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WO1997010023A2 - Equipement destine au transport d'agents chimiques et biologiques a travers des tissus - Google Patents

Equipement destine au transport d'agents chimiques et biologiques a travers des tissus Download PDF

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Publication number
WO1997010023A2
WO1997010023A2 PCT/US1996/011289 US9611289W WO9710023A2 WO 1997010023 A2 WO1997010023 A2 WO 1997010023A2 US 9611289 W US9611289 W US 9611289W WO 9710023 A2 WO9710023 A2 WO 9710023A2
Authority
WO
WIPO (PCT)
Prior art keywords
tissue
cap
pump
agent
container
Prior art date
Application number
PCT/US1996/011289
Other languages
English (en)
Other versions
WO1997010023B1 (fr
WO1997010023A3 (fr
Inventor
Hans J. Von Der Pfordten
William C. Landgraf
Original Assignee
Apex Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Apex Laboratories filed Critical Apex Laboratories
Publication of WO1997010023A2 publication Critical patent/WO1997010023A2/fr
Publication of WO1997010023A3 publication Critical patent/WO1997010023A3/fr
Publication of WO1997010023B1 publication Critical patent/WO1997010023B1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis

Definitions

  • 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.
  • a specific target e.g. a cell, a nerve bundle or a blood vessel for distribution to other locations of action.
  • 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.
  • 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.
  • a target like a blood vessel or a nerve bundle
  • 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.
  • 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.
  • 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.
  • 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.).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • state counter 272 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pressure stroke in the order of 20 to 50 microliters
  • 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.
  • control module 270 which also keeps track of the number of strokes of known volume by pistons 30 and 60.
  • the pump action is discontinued and the fluid medium is sucked back into reservoir 100.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Reciprocating Pumps (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

Cette invention concerne un système de pompe permettant d'administrer par diffusion dans les tissus, des agents chimiques et biologiques liquides à partir d'un récipient remplaçable préemballé, en faisant appel à une combinaison d'ondes de pression comprenant une pression de base. Ce système de pompe comprend une pompe possédant une pluralité de pistons entraînés par des actionneurs et commandés par une unité de commande électronique, ceci selon une certaine fréquence de répétition et selon certaines formes d'onde (rampe ascendante, pic, rampe descendante) en combinaison avec d'autres signaux de fréquences acoustiques (soniques ou ultrasoniques). Ce système de pompe comprend également une capsule qui se trouve en communication fluidique avec la pompe par l'intermédiaire d'une tubulure, et qui est pressé contre le tissu. Le récipient est placé entre les tissus et une membrane située dans la capsule. Cette membrane transmet les formes d'ondes de pression et fait office de piston chassant l'agent du récipient et le faisant passer dans les tissus. Cette capsule peut également transmettre des impulsions laser de manière à générer des ondes de choc thermique dans les tissus, ceci afin de favoriser le processus de diffusion en combinaison avec les variations de pression.
PCT/US1996/011289 1995-07-07 1996-07-05 Equipement destine au transport d'agents chimiques et biologiques a travers des tissus WO1997010023A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US97995P 1995-07-07 1995-07-07
US60/000,979 1995-07-07

Publications (3)

Publication Number Publication Date
WO1997010023A2 true WO1997010023A2 (fr) 1997-03-20
WO1997010023A3 WO1997010023A3 (fr) 1997-05-29
WO1997010023B1 WO1997010023B1 (fr) 1997-08-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/011289 WO1997010023A2 (fr) 1995-07-07 1996-07-05 Equipement destine au transport d'agents chimiques et biologiques a travers des tissus

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0989879A1 (fr) * 1997-06-19 2000-04-05 Mile Creek Capital, LLC Systeme d'administration de medicament dote d'un mecanisme d'activation du transport d'un medicament
EP1311311A2 (fr) * 2000-08-24 2003-05-21 Encapsulation Systems, Inc. Methode d'administration d'une substance amelioree par ultrasons
US9067015B2 (en) 2007-12-21 2015-06-30 Carticept Medical, Inc. System for injecting fluids in a subject
WO2017089785A1 (fr) * 2015-11-23 2017-06-01 Owen Mumford Limited Appareil pour administration transdermique de médicament

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2231230A4 (fr) 2007-12-21 2013-01-23 Carticept Medical Inc Système d'injection articulaire
US9044542B2 (en) 2007-12-21 2015-06-02 Carticept Medical, Inc. Imaging-guided anesthesia injection systems and methods

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63135179A (ja) * 1986-11-26 1988-06-07 立花　俊郎 薬物の経皮投与具
US4787888A (en) * 1987-06-01 1988-11-29 University Of Connecticut Disposable piezoelectric polymer bandage for percutaneous delivery of drugs and method for such percutaneous delivery (a)
US5386837A (en) * 1993-02-01 1995-02-07 Mmtc, Inc. Method for enhancing delivery of chemotherapy employing high-frequency force fields
EP0683657B2 (fr) * 1993-02-10 2005-06-15 Siemens Aktiengesellschaft Appareil de therapie analgesique et/ou permettant d'agir sur le systeme nerveux vegetatif

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0989879A1 (fr) * 1997-06-19 2000-04-05 Mile Creek Capital, LLC Systeme d'administration de medicament dote d'un mecanisme d'activation du transport d'un medicament
EP0989879A4 (fr) * 1997-06-19 2001-05-30 Mile Creek Capital Llc Systeme d'administration de medicament dote d'un mecanisme d'activation du transport d'un medicament
EP1311311A2 (fr) * 2000-08-24 2003-05-21 Encapsulation Systems, Inc. Methode d'administration d'une substance amelioree par ultrasons
EP1311311A4 (fr) * 2000-08-24 2007-09-26 Encapsulation Systems Inc Methode d'administration d'une substance amelioree par ultrasons
US9067015B2 (en) 2007-12-21 2015-06-30 Carticept Medical, Inc. System for injecting fluids in a subject
WO2017089785A1 (fr) * 2015-11-23 2017-06-01 Owen Mumford Limited Appareil pour administration transdermique de médicament
CN108367141A (zh) * 2015-11-23 2018-08-03 Om有限公司 用于经皮药物递送的设备
US11565100B2 (en) 2015-11-23 2023-01-31 Owen Mumford Limited Apparatus for transdermal medicament delivery

Also Published As

Publication number Publication date
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