HRP20020790A2 - Directional system of coordinated electro and ultrasound poring for administering medicines - Google Patents

Description

The field of technology

This invention relates to medical technology, and in particular to the technique of administering drugs or chemotherapeutics supported by ultrasound waves and electric fields.

Technical problem

A particular problem that often occurs in the administration of drugs that act at the cellular level is the insufficient permeability of the cell membranes for the drug that has been brought into the intercellular space around the diseased cells in some of the usual ways. In very common cases when the cell membrane does not have specific receptors for a specific drug or active medical substance, the introduction of that substance into the cell is achieved by increasing its concentration in the intercellular space and diffusion. However, this most often means the need to increase the concentration of the drug throughout the body, even where it is unnecessary. Such a procedure can be dangerous when it comes to very active or aggressive substances such as cytostatics, genetic drugs and the like. By applying electric fields and ultrasound waves, it is possible to temporarily and locally open pores - passageways on cell membranes in the diseased area and thereby locally increase the efficiency of drug introduction while at the same time reducing the total concentration of the drug in the patient's body.

State of the art

Cancer chemotherapy is often limited by severe side effects caused by chemotherapy drugs. Such drugs are often administered systemically, through the bloodstream. A significant part of the drug travels through the bloodstream and thus affects tissues that are not affected by cancer, which limits the maximum acceptable doses of the drug. A desirable improvement in therapy would be to decrease the total dose while increasing the dose to the target area - the area of interest. The advantage of localized internal drug administration is described in US5286254. However, if the target for the drug is intracellular, usually local administration of the drug does not simultaneously enhance the penetration of the drug through the surface barriers of the cell membrane. Some active medicinal agents have difficulty crossing intact cell membranes by ordinary diffusion and may require specific carriers. Exposing the cells to electric or ultrasonic fields helps this process.

Application of electric fields can cause cell membranes to temporarily and transiently increase membrane permeability, allowing otherwise impermeable molecules to enter cells. This state of temporary permeability is related to the formation of pores in the biomembrane and is called electroporation. Since electroporation was discovered in 1970, many experiments have been conducted in this field. Many devices and constructions of electrodes have been developed for the therapeutic application of electroporation. Most of these devices are used in the treatment of subcutaneous tumors that also affect the skin, so parallel plate electrodes are used for this purpose, which are placed on both sides of the tumor, e.g. according to patents US5810762, WO0004949, EP1224949, US6022316. For cases when the electrodes cannot be held stably in the working position, flexible plate electrodes, US6424862, and needle electrodes US6418341, US2002065480, and flexible electrodes according to US6418341 have been developed.

In-vitro research has shown that cell membranes become temporarily permeable to molecules and close again when relatively low-amplitude ultrasound is applied to them. Cell membranes, in that case, become temporarily porous for genetically active or other active molecules as shown by K. Tachibana et al. in the paper "Induction of cell-membrane porosity by ultrasound", The Lancet, Vol. 353, 199, p. 1409. This phenomenon is called sonoporation. An ultrasound-activated system for the delivery of active medicinal substances can be developed into an important new method for the enhanced delivery of active medicinal substances to specific and specified tissue areas in the body. Details of existing systems are described in WO9921584, US6066123, WO0108709. The advantage of ultrasound-stimulated drug delivery systems is that it not only opens the endothelial barrier, but also creates a pushing radiation force that pushes drugs through the membrane, see Zauhar G., Starritt H.C., Duck F.A.: Studies of acoustic streaming in biological fluids with an ultrasound Doppler technique. No. J. Radiol. 71: 297-302; in 1998

Coordinated electro and sonoporation can further enhance the introduction of the active medicinal substance into the cells. Coordinated sono and electroporation can reduce the total amount of active medicinal substance, for example cytostatics, to be administered throughout the body, which would reduce toxic effects and the cost of the procedure.

