TEA), in controlled spatial-temporal relation with Electric Signal Administration, (ESA).
There are many benefits and advantages to certain implementations based on current principles. Some implements allow for the adjustment of the depth of the needle and electrode insertion. This allows for insertion in various types of tissue (e.g. dermis, muscle, etc.). It can be used to treat heterogeneous populations with varying body masses and body compositions. These implementations allow for the adaptation of methods to specific target populations. For example, pregnant women who are vaccinated or treated with Zika virus vaccines or treatments, men for prostate cancer therapeutic drugs, men for vaccines and/or treatments, as well as individuals for vaccinations and/or treatment. Small children can also be used for vaccines for their pediatrics. Systems and methods described herein include design features that render them resistant to accidental discharge and misuse, such as dropping, jarring, or falling. Devices may be configured to allow multiple injection depths in some embodiments. Many safety interlocks are available in systems and methods that follow the present principles to reduce the risk of human error. These features include the ability to properly prepare and configure the dose, ensure that the device is applied with the required force to the recipient’s tissue, and remove any safety caps. These systems, apparatus, and methods can be used to deliver a consistent therapy regardless of the recipient’s type or administrator. These systems, apparatus, and methods can enable, for example, the creation of a consistent force profile prior to and during delivery. This allows recipients with different skin and muscle characteristics to receive consistent doses.
“Provided is an apparatus for controlled delivery of therapeutic agent to a tissue site in a subject. It comprises: an outer cartridge, an inner cart, and a needle hub. An applicator, which includes a receiver for the cartridge assembly and an insertion detector. A vessel interlock is a device that locks out the apparatus until it is properly loaded in the vessel receiver.
“In some embodiments, an additional needle is included in the apparatus. Some emdociments have multiple elongate electrodes. Another embodiment of the vessel interlock prevents accidental actuation or a malfunction in cartridge function. A mechanical interlock could be used as the vessel interlock. The apparatus may include a second interlock that includes a light emitter/collector and a cartridge breech. A force interlock, a cartridge interlock, an alignment shield, a force interlock and a force interlock. The mechanical interlock may include tabs that can be moved by the vessel from a first to a second position when it is properly loaded. When the tabs are in their second position, the device can be actuated. Another embodiment of the vessel interlock includes at least one vessel locking hole. Another embodiment provides an optical line through the vessel lockout hole via the cartridge breech. In another embodiment, a vessel detector cap can be used to engage the cartridge breech via a vessel detection spring. The vessel detection spring may be configured to push the reservoir into contact with the needle hub in some embodiments. The vessel interlock may also include a tab that extends from the cartridge surface. In these embodiments, the tab interacts with the detent feature in the applicator so that the cartridge is not physically loaded into the applicator unless the tab has been deflected by properly loaded vessels.
“In some embodiments, a first interlock is a splay-shield, wherein said outer cartridge cap comprises an inner face proximal said splayshield, and said inner surface further contains at least one hook that can engage a wall on said splayshield. In some cases, the apparatus may also include a third interlock. Another example is the force interlock. Another example is the force interlock. It senses force against a predetermined site on the tissue of the subject, and prevents the administration of the therapeutic drug to that site if the force is insufficient. The force interlock may also form an electrical lock within the applicator in some embodiments. A minimum of one contact for a cartridge force sensor may be included in the force interlock.”
“In some cases, the apparatus described herein also includes a key to a vessel. The key is designed to slide over the barrel of the vessel in order to ensure proper mating within the cartridge assembly. The first interlock may include a splay guard that has a rib and an edges designed to engage with predetermined tissue sites of the subject. It is configured to put the apparatus in tension perpendicularly to the direction of needle deployment to administer the therapeutic agent. A splay shield that includes a force contact pick-up may be the first interlock in the apparatus described herein. A force contact pick-up may include at least one pad, at most one second pad, as well as a flexible circuit. In some embodiments, the first contact spring is mechanically biased to create a splay cover.
The cartridge assembly of an apparatus described herein may also include a stick shield. The stick shield may also include a stick nub, stick shield hole and stick shield spring in some embodiments. In some embodiments, this first interlock is the splay-shield that has at least one hole to allow for the sliding of the stick shield. The apparatus described herein may also include at least one stick support to interface with an outer cartridge. The stick shield support in an exemplary embodiment is a support arm made of stamped metal. Another exemplary embodiment has the stick shield supports moving over at least one of the retaining walls in a sequential manner. The apparatus described herein may include a first retaining walls that can stop proximal movement in the case of discharge at a selected depth. A second retaining wall can also prevent proximal movements of the stick guard after discharge at a selected depth. Some embodiments integrate the stick shield support as an injection-molded plastic feature in an outer cartridge cap.
“Another embodiment of the stick support prevents the stick from moving in the proximal direction by preventing it from being ratcheted in a ratcheting manner. Another embodiment of the apparatus includes a gear rack that is attached to the stick shield in order to limit proximal movement. The stick shield support can be used to stop the stick shield supporting from moving in the proximal direction if at least 5 N is applied. Another case is that the stick support stops the stick shield moving in the proximal direction if at least 15 N force is applied. The stick shield support can be integrated into the alignment guide or splay shield as an injection-molded plastic component. Some embodiments allow the cartridge to be loaded into the applicator and the vessel will move forward to mate the needle hub. The cartridge then contacts the needle during administration of the therapeutic drug. Another embodiment of the inner cartridge is slidable relative to the outer cartridge along the same longitudinal axis. Sometimes, the inner cart engages with the inner cap at the distal end. This locks the electrodes in position and provides a bearing surface to the stick shield.
“The apparatus described herein may also include a sensor. The sensor may be selected from the following: a cartridge loading sensor; a cartridge loaded sensor; a cartridge force sensor; an insertion mechanism position sensor; an optical detector; and an electrical sensor. A loading drive subassembly may include a cartridge loading sensor or a loaded sensor. The loading drive subassembly may also include a cartridge guide rail and a motor. The loading drive subassembly may also include a connection to the pinion gear assembly that pulls the cartridge assembly into the receiver. This rack is located on the base of the outer cartridge. The pinion gear assembly may engage the rack on an outer cartridge in some embodiments. Some embodiments include at least one rack tooth. The first tooth of the rack provides a tactile sensation as the cartridge assembly is inserted into its receiving volume. The first tooth may provide torsional stability in some embodiments. Some embodiments detect a cartridge loading sensor that is attached to the cartridge assembly and initiates loading. Some embodiments detect a cartridge loaded sensor to stop loading. The apparatus may also include a continuing flag to allow the cartridge loading process to continue. The apparatus may also include an insertion detector, which is a light emitter/collector of IR sensors. The sensor can detect a vessel label to verify that the therapeutic agent is being administered.
