WO1997010023A2

WO1997010023A2 - Equipment for transporting chemical and biological agents through tissue

Info

Publication number: WO1997010023A2
Application number: PCT/US1996/011289
Authority: WO
Inventors: Hans J. Von Der Pfordten; William C. Landgraf
Original assignee: Apex Laboratories
Priority date: 1995-07-07
Filing date: 1996-07-05
Publication date: 1997-03-20
Also published as: WO1997010023A3

Abstract

A pump system for the delivery of liquid chemical and biological agents by diffusion from a prepackaged replaceable container into tissue by means of a combination of pressure waves including a base pressure. The pump system comprising a pump having a plurality of pistons driven by actuators, controlled by an electronic controller, at a certain repetition frequency and certain waveforms (up-ramp, peak and downramp) in combination with other signals of acoustic (sonic or ultrasonic) frequencies. The pump system also comprising a cap, in fluid communication with the pump via tubing and pressed against the tissue. The container being placed between the tissue and a membrane within the cap which transmits the pressure waveforms and acts as a piston pushing the agent out of the container and into the tissue. The cap also being capable of transmitting laser pulses to generate heat shock waves in the tissue aiding in the diffusion process in combination with the pressure variations.

Description

EQUIPMENT FOR TRANSPORTING CHEMICAL AND BIOLOGICAL AGENTS THROUGH TISSUE.

BACKGROUND.

1. Field of the Invention.

The present invention generally relates to equipment for the delivery of chemical and biological agents into tissue and more specifically to equipment for transpor¬ ting chemical or biological agents through biological tissue by transport, activated by pressure waves, to a specific target, e.g. a cell, a nerve bundle or a blood vessel for distribution to other locations of action.

2. Description of the Prior Art. The administration of chemical or biological compounds as medicinal drugs (in the following called "agents") into the human body is traditionally done by ingestion into the stomach (pills, tablets or capsules) , by absorption through the outer skin (ointments or patches) , by inhalation (vapors or air-dispersed agents) , through mucuous membranes (swabs) or by injec¬ tion via a needle. Oral delivery, for example, employes a significant overdose of an agent due to the detoxifi¬ cation activity of stomach, liver and kidneys. The skin consists of multiple layers of cells (the epidermic barrier) for the protection of the tissue underneath. Solutions of therapeutic agents are usually deliv-ered by using a needle which punctures the skin and discharges the agent near the target (a blood vessel or a nerve bundle) . It is desirable to introduce these agents into the tissue near the target without the use of a needle, thus alleviating "needle anxiety", espe¬ cially for children, by providing a painless alterna- tive.

SUMMARY OF THE INVENTION.

Amelioration of the disadvantages of the injection method is the subject of the present invention. Its goal is to provide a means to introduce liquid chemical or biological agents, for example medicinal drugs, into the body near a target, like a blood vessel or a nerve bundle, without the use of a needle. Normally drug deli¬ very is based on diffusion into tissue. A factor influencing the diffusion rate of the agent is its molecular size as well as the concentration gradient and the osmotic pres-sure differential across cell layers. Smaller molecules diffuse into tissue faster than larger molecules. The transport of agents across tissue can be enhanced by at least three actions, namely by low frequency pressure pulses superimposed on a base pressure with a minimum value of zero, by acoustic wave (sonic or ultrasonic) excitation and by heat-induced shock waves, for instance generated by laser pulses of suitable power, duration and wavelengths (from less than 300 nm to several microns) impinging on the tissue in a beam of several square millimeters cross-section or by a combination of these actions. The proposed equipment is based on pressure-variation enhanced diffusion with provisions for a combination of the described forms of action.