The essence of the invention

The invention consists of the following parts

- a set of electrodes capable of forming an electric field in a predetermined part of the body

- a set of ultrasonic transducers that are in a known geometric relationship with said electrodes

- systems for administering drugs or active substances locally or throughout the body

The aim of this invention is to improve the efficiency of administration of drugs, chemical or genetic substances into the living cells of the human body

Another object of this invention is to localize the administration of said drugs to the areas of the body where they should be administered, while avoiding the administration of drugs to cells in other parts of the body

The targeted drug delivery system by coordinated electro and sonoporation uses electroporation and sonoporation effects on cell membranes to open pathways into the cells, and sonophoresis enhances the transfer of various active agents across the membrane barrier.

Said electrodes are, in various embodiments, placed inside or outside the human body in an arrangement that enables the generation of electric fields of controlled size and direction. Ultrasonic fields are known to open pores in the cell membrane, making it permeable to agents that reside in the intercellular space. Additionally, ultrasonic waves induce physical movement of damping fluids and enhance the diffusion of dispersed or dissolved particles.

Said devices for generating ultrasound are, in various implementations, located inside and outside the human body so that it is possible to generate ultrasound fields of controlled direction and size. It is known that ultrasound waves open the pores on the cell membrane, making them more permeable to active substances that are outside these cells. Additionally, ultrasonic waves cause the physical movement of most absorbing agents and promote the diffusion of dissolved or dispersed particles.

The opening of pores on the membrane by an electric field or ultrasonic waves also depends on their direction in relation to the cell. The invention also consists of a device that can generate an electric and ultrasonic field coordinated in space and time. This is achieved by using a set of ultrasound transmitters combined with electrodes that locally generate electric fields to simultaneously open pores on cell membranes and push the active substance into the cell. Since the effects are directional, this invention makes it possible to act on the cells from various directions and thereby cover all the cells in a certain volume.

Placement of electrodes and ultrasound transducers in the body is achieved with catheters and similar devices for minimally invasive surgery, and field generation can be assisted by placing auxiliary electrodes on the outside of the body. Said catheter can, when necessary, be used to administer medicine or an active substance directly to the place where it is placed.

Short description of the pictures

Figure 1 is a schematic representation in three projections of a part (block) of tissue consisting of cells 3 and intercellular space 4. For the sake of clarity, the cells are shown in a less frequent arrangement than in reality. Active substance 5 can be distributed in the intercellular space. This part of the tissue can be exposed to the electric field E and 7 drawn by the electrodes 20. The same block of tissue is exposed to ultrasound waves US and 6 which are coordinated in direction and time with said electric field.

Figure 2 is a schematic representation of the general composition of a directed system for administering drugs by coordinated electro and sonoporation. A device for delivering therapy or a device for minimally invasive surgery, which may also be a catheter 10, is inserted into the human body 1 and placed in an area of interest for therapy 2. Multiple means 11 and 12 for generating ultrasound waves, electric fields and currents are mounted to the delivery device 10 and placed in said area of interest. Another set of devices for generating electric fields and ultrasonic waves 15 and 16 is placed outside the body 1. Active means for generating ultrasonic and electric fields 11, 12, 15, 16 are connected to the electric voltage and current generator 30 in the ultrasonic generator 20. Medicine or another active substance can be added through the device 10 or in another way. A drug within the meaning of this invention includes active agents such as cytostatics, gene therapy agents and other chemotherapeutic agents.

Figure 3 is an illustration of a possible situation where the system of Figure 2 transmits ultrasound waves 60 from the ultrasound generating means 11 and 12 to the body 1 and especially to the area of interest 2.

Fig. 4 is an illustration of a possible situation where the system from Fig. 2 applies an electric field 70 using the devices for creating fields 11, 12 and 15, 16 to the body 1 including the area of interest 2.

Figure 5 is an illustration of another possible realization of a directed system for administering drugs by coordinated electro and sonoporation. In this case, two devices for minimally invasive surgery 10 and 13 are used so that they are invested in the patient's body and so that they encompass the area of interest 2 and thus can expose said area to the electric field 70 by simultaneously transmitting ultrasound waves 60. Ultrasound signal generator and generator of electric voltage are shown implanted in the patient's body.