“Provided is an apparatus for controlled delivery of therapeutic agent to a tissue site in a subject. It comprises: A cartridge assembly comprising an housing, a needle receiver, and a vessel to hold the therapeutic drug. An applicator consisting of a cartridge receiver and an applicator. The receiver is designed to detect the loading of the vessel. An electrode support comprising an array of apertures that correspond to the predetermined special relationship between the electrodes.
“In some embodiments, an apparatus also includes a needle. In some embodiments, an electrode insertion spring is included or a needle insert spring. An electrode shoulder or electrode bend can be used to separate the electrode’s proximal and distal portions. The electrode support can be used to provide an operative connection between the conductive contact area on the electrodes’ distal end and the controlled source energy for when the electrodes are placed into the patient’s predetermined tissue site. The electrode support may include a needle hole that allows for the passage of an injection needle. The electrode support may include a planar structure that is perpendicular to the electrodes’ elongate orientation. The planar structure may also include an aperture, which is a hole or slot that allows the electrode to pass through to the predetermined tissue site. The aperture may include at least one tubular structure that is perpendicular to the planar structure in some embodiments. The planar structure may be perpendicularly to the longitudinal axes for the electrodes in some embodiments. The electrode support may be an adaptive electrode support in some embodiments. The adaptive electrode support may be a compression spring in some instances. The compression spring can be made from metal, polymer, or an elastic material. The electrode support may include at least one telescoping tub in some embodiments. The electrode support may also include a stick shield spring in some cases. The electrode support may also include at least one lateral support member attached with the electrodes and at least one optional hinge feature. The electrode support may be made of a metal, a plastic, a ceramic, or a compressible material. The compressible matrix material can be selected from any of the following: a cellulose, a polymer, a rubber, a foamed, or a foamed resin, a microcellular, foamed, foamed silicon, polychloroprene, carbon-foam matrix, and a foamed cellulose. The electrode support may be made of an unconducive material in some embodiments. The electrode support may be made from a thermoplastic material in some embodiments. Some embodiments use a thermoplastic material, which can be a polycarbonate or polystyrene, a plastic propylene, acrylic, or polyethylene.
“In some embodiments, an electrode support supports transcutaneous electrode deployment and maintains tissue depths up 60mm. An electrode proximal part of each electrode is connected to or contacts an electro contact in some embodiments. Each electrode is placed on the outer cartridge of the cartridge assembly. The electrode contact is designed for power communication with the applicator. In some embodiments, an outer cartridge contact is added to the electrode contact. The electrode contact may provide an electrically conductive interface to the corresponding electrodes without interfering with the forward travel of the inner cartridge’s electrodes. The cartridge assembly may also include a port for loading a vessel. An outer cartridge is included in some embodiments. This outer cartridge contains an inner cartridge containment quantity. The applicator may also include an injection drive assembly. In these cases, the injection drive assembly is paired with the cartridge assembly. The applicator may also include an applicator cartridge assembly receiving point. The applicator may also include a procedure activation trigger in some embodiments. The applicator may also include a connector to connect to the controller, a top and side housings, as well as an inner protective shell. The vessel may also include a cap. In some embodiments, an egress port is added to the apparatus. The apparatus may also include a plunger stopper. The apparatus may also include a multiconductor cable. The exterior cartridge cap chamfer surface may also be included in some embodiments. The apparatus may also include an exterior cap hook. The apparatus may also include a main power port. The apparatus may also include a main power switch and a power button in some embodiments. The apparatus may also include at least one connector to allow for a switch in some embodiments.
“Provided are embodiments in which an apparatus described herein includes a hybrid motor/spring mechanism to contact at least one said injection orifice, or said plurality electrodes with said tissue site.”
“In some embodiments, at least one connector is included in the apparatus for switching. The apparatus may also include a USB port in some embodiments. The apparatus may also include a reminder tab in some embodiments. The apparatus may also include a battery indicator in some embodiments. The apparatus may also include a mute switch in some embodiments. In some embodiments, at least one menu navigation button is included in the apparatus. In some embodiments, an eject button is added to the apparatus. The apparatus may also include a display screen in some embodiments. The apparatus may also include a tray in some embodiments. The apparatus may also include an applicator connector port. The apparatus may also include an applicator tray. The apparatus may also include a cradle in some embodiments. The apparatus may also include a storage bin. The apparatus may also include a handle in some embodiments. The apparatus may also include abutment walls in some instances. In some embodiments, at least one electrode contact for the applicator electroporation is included in the apparatus. In some embodiments, at least one electrical connector is included in the apparatus. In some embodiments, an additional cartridge loading subassembly is included. The apparatus may also include a motor drive and at most one electrical contact to drive the motor. The apparatus may also include a loading drive motor. In some embodiments, the apparatus also includes a motor trigger connector. In some embodiments, the apparatus also includes a motor drive shaft. In some embodiments, at least one electromechanical component is included in the apparatus. The apparatus may also include at least one cartridge loading, electrode insert, and injection subassembly. The apparatus may also include at least one injection level selection button and an indicator. The apparatus may also include a procedure countdown clock. The apparatus may also include at least one bracket for mounting and a gear cover bracket.
“In some embodiments, an additional system trigger switch is included in the apparatus. In some embodiments, an additional system trigger switch is included in the apparatus. In some embodiments, an indicator for procedure fault and a complete indicator are included in the apparatus. The apparatus may also include a depth selection button. The depth selection button can be selected from a group that includes a toggle, switch, or sliding switch. The apparatus may also include a plurality channel and a plurality retaining posts in some embodiments. In some embodiments, an insertion mechanism gear drive and ring are included in the apparatus. Rotation of the insertion mechanism ring can rotate the retaining pin into the channel in some embodiments.
