WO1997007734A1 - Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage - Google Patents

Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage Download PDF

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Publication number
WO1997007734A1
WO1997007734A1 PCT/US1996/013865 US9613865W WO9707734A1 WO 1997007734 A1 WO1997007734 A1 WO 1997007734A1 US 9613865 W US9613865 W US 9613865W WO 9707734 A1 WO9707734 A1 WO 9707734A1
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WIPO (PCT)
Prior art keywords
stratum comeum
selected area
skin
stratum
wire
Prior art date
Application number
PCT/US1996/013865
Other languages
English (en)
Inventor
Jonathan A. Eppstein
Michael R. Hatch
Difei Yang
Original Assignee
Spectrx, Inc.
Altea Technologies, Inc.
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 Spectrx, Inc., Altea Technologies, Inc. filed Critical Spectrx, Inc.
Priority to JP51055297A priority Critical patent/JP3899427B2/ja
Priority to GB9702766A priority patent/GB2307414B/en
Priority to EP96929098A priority patent/EP0858285A4/fr
Priority to BR9610012-5A priority patent/BR9610012A/pt
Priority to IL12337996A priority patent/IL123379A/en
Priority to AU68631/96A priority patent/AU707065B2/en
Priority to US08/776,863 priority patent/US5885211A/en
Publication of WO1997007734A1 publication Critical patent/WO1997007734A1/fr
Priority to NO19980878A priority patent/NO334437B1/no
Priority to HK98110113A priority patent/HK1009321A1/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0047—Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/32—Surgical cutting instruments
    • A61B17/3203—Fluid jet cutting instruments
    • 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
    • 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, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00137—Details of operation mode
    • A61B2017/00154—Details of operation mode pulsed
    • A61B2017/00172—Pulse trains, bursts, intermittent continuous operation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00747—Dermatology
    • A61B2017/00761—Removing layer of skin tissue, e.g. wrinkles, scars or cancerous tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • 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
    • 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
    • A61B2018/0047—Upper parts of the skin, e.g. skin peeling or treatment of wrinkles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • 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
    • 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

  • This invention relates generally to the field of monitoring of analytes in the body and the transdermal delivery of drugs to the body. More particularly, this invention relates to a minimally invasive to non-invasive method of increasing the permeability of the skin through microporation of the stratum comeum, which can be combined with sonic energy, chemical permeation enhancers, pressure, and the like for selectively enhancing outward flux of analytes
  • the stratum comeum is chiefly responsible for the well known barrier properties of skin. Thus, it is this layer that presents the greatest barrier to transdermal flux of drugs or other molecules into the body and of analytes out of the body.
  • the stratum co eum the outer homy layer of the skin, is a complex structure of compact keratinized cell remnants separated 25 by lipid domains. Compared to the oral or gastric mucosa, the stratum comeum is much less permeable to molecules either extemal or intemal to the body.
  • the stratum comeum is formed from keratinocytes, which comprise the majority of epidermal cells, that lose their nuclei and become comeocytes. These dead cells comprise the stratum comeum, which has a thickness of only about 10-30 ⁇ m and, as noted above, is a very resistant waterproof membrane that
  • the stratum comeum is continuously renewed by shedding of comeum cells during desquamination and the formation of new comeum cells by the keratinization process.
  • the flux of a drug or analyte across the skin can be increased by changing either the resistance (the diffusion coefficient) or the driving force (the gradient for diffusion). Flux may be enhanced by the use of so-called penetration or chemical enhancers. Chemical enhancers are well known in the art and a more detailed description will follow.
  • Iontophoresis Another method of increasing the permeability of skin to drugs is iontophoresis.
  • Iontophoresis involves the application of an exte al electric field and topical delivery of an ionized form of dmg or an un-ionized drug carried with the water flux associated with ion transport (electro-osmosis). While permeation enhancement with iontophoresis has been effective, control of drug delivery and irreversible skin damage are problems associated with the technique.
  • Sonic energy has also been used to enhance permeability of the skin and synthetic membranes to d gs and other molecules.
  • Ultrasound has been defined as mechanical pressure waves with frequencies above 20 kHz, H. Lutz et al., Manual of Ultrasound 3-12 (1984).