Figure 6 is an illustration of the use of two devices for minimally invasive surgery embedded in the body with the orientation of the ultrasound and electric fields rotated by approximately 90 degrees compared to Figure 5. Additional electrodes 15 and 16 outside the body generate an electric field defined by field lines 70. The direction of the ultrasound waves is here rotated by approximately 90 degrees using a phase-controlled transducer 11. In the actual case, both regimens of Figures 5 and 6 would be used to treat area 2. Area of interest 2 is reached using minimally invasive therapy devices 10 and 13.

Figure 7 is an illustration of the possibility of changing the direction of the electric field when a directed drug delivery system by coordinated electro and sonoporation is implanted in the body, i.e. intracavitarily or interstitially including the kidney, intestines, genital organs, heart, breast, brain and abdomen. The direction of the electric field is changed by reversing the polarity of the voltage as illustrated in Figures 8a and 8b. The area of interest is reached with the device for administering minimally invasive therapy 10 and the electric field is applied with the electrode 11.

Figure 8 is an illustration of the electro and sonoporation catheter 10 inserted into the renal canal system with complementary electrodes outside the body, in contact with it. The electric field is generated by applying the appropriate voltage to the electrically insulated electrode 11 and the external electrodes 16. At the same time, the active part of the catheter 11 is also an ultrasound transmitter that emits ultrasound waves radially and thus synergistically enhances the diffusion of the active substance into the cells within the area of interest 2.

Figure 9 illustrates enhanced delivery of a chemotherapeutic agent to the heart (Figure 8A) and brain (Figure 8B) using this targeted drug delivery system by coordinated electro and sonoporation where in Figure 8A an electric and ultrasonic field is used to open pores in cell membranes while in Figure 8B, in the brain, only the ultrasound part is included to open the pores on the brain cells.

Description of the invention

According to Figure 1, which shows a block of tissue in three orthogonal projections, cells 3 can be exposed to an electric field E and ultrasound waves US. Human tissue consists of cells 3 and an intercellular space in which various fluids flow and transport the material needed for cell function. The fluid may be in the blood or lymph vessels, but it eventually engulfs the body's cells. Cell membranes control and sometimes prevent the entry of active medicinal substances into cells. This property is essential for the normal function of a normal cell and the life of an organism, but it can significantly reduce or even prevent certain types of therapy. This includes special cases such as cancer cells, which should preferably be made sensitive to cytostatics brought into the intercellular space, or genetically active substances that may need to be inserted into cells for specific gene therapy, or hormones (steroids, insulin, etc.) that may be needed introduced into cells in order to stimulate some property of the cell, eg metabolic rate, saturation of sex hormone receptors in the treatment of certain types of cancer, eg breast cancer. Looking at Figure 1, we see that, provided that the active substance is brought into the intercellular space, the increase in uptake into the cells is obtained by applying electroporation with electric field E and sonoporation with ultrasound waves US. Ultrasound not only helps to open the pores on cell membranes, but additionally it can actively suppress with ultrasonic pressure (change of pulse), Bernoulli and Oseen forces. Both modes can be used together or separately. Since the pores on the cells are geometrically symmetrical, it is an advantage if the field E and ultrasonic waves US can be applied so that they cover as many angles as possible.

The useful range of ultrasonic frequencies is 20kHz to 4MHz, and ultrasonic intensities range between 50 mW/cm2 and 3W/cm2. Usable electric fields are in the range of 0.1 - 2kV/cm.

In accordance with Figure 2, the general composition of the system consists of the following parts:

Inside the body of the patient 1, a delivery device is brought to the area of interest 2, for example a catheter 10 with active members that are electrodes and ultrasound generators 11 and 12. The delivery device 10 is connected to a block 20 that generates the electrical signals necessary to generate ultrasound waves by means 11 and 12, if and when necessary, pumps the active therapeutic substance into the area of interest 2. Block 20 may contain a reservoir of active medical substance, e.g., a drug or hormone that it delivers through a device for delivery or delivery to the area of interest 2. Said active medicinal substance can be delivered in other ways, for example by intravenous injection. Electric generator 30 generates an electric voltage with which it generates an electric field via electrodes 15, 16, 11, 12. Electrodes 15 and 16 can be electrically galvanic in contact or isolated, resulting in different electric fields in the region of interest.