“In some embodiments, a insertion mechanism flag, a insertion motor drive motor, an insert mechanism position sensor, an insertion drive plunger, or an inject drive motor are all included in the apparatus. The apparatus may also include a cartridge lock rings in some instances. The retaining posts can be rotated by the rotation of the cartridge lock rings in some embodiments. The cartridge assembly may only be used once in some cases. The applicator can be used for multiple purposes in some embodiments. The applicator may also include a top housing and a side housing. An inner protective shell is included. A front cap and an end cap are optional. The applicator may also include a user interface and a procedure activation trigger. The apparatus may also include a controller in some embodiments. The controller may also include a controller assembly in some embodiments. The applicator may also include a connector to connect to the controller in some embodiments. The controller may also include an electrical field controller in some embodiments.
“In some embodiments, penetrating electrodes or the injection needle contact the predetermined tissue site at a velocity of at most 50 mm/second. In some embodiments the penetrating needle and/or the injecting needle contact the predetermined tissue site at a velocity of at most 500 mm/second. Some embodiments use a nucleic acids as the therapeutic agent. In some cases, the nucleic acids is DNA. Some embodiments place the predetermined tissue site in the subject’s skeletal muscle. In some embodiments, the subject’s skeletal muscle is the medial deltoid or vastus lateralis muscles. Some embodiments allow for injection depths of 19-30mm at the medial deltoid muscles. Some embodiments allow for injection depths of 25-38mm at the vastus lateralis muscles.
“In some embodiments, an apparatus is provided that comprises a motor/spring mechanism to contact at least one said injection site or said plurality electrodes. The apparatus may also include a measurement circuit and logic circuit that monitors the motor’s usage during injection strokes and compares it to a predetermined standard.
“Provided herein is an apparatus that includes a controller and a force circuit. A feedback loop between said controller, said force contact circuit and said controller detects a change in applied force and prompts the initiation of a check to ensure that the electrodes are properly placed in the predetermined tissue location.
“In certain cases, the apparatus described herein allows for the deployment of a plurality or more electrodes/needles by rotational motion.”
“Provided are methods of providing therapeutic agents to predetermined tissue sites in subjects in need. This includes contacting the subject with the apparatus described herein. Systems for administering a therapeutic agent to a predetermined site of tissue in a subject who is in need thereof are provided, which include an apparatus described herein.
This Summary is intended to provide a summary of selected concepts in a simplified format. Further details are provided in the Detailed Description section. It is possible to include elements or steps that are not described in the Summary. However, no step or element is required. This Summary does not identify the key features or essential features in the claimed subject material. It is also not intended to be used as an aid in determining its scope. The claimed subject matter does not include implementations that eliminate all or some of the disadvantages described in this disclosure.
“The following descriptions and examples show embodiments of the invention in depth. This invention is not limited by the specific embodiments listed herein. It is possible to vary. The scope of the invention includes many modifications and variations, as will those skilled in the art.
“All terms are meant to be understood in the same way that they would be understood by someone skilled in the art. All technical and scientific terms are understood as they would be by someone of ordinary skill in art.
“The section headings in this document are used for organizational purposes only. They should not be construed to limit the subject matter.
“Various features of the invention can be described in the context a single embodiment. However, they may also be provided separately or in any combination. The invention can also be described in the contexts of different embodiments to increase clarity. However, the invention could be implemented in one embodiment.
The following definitions are intended to supplement the art and to the current application. They are not to be attributed to any other case or related matter, e.g. to any patent or application that is commonly owned. While any method or material similar to the ones described herein may be used for the practice of testing the present disclosure, the preferred methods and materials are described herein. The terminology used in this document is intended to describe particular embodiments and not be considered limiting.
“Unless otherwise stated, the singular is used in this application. The specification uses the singular forms?a and?an. ?an? ?an? If the context requires otherwise, plural referents should be used unless they are clearly defined. The use of the?or? in this application is not permitted. means ?and/or? Except where stated otherwise. Additionally, the term “including” is allowed. As well as other forms such as ‘include’,?includes?, and?includes? as well as other forms such as?include?,?includes?? It is not restrictive.”
“Refer to the specification for?some embodiments? ?an embodiment,? ?one embodiment? Or?other embodiments? This means that at least some embodiments of the inventions include a specific feature, structure, or characteristic. However, not all embodiments.
“As used herein, the words ‘comprising? are used in this specification. (and any other form of including, such as ‘comprise? ?comprises? ), ?having? (and any other form of having, like?have? (and any form of having, such as?have? ), ?including? (and any other form of including, such?includes? (and any form of including, such as?includes? or?containing? (and any other form of containing, like?contains?) (and any form of containing, such as?contains? These terms are inclusive or unrestricted and don’t exclude any additional elements or steps. Any embodiment described in this specification may be used with any method or composition according to the invention. You can also use compositions of invention to realize methods of the invention.
“The term “about” is defined as: “About” can be used in reference to a reference number value or its grammatical equivalents, as it is used herein. It can also include the numerical value and any range plus or minus 10% of that numerical value. The amount of 10 is an example. The amount?about 10? includes 10, and any amount between 9 and 11. The term “about” can be used to refer to the term. In relation to a reference number value, the term?about? can also be used. It can include a range plus or minus 10% 9%, 88%, 76%, 66%, 5% or 4% from that value.
“The present disclosure provides an improved system, methods, and apparatus for the consistent, reproducible, and efficacious delivery therapeutic agents such as drugs, peptides and proteins, together with combinations thereof using Electrically Mediated Therapeutic Agent Deliver (EMTAD)”
“In one embodiment, the present disclosure provides an apparatus to deliver a therapeutic drug to a predetermined location within a subject. It includes an administrator to control the administration of the therapy agent to the subject. The administrator has a reservoir or vessel that holds the therapeutic agent and an orifice through which it is administered. A controlled source of energy can be used to transfer the prescribed amount of therapeutic agent from the reservoir or vessel to the site. The apparatus also includes a number of penetrating electrodes that are arranged in a predetermined relationship to the orifice and an electrical signal generator. In the specification, the terms reservoir and vessel can be interchanged to mean a container for the therapeutic agents.