  • Sonic energy is generated by vibrating a piezoelectric crystal or other electromechanical element by passing an alternating current through the material, R. Brucks et al., 6 Pharm. Res. 697 (1989).
  • the use of sonic energy to increase the permeability of the skin to dmg molecules has been termed sonophoresis or phonophoresis.
  • U.S. Patent No. 5,139,023 to Stanley et al. discloses an apparatus and method for noninvasive blood glucose monitoring.
  • chemical permeation enhancers are used to increase the permeability of mucosal tissue or skin to glucose.
  • Glucose then passively diffuses through the mucosal tissue or skin and is captured in a receiving medium. The amount of glucose in the receiving medium is measured and correlated to determine the blood glucose level.
  • sonic energy optionally with modulations of frequency, intensity, and/or phase, to controllably push and/or pump molecules through the stratum comeum via perforations introduced by needle puncture, hydraulic jet, laser, electroporation, or other methods.
  • micropores i.e. microporation
  • Jacques et al. 88 J. Invest. Dermatol. 88-93 (1987)
  • Jacques et al. 88 J. Invest. Dermatol. 88-93 (1987)
  • pulsed laser light of wavelength, pulse length, pulse energy, pulse number, and pulse repetition rate sufficient to ablate the stratum comeum without significantly damaging the underlying epidermis and then applying the dmg to the region of ablation.
  • Tankovich U.S. Patent No. 5,165,418 (hereinafter, "Tankovich '418"), discloses a method of obtaining a blood sample by irradiating human or animal skin with one or more laser pulses of sufficient energy to cause the vaporization of skin tissue so as to produce a hole in the skin extending through the epidermis and to sever at least one blood vessel, causing a quantity of blood to be expelled through the hole such that it can be collected.
  • Tankovich '418 thus is inadequate for noninvasive or minimally invasive permeabilization of the stratum co eum such that a drug can be delivered to the body or an analyte from the body can be analyzed.
  • Tankovich et al. U.S. Patent No. 5,423,803 (hereinafter, "Tankovich '803”) discloses a method of laser removal of superficial epidermal skin cells in human skin for cosmetic applications.
  • the method comprises applying a light-absorbing "contaminant" to the outer layers of the epidermis and forcing some of this contaminant into the intercellular spaces in the stratum comeum, and illuminating the infiltrated skin with pulses of laser light of sufficient intensity that the amount of energy absorbed by the contaminant will cause the contaminant to explode with sufficient energy to tear off some of the epidermal skin cells.
  • Tankovich '803 further teaches that there should be high abso ⁇ tion of energy by the contaminant at the wavelength of the laser beam, that the laser beam must be a pulsed beam of less than 1 ⁇ s duration, that the contaminant must be forced into the upper layers of the epidermis, and that the contaminant must explode with sufficient energy to tear off epidermal cells upon abso ⁇ tion of the laser energy.
  • This invention also fails to disclose or suggest a method of dmg delivery or analyte collection.
  • Raven et al., WO 92/00106 describes a method of selectively removing unhealthy tissue from a body by administering to a selected tissue a compound that is highly absorbent of infrared radiation of wavelength 750-860 nm and irradiating the region with corresponding infrared radiation at a power sufficient to cause thermal vaporization of the tissue to which the compound was administered but insufficient to cause vaporization of tissue to which the compound had not been administered.
  • the absorbent compound should be soluble in water or serum, such as indocyanine green, chlorophyll, po ⁇ hyrins, heme-containing compounds, or compounds containing a polyene structure, and power levels are in the range of 50-1000 W/cm 2 or even higher.
  • Konig et al., DD 259351 teaches a process for thermal treatment of tumor tissue that comprises depositing a medium in the tumor tissue that absorbs radiation in the red and/or near red infrared spectral region, and irradiating the infiltrated tissue with an appropriate wavelength of laser light.
  • Absorbing media can include methylene blue, reduced po ⁇ hyrin or its aggregates, and phthalocyanine blue. Methylene blue, which strongly absorbs at 600-700 nm, and a krypton laser emitting at 647 and 676 nm are exemplified.
  • the power level should be at least 200 mW/cm 2 .
  • pulsed lasers such as the excimer laser operating at 193 nm, the erbium laser operating near 2.9 ⁇ m or the C0 2 laser operating at 10.2 ⁇ m, can be used to effectively ablate small holes in the human stratum comeum.