Referring to Figure 3, the ultrasound waves 60 emanating from the ultrasound generating means 11 and 12 are illustrated. The ultrasound waves can be generated using one or more transducers depending on the desired direction and dimensions of the ultrasound field. The shape of the ultrasound field, determined by the directivity function, can be processed in various ways depending on the ratio of the dimensions of the devices 11 and 12 and the ultrasound wavelength. If this ratio is large, the directionality of the waves 60 can be changed by the phase shifts of devices 11 and 12, and if this ratio is small, then the waves become close to spherical waves.

Looking at Figure 4, we see the electric field lines whose orientation depends on the geometric arrangement of the electrodes 11, 12, 15, 16. The field lines are modified in the conductive environment of human tissues, but there is still a limited possibility of the direction of the field forces with different arrangements of the external electrodes 15 and 16.

Looking at Figure 5, we see that it is possible to introduce into the body more than one delivery device, for example two catheters, or two devices for minimally invasive surgery, for example endoscopes marked with 10 and 13. All the possibilities presented so far still exist, but it is easier this way achieve strong electric fields 70 (V/cm) with lower voltages between the electrodes 11 and 16 that comprise the area of interest 2. Depending on the shape of said electrodes, the range of the ultrasonic waves 60 sent from the ultrasonic transducer 11 may be limited. Additionally, ultrasound signal and electric voltage generators together with delivery devices can be implanted in the patient's body if therapy with enhanced sono and electroporation needs to be administered over a long period of time, i.e. for months or years. The arrangement of elements that reflect ultrasound in the vicinity of the means for generating ultrasound waves 11 must be such that there are no parallel surfaces in order to avoid standing waves.

Looking at Figure 6, we see that different directions of the electric field 70 and ultrasonic waves 60 can be achieved by using high-frequency ultrasound transmitted by the transducer phase-controlled array 11, or by using additional external electrodes 15 and 16. The internal electrodes 166 function as described in the previous description of Figure 5. In practice, the ultrasonic transducer 11 can also be used as an additional electrode 166.

Looking at Figure 7, we see that the direction of the electric field can be changed by changing the polarity of the electrodes. In certain situations, this may be the only way to change the direction of the field at our disposal, and it should be used in terms of the description of the electroporation mechanism according to Figure 1. In this case, the body serves as a second electrode.

Looking at Figure 9, we see that delivery of a chemotherapeutic or other active agent to the heart (Figure 9A) or brain (Figure 9B) is possible using this targeted drug delivery system by coordinated electro and sonoporation. According to Figure 9A, both modes of operation are included, i.e., sonoporation and electroporation to stimulate the increase of cell membrane permeability, while according to the figure, only the electroporation mode of operation is included. The ultrasound waves 60 and the electric field cover the region of interest 2 so that the insertion of the active agent into the cells is enhanced only in that region. The generators 20 and 30 of the necessary signals may be implanted in the body or connected outside the body via the therapy delivery device 10. The generator 20, 30 may also include a reservoir of an active medical agent, e.g., a drug, or a preparation to deliver such a drug to the area of interest 2 coordinated with the activation of the ultrasonic and electric fields.

The complete device including the generators 23, 30, the therapy delivery device 10, the ultrasound wave and electric field generators 11, 12 can be built in the form of a single block when such a form is preferred and when it can be fully incorporated into the patient's body. On the other hand, this device can also be used for surface action, in which case no part is embedded in the patient's body, but the active medical agent is delivered through the skin or through the mucous membrane in the case of intracavitary work.