EMTAD is defined as the administration of a therapeutic drug to a biological tissue and subsequent, concurrent, or earlier application of electrical signals to that tissue in order to increase movement and/or uptake. The EMTAD process consists of two components: 1) Therapeutic Agent Administration, and 2) an Electrical Signal Application. These elements are sufficient to produce the desired EMTAD effect. The present disclosure reveals that therapeutic agent administration can be done in a controlled manner, called Controlled Therapeutic Agent Administration. This term CTAA refers to apparatus and methods that allow for spatial and/or time-controlled administration of therapeutic agents relative to inducing an EMTAD effect. Variations on the traditional needle-syringe can be used to control administration (e.g. Automatic injection device) or other needleless methods (e.g. jet injector, transdermal/transcutaneous patch, oral, gel, cream, or inhaled administration). ESA refers to the use of electrical signals to enhance or facilitate the delivery of therapeutic agent by increasing movement and/or uptake within tissues. This is known as an EMTAD effect. When used to facilitate or enhance delivery of a therapeutic agent, ESA processes such as electroporation, iontophoresis, electroosmosis, electropermeabilization, electrostimulation, electromigration, and electroconvection all represent various modes of EMTAD.”
“Specific uses for apparatus and systems described in this document include the delivery of vaccines and therapeutic proteins as well as chemotherapeutic drug. EMTAD is traditionally initiated using a needle-syringe to inject the therapeutic agent. Once the agent has been administered, an ESA device is used to apply the drug to the patient at the designated site. An appropriate ESA protocol is used to facilitate or enhance therapeutic agent delivery. Traditional EMTAD may not allow for the desired spatial and/or temporal relationship between agent administrations and ESA.
“Spatial Parameters”
“Some embodiments of the methods, apparatus, and systems described herein allow therapeutic agent administration to be performed with a standard needle syringe. TAA is complicated because certain agents must be delivered with EMTAD. FIG. FIG. 1 shows that in conventional needle-syringe injections, the needle 5 is inserted into tissue at a depth of 1 and angle 2 respectively. This can make it difficult to control the depth and angle. The needle’s point of penetration at the tissue surface may not correspond to the site of the agent administration 7 and the orifice 6. A transcutaneous intramuscular injectable may not be the same as the point of needle penetration on the skin. These tissues are often in close proximity and can move in different directions.
This conventional approach can be used to deliver many therapeutics, but it is not suitable for EMTAD. Variables in the distribution of therapeutic agents after injection can cause inconsistent or indeterminate distributions. This can hinder effective EMTAD. The best use of EMTAD is based on a predetermined relationship between the therapeutic agent in the subject and the ESA. In other words, if there is no spatial control of TAA in target tissue, a conventional needle-syringe may result in less effective EMTAD applications than an apparatus, method, or system that does so. This concept can be illustrated by electroporation, which facilitates the delivery of therapeutic agents. When TAA and ESA co-localize within the tissue target, electroporation is most effective in increasing therapeutic agent delivery. If the agent to deliver and the induced electroporation effect do not co-locate within the tissue target area, delivery is often suboptimal.
Iontophoresis is another example of the need to have adequate spatial control over TAA in EMTAD. EMTAD in this mode uses electric fields to move charged molecules. To achieve the desired agent movement, it is necessary to establish the correct spatial relationship between electrodes and therapeutic agent. A negatively charged agent placed close to a positive electrode would result in little or no movement through the tissue. However, if the negatively charged agent is placed near the negative electrode, it will cause significant movement through the tissue in the opposite direction.
“As shown by the examples above, it is crucial to control TAA’s exact location relative to ESA in order to achieve the desired effect. The apparatus and methods described herein allow for precise control over the location of TAA relative the application of ESA. They are therefore useful in achieving consistent, reproducible, and well-characterized distributions of one or more therapeutic drugs.
“Temporal Parameters”
“The problem with conventional needle-syringe injection is that the rate at which the agent is injected may differ from one operator to the next. This can lead to inconsistent distribution of the agent in the tissue. Multiple device placements can introduce additional temporal variability to the EMTAD process. For example, one application of EMTAD calls for the administration of plasmid DNA encoding for a therapeutic protein, followed by generation of an electroporation-inducing electrical field. The traditional EMTAD method involves injecting the plasmid with a needle-syringe. Next, place and activate the electroporation devices. This procedure requires two separate device placements: the initial needle syringe and the ESA device. This can lead to intersubject variability due to inconsistent temporal application by the operator. The clinician must place each device twice, which creates an inexorable time delay between activation and placement. Multiple application sites may be required to deliver the agent to the desired area of target tissue.
These issues are particularly important for agents such as nucleic acid, which can be inactivated or degraded in the extracellular environment. The therapy’s efficacy can be affected by the agent’s degradation. The inter-subject rate for therapeutic agent degradation is variable, which can lead to therapeutic inconsistency when combined with ESA and, more specifically, electroporation therapy.
Due to the spatial and temporal variability inherent in conventional needle-syringe combination with ESA, it is difficult to know the exact location and timing of TAA relative ESA. EMTAD can make it difficult to administer and dose therapeutic agents effectively. Although conventional needle-syringe injection can sometimes be sufficient for therapeutic agent administration. However, consistent and reproducible agent delivery can be significantly improved by controlling the spatial/temporal relationship between the administration of the therapeutic drug and the induction of the desired EMTAD effect.
“Thus, although the traditional EMTAD procedure is suitable for some applications, it is not ideal for clinical applications that require high levels of consistency and reproducibility. Contrary to the traditional EMTAD approach described above, the embodiments of systems, methods, and apparatus described herein enable CTAA and ESA, which provide more beneficial methods and apparatus for clinical application of EMTAD. In order to deliver therapeutic agent consistently, efficiently, and reproducibly, the present disclosure uses various aspects of CTAA with ESA. This disclosure describes apparatus and methods for spatial and temporal control of administration of a therapeutic drug relative to electrical signals. This improves the uptake and movement of the agent in target tissues.
