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WO2000069515A1 - Liberation controlee a distance et locale de composes pharmaceutiques faisant appel a l'energie electromagnetique - Google Patents

Liberation controlee a distance et locale de composes pharmaceutiques faisant appel a l'energie electromagnetique Download PDF

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Publication number
WO2000069515A1
WO2000069515A1 PCT/US2000/013559 US0013559W WO0069515A1 WO 2000069515 A1 WO2000069515 A1 WO 2000069515A1 US 0013559 W US0013559 W US 0013559W WO 0069515 A1 WO0069515 A1 WO 0069515A1
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WO
WIPO (PCT)
Prior art keywords
patch
subject
electromagnetic energy
drug
pharmaceutical
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Application number
PCT/US2000/013559
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English (en)
Inventor
Kevin S. Marchitto
Stephen T. Flock
Original Assignee
Marchitto Kevin S
Flock Stephen T
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 Marchitto Kevin S, Flock Stephen T filed Critical Marchitto Kevin S
Priority to AU50242/00A priority Critical patent/AU771818B2/en
Priority to CA002372919A priority patent/CA2372919A1/fr
Priority to JP2000617972A priority patent/JP2002543942A/ja
Priority to EP00932535A priority patent/EP1180053A4/fr
Publication of WO2000069515A1 publication Critical patent/WO2000069515A1/fr

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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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/203—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser applying laser energy to the outside of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00747—Dermatology
    • A61B2017/00765—Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00452—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
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/35—Communication
    • A61M2205/3546—Range
    • A61M2205/3553—Range remote, e.g. between patient's home and doctor's office
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/35—Communication
    • A61M2205/3546—Range
    • A61M2205/3561—Range local, e.g. within room or hospital
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14276—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body specially adapted for implantation

Definitions

  • the present invention relates generally to the fields of medical physics and drug delivery. More specifically, the present invention relates to methods and devices for controlling the delivery of pharmaceutical compounds through the skin and other tissue interfaces.
  • Drug delivery is a critical aspect of medical treatment. In many cases, correct administration of drugs is critical to th e overall efficacy of its action, and thus, patient compliance becomes a significant factor in therapy. For this reason, the physician should carefully monitor drug delivery.
  • Drug delivery is particularly important in acute care settings. Patients must often endure long hospital stays post- surgery or other treatment to ensure that drugs are administered properly. In this case, and many others, a patient must remain in close contact with the physician during the course of treatment. This compliance issue, and the cost of long-term hospital stays, has resulted in significant research and development of devices capable of delivering controlled, continuous and sustainable release of therapeutics.
  • Skin has a very thin layer of dead cells, called th e stratum corneum, which acts as an impermeable layer to m atter on either side of the layer.
  • the stratum corneum is wh at primarily provides the skin's barrier function. If the stratum corneum is removed or somehow altered, then materials within the body can more easily diffuse out to the surface of the skin, and materials outside the body can more easily diffuse into th e skin.
  • compounds referred to as permeation enhancers (e.g. alcohol) or drug carriers (e.g. liposomes) can b e used, with some success, to penetrate the stratum corneum. I n any case, the barrier function of the skin presents a very significant problem to pharmaceutical manufacturers who may b e interested in topical administration of drugs, or in transcutaneous collection of bodily fluids.
  • Mucosa which is the moist lining of many tubular structures and cavities (e.g. nasal sinuses and mouth), consists in part of an epithelial surface layer.
  • This surface layer which consists of sheets of cells with strong intercellular bonds, in single or multiple layers, and that have a non-keratinized or keratinized epithelium.
  • On the basolateral side of the epithelium is a thin layer of collagen, proteoglycans and glucoproteins called the basal lamina, and which serves to bind the epithelial layer to th e adjacent cells or matrix.
  • the mucosa acts as a barrier to prevent the significant absorption of topically applied substances, as well as the desorption of biomolecules and substances from within th e body.
  • the degree to which mucosa acts as a barrier, and the exact nature of the materials to which the mucosa is impermeable o r permeable, depends on the anatomical location. For example, th e epithelium of the bladder is 10,000 times less "leaky" to ions th an the intestinal epithelium.
  • the mucosa is substantially different from skin in many ways. For example, mucosa does not have a stratum corneum. Despite this difference, permeation of compounds across mucosa is limited and somewhat selective.
  • the most recent model of the permeability of mucosa is that the adjacent cells in th e epithelium are tightly bound by occluding junctions, which inhibit most small molecules from diffusing through the mucosa, while allowing effusion of mucoid proteins.
  • the molecular structure of the epithelium consists of strands of proteins that link together between the cells, as well as focal protein structures such a s desmosomes.