  • These laser ablation techniques offer the potential for a selectiv'e and potentially non-traumatic method for opening a delivery and/or sampling hole through the stratum comeum.
  • due to the prohibitively high costs associated with these light sources there have been no commercial products developed based on this concept.
  • the presently disclosed invention by defining a method for directly conducting thermal energy into the stratum comeum with very tightly defined spatial and temporal resolution, makes it possible to produce the desired micro-ablation of the stratum comeum using very low cost energy sources.
  • An object of the invention is to minimize the barrier properties of the stratum co eum using poration to controllably collect analytes from within the body through perforations in the stratum co eum to enable the monitoring of these analytes. It is also an object of the invention to provide a method of monitoring selected analytes in the body through micropores in the stratum comeum in combination with sonic energy, permeation enhancers, pressure gradients, and the like.
  • Another object of the invention is to provide a method for controlling transdermal flux rates of dmgs or other molecules into the body and, if desired, into the bloodstream through minute perforations in the stratum comeum.
  • the method further comprises applying sonic energy to the porated selected area at a frequency in the range of about 5 kHz to 100 MHz, wherein the sonic energy is modulated by means of a member selected from the group consisting of frequency modulation, amplitude modulation, phase modulation, and combinations thereof.
  • the method further comprises contacting the selected area of the individual's body with a chemical enhancer with the application of the sonic energy to further enhance analyte withdrawal.
  • Porating of the stratum comeum is accomplished by means selected from the group consisting of (a) ablating the stratum comeum by contacting a selected area, up to about 1000 ⁇ m across, of the stratum corneum with a heat source such that the temperatureu of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances thereby removing the stratum comeum in the selected area; (b) puncturing the stratum comeum with a micro-lancet calibrated to form a micropore of up to about 1000 ⁇ m in diameter; (d) ablating the stratum comeum by focusing a tightly focused beam of sonic energy onto the stratum comeum; (d) hydraulically puncturing the stratum comeum with a high pressure jet of fluid to form a micropore of up to about 1000 ⁇ m in diameter and (e) puncturing the stratum comeum with short pulses of electricity to form a micropore of up to about 1000 ⁇ m in diameter.
  • thermally ablating the stratum comeum comprises treating at least the selected area with an effective amount of a dye that exhibits strong abso ⁇ tion over the emission range of a pulsed light source and focusing the output of a series of pulses from the pulsed light source onto the dye such that the dye is heated sufficiently to conductively transfer heat to the stratum comeum to elevate the temperature of tissue-bound water and other vaporizable substances in the selected area above the vaporization point of the water and other vaporizable substances.
  • the pulsed light source emits at a wavelength that is not significantly absorbed by skin.
  • the pulsed light source can be a laser diode emitting in the range of about 630 to 1550 nm, a laser diode pumped optical parametric oscillator emitting in the range of about 700 and 3000 nm, or a member selected from the group consisting of arc lamps, incandescent lamps, and light emitting diodes.
  • a sensing system for determining when the barrier properties of the stratum comeum have been surmounted can also be provided.
  • One preferred sensing system comprises light collection means for receiving light reflected from the selected area and focusing the reflected light on a photodiode, a photodiode for receiving the focused light and sending a signal to a controller wherein the signal indicates a quality of the reflected light, and a controller coupled to the photodiode and to the pulsed light source for receiving the signal and for shutting off the pulsed light source when a preselected signal is received.
  • the method further comprises cooling the selected area of stratum comeum and adjacent skin tissues with cooling means such that said selected area and adjacent skin tissues are in a selected precooled, steady state, condition prior to porafion.
  • the method comprises ablating the stratum comeum such that interstitial fluid exudes from the micropores, collecting the interstitial fluid, and analyzing the analyte in the collected interstitial fluid.
  • the micropore can be sealed by applying an effective amount of energy from the laser diode or other light source such that interstitial fluid remaining in the micropore is caused to coagulate.
  • vacuum is applied to the porated selected area to enhance collection of interstitial fluid.
  • the method comprises, prior to porating the stratum comeum, illuminating at least the selected area with unfocused light from the pulsed light source such that the selected area illuminated with the light is sterilized.