A special pump produces low frequency pressure vari- ations in a fluid medium (e.g. water, glycerin, glycol, air or gas etc.) which by a fluid link are transmitted into the liquid agent, contained in a porous container in contact with the tissue, to enhance its transport towards the target through the epidermal and underlying layers of tissue. The fluid medium should be biologi¬ cally compatible and non-toxic to assure safety stan¬ dards in case of a leak. A cup-shaped cap has a cavity in liquid communication with the pump by means of tubing and is pressed against the tissue or skin closest to the location of the target. Across the main opening of the cap stretches an elastic non-permeable membrane or a bladder (in the following called "membrane") . A replace¬ able, disk-shaped sponge or a disk- or toroid-shaped bladder container, made out of a semipermeable, porous material with a pore size approximately between 0.1 and 100 microns and filled with a predetermined amount of agent, is placed between the tissue and the membrane. The membrane acts like a piston, driven by the dynamic pressure within the cap and squeezing the agent out of the container, thus enhancing the diffusion of the agent into the tissue. The dynamic pressure comprises a base pressure with a minimum value of zero and superimposed pressure pulses of a shape, amplitude and pulse repeti¬ tion frequency suitable for a specific type of tissue. It may be advantageous to employ different pulse ampli¬ tudes within a sequence of pulses or form ramp-shaped pulses, possibly with points of inflection within the ramps. The transport rate of agents into tissue can be in¬ creased by acoustic waves superimposed on the lower fre¬ quency pressure waves. Laser radiation in the form of pulses of specific wavelengths, power, duration and repetition rates can be transmitted through the cap into the tissue to generate pressure waves by sudden heat expansion for further enhancement of the diffusion rate of the agent into the tissue.

An advantage of the present invention is that the agent is administered in a noninvasive way, thus allevi- ating the general anxiety caused by the use of a needle. Another advantage of the present invention is that the diffusion enhancing action in a body cavity (for in¬ stance in the mouth) can be induced via hydraulic tubing and optical fiber without the use of any electrical wires, thus assuring compliance with safety standards. Another advantage of the present invention is that the agent can be delivered in medically prescribed doses rather than in overdoses due to partial destruction of the agent by gastric or intestinal fluids, thus allevi- ating sideeffects caused by overdosing.

Another advantage of the present invention is that the agent can be commercially encapsulated in a sterile replaceable permeable container. Another advantage of the present invention is that the features of pressure waves, acoustic waves and la¬ ser-radiation-induced shock waves can be combined and adapted to the specific kind of tissue to be penetrated by the agent.

Another advantage of the present invention is the delivery of agents through tissue or the skin towards a blood vessel which is convenient for the delivery of agents normally destroyed by gastric fluids. Another advantage of the present invention is the convenient introduction of agents which otherwise have to be delivered by frequently repeated injections caus¬ ing pain, trauma and scarring to tissue at injection sites. Another advantage of the present invention is the capability to deliver agents according to a preprogram¬ med timing schedule by means of timers in the control module.

IN THE DRAWINGS.

Fig. 1 is an overview of the pump system including the cap;

Fig. 2 is an overview of the pump system controls; Fig. 3 illustrates the proposed pressure waveforms; Fig. 4 shows a version of the cap with an inner con- centric cylindrical optical waveguide;

Fig. 5 shows a version of the cap with its cylindri¬ cal part as an optical waveguide. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS.

The transport of agents through tissue is enhanced by pressure variations of acoustic (sonic or ultrasonic) frequency combined with a base pressure with a minimum value of zero in a biologically compatible fluid medium (e.g. water, glycerin, glycol, air or gas etc.). These pressure variations can be generated by a pump with a fluid link to the target tissue or even by laser pulses in the tissue itself, or by a suitable combination. If the target tissue is located in a body cavity, like the mouth, these actions can be conveniently and safely in¬ troduced into that cavity by plastic tubing and a plas¬ tic optical fiber, respectively, without the use of electrical wires, thus complying with safety regula¬ tions and avoiding electrical shock hazards.