It is important to note that an electric field would appear around all conductors through the body, and electroporation would occur in all places where such conductors pass between the voltage generator and the electrodes. However, only at the position of the ultrasonic transducer 11 would there be a synergism of electro and sonoporation. Electroporation along power lines can be avoided by using shielded cables with a grounded outer shield as the lines.

Method of application of the invention

The invention represents a device and a method for significantly improving the administration of active medical substances such as drugs and genetically active substances, by means of procedures that promote the introduction of said substances into the very cells of the human organism, targeting diseased areas in the patient's body. The application is carried out by first using the methods of surgery or minimally invasive surgery, or by catheterization or intracavitary placement of the devices described in this invention to reach the target area in the body for treatment. Then, a medically active substance (drug, cytostatic, gene drug, etc.) is introduced in a coordinated manner into the whole body or only in that area, and coordinated or simultaneous electric and ultrasound fields are activated, which, through sonoporation, electroporation, and sonophoresis, accelerate the introduction of the drug into the cells, thereby reducing potentially harmful general drug concentration throughout the body or locally.

Claims (8)

1. Directed system for administering drugs by coordinated electro and sonoporation, characterized by the fact that it consists of: - at least one ultrasonic transducer assembly adapted for use in sonoporation of membranes of living cells - at least one electrode connected by an electrical conductor - at least one outdoor unit containing electric circuits - with said ultrasonic shape transducer assembly that can be mounted on a device for introduction into the body - where said ultrasonic transducer consists of one or more piezoelectric transducers - where said converter assembly is connected to external electrical circuits via electrical lines installed along said device for introduction into the body - at least one electrode mounted on the said device for introduction into the body adapted to apply an electric field to the said cells exposed to the said ultrasound waves - where said electrodes are connected to external electrical circuits via electrical lines installed along said device for introduction into the body - where said external electrical circuits in the external unit are adapted to generate electric voltages and signals adapted to generate electric fields and ultrasonic waves via said electrodes and said ultrasonic transducer assembly - with said external unit containing a reservoir of active medical agent. - including a programming device adapted to activate said electrical circuits for generating ultrasound and electric fields. 2. Directed system for administering drugs by coordinated electro and sonoporation from claim 1, characterized in that said ultrasound transducer has one or more ultrasound transducers capable of converting electrical signals into ultrasound waves 3. Directed system for administering drugs by coordinated electro and sonoporation from claims 1 and 2, characterized in that said ultrasound transducer assembly is connected to electrical connectors located on the proximal side of said device for introducing into the body from claim 1 via longitudinal electrical lines. 4. Directed system for administering drugs by coordinated electro and sonoporation from claims 1 - 3, characterized by the fact that it contains a generator of electric signals adapted to the generation of ultrasound waves while it is connected by longitudinal conductors from claim 3 to ultrasound transducers from claims 1 and 2. 5. Directed system for administering drugs by coordinated electro and sonoporation from claim 1, characterized in that there are one or more electrodes mounted on the device for introduction into the body from claims 1 and 3 and which are connected by longitudinal conductors from claim 3 to connectors on the proximal side. 6. Directed system for administering drugs by coordinated electro and sonoporation from claims 1 - 4, characterized by the fact that it contains the voltage generator from claim 1 connected to one or more electrodes mounted on the device for introduction into the body from claim 1 and 3 connectors from claim 5. 7. Directed system for administering drugs by coordinated electro and sonoporation from claims 1 - 6, characterized in that the electric signal generators from claim 4 and claim 6 are adapted to the activation of the electric field from claims 1, 4, 5, 6 and the transmission of ultrasound waves from claim 1 -4 temporally and spatially coordinated by simultaneous or sequential activation. 8. Directed system for the administration of drugs by coordinated electro and sonoporation from claims 1 - 7, characterized by the fact that it is adapted to be incorporated into the human body and that it contains a reservoir of an active medical agent and a pump adapted to pump said active medical agent through said device for introduction into the body from the claim 1, simultaneously with the inclusion of the electric and ultrasonic fields.