  • Another preferred method of porating the stratum comeum comprises contacting the selected area with a metallic wire such that the temperature of the selected area is raised from ambient skin temperature to greater than 100°C within about 10 to 50 ms and then retuming the temperature of the selected area to approximately ambient skin temperature within about 30 to 50 ms, wherein this cycle of raising the temperature and retuming to approximately ambient skin temperature is repeated a number of time effective for reducing the barrier properties of the stratum comeum.
  • the step of retuming to approximately ambient skin temperature is carried out by withdrawing the wire from contact with the stratum comeum.
  • the wire can be heated by an ohmic heating element, can have a current loop having a high resistance point wherein the temperature of the high resistance point is modulated by passing a modulated electrical current through said current loop to effect the heating, or can be positioned in a modulatable alternating magnetic field of an excitation coil such that energizing the excitation coil with alternating current produces eddy currents suffient to heat the wire by intemal ohmic losses.
  • a method for enhancing the transdermal flux rate of an active permeant into a selected area of an individual's body comprising the steps of enhancing the permeability of the stratum comeum layer of the selected area of the individual's body surface to the active permeant by means of (a) porating the stratum comeum of the selected area by means that form a micro-pore in the stratum comeum without causing serious damage to the underlying tissues and thereby reduce the barrier properties of the stratum co eum to the flux of the active permeant; and (b) contacting the porated selected area with a composition comprising an effective amount of the permeant such that the flux of the permeant into the body is enhanced.
  • the method further comprises applying sonic energy to the porated selected area for a time and at an intensity and a frequency effective to create a fluid streaming effect and thereby enhance the transdermal flux rate of the permeant into the body.
  • a method for appyling a tatoo to a selected area of skin on an individual's body surface comprising the steps of: (a) porating the stratum comeum of the selected area by means that form a micro-pore in the stratum comeum without causing serious damage to the underlying tissues and thereby reduce the barrier properties of the stratum co eum to the flux of a permeant; and
  • a method is still further provided for reducing a temporal delay in diffusion of an analyte from blood of an individual to said individual's interstitial fluid in a selected area of skin comprising applying means for cooling to said selected area of skin.
  • a method is yet further provided for reducing evaporation of interstitial fluid and the vapor pressure thereof, wherein said interstitial fluid is being collected from a micropore in a selected area of stratum comeum of an individual's skin, comprising applying means for cooling to said selected area of skin.
  • FIG. 1 shows a schematic representation of a system for delivering laser diode light and monitoring the progress of poration.
  • FIG. 2 shows a schematic representation of a closed-loop feedback system for monitoring poration.
  • FIG. 3 A shows a schematic representation of an optical poration system comprising a cooling device.
  • FIG. 3B shows a top view of a schematic representation of an illustrative cooling device according to FIG. 3A.
  • FIG. 4 shows a schematic representation of an ohmic heating device with a mechanical actuator.
  • FIG. 5 shows a schematic representation of a high resistance current loop heating device.
  • FIG. 6 shows a schematic representation of a device for modulating heating using inductive heating.
  • FIG. 7 shows a schematic representation of a closed loop impedance monitor using changes in inpedance to determine the extent of poration.
  • FIGS. 8A-D show cross sections of human skin treated with copper phthalocyanine and then subjected, respectively, to 0, 1, 5, and 50 pulses of 810 nm light with an energy density of 4000 J/cm 2 for a pulse period of 20 ms.
  • FIGS. 9-11 show graphic representations of temperature distribution during simulated thermal poration events using optical poration.
  • FIGS. 12 and 13 show graphic representations of temperature as a function of time in the stratum comeum and viable epidermis, respectively, during simulated thermal poration events using optical poration.
  • FIGS. 14-16 show graphic representations of temperature distribution, temperature as a function of time in the stratum comeum, and temperature as a function of time in the viable epidermis, respectively, during simulated thermal poration events using optical poration wherein the tissue was cooled prior to poration.
  • FIGS. 17-19 show graphic representations of temperature distribution, temperature as a function of time in the stratum comeum, and temperature as a function of time in the viable epidermis, respectively, during simulated thermal poration events wherein the tissue was heated with a hot wire.
  • FIGS. 20-22 show graphic representations of temperature distribution, temperature as a function of time in the stratum comeum, and temperature as a function of time in the viable epidermis, respectively, during simulated thermal poration events wherein the tissue was heated with a hot wire and the tissue was cooled prior to poration.