An overview of the fluid pump system 10 according to the present invention is shown in Fig. 1. Pump housing 20 comprises pump chamber 30, acted upon by piston 40 which is driven by actuator 50, and pump chamber 60, acted upon by piston 70 driven by actuator 80. Valve 90 is located between chambers 30 and 60 and is also con¬ nected to reservoir 100. Tubing 110 extends between ope¬ ning 132 of pumping chamber 30 and opening 122 of cylin- drical cup-shaped cap 120. A non-permeable elastic blad¬ der or membrane 126 stretches across the inside of cap 120, forming cavity 127 inside cap 120. In this way a closed fluid system, filled with the fluid medium, is formed by reservoir 100, pumping chambers 30 and 60 of pump 20, tubing 110 and cavity 127, closed off by mem- brane 126 within cap 120. Air or gas operation is pos¬ sible, although less practical. A certain amount of agent, determined by volume and concentration, is held in prepackaged, sterile container 130 which preferably is disk- or toroid-shaped and made out of porous, ela¬ stic or spongy material or porous, permeable film, and which is placed within cap 120 between membrane 126 and target tissue 125. This container 130 may be partitioned into several parts, for example into two or more parts with one containing the agent in a stable salt form and the other containing a base to generated the most potent agent in free form when the contents of both container parts are chemically reacted by breaking a separating wall within container 130 by means of fluid pressure waves, before the agent is diffused into the tissue 125. Dynamic fluid pressure generated by pump 20 in cavity 127 causes membrane 126 to act as a piston pushing con¬ tainer 130 against the tissue 125 and squeezing its con¬ tents into tissue 125. In operation, cap 120 has to be held against tissue 125 by externally applied mechanical pressure. This ac¬ tion in turn presses against the deeper tissue layers and defines an annular ring-shaped area with a certain circular cross-section in tissue 125 through which the agent is diffused.

Fig. 2 illustrates a preferred version of the con¬ troller 210 for pump 10. A control module 270 which can be implemented by logic circuits (better yet by a micro¬ controller or microprocessor) generates the pulse repe- tition frequency which periodically resets a four-state counter 272 (00 = upramp, 01 = peak, 10 = down-ramp, 11 = pause) to start a new pulse. Frequency generators 220, 230 and 240 individually feed squarewave frequencies into multiplexer (mux) 250 which in turn feeds the se¬ lected frequency into updown counter 260 and into peak counter 262. When for example, counter 260 has reached one count before upcount rollover, state counter 272 is advanced to state 01, stopping counter 260 and activa- ting counter 262. When counter 262 times out, state counter 272 is advanced again to state 10, stopping counter 262 and activating the downcount of the pre¬ viously stored value of counter 260, whose rollover output pulse advances state counter 272 to state 11, which stops all counting until the pulse repetition generator of control module 270 initiates another sequence by resetting counter 272 to state 00.

The binary output lines of counter 260 are connected to digital-to-analog converter 280 which generates, by means of operational amplifier circuits, an upramp for an increasing count of counter 260, a peak value for an increasing count of counter 262 and a downramp for a de¬ creasing count of counter 260. This analog voltage wave¬ form as well as possibly an acoustic frequency waveform and of a specific shape and amplitude from oscillator

285 are fed into the summing input of operational ampli¬ fier 290. The resulting waveform of about 100 volts base-to-peak in turn drives piezoelectric actuators 50 and 80. Another mode uses actuator 50 to produce the lower frequency pressure waves and actuator 80 to pro¬ duce higher frequency acoustic waves. Control module 270 also controls valve 90 and facilitates other functions of pump 20, like using actuator 80 for the generation and maintenance of a base pressure (with a minimum of zero) as well as for a suckback of hydraulic liquid into reservoir 100 in preparation for another agent delivery cycle using a new container 130. Actuators 50 and 80 can be made out of piezoelectric, magnetostrictive or any other electrically controllable material.