“In some embodiments, methods and apparatus are provided that allow for the controllable spatial relationship between the administration of therapeutic agents relative to the application electrical signals. The optimal location of TAA relative to ESA must be determined before treatment. The treatment parameters (e.g., the type of agent and properties of the target tissue) determine the spatial relationship between TAA/ESA. In one example, the electrical signals are preferred to be applied distal of the site of therapeutic agent administration. Other embodiments prefer to apply EMTAD-inducing electric signals proximal the agent administration site. Co-localization of TAA and ESA may be desirable in certain situations. This is usually the case when electroporation or iontophoresis is used to induce the desired EMTAD effect.
“Another aspect of the disclosure is that the apparatus described herein allows for a controlled temporal relationship between the timing and sequence of TAA relative ESA. The optimal sequence and timing of TAA/ESA combination is determined prior to treatment. The desired temporal relationship between TAA/ESA is determined in the same way as for the spatial relationship. This is determined by factors such as the type of agent and properties of the target tissues. The therapeutic agent may be adversely affected by exposure to ESA’s electrical fields in certain situations. CTAA is used to generate such electrical fields in the practice of such applications. The typical temporal relationship is CTAA and ESA.
“The present disclosure provides improved methods for the consistent, reliable, and effective delivery of therapeutic agents such as pharmaceutical compounds, drugs, nucleic acids, and proteins with EMTAD. This is achieved by controlling the timing and spatial distribution of therapeutic agents relative to electrical signals. EMTAD can be achieved by delivering vaccines, therapeutic proteins and chemotherapeutic medications. EMTAD can be initiated using a standard needle-syringe to inject the therapeutic agent. Once the agent has been administered, an ESA device is applied to the subject at the designated location. To provide therapeutic agent delivery enhancement or facilitation, an appropriate ESA protocol will be used. Electroporation is an excellent ESA technique that has been proven to work in almost all cell types. Other exemplary methods of electrically mediated delivery include, but not limited to, iontophoresis, electroosmosis, electropermeabilization, electrostimulation, electromigration, and electroconvection. These terms are intended to be used as examples only and should not be taken to mean that the disclosure is limited in any way.
Electroporation is a technique that uses electric fields to temporarily increase cell membrane permeability, and move charged particles. Electroporation improves intracellular uptake of exogenous drugs administered to target tissues by permeating cell membranes. Electroporation can increase cell membrane permeability, and molecular movement. This allows for the removal of cell membrane barriers that prevent therapeutic agent delivery. Electroporation can be used to induce EMTAD in many tissue types. The present disclosure discusses, but is not limited to, the use of electroporation in inducing EMTAD.
“Therapeutic Agents”
“The term “therapeutic agent” is used in a broad sense. “The term?therapeutic agent?” is used in this context to mean any agent that has the potential to have a beneficial or desired effect on living tissue. The term can be used to refer to both therapeutic and prophylactic agents. The scope of the disclosure is sufficient to allow controlled delivery of any agent regardless of its classification. The therapeutic agents covered by the present disclosure include pharmaceutical drugs and vaccines as well as nucleic acids sequences (such supercoiled, relaxed and linear plasmidDNA, RNA and antisense constructs artificial chromosomes or any other nucleic-based therapeutic), and any formulations thereof. These agents include, but not limited to, cationic, nonionic, cationic, and liposomes, liposomes and saline. They also contain nuclease inhibitors and anesthetics. Agents and additives that can control the viscosity or electrical impedance of the administered drug may also be used in other formulations.
“In the case nucleic acid, plasmid DNA would be a therapeutic agent. It would be dissolved in a phosphate-buffer sodium chloride solution and a competitive nuclease inhibitor like aurintricarboxylic acids (ATA) added. It may be beneficial to include a signaling protein onto a construct in some cases that use nucleic acid-based therapeutics. Some peptides that could be useful include nuclear localization signals and endosomal-lyric peptides. These signals can improve the delivery and/or processing the therapeutic agents delivered to cells via EMTAD. These signals can be achieved using methods described in U.S. Pat. No. No. 6,165,720 (the complete disclosure is included by reference herein). These techniques can be used with other delivery systems but the EMTAD’s ability to deliver nucleic acids constructs to target tissue makes them particularly well-suited to use with these signals.
“Target Tissues”
EMTAD is a technique that targets healthy or diseased tissues. These include the epidermis and dermis as well as connective and muscle tissue. This technique can be used to access healthy or diseased organs using minimally invasive surgical procedures or other surgical methods. These target tissues include the liver and lungs, heart, blood vessels. lymphatic, brain, liver, heart, kidneys, stomach, intestines. colon, bladder, reproductive organs. A method or apparatus described herein can deliver the desired therapeutic effect to cells that are normally found in target tissues. It may also be used to deliver additional agent to other cells not normally found within those tissues. “chemotherapeutic treatment for tumors.”
“As previously discussed and illustrated in FIG. 1. Traditional EMTAD has a problem with precision and reproducibility in the spatial-temporal relationship between the administration and reception of the therapeutic agent. The present disclosure, which describes the apparatus and methods for combined CTAA/ESA to offer a more beneficial clinical application of EMTAD, is a departure from the traditional EMTAD approach. To provide consistent, reliable, and efficient therapeutic agent delivery, the present disclosure uses various aspects of CTAA with ESA. These methods and apparatus provide spatial and time control of administration of therapeutic agents relative to electrical signals. This improves the movement and/or uptake in target tissues.
“Methods”
“In one aspect, this disclosure describes systems and apparatus that can be used in controlled administration of a therapeutic drug followed by ESA. The present disclosure describes systems and apparatus that can be used in controlled administration of therapeutic agents prior to ESA. The present disclosure describes systems and apparatus that can be used in controlled administration of therapeutic agents accompanied by ESA. These methods can be used to determine treatment parameters, subject preparation, CTAA, ESA and other measures.
“Determination Treatment Parameters”
“In some cases, the treatment parameters are determined by the amount and/or length of dosing of therapeutic agent. Dosing of therapeutic agent can be determined by the specific indication or treatment application, such as the type and position of the target tissue, as well as other subject parameters, like age and body weight. The parameters that govern the administration of the therapeutic agents and ESA can control the dosing of the agent. Examples of controllable parameters for CTAA include agent volume, agent viscosity and injection rate. ESA is a good example of controllable parameters. They include the characteristics and exposure to electrical signals as well as the format of the electrode array. Further control is possible by adjusting the relative timing and position of CTAA or ESA.