  • FIGS. 23 and 24 show graphic representations of temperature distribution and temperature as a function of time in the stratum comeum, respectively, during simulated thermal poration events wherein the tissue is heated optically according to the operating parameters of Tankovich '803.
  • FIG. 25 shows a graphic representation of interstitial fluid (ISF; o) and blood (*) glucose levels as a function of time.
  • FIG. 26 shows a scatter plot representation of the difference term between the ISF glucose and the blood glucose data of FIG. 25.
  • FIG. 27 shows a histogram of the relative deviation of the ISF to the blood glucose levels from FIG. 25.
  • FIG. 28 shows a cross section of an illustrative delivery apparatus for delivering a drug to a selected area on an individual's skin.
  • FIGS. 29A-C show graphic representations of areas of skin affected by delivery of lidocaine to selected areas where the stratum co eum is porated (FIGS. 29A-B) or not porated (FIG. 29C).
  • FIG. 30 shows a plot comparing the amount of interstitial fluid harvested from micropores with suction alone (o) and with a combination of suction and ultrasound (*).
  • FIGS. 31, 32, and 33 show a perspective view of an ultrasonic transducer/vacuum apparatus for harvesting interstitial fluid, a cross section view of the same apparatus, and cross sectional schematic view of the same apparatus, respectively.
  • FIGS. 34A-B show a top view of a handheld ultrasonic transducer and a side view of the spatulate end thereof, respectively.
  • reference to a method for delivery of "a dmg” includes reference to delivery of a mixture of two or more drugs
  • reference to “an analyte” includes reference to one or more of such analytes
  • reference to “a permeation enhancer” includes reference to a mixture of two or more permeation enhancers.
  • hole or pore means the formation of a small hole or pore in the stratum comeum in a selected area of the skin of an individual to lessen the barrier properties of this layer of the skin to the passage of analytes from below the skin surface for analysis or the passage of active permeants or dmgs into the body for therapeutic pu ⁇ oses.
  • the hole or pore will be no larger than about 1 mm in diameter, and more preferably no larger than about 100 ⁇ m in diameter, and will extend into the stratum comeum sufficiently to break the barrier properties of this layer without adversely affecting the underlying tissues.
  • ablation means the controlled removal of cells caused by kinetic energy released when the vaporizable components of the cells have been heated to the point that vaporization occurs and the resulting rapid expansion of volume due to this phase change causes cells and possibly some adjacent cells to be "blown away" from the abaltion site.
  • puncture or “micro-puncture” means the use of mechanical, hydraulic, or electrical means to perforate the stratum comeum.
  • ablation and “puncture” accomplish the same pu ⁇ ose of poration, i.e. the creating a hole or pore in the stratum comeum without significant damage to the underlying tissues, these terms may be used interchangeably.
  • penetration enhancement means an increase in the permeability of skin to a dmg, analyte, dye, stain, or other chemical molecule (also called “permeant”), i.e., so as to increase the rate at which a dmg, analyte, or chemical molecule permeates the stratum comeum and facilitates the poration of the stratum comeum, the withdrawal of analytes out through the stratum comeum or the delivery of dmgs through the stratum comeum and into the underlying tissues.
  • the enhanced permeation effected through the use of such enhancers can be observed, for example, by observing diffusion of a dye, as a permeant, through animal or human skin using a diffusion apparatus.
  • chemical enhancer includes all enhancers that increase the flux of a permeant, analyte, or other molecule across the skin, and is limited only by functionality. In other words, all cell envelope disordering compounds and solvents and any other chemical enhancement agents are intended to be included.
  • die As used herein, “dye,” “stain,” and the like shall be used interchangeably and refer to a biologically suitable chromophore that exhibits strong abso ⁇ tion at the emission range of a pulsed light source used to ablate tissues of the stratum comeum to form micropores therein.
  • transdermal or “percutaneous” means passage of a permeant into and through the skin to achieve effective therapeutic blood levels or deep tissue levels of a dmg, or the passage of a molecule present in the body ("analyte”) out through the skin so that the analyte molecule may be collected on the outside of the body.