  • the permeation characteristics of mucosa are not fully understood, but it is conceivable that the selective permeability of the mucosa may depend on this epithelial layer, which may or may not be keratinized, as well as the basal lamina. While it has been shown that removal or alteration of the stratum corneum of skin can lead to an increase in skin permeability, there is no corresponding layer on the mucosa to modify. Thus, it is not obvious that electromagnetic energy irradiation will cause a modification of the permeability of mucosa.
  • Iontophoresis uses an electric current to increase the permeation rate of charged molecules. Iontophoresis however is dependent on charge density of the molecule, and furthermore, has been known to cause burning in patients.
  • Use of ultrasound has also been tested whereby application of ultrasonic energy to the skin results in a transient alteration of the skin, resulting in increased permeability to substances.
  • Electromagnetic energy produced b y lasers may be used to ablate stratum corneum in order to m ake the skin more permeable to pharmaceutical substances (U.S. Patent No. 4,775,361), and, impulse transients generated by lasers or by mechanical means may be used to make alterations in epithelial layers that result in improved permeation of compounds (U.S. Patent No. 5,614,502).
  • lidocaine local anesthetics
  • an antineoplastic drug into the bladder wall could greatly minimize the time required for a patient to hold a drug in th e bladder during chemotherapy.
  • Electrosurgery which is a method whereby tissue coagulation and/or dissection can be effected.
  • radiofrequency (RF) current is applied to tissue applied by a n (active) electrode.
  • n active
  • the current is pas sed through tissue between two electrodes on the same surgical instrument, such as a forceps.
  • a return- path (ground) electrode is affixed in intimate electrical contact, with some part of the patient. Because of the importance of th e ground electrode providing the lowest impedance conductive p ath for the electrical current, protection circuits monitoring the contact of the ground with the patient are often employed whereupon a n increase in ground electrode-skin impedance results in th e instrument shutting down.
  • Factors involved in electrosurgical system include treatment electrode shape, electrode position (contact or non-contact) with respect to the tissue surface, frequency and modulation of the RF, power of the RF and time for which it is applied to the tissue surface, peak-to-peak voltage of the radiofrequency, and tissue type.
  • radiofrequency frequencies of 300 kHz to 4 MHz are u sed since nerve and muscle stimulation cease at frequencies beyond 100 kHz.
  • decreasing electrode size translates into increased current density in the tissue proximal to the electrode and so a more invasive tissue effect, such as dissection, as compared to coagulation.
  • the electrode is held close to the tissue, but not in contact, then the area of RF-tissue interaction is small (as compared to the area when the electrode is in contact with th e tissue), and so the effect on the tissue is more invasive.
  • the waveform of the applied RF from a continuous sinusoid to packets of higher peak voltage sinusoids separated b y dead time (i.e. a duty cycle of, say, 6%)
  • the tissue effect can be changed from dissection to coagulation.
  • increasing the voltage of the waveform increases the invasiveness of the tissue effect. Of course, the longer the tissue is exposed to the radiofrequency, the greater the tissue effect.
  • the present invention provides a microprocessor which may be controlled, and may be communicated with, over analog and digital telecommunication links, including the Internet.
  • the present invention describes microprocessor-controlled transdermal patches that use electromagnetic energy to enhance the uptake of a pharmaceutical formulation in contact with a membrane or skin.
  • the devices could also be used to increase the diffusion of the substances, as well as endogenous biomolecules, out of tissue.
  • the electromagnetic energy inherent to the inventions described herein is often referred to a s microwave (MW) and radiofrequency (RF).
  • MW s microwave
  • RF radiofrequency
  • the application of the present invention is not limited to delivery across oral mucosa or skin.
  • anatomical structures including, for example, vaginal, uterine, intestinal, buccal, tongue, nasopharyngeal, anal, and bladder walls, as well a s vascular, lymphatic and urethral vessels are also applicable.
  • the present invention can be used to breach compromised or intact stratum corneum and the tissue layers underneath in order to deliver compounds across skin, and with many drugs, through intact skin.
  • this method m a y be used to control systems that drive substances across non- biological membranes and films.
  • a method for controlling delivery of a pharmaceutical compound in a subject comprising the steps of: irradiating th e subject with electromagnetic energy; and applying th e pharmaceutical compound to the subject, wherein the compound is contained in a patch.
  • the electromagnetic energy is selected from the group consisting of radiofrequency, microwave and light.
  • the patch may be implanted in the subject or topically positioned in relation to the subject, and controlled locally or remotely by an external controller, such as a microprocessor.
  • a system for controlling the rate of pharmaceutical delivery or biomolecule collection in a subject comprising: a means to generate electromagnetic energy; a means to deliver th e electromagnetic energy to the subject; and a means to administer the pharmaceutical to or collect the biomolecule from the subject, wherein the pharmaceutical is contained in a patch controlled locally or remotely by an external controller.
  • th e electromagnetic energy is selected from the group consisting of radiofrequency, microwave and light, and means to generate electromagnetic energy include lasers and ultrasound transducers .