Referring to Fig. 3, oscillators 220, 230 and 240 generate the squarewave timing freqencies for upramp Tl, peak T2 and downramp T3, respectively. The function of oscillators 220, 230, 240 and mux 250 can also be imple- mented by a reference oscillator and a phase-locked loop circuit under the control of a microprocessor within control module 270. A timer in control module 270 con¬ trols the time of the start of upramp Tl and therefore the pulse repetition frequency. Fig. 3 displays the pressure waveforms as electroni¬ cally generated waveforms applied to actuator 50. One implementation is a waveform shaped as an upramp Tl followed by a peak T2 and then a downramp T3 to return to the base pressure, the original state. The pulses generate a periodic pressure gradient within the agent and in the underlying tissue, which will promote the diffusion of the agent across cell membranes towards the target. Tl, T2 and T3 have time durations to be de¬ termined and optimized for different kinds of tissue. It is possible to use a longer upramp Tl, and very short peak T2 and downramp T3, thus emulating a positive ramp (a forward sawtooth) , or very short upramp Tl and peak T2 with a longer downramp T3, emulating a negative ramp (a backward sawtooth) , or any other piecewise linear shape including different pulse amplitudes within a sequence of pulses or form ramp-shaped pulses, possibly with points of inflection within the ramps. The optimum pressure wave form will most likely be different for different types of tissue into which the agent is to be delivered. Fig. 3 also depicts a refinement of the pressure wave ramp. As an example, upramp Tl can extend upwards from point A to B whereupon the logic UP/DN signal for the counter is negated, thus generating a down-ramp B to C. Subsequently the UP/DN signal is returned to its former state (up) , generating up-ra p CD. At D a smaller than the present count is preloaded into the counter, causing the count and consequently the D/A converter to output drop DE. Thereupon the count is resumed to produce upramp EF, from where the flat por¬ tion FG and the downramp GH follows. While points A, H represent zero count and points F, G represent (full count - 1) in the counter, points B,C,D and E each have to be implemented as setpoints with a comparator plus appropriate logic, which translates to additional cir¬ cuitry or a program addition for a microprocessor in control module 270.

Another way to enhance the transport of agents through tissue is the application of laser pulses in the wavelength range from less than 300 nanometers to seve¬ ral micrometers, having a certain pulse power, pulse duration and pulse repetition frequency in a beam of several square millimeters cross-section to generate shock waves in the target tissue 125. As optical wave¬ guides to the tissue one can use either the annular cross-section of a transparent cylindrical or a small- diameter cylindrical rod concentric with the cap axis. Fig. 4 shows a version of cap 120 with a concentric transparent cylinder 121 acting as an optical waveguide extending from its lid down its middle with its end coplanar with rim of cap 120. Cylinder 121 carries mir¬ ror 127 which is oriented at a 45 degree angle with respect to the axis of cap 120. Optical fiber 128 pene- trates cap 120 radially and extends close to mirror 127. Laser pulses are introduced by fiber 128, reflected by mirror 127 and propagate via cylinder 121 onto tissue 125. In this case membrane 126 and container 130 are toroid- or washer-shaped. As shown in Fig. 5 the laser pulses can be carried into the cylindrical part of cap 120, made out of transparent material, by an optical fiber 128 to be transmitted by the cap rim onto tissue 125.

Summarizing, the operation of the preferred e bodi- ment proceeds as follows. Pump 20 generates the periodic micro-staircase-shaped pressure pulse (as in Fig. 3) on top of a selectable base pressure within a fluid pump system which includes connecting tubing 110 and cap 120 holding agent container 130. The membrane 126 within cap 120, preferrably implemented as a bladder, expands and acts as a piston on container 130. This action squeezes medicinal agent out of the agent-filled container in contact with skin tissue, where the agent is absorbed due to the action of pressure waves ranging from con¬ stant pressure to ultrasonic frequencies.

As soon as the bias pressure drops as a consequence of the absorption of a small volume of agent into the tissue, valve 90 switches the action of piston 70 from reservoir 100 (suction stroke) to chamber 30 (pressure stroke, in the order of 20 to 50 microliters) to restore the previously selected base pressure by replenishing in the fluid space the volume of liquid agent absorbed into the tissue. After cap 120 is filled entirely with fluid indicating that the entire agent volume of container 130 (for example 0.5 L) has been pressed into and absorbed by the tissue, an equivalent amount of fluid is pumped back into reservoir 100 to prepare the pump system for another action round with a new agent-filled container 130 inserted into cap 120. The exhaustion of container

130 can be sensed by entering its agent volume into the control module 270, which also keeps track of the number of strokes of known volume by pistons 30 and 60. When the combined accumulated stroke volume equals the agent volume of the container, the pump action is discontinued and the fluid medium is sucked back into reservoir 100.