  • the term "permeant,” “drug,” or “pharmacologically active agent” or any other similar term means any chemical or biological material or compound suitable for transdermal administration by the methods previously known in the art and/or by the methods taught in the present invention, that induces a desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the organism and preventing an undesired biological effect such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, and/or (3) either alleviating, reducing, or completely eliminating the disease from the organism.
  • the effect may be local, such as providing for a local anaesthetic effect, or it may be systemic.
  • This invention is not drawn to novel permeants or to new classes of active agents. Rather it is limited to the mode of delivery of agents or permeants that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention.
  • agents or permeants that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention.
  • Such substances include broad classes of compounds normally delivered into the body, including through body surfaces and membranes, including skin.
  • antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sy pathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including deconges
  • an "effective" amount of a pharmacologically active agent means a sufficient amount of a compound to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
  • An "effective" amount of a permeation or chemical enhancer as used herein means an amount selected so as to provide the desired increase in skin permeability and the desired depth of penetration, rate of administration, and amount of drug delivered.
  • carriers or “vehicles” refer to carrier materials without significant pharmacological activity at the quantities used that are suitable for administration with other pharmaceutically active materials, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or the like, that is nontoxic at the quantities employed and does not interact with the dmg to be administered in a deleterious manner.
  • Suitable carriers for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly, and a variety of other oils and polymeric materials.
  • a biological membrane is intended to mean a membrane material present within a living organism that separates one area of the organism from another and, in many instances, that separates the organism from its outer environment. Skin and mucous membranes are thus included.
  • “individual” refers to both a human and an animal, to which the present invention may be applied.
  • analyte means any chemical or biological material or compound suitable for passage through a biological membrane by the technology taught in this present invention, or by technology previously known in the art, of which an individual might want to know the concentration or activity inside the body.
  • Glucose is a specific example of an analyte because it is a sugar suitable for passage through the skin, and individuals, for example those having diabetes, might want to know their blood glucose levels.
  • Other examples of analytes include, but are not limited to, such compounds as sodium, potassium, bilimbin, urea, ammonia, calcium, lead, iron, lithium, salicylates, and the like.
  • transdermal flux rate is the rate of passage of any analyte out through the skin of an individual, human or animal, or the rate of passage of any dmg, pharmacologically active agent, dye, or pigment in and through the skin of an individual, human or animal.
  • intensity amplitude As used herein, the terms “intensity amplitude,” “intensity,” and “amplitude” are used synonymously and refer to the amount of energy being produced by the sonic energy system.
  • frequency modulation means a continuous, graded or stepped variation in the amplitude or frequency of ultrasound in a given time period.
  • a frequency modulation is a graded or stepped variation in frequency in a given time period, for example 5.4-5.76 MHz in 1 sec, or 5-10 MHz in 0.1 sec, or 10-5 MHz in 0.1 sec, or any other frequency range or time period that is appropriate to a specific application.
  • a complex modulation can include varying both the frequency and intensity simultaneously.
  • FIGS. 4A and 4B of U.S. Patent No. 5,458,140 could, respectively, represent amplitude and frequency modulations being applied simultaneously to a single sonic energy transducer.
  • phase modulation means the timing of the signal has been changed relative to its initial state shown in Fig. 4C of U.S. Patent No. 5,458,140.
  • the frequency and amplitude of the signal can remain the same.
  • a phase modulation can be implemented with a variable delay such as to selectively retard or advance the signal temporarily in reference to its previous state, or to another signal.
  • the sonic energy in its various applications such as with frequency, intensity or phase modulation, or combinations thereof and the use of chemical enhancers combined with modulated sonic energy, as described herein, can vary over a frequency range of between about 5 kHz to 100 MHz, with a range of between about 20 kHz and 30 MHz being preferred.
  • non-invasive means not requiring the entry of a needle, catheter, or other invasive medical instrument into a part of the body.
  • minimally invasive refers to the use of mechanical, hydraulic, or electrical means that invade the stratum comeum to create a small hole or micropore without causing substantial damage to the underlying tissues.
  • the lower threshold of radiant exposure that must be absorbed by the stratum comeum within the limit of the thermal relaxation time to cause suitable micro-explosions that result in tissue ablation is about 70 mJ/cm 2 within a 50 millisecond (ms) time. In other words, a total of 70 mJ/cm 2 must be delivered within a 50 ms window. This can be done in a single pulse of 70 mJ/cm 2 or in 10 pulses of 7 mJ/cm 2 , or with a continuous illumination of 1.4 watts/cm 2 during the 50 ms time.