  • the controller is a microprocessor, powered by a battery, a solar cell, an electrochemical generator, a thermal energy generator, or an piezeoelectric generator.
  • the patch m a y be implanted in the subject or topically positioned in relation to the subject, and furthermore, the patch may be made of material selected from the group consisting of a dressing material, a gel, a viscous material, and an adhesive material.
  • the patch contains one or more reservoirs separated by a rupturable membrane(s).
  • a rupturable membrane(s) In th e case of multiple reservoir-containing patch, lyophilized crystal portion of an unstable pharmaceutical compound is stored in one reservoir, while liquid portion of the compound is stored in another reservoir.
  • An example of such compound is prostaglandin El .
  • the above disclosed system can further comprise a n electrode, wherein the electrode is in contact with both the patch and controller, and transmits an electrical current or electromagnetic radiant energy.
  • the same system can further comprises a computer monitor connected to the Internet, wherein a signal is sent over the Internet, through the computer monitor, and into the patch.
  • a drug delivery or biomolecule collection patch wherein the patch is electronically monitored by global positioning system.
  • Figure 1 shows a transdermal patch with electromagnetic energy controller, electrode for transmitting energy, drug reservoir containing the formulation and adhesive backing for attachment to skin.
  • Electromagnetic devices described herein including laser systems, are used to effect drug delivery and may be controlled locally or remotely by microprocessors integrated into the devices, which are in turn programmed to receive or transmit data over telecommunication networks .
  • Controlled electromagnetic energy driven systems may b e integrated into patches and other delivery devices that may b e worn on the skin, or may be implanted.
  • the presently disclosed devices contain microprocessors or other electronically controlled elements th at can be interrogated remotely or locally using integrated or remote transmitters. The transmitters in turn may be communicated with via telecommunication networks.
  • Equipment used in paging systems is built into a transdermal patch that receives a signal, or code, sent by the operator over telecommunication networks .
  • Control may also be exerted by coding systems, including bar and magnetic coding, communicated by devices that generate and re ad such code.
  • Code may also be communicated via the Internet, either directly in the case of visible code, or through the use of dedicated communications devices that receive and process code.
  • a method for controlling delivery of a pharmaceutical compound in a subject comprising the steps of: irradiating th e subject with electromagnetic energy; and applying the pharmaceutical compound to the subject, wherein the compound is contained in a patch.
  • the electromagnetic energy is selected from the group consisting of radiofrequency, microwave and light.
  • the patch is implanted in the subject o r topically positioned in relation to the subject, and controlled locally or remotely by an external controller, such as a microprocessor.
  • the patch is made of material selected from the group consisting of a dressing material, a gel, a viscous material, and an adhesive material.
  • the pharmaceutical compound is selected from the group consisting of an anesthetic drug, an anti-neoplastic drug, a photodynamic therapeutical drug, an anti-infection drug, and an anti-inflammatory drug. More preferably, the anesthetic drug is lidocaine.
  • a system for controlling the rate of pharmaceutical delivery or biomolecule collection in a subject comprising: a means to generate electromagnetic energy; a means to deliver th e electromagnetic energy to the subject; and a means to administer the pharmaceutical to or collect the biomolecule from the subject, wherein the pharmaceutical is contained in a patch controlled locally or remotely by an external controller.
  • th e electromagnetic energy is selected from the group consisting of radiofrequency, microwave and light
  • means to generate electromagnetic energy include lasers and ultrasound transducers .
  • the controller is a microprocessor, powered by a battery, a solar cell, an electrochemical generator, a thermal energy generator, or an piezeoelectric generator.
  • the patch is implanted in the subject or topically positioned in relation to the subject, and made of material selected from the group consisting of a dressing material, a gel, a viscous material, and an adhesive material.
  • the patch contains one or more reservoirs separated by a rupturable membrane(s).
  • a rupturable membrane(s) In th e case of multiple reservoir-containing patch, lyophilized crystal portion of an unstable pharmaceutical compound is stored in one reservoir, while liquid portion of the compound is stored in another reservoir.
  • An example of such compound is prostaglandin El.
  • the above disclosed system can further comprise a n electrode, wherein the electrode is in contact with both the patch and controller, and transmits an electrical current o r electromagnetic radiant energy.
  • the same system can further comprises a computer monitor connected to the Internet, wherein a signal is sent over the Internet, through the computer monitor, and into the patch.
  • a drug delivery or biomolecule collection patch wherein the patch is electronically monitored by global positioning system.
  • the global positioning system is a global positioning satellite receiver.
  • Pressure waves created through the interaction of electromagnetic energy with tissue or non-biological matter m a y be used to drive molecules in a medium across tissue interfaces o r between cellular junctions such as those found in membranes , between cells, or even through cellular membranes.