Although the present invention has been described in terms of the presently preferred embodiment, it is to be understood that such disclosure is not to be construed as limiting. Various alterations and modifications will no doubt become apparent to those skilled in the art after having read the above disclosure. Accordingly, it is intended that the appended claims be interpreted as covering all alterations and modifications as fall within the true spirit and scope of the invention.

Claims

IN THE CLAIMS.What is claimed is

1. A pump system (10) for the delivery of a medically active chemical or biological agent in liquid solution into biological tissue (125) by transport enhanced by a combination of pressure waves in a fluid acting on said agent, comprising, in combination: a cup-shaped cap (120) with an elastic non-permeable membrane (126) enclosing part of its volume, the cap having at least one opening; a replacable porous container (130) holding said agent, located within the cap (120) between said mem- brane (126) and said tissue (125); a pump (20) comprising a plurality of pump chambers (30,60) with respective pistons (40, 70), each activated by electrical pulses to its respective actuator (50,80) for generating said pressure waves in said fluid in fluid communication with the cap (120) via tubing (110) connected to said opening of the cap (120) , for trans¬ mitting said pressure waves within said fluid to the container (130) and to said tissue (125), the pump also having at least a valve (90) for connecting said plura- lity of chambers with a reservoir (100) of fluid medium; a controller (210) for generating electrical pulses for a plurality of actuators (50,80) for activation said plurality of pistons (30,60) activating the pump (20), wherein the container (130) is placed inside the cap (120) which is pressed against said tissue (125) and wherein the fluid within the cap (120) transmits said pressure waves via said membrane (126) to said agent in contact with the tissue (125) for dispensing and diffusing said agent into the tissue (125) .

2. The pump system (10) of claim 1, wherein said membrane (126) forms a bladder with an opening, said opening being connected to said opening of the cap (120) in fluid communication with the pump ("20) .

3. The pump system (10) of claim 1, wherein the container (130) holding said agent is made out of porous material and is shaped as a prepackaged repla¬ ceable closed bladder fitting the inside cross-section of the cap (120) .

4. The pump system (10) of claim 1, wherein the container (130) holding said agent is shaped as a replacable disk made out of porous elastic material fitting the inside cross-section of the cap (120) .

5. The pump system (10) of claim 1, wherein the container (130) comprises a plurality of compart¬ ments holding different agents, for mixing their con¬ tents by said pressure waves before being transported into the tissue (125) .

6. The pump system (10) of claim 1, wherein the cap (120) is formed out of material transparent for radiation in the visible and infrared range with provisions for coupling to an optical fiber for the transmission of laser pulses from a laser via the annular cross-section of the cap to the tissue for generating pressure waves within the tissue.

7. The pump system (10) of claim 1, wherein the cap (120) is formed out of material transparent for radiation in the visible and infrared range with a small-diameter coaxial cylinder in its cavity, said cylinder having means, like a specifically placed mirror, for coupling laser pulses via an optical fiber via a cross-section of said cylinder to the tissue for generating pressure waves within the tissue.

8. The pump system (10) of claim 1, wherein the controller (210) comprises frequency generators (220, 230 and 240) feeding via controlled counters (260, 270) into a digital-to-analog converter (280) for gene¬ rating piecewise linear waveforms, like upramp, peak, downramp and pause, at a certain repetition frequency, said digital-to-analog converter (280) driving ampli¬ fiers (290) for feeding electromechanical actuators (50,80) driving pistons (40,70) in the pump (20) for generating pressure waveforms, including a base pressure with a minimum of zero, to be communicated via tubing (110) to the cap (120) and via the membrane (126) to the agent to be transported into the tissue (125) , said pressure waveforms being adaptable to specific kinds of tissue.

9. The pump system (10) of claim 8, wherein the controller (210) comprises circuitry controlling via a plurality of actuators (50,80) a plurality of pis¬ tons (40,70) allowing one piston (30) to generate dyna¬ mic pressure waves and another piston (80) to maintain a constant base pressure in the cap compensating for vol- ume of agent diffused into tissue (125) .

10. The pump system (10) of claim 8, wherein the controller (210) and said plurality of pistons (40,70) allow for a suckback of said fluid medium via a valve (90) into said reservoir (100) allowing the inser¬ tion of another container (130) and the start of another pump process.