“Patient/Subject Preparation”
“In embodiments described herein, methods described herein may include a patient/subject preparation step. Subject preparation can include antiseptic cleaning and anesthetic administration. This may include local, regional, spinal, epidural, or general anesthesia. An example of intramuscular (IM), ESA may include protocols to reduce the effects of electrical stimulation on the muscle. This could include thermal control (e.g. The administration of anesthetics and/or other stimulation patterns that can be used to reduce discomfort may be included in cooling the muscle. If there are alternatives, it is important to understand that therapeutic efficacy does not suffer from the chosen subject preparation methods. It has been demonstrated that intramuscular administrations of amide-based anesthetics can sometimes have an adverse effect on intramuscular DNA-based therapies. This is likely due to mild myotoxicity, which can prevent the muscles from expressing the DNA sequence.
“CTAA and ESA.”
“In some embodiments, CTAA and ESA can be combined to enable consistent and reproducible therapeutic agents delivery. There are some apparatus that can be used for CTAA. This includes apparatus with at least one automatic injection device and jet injectors.
The present disclosure relates to methods and apparatus that enable the transcutaneous deployment in safe and consistent fashion of a plurality elongate electrodes at a target depth to treat recipients with heterogeneous skin composition and thickness. This is done in support of the application of electric fields in tissue to increase intramuscular, subcutaneous, and/or intradermal administrations of therapeutic or prophylactic drugs such as nucleic acid, pharmaceuticals and antibodies, peptides and proteins or combinations thereof.
“Systems and methods based on the present principles allow the continuous transcutaneous deployment of a plurality elongate, tissue-penetrating electrodes to a predetermined target tissue site to propagate electric fields in the skin, subcutaneous tissue, and/or muscle. This disclosure is intended to allow a user to deploy electrodes at a desired depth and maintain the correct spatial relationships among the plurality, even when they are applied to sites with different skin characteristics. Variation in skin characteristics can occur at different locations within an individual, or between heterogeneous recipients. Systems and methods based on the present principles should permit consistent profiles regardless of who the administrator is or who the recipient is. Some embodiments allow for the deployment of electrodes with one or more injections needles. These are designed for administering therapeutic agents to target tissue regions and are arranged in a predetermined spatial relationship to the electrodes to be used to provide ESA. An exemplary embodiment of the electrodes is such that the electrical signals from the electrodes are preferredentially applied distal of the site for therapeutic agent administration through the insertion one or more injections needles. Another embodiment is to arrange the electrodes so that any electrical signals are preferredentially applied proximal the site for therapeutic agent administration through the insertion one or more injections needles.
“Aspects can be used alone or in combination with other aspects of the disclosure to support transcutaneous insertion electrodes for in vivo electrical field stimulation to increase intramuscular, subcutaneous, and/or intradermal administrations of nucleic acid, small molecule drugs and antibodies, peptides and proteins and combinations thereof. Some embodiments coordinate the deployment of electrodes and the subsequent propagation of electrical fields with the distribution of the agent to the target tissue site. An exemplary embodiment of the agent’s administration and application of an electrical field is controlled and monitored so that there is the best chance of co-localization of the agent’s distribution with the electric field application site.
The present disclosure describes methods and apparatus that enable transcutaneous deployments of electrodes at predetermined sites within the skin, subcutaneous tissue and/or muscle of a recipient. This is in addition to the administration of an agent and local application of electric fields to enhance the delivery, uptake and/or biological effects of the agent. The present disclosure is implemented in a way that users can set up and use the device quickly and easily. The present disclosure includes numerous interlocks and sensors that can be used to reduce errors made by users during set-up and usage. Referring to FIG. Referring to FIG. 2, one embodiment described in this article is a ‘cartridge assembly? 100 are detachably connected to an ‘applicator? 400 that can be detachably interfaced to an?applicator? A user interface, tray and holster are all provided by controller 700. FIG. 2. A reservoir 101 can be inserted into the cartridge assembly 100 to provide a method for use.
FIGS. 3A-12 and the corresponding cooperating parts of the applicator 400 are shown in FIGS. FIGS. FIGS. 19-20D. 19-20D.
“Referring to FIGS. “Referring in addition to FIGS. The electrode mounting structure must be designed and constructed so that the dielectric barrier is adequate between opposite polarities within the device to prevent unwanted propagation of electric currents. The electrodes’ distal regions 137 are connected to the mounting structure by using standard mechanical features or bonding agents that correspond with the material composition of both the electrode mount structure, and the electrodes.
“In one exemplary embodiment, the cartridge’s outer housing structure 102 can interface with a fluid reservoir 101 or vessel 101 that contains the agent of interest. The reservoir 101 or vessel 101 and the cartridge housing structure102 are designed to connect to at least one injection port (needle 105) through the which the agent is administered to the target tissue. This configuration allows for co-localization between the location of electrical field application and the distribution of the agent. This configuration allows for the establishment of a pre-determined spatial relationship among the apparatus for ESA/CTAA. Another example is where a syringe 101 can be inserted into a cartridge 100. Then, upon loading the cartridge into an application 400, the Syringe 101 will move forward to mate the needle hub 152, and connect the cartridge to it.”
“Some embodiments of this disclosure may include the use of vials, ampoules or cartridges for the storage of one or more therapeutic agent. The reservoir or vessel may be made of at least one type of plastic or glass, depending on the compatibility of the agent. The reservoir or vessel may have protective or lubricious coatings. The electrodes 122 can be hollow or equipped with injection ports that can be connected to fluid vessels. Alternately, the injection port can be constructed with one or more needle-free injection ports or hypodermic needles. The desired route of administration, tissue distribution and physical characteristics of your agent of interest will all play a role in the selection of the size and type of injection orifice. The cartridge structure in a particular embodiment is designed to establish a pre-determined spatial relationship among the injection orifice, electrodes and their deployed states so that the distribution of agent of interest occurs substantially within the tissue bordered by the plurality electrodes. A cartridge 100 is designed to accommodate hypodermic needles. It allows the needle to be mated directly to the cartridge, rather than being matched to the syringe during use. Certain embodiments of the present disclosure may include features in the cartridge or the needle that ensure needle retention during manufacturing, distribution, handling, and usage. These features can also be used to ensure proper mating of reservoir or vessel to needle before use. These features may reduce the risk of agent leakage from the reservoir, reservoir orifice interface or due to improper mating.