  • the interaction of radiofrequency or microwave irradiation with tissue or another absorber and various pharmaceutical formulations can lead to the generation of propagating pressure waves (generated from a rapid volumetric change in the medium by heating, or b y the generation of plasma) which are in the form of low pres sure acoustic waves propagating at the speed of sound or high pre s sure shock waves propagating at supersonic speeds.
  • These waves can also be a consequence of a generation of waves in a non-biological target which is in intimate acoustic contact with the biological media.
  • Continuously pulsing electromagnetic energy delivered in discrete short duration pulses propagates the pressure waves which thereby physically move the molecules between cellular junctions or across membranes.
  • the "pumping" effect may occur through the creation of increased pressure, including osmotic or atmospheric pressure.
  • a separation results, which is due to the differential resistance of the tissues or membranes relative to th e fluid medium, which is the mobile phase.
  • the degree of pumping will be related to the shape, duty cycle, and power of the driving RF.
  • a target material which preferentially absorbs energy at these radiofrequency frequencies, may be placed adjacent to the tissue, in order to transfer energy effectively.
  • This target could effectively act as a n antenna and may optionally be composed of metals or metal containing compounds.
  • Pressure waves can be used to alter the skin o r membrane itself thereby reducing its barrier function.
  • This barrier function alteration will be transient; the integrity of th e barrier function will reestablish itself soon after th e radiofrequency energy ceases to impinge on the tissue.
  • the degree to which the barrier function is reduced will be dependent on the frequency and intensity of the radiofrequency radiation.
  • the pharmaceutical to be applied to the tissue is preferentially in place during irradiation.
  • the force arising from a coherent interaction with light is also called the dipole force.
  • a laser field polarizes the atom, an d the polarized atom experiences a force in the gradient of a n electromagnetic filed.
  • the strong electric filed of a laser beam can be used to induce a dipole moment in a process called optical trapping.
  • the frequency of the laser field is below th e natural resonance of the particle being trapped (e.g. below the atomic transition of an atom or the absorption edge of a polystyrene sphere), the dipole moment is in phase with th e driving electrical field.
  • a dipole is formed using radiofrequency or microwave energy, rather than laser energy .
  • the trap is formed at the interface between molecules in a formulation and a tissue or membrane interface. This trap is then moved vectorially in the desired direction of movement. In th e case of drug delivery, the desired direction is into the tissues.
  • the focal point of the trap is moved along a vector th at penetrates the tissue of interest, while a formulation containing the drug is applied to the surface of the tissue.
  • the focal point of a single beam or multiple beam trap would then be moved progressively into the tissue, which could occur cyclically so as to ensure the maximum pumping effect.
  • Small pores are made in the skin or membrane b y applying the electromagnetic energy with needle-like probes.
  • a patch-like device with thousands of tiny, needle-like probes which conduct electomagnetic energy can deliver th e energy to create pores.
  • These probes can be made of silicon with a metallic conducting material.
  • Radiofrequency or microwave energy is applied directly to the surface of the tissue, or to a target adjacent to th e tissue, in such a way that the epithelial layers of the tissue are altered to make the layers "leaky” to substances such a s pharmaceuticals.
  • the stratum corneum may b e ablated through the application of electromagnetic energy to generate heat.
  • shear forces may be created b y targeting this energy on an absorber adjacent to the skin, which transfers energy to create stress waves that alter or ablate the stratum corneum.
  • radiofrequencies producing a desired rapid heating effect on stratum corneum result in a n ablative event, while minimizing coagulation.
  • delivery of electromagnetic energy a t these wavelengths may be optimized, by adjusting pulse duration, dwell time between pulses, and peak-power to result in a rapid, intermittent excitation of molecules in the tissues of interest, such that there is no net coagulation effect from heating, but molecules are altered transiently to effect a transient change in membrane conformation that results in greater "leakiness" to substances such as pharmaceuticals.
  • energy with the appropriate pulse mode characteristics is continuously applied that these transient alterations are maintained during the energy cycle, thu s creating a means for maintaining increased membrane permeability over time. This method allows substances to b e continually delivered over a desired period of time.
  • a "leaky" membrane or ablation site in skin is created by first applying electromagnetic energy, including light, microwave or radiofrequency, such that membrane or intramembrane structures are realigned, or the membrane is compromised otherwise, so as to improve permeation. This step is followed by application of electromagnetic energy induced pressure to drive molecules across tissue interfaces and between cellular junctions at a greater rate than can be achieved by either method alone.
  • the laser energy may be delivered continuously o r in discrete pulses to prevent closure of the pore.
  • a different wavelength laser may be used in tandem to pu mp molecules through the pore than is used to create the pore.
  • a single laser may be modulated such that pulse width and energy vary and alternate over time to alternately create a pore through which the subsequent pulse drives th e molecule.
  • a electromagnetic energy generated pressure wave to drive molecules across membranes and between cellular junctions at a greater rate than can b e achieved by either method alone.
  • Laser energy is directed through optical fibers or guided through a series of optics such that pressure waves are generated to come in contact with or create a gradient across th e membrane surface.
  • These pressure waves may be optionally u sed to create a pressure gradient such that the pressure waves move through a liquid or semi-solid medium thereby "pumping" compounds through the medium, into and across the membrane.
  • This technology may optionally be used to deliver laser energy for the purpose of drug delivery across, for example, buccal, uterine, intestinal, urethral, vaginal, bladder and ocular membranes.
  • Pharmaceutical compounds may be delivered into cellular spaces beyond these membranes or into chambers encompassed by these membranes. Compromised or intact stratum corneum may also be breached by applying appropriate optical pressure.
  • compositions are chosen such that electromagnetic energy absorption is maximized relative to th e surrounding medium.
  • many pharmaceutical or diagnostic compounds can be modified by the addition of such energy absorbing groups (or selecting those that minimize absorption) so as to maximize the effects of the electromagnetic energy on a particular formulation relative to the surrounding medium or tissue.
  • a new class of compounds is therefore defined that h ave unique permeability and migration characteristics in the presence of, or following a treatment of electromagnetic energy a s described here.
  • These molecules possess different characteristics by virtue of the addition of groups or structures that absorb energy in a characteristic way that may impart momentum to th e molecule causing it to move relative to the medium which contains it, or may result in excitation of the molecule to result in a desired alteration of that molecule.
  • pharmaceutically active compounds may b e modified by the addition of groups that readily form a dipole when exposed to appropriate electromagnetic energy, such a s radiofrequencies or microwaves.
  • groups that readily form a dipole when exposed to appropriate electromagnetic energy, such a s radiofrequencies or microwaves.
  • the addition of such groups would result in enhanced ability to use optical trapping methods for the delivery of these types of compounds as described herein.
  • any compound which may interact with electromagnetic energy in such a way that it is propelled through a medium can b e used.
  • the present study defines a means by which molecules may be propelled through a medium at differential rates relative to the medium and other molecules in the medium, and a means by which molecules may be separated from one another based on their optical characteristics.
  • the application is not limited to delivering pharmaceuticals.
  • separations of molecules may be achieved by the methods described herein, such as separating protein species in polyacrylamide gels, or separating oligonucleotides on microarray devices. These examples also include using magnetic fields alone to propel molecules through a medium or tissue based on intrinsic magnetic properties or by the addition of magnetic groups, metals, etc. Such methods may also be enhanced by using them in combination with methods to alter membranes an d tissues to work synergistically. Thermal or electronic disruption of a molecule may b e a problem, however, appropriate carriers may be selected to solve this problem. The carriers selected act as "sinks" for the energy, while functional groups are selected that are stable.
  • Patches such as transdermal drug delivery patches, are controlled by remote or local operation through microprocessors. Such patches are designed and used together with electromagnetic energy driven delivery systems.
  • Patches used herein include a dressing material which contains a gel or adhesive that in turn contains the drug formulation to be delivered.
  • the dressing is in contact with an electrode, which is, in turn, in contact with the controller (see Figure 1).
  • the controller regulates the flow of electromagnetic energy that contacts the electrode.
  • the electrode distributes th e energy to the formulation, and further into the tissue of interest.
  • the patch may be a gel, viscous material, o r other patch material that covers the site of treatment.
  • the patch may contain one or more reservoirs.
  • a rupturable membrane may separate different chambers, thus preventing mixing of components until the membrane is ruptured.
  • an unstable compound such as prostaglandin El (e.g. Caverject, UpJohn)
  • lyophilized crystals could be stored in one reservoir while the liquid components to be mixed with the drug could be stored in another reservoir.
  • the two reservoirs are separated by a membrane that may be ruptured by crushing or other physical means, thereby allowing the components to mix freely to make available for dosing.
  • This multi-reservoir concept may be further extended to include mixing of chemicals that will generate an electrical current, for the purpose of iontophoresis or electroporation.
  • the controller may be comprised of a current generator driven by a transportable battery, a solar powered generator, an electrochemical generator, a thermal energy generator, a piezoelectric generator, a radiofrequency generator, a microwave generator, etc.
  • the electrode of the patch may b e replaced by a laser, multiple lasers, or optical fibers which conduct and transmit light at a desired wavelength, pulse length, pulse energy, pulse number and pulse repetition rate to ablate or alter the tissue directly beneath the patch.
  • continuous wave lasers may be used to effect alterations in the tissues th at would lead to a permeabilizing effect.
  • Lasers and other electromagnetic energy generators, as well as ultrasound transducers, may be used in controller-electrode combinations that will result in the desired effects.
  • Telecommunication networks transmit data between the operator and the remotely sited controller (on the patch).