“In some embodiments, the cartridge may include a tissue interface at the distal end. The tissue contact interface can be a substantially planed structure perpendicularly to the elongate orientations of the electrodes. It may also have one or more apertures that allow the passage of the electrodes through it. The interface can also be used to allow needle-free injections or injections, if there is an integrated reservoir or vessel. In certain embodiments, the apertures for the injection needle and electrodes are sufficiently large to avoid accidental contact. This reduces the chance of needle-related injuries and contamination. The tissue contact interface is usually composed of one or more plastics that are suitable for contact with tissue, at most for a short time.
The cartridge assembly 100 can be set up for one-time use to avoid cross contamination of biological material among recipients. Sometimes, the cartridge may contain one or more identification, mechanical, and/or electrical elements that limit the use of the cartridge to one administration. This includes, but is not limited to, lockouts or detents that secure the stick shield and/or electrode mount structure in their deployed state. For example, fuses and links that are connected to one or more electrodes can be considered electrical elements. These elements are activated by the source for electrical energy after the cartridge is used. For example, identification elements could be serialized radio frequency identification devices or bar codes. These codes can also be used to identify the source of electricity and the applicator. To prevent the accidental or deliberate re-use by the applicator and/or source of energy of a particular cartridge, the identification information can be used. One or more redundant features may be incorporated in an embodiment to reduce the possibility of reusing the cartridges.
“In the embodiment of an apparatus described in this invention, as shown at FIG. 2. The applicator 400 includes a support structure that interfaces with the cartridge assembly 100. A user interface 410-418 is also included (FIG. 13B), electrically conductive electrical connections that provide an operative connection between a conductive contact area on the distal end of the elongate electrodes and the source for electrical energy when the electrodes have been deployed in the recipient’s target tissue. In some cases, the user interface includes a handle and one or more display elements that convey information to the user. There may also be one or more features that can accept input from the user. The display features can be used to show the operating status of the device, as well as any warning/error messages. These displays may include mechanical features, electronic screens, or alphanumeric display screens. Some features that can accept user input may be configured to allow the user to, at the appropriate time during the procedure, deactivate safety features in the device to prevent accidental discharge. They also enable the user to make selections about particular parameters (e.g. the intended depth of injection) and initiate procedure administration. These features include buttons, triggers and mechanical slides as well as levers.
“In some embodiments, the applicator400 also contains actuation mechanisms that interface with the cartridge assembly. These are designed for transcutaneous deployment and positioning of electrodes relative to target tissues. The agent of interest is then released from the reservoir/vessel through the orifice into the target tissue site. Additionally, electrical signals can be transmitted from an electric field generator, such as a controller 700, to the cartridge 100. The applicator 400 may be designed so that energy is supplied by the user. More preferably, the apparatus can include one or more inanimate energy sources operatively connected with the actuation mechanism within the applicator. These inanimate energy sources include, for example, electromechanical devices (solenoids and motors, lead screws), mechanical parts (springs and similar devices), and compressed gas.
FIG. 3A shows an exemplary cartridge assembly 100. 3A shows a cartridge 100 that includes a reservoir/vessel loading port 140 and reservoir/vessel containment volume 142. These are used to hold and contain a medicine reservoir 101. An electric field generator, such as a controller 700, is needed to create an electrical field and use it in therapy. A cartridge 100 is necessary because the device that contains the electrodes is designed to contact the target tissues requires an electronic interface. The controller can be set up for multiple purposes, while the reservoir 101 or vessel 101 can only be used once. Therefore, the cartridge 100 can be used to store the electrodes 122, 101 and 101. This allows the cartridge 100 to be used for one-time use. The applicator 400 is a reusable part and the cartridge 100 can be set up for single-use. You can also make sure that the cartridge 100 is in good condition so that it cannot be used again in case of errors or tampering in the inserting of a reservoir 101 or any other defects.
“Reservoir or vessel 101” can be used to refer to a vial, syringe or other device that can contain a medication or therapeutic agent. It can also include a vial, syringe or other device that can interface with a device with an orifice such as a needle. FIG. 4. A needle 105 with a needle hub 152. For a particular type of cartridge assembly 100 the reservoir 101 has a generally common shape and size. Although there are many components in the cartridge assembly 100 that allow for some variation in sizing and/or manufacturing tolerances; generally, a common form and size is required to minimize the possibility of drugs not being labeled for cartridge 100 being incorrectly delivered. The cartridge assembly 100 could be inoperable if the user does not provide a sufficient-sized reservoir 101. If this happens, the system will be unusable until the proper-sized reservoir 101 has been inserted.
“As shown in FIG. “As seen in FIG. To maintain the integrity and sterility of the agent, a removable cap 158 may be added to the reservoir until it is inserted. The needle hub 152 can be located proximal to this port, while the plunger can be placed opposite it. An alternative to an open port for drug escape, some embodiments provide a septum component that covers and seals the end container. You can make the septum from silicone or butyl rubber. The specific formulation and coating will be determined to ensure compatibility with the agent within the container or reservoir. A crimp seal or another fastening mechanism holds the septum component in place. This septum seal configuration eliminates the need to use a removable cap. However, needle 105 must be equipped with a suitable needle, spike or other piercing members to access the fluid in the reservoir. This configuration can be used in two-sided needle configurations or spike vial adapters.
“The cartridge assembly 100 can be used to receive the reservoir or vessel 101, but it can also be received by an application 400 in an applicator assembly receiving port 41 (FIG. 2). The cartridge assembly 100 contains a device that allows the applicator 400 pull the cartridge and keep it within an interior volume. The device may be one or more racks located on the surface of the cartridge 100 that engage the corresponding motorized gear assembly in the applicator 405. Other implementations allow the applicator 400 to interface with the cartridge 100 without having to pull it into an interior volume. Other techniques can be used to get the cartridge 100 to engage the 400, such as motorized brackets or tracks, onto which the 100 cartridge assembly can interface.