  • the device includes a telemetry transceiver for communicating data and operating instructions between the device and an external patient communications control device that is either worn by, located in proximity to the patient, or at a remote location within the device transceiving range.
  • the control device preferably includes a communication link with a remote medical support network through telecommunication network(s) and may include a global positioning satellite receiver for receiving positioning data identifying the global position of the control device.
  • the device may also contain a patient activated link for permitting patient initiated personal communication with the medical support network.
  • a system controller in the control device controls data and digital communications for selectively transmitting patient initiated personal communications and global positioning data to the medical support network, for receiving telemetry out of data and operating commands from the medical support network, and for receiving and initiating re-programming of the device operating modes and parameters in response to instructions received from the medical support network.
  • the communication link between the medical support network and th e patient communications control device may comprise a world wide satellite network, hard-wired telephone network, a cellular telephone network or other personal communication system.
  • An objective of the device is to provide the patient greater mobility.
  • the patient is allowed to be ambulatory while his medical condition is monitored and/or treated by the medical device.
  • Programming devices may be controlled by the physician or pharmacy, and code or data transmitted over telecommunication networks to the site of the device. This can happen remotely or locally.
  • telemetry systems used to communicate with medical devices are positioned within a short distance of the device.
  • transdermal patch systems are currently regulated only by passive controls, built into th e patch, which regulate the dosage. These controls are typically not electronic, but rather based on membrane and diffusion characteristics of the patch and formulation.
  • the present device provides a means for a remote operator to adjust the dosage and timing of drug delivery, while the patient is ambulatory.
  • Another object of the device is to provide a patient data communication system for world wide patient re - programming telemetry with a medical device worn by the patient.
  • the device described herein is a transdermally w orn patch containing a drug formulation which may or may not include electromagnetic energy permeation enhancement.
  • the invention is not limited to transdermal drug delivery and may include communication with implanted dru g delivery devices using the aforementioned electromagnetic energy based delivery technology.
  • the presently disclosed device transmits and receives coded information from a remote or local source.
  • the operator a t the device is positioned at a location, and can transmit information from the medical support network.
  • the device incorporates a wireless interface including a control device telemetry transceiver for receiving and transmitting coded communications between th e system controller and the device telemetry transceiver, a global positioning system coupled to the system controller for providing positioning data identifying the global position of the patient to the system controller; communication means for communicating with the remote medical support network; and communication network interface means coupled to the system controller and th e communication means for selectively enabling the communication means for transmitting the positioning data to the medical support network and for selectively receiving commands from the medical support network.
  • the communication interface may include capabilities for transfer of data between the patient and the operator by cellular telephone network, paging networks, satellite communication network, land-based telephone communication system, or modem-based communication network, including th e Internet. Communications may include but not be limited to microwave, radiofrequency and digital communication via optical means.
  • the communication and monitoring systems provide a means for exchanging information with and exercising control over one or more medical devices attached to the body of a patient. The devices are intended to function no matter how geographically remote the patient may be relative to th e monitoring site or medical support network.
  • the operator usually a physician, types in a code, which is transmitted over the medical support network to the patient, who may be located by a geopositioning satellite or in relation to other telecommunication network.
  • the code contains information which activates the device and controls dosage.
  • Data transmission to and from the operator to th e device is accomplished by means of a control device that transmits data over the communication network.
  • a telemetry antenna and associated transmitter/receiver can both download and upload data.
  • the antenna may function on radiofrequencies.
  • Control of dosage in the device itself is provided by a digital controller/timer circuit with associated logic circuits connected with a microcomputer.
  • the microcomputer controls the operational functions of a digital controller and a timer. It specifies activation, timing and duration of events.
  • the microcomputer contains a microprocessor and associated RAM and ROM chips, depending on the need for additional memory and programmable functions.
  • a base station may exist at the operator's location.
  • the base station may be comprised of a microprocessor-controlled computer with hardware and software, and associated modem for transmission of information that is relayed through th e appropriate communication network.
  • the system controller m ay also be coupled to a GPS receiver for receiving positioning data from an earth satellite.
  • the GPS receiver may use currently available systems.
  • Dosage schedules for certain medications can be pre - encoded by the manufacturer or pharmacy, using bar code symbols.
  • the encoded bar code symbols can be compiled on one or more menu sheets accessible at the physician office or pharmacy counter where the controller is installed.
  • a bar code symbol reading device can be linked to a data communication port of the medical support network and located on the patch, which can then be used to program th e proper dosage into the device.
  • the code could be transmitted over the Internet, or via other telecommunication networks into a device in the possession of the patient, who can then read the b ar code into the patch.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Anesthesiology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Electrotherapy Devices (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé/système permettant la libération contrôlée à distance et locale de composés pharmaceutiques ou le recueil de biomolécules grâce à l'énergie électromagnétique. Les systèmes contrôlés à alimentation en énergie électromagnétique de l'invention sont intégrés dans des timbres adhésifs ou autres dispositifs de délivrance. L'invention se rapporte également à un timbre de délivrance de médicament ou de recueil de biomolécules surveillé électroniquement par un système de positionnement global.
PCT/US2000/013559 1999-05-17 2000-05-17 Liberation controlee a distance et locale de composes pharmaceutiques faisant appel a l'energie electromagnetique WO2000069515A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU50242/00A AU771818B2 (en) 1999-05-17 2000-05-17 Remote and local controlled delivery of pharmaceutical compounds using electromagnetic energy
CA002372919A CA2372919A1 (fr) 1999-05-17 2000-05-17 Liberation controlee a distance et locale de composes pharmaceutiques faisant appel a l'energie electromagnetique
JP2000617972A JP2002543942A (ja) 1999-05-17 2000-05-17 遠隔制御および現場制御された、電磁エネルギーを用いた医薬化合物の輸送
EP00932535A EP1180053A4 (fr) 1999-05-17 2000-05-17 Liberation controlee a distance et locale de composes pharmaceutiques faisant appel a l'energie electromagnetique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13448699P 1999-05-17 1999-05-17
US60/134,486 1999-05-17

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WO2000069515A1 true WO2000069515A1 (fr) 2000-11-23

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EP (1) EP1180053A4 (fr)
JP (1) JP2002543942A (fr)
AU (1) AU771818B2 (fr)
CA (1) CA2372919A1 (fr)
WO (1) WO2000069515A1 (fr)

Cited By (19)

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EP1204469A1 (fr) * 1999-05-17 2002-05-15 Kevin S. Marchitto Procedes de separation par energie electromagnetique
WO2002092163A2 (fr) * 2001-05-17 2002-11-21 Transpharma Ltd. Carte electronique pour administration transdermique de medicaments et extraction d'analyte
WO2002068044A3 (fr) * 2001-02-28 2002-11-28 Johnson & Johnson Consume Comp Electroperforation de tissus ameliorant la distribution de medicaments et l'echantillonnage a des fins de diagnostic
US6611706B2 (en) 1998-11-09 2003-08-26 Transpharma Ltd. Monopolar and bipolar current application for transdermal drug delivery and analyte extraction
US6615079B1 (en) 1998-11-09 2003-09-02 Elecsys Ltd. Transdermal drug delivery and analyte extraction
US7113821B1 (en) 1999-08-25 2006-09-26 Johnson & Johnson Consumer Companies, Inc. Tissue electroperforation for enhanced drug delivery
WO2006111429A1 (fr) * 2005-04-18 2006-10-26 Pantec Biosolutions Ag Systeme d'administration transmembranaire d'un infiltrant
WO2006111199A1 (fr) * 2005-04-18 2006-10-26 Pantec Biosolutions Ag Dispositif de microporation destine a former des pores dans une membrane biologique, et systeme integre d'administration de permeants
WO2007039646A1 (fr) * 2005-10-06 2007-04-12 Pantec Biosolutions Ag Dispositif d'administration transdermique pour traiter la stérilité
WO2008073806A1 (fr) * 2006-12-08 2008-06-19 Sabic Innovative Plastics Ip B.V. Système actif d'administration d'un médicament par voie transdermique
US7483737B2 (en) 2003-11-18 2009-01-27 Hisamitsu Pharmaceutical Co., Inc Electrode chip for biological application and its using method
GB2453455B (en) * 2006-05-04 2010-12-22 Searete Llc Controllable release nasal system
JP2013256500A (ja) * 2000-09-08 2013-12-26 Alza Corp 経路閉鎖を阻害することによる経皮的薬物流動の減少の抑制方法
US8694092B2 (en) 2006-04-12 2014-04-08 The Invention Science Fund I, Llc Lumen-traveling biological interface device and method of use
US9011329B2 (en) 2004-04-19 2015-04-21 Searete Llc Lumenally-active device
US9198563B2 (en) 2006-04-12 2015-12-01 The Invention Science Fund I, Llc Temporal control of a lumen traveling device in a body tube tree
US9283037B2 (en) 2005-04-18 2016-03-15 Pantec Biosolutions Ag Laser microporator
US9801527B2 (en) 2004-04-19 2017-10-31 Gearbox, Llc Lumen-traveling biological interface device