“The applicator 400 also has interface elements that allow it to control certain actions in the cartridge assembly 100. The applicator 400 can be used to control various actions, including needle insertion, medicament delivery and electrode insertion. These steps can be linked in some cases so that one action of the applicator 400 triggers multiple of them. Some implementations allow all these steps to be initiated by one action. This includes the electrode activation and medicament delivery.
The applicator 400 can be used to activate the cartridge assembly 100 by using electrical or optical signals to the mechanical, electrical, and optical elements. This will ensure that all subsystems are functioning properly and are ready for electric field application. The applicator 400 can check for such things as whether the cartridge 100 has been used before, the location of the reservoir or vessel within the cartridge, the application force against the subject’s body through the alignment guide/splay shield (108), a test that the user has selected a depth and the removal of the exterior cartridge cap 110. The applicator 400 is also able to monitor the operation of the cartridges during the execution of the procedure. These subsystems can be used to test, for example, whether electrodes 122 have been properly deployed in a subject before administering the medicament. Also, the applicator 400 will check that the plunger or reservoir has been properly actuated prior the application of the electric fields. The user has applied the appropriate force against the subject’s body during administration.
The applicator 400 can operate subsystems. However, the cartridge 100 can also include appropriate subsystems. These subsystems may interact with the applicator400, but not all, to achieve the objectives of electric field application therapy and medicament delivery. They include a subsystem that causes needle and electrode insertion; a system for protecting users against sharps after therapy administration; a subsystem that provides different depths for needle/electrodes inserting; a system for ensuring adequate force is applied against tissue of the recipient before initiating the procedure and then during administration. Although deployable needles are often used, there is no requirement for them. Systems with fixed or non-deployable needles or electrodes can also benefit from the present principles.
“In an exemplary implementation as shown in FIG. The cartridge assembly 100 contains an outer cartridge 102. In some cases, it is called a housing. An outer cartridge cap (106) terminates the outer cartridge 102 at its distal end. The outer cartridge 101 includes an inner containment volume 150 for receiving an inner cart 103. This inner cartridge is received and can be moved in a sliding manner relative to the outer one 102. The inner cartridge103 contains a reservoir/vessel containment volume of 142, in which the reservoir 101 or vessel 101 might be located. An inner cartridge cap 104 is located at the distal end of inner cartridge 103. The inner cartridge cap104 serves a variety of functions. It locks electrodes 122 into place (the inner cart 103 has seams where the electrodes are placed into), and provides a bearing surface to a stick shield. The inner cartridge cap104 locks onto the inner cart 103.
“A cartridge breech 112 can be found in the reservoir or vessel containment volumes 142, 103 and 104. It is located in the area opposite the inner cartridge cap. The vessel detection cap 118 encloses the cartridge’s breech 112 via a vessel detection spring. The system is locked in place by a cartridge lock ring (114), which connects the cartridge breech 112 with the inner cartridge. The vessel detection spring 112 pushes the reservoir 101 into engagement with needle hub 152 and allows for tolerances in the reservoir 101’s size.
“A vessel interlock 120 acts as a mechanical lock to prevent accidental or unintentional actuation of cartridge functions. The vessel interlock 120 is also known as a first cartridge insertion trigger and is located below the inner cartridge. It has fingers 121 that pass through the slots or holes in the inner cartridge. (see FIG. 5B). The fingers 121 stop the cartridge breech 112 slidably moving in relation to the inner cart 103. In particular, the cartridge breech 112 cannot move within the inner capsule 103 towards the cap 104.
“When a container 101 is correctly inserted into the reservoir/vessel containment volume 142, the reservoir/vessel interlock 120 is pushed to the bottom and the fingers 121 are pushed to the bottom, but not extending into the vessel containment volumes 142. The vessel interlock 120 can also be pushed down or depressed to produce an audible, tactile or haptic click. This can be used to inform the user that proper insertion has been done. After being depressed, the cartridge’s breech 112, which is no longer blocked by fingers 121 or vessel interlock 120 is allowed to move. In particular, it is permitted to move towards the inner cartridge cap.104
The spring cap/cartridge interface (470) causes the cartridge breech 112 to move in a manner described below. The cartridge breech 112 locks when it moves forward enough, secures the reservoir 101 or vessel 101 within the vessel containment volume 142, and ensures that the needle hub 152 is correctly positioned relative it to the needle hub 152. This allows for a fluid path from the reservoir 101 to the needle 105.
“For devices where the injection needle is integrated into the cartridge 100, standard ‘off-the-shelf? products are recommended. The device may use single-use hypodermic injections needles. The device’s reliability and operational characteristics may be enhanced by the addition of custom design elements. These elements are not found in conventional hypodermic needles for parenteral administration. The needle hub 152 may include the material it is made from, retention features that prevent the needle from being removed from the inner cartridge 103 during distribution or use, and orientation of any bevel elements in the needle relative the hub.
“Custom injection needles are used in embodiments. One or more mechanical features allow the device to be inserted into inner cart 103. These features could include snaps, tabs, or ridges that correspond to the mechanical features on inner cartridge.103 Some features are designed so that the hub matches the inner cartridge 103 with a consistent orientation. This is combined with a needle manufacturing process capable of consistently orienting any needle orifice features, ensuring that there are no biases in injector location or distribution of medicament due to the design and location of the orifice. A needle with an asymmetrical tip feature (e.g., bevel cut) may exhibit a bias in its deployment into tissue because of the interaction between the tissue layer and the needle’s asymmetrical penetration. The electrodes that have a symmetrical tip feature (e.g., trocar tip) will not show a bias in their deployment characteristics. To account for the expected deployment characteristics due to the asymmetrical needle bevel, the mounting feature for inner cartridge 103 for needle hub 152 can include an offset in needle 105’s injection orifice relative to electrodes 122. The exact dimension of the offset will depend on the nature and depth of the target tissue. However, certain embodiments offset the needle by 0.5-1mm for every 10 mm of penetration depth. These features are useful for ensuring co-localization of medicament distribution when using injection needles or electrodes with different tip profiles.
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