EP3572119A4 (fr) * 2017-01-18 2020-10-28 Changzhou Hualian Health Dressing Ltd. Dispositif transdermique d'administration portable et son procédé de préparation

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JP2005149956A (ja) * 2003-11-17 2005-06-09 Ulvac Japan Ltd 大面積高均一プラズマ処理方法及び装置
JPWO2007032398A1 (ja) * 2005-09-14 2009-03-19 Ｔｔｉ・エルビュー株式会社 イオントフォレーシス装置及びイオントフォレーシス装置用電源装置
RU2009125062A (ru) 2006-12-01 2011-01-10 ТиТиАй ЭЛЛЕБО, ИНК. (JP) Системы, устройства и способы для питания и/или управления устройствами, например устройствами трансдермальной доставки
WO2014100259A1 (fr) * 2012-12-18 2014-06-26 Abbott Cardiovascular Systems Inc. Implant médical piézoélectrique

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6597946B2 (en) 1998-11-09 2003-07-22 Transpharma Ltd. Electronic card for transdermal drug delivery and analyte extraction
US6615079B1 (en) 1998-11-09 2003-09-02 Elecsys Ltd. Transdermal drug delivery and analyte extraction
US6611706B2 (en) 1998-11-09 2003-08-26 Transpharma Ltd. Monopolar and bipolar current application for transdermal drug delivery and analyte extraction
EP1204469A1 (fr) * 1999-05-17 2002-05-15 Kevin S. Marchitto Procedes de separation par energie electromagnetique
EP1204469A4 (fr) * 1999-05-17 2003-04-16 Kevin S Marchitto Procedes de separation par energie electromagnetique
US7113821B1 (en) 1999-08-25 2006-09-26 Johnson & Johnson Consumer Companies, Inc. Tissue electroperforation for enhanced drug delivery
US7133717B2 (en) 1999-08-25 2006-11-07 Johnson & Johnson Consumer Companies, Inc. Tissue electroperforation for enhanced drug delivery and diagnostic sampling
JP2013256500A (ja) * 2000-09-08 2013-12-26 Alza Corp 経路閉鎖を阻害することによる経皮的薬物流動の減少の抑制方法
WO2002068044A3 (fr) * 2001-02-28 2002-11-28 Johnson & Johnson Consume Comp Electroperforation de tissus ameliorant la distribution de medicaments et l'echantillonnage a des fins de diagnostic
WO2002092163A3 (fr) * 2001-05-17 2003-02-27 Transpharma Ltd Carte electronique pour administration transdermique de medicaments et extraction d'analyte
WO2002092163A2 (fr) * 2001-05-17 2002-11-21 Transpharma Ltd. Carte electronique pour administration transdermique de medicaments et extraction d'analyte
US7483737B2 (en) 2003-11-18 2009-01-27 Hisamitsu Pharmaceutical Co., Inc Electrode chip for biological application and its using method
US9801527B2 (en) 2004-04-19 2017-10-31 Gearbox, Llc Lumen-traveling biological interface device
US9011329B2 (en) 2004-04-19 2015-04-21 Searete Llc Lumenally-active device
US9173837B2 (en) 2004-04-19 2015-11-03 The Invention Science Fund I, Llc Controllable release nasal system
WO2006111199A1 (fr) * 2005-04-18 2006-10-26 Pantec Biosolutions Ag Dispositif de microporation destine a former des pores dans une membrane biologique, et systeme integre d'administration de permeants
US9283037B2 (en) 2005-04-18 2016-03-15 Pantec Biosolutions Ag Laser microporator
WO2006111429A1 (fr) * 2005-04-18 2006-10-26 Pantec Biosolutions Ag Systeme d'administration transmembranaire d'un infiltrant
WO2007039646A1 (fr) * 2005-10-06 2007-04-12 Pantec Biosolutions Ag Dispositif d'administration transdermique pour traiter la stérilité
US8372806B2 (en) 2005-10-06 2013-02-12 Pantec Biosolutions Ag Transdermal delivery system for treating infertility
US8694092B2 (en) 2006-04-12 2014-04-08 The Invention Science Fund I, Llc Lumen-traveling biological interface device and method of use
US9198563B2 (en) 2006-04-12 2015-12-01 The Invention Science Fund I, Llc Temporal control of a lumen traveling device in a body tube tree
US9408530B2 (en) 2006-04-12 2016-08-09 Gearbox, Llc Parameter-based navigation by a lumen traveling device
GB2453455B (en) * 2006-05-04 2010-12-22 Searete Llc Controllable release nasal system
WO2008073806A1 (fr) * 2006-12-08 2008-06-19 Sabic Innovative Plastics Ip B.V. Système actif d'administration d'un médicament par voie transdermique
EP3572119A4 (fr) * 2017-01-18 2020-10-28 Changzhou Hualian Health Dressing Ltd. Dispositif transdermique d'administration portable et son procédé de préparation

Also Published As

Publication number Publication date
CA2372919A1 (fr) 2000-11-23
JP2002543942A (ja) 2002-12-24
AU5024200A (en) 2000-12-05
AU771818B2 (en) 2004-04-01
EP1180053A4 (fr) 2006-11-08
EP1180053A1 (fr) 2002-02-20

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