  • the upper limit of radiant exposure is that which will ablate the stratum comeum without damage to underlying tissue and can be empirically determined from the light source, wavelength of light, and other variables that are within the experience and knowledge of one skilled in this art.
  • deliver is meant that the stated amount of energy is absorbed by the tissue to be ablated.
  • the excimer laser wavelength of 193 nm essentially 100% abso ⁇ tion occurs within the first 1 or 2 ⁇ m of stratum comeum tissue. Assuming the stratum comeum is about 20 ⁇ m thick, at longer wavelengths, such as 670 nm, only about 5% of incident light is absorbed within the 20 ⁇ m layer. This means that about 95% of the high power beam passes into the tissues underlying the stratum comeum where it will likely cause significant damage.
  • the ideal is to use only as much power as is necessary to perforate the stratum comeum without causing bleeding, thermal, or other damage to underlying tissues from which analytes are to be extracted or drugs or other permeants delivered.
  • Excimer lasers which emit light at wavelengths in the far UV region, are much more expensive to operate and maintain than, for example, diode lasers that emit light at wavelengths in visible and IR regions (600 to 1800 nm). However, at the longer wavelengths, the stratum comeum becomes increasingly more transparent and abso ⁇ tion occurs primarily in the underlying tissues.
  • the present invention facilitates a rapid and painless method of eliminating the barrier function of the stratum comeum to facilitate the transcutaneous transport of therapeutic substances into the body when applied topically or to access the analytes within the body for analysis.
  • the method utilizes a procedure which begins with the contact application of a small area heat source to the targeted area of the stratum comeum.
  • the heat source must have several important properties, as will now be described.
  • the heat source must be sized such that contact with the skin is confined to a small area, typically about 1 to 1000 ⁇ m in diameter.
  • an inherent depth limiting feature of the microporation process can be facilitated if the heat source has both a small enough thermal mass and limited energy source to elevate its temperature such that when it is placed in contact with tissues with more than 30% water content, the thermal dispersion in these tissues is sufficient to limit the maximum temperature of the heat source to less than 100°C. This feature effectively stops the thermal vaporization process once the heat probe had penetrated through the stratum comeum into the lower layers of the epidermis.
  • the heat source placed in contact with the skin, it is cycled through a series of one or more modulations of temperature from an initial point of ambient skin temperature to a peak temperature in excess of 123°C to approxmiately ambient skin temperature.
  • these pulses are limited in duration, and the inte ⁇ ulse spacing is long enough to allow cooling of the viable tissue layers in the skin, and most particularly the enervated dermal tissues, to acheive a mean temperature of less than about 45°C.
  • These parameters are based on the thermal time constants of the viable epidermal tissues (roughly 30-80 ms) located between the heat probe and the enervated tissue in the underlying dermis.
  • the stratum lucidum By limiting the duration of the heat pulse to less than one thermal time constant of the epidermis and allowing any heat energy conducted into the epidermis to dissipate for a sufficiently long enough time, the elevation in temperature of the viable layers of the epidermis is minimal. This allows the entire microporation process to take place without any sensation to the subject and no damage to the underlying and surrounding tissues.
  • the present invention comprises a method for painlessly creating microscopic holes, i.e. micropores, from about 1 to 1000 ⁇ m across, in the stratum comeum of human skin.
  • the key to successfully implementing this method is the creation of an appropriate thermal energy source, or heat probe, which is held in contact with the stratum comeum.
  • the principle technical challenge in fabricating an appropriate heat probe is designing a device that has the desired contact with the skin and that can be thermally modulated at a sufficiently high frequency.
  • an appropriate heat probe by topically applying to the stratum comeum a suitable light- absorbing compound, such as a dye or stain, selected because of its ability to absorb light at the wavelength emitted by a selected light source.
  • the selected light source may be a laser diode emitting at a wavelength which would not normally be absorbed by the skin tissues.
  • the targeted area can be temperature modulated by varying the intensity of the light flux focused on it.
  • a suitable light-absorbing compound such as a dye or stain, selected because of its ability to absorb light at the wavelength emitted by the laser source.
  • a suitable light-absorbing compound such as a dye or stain
  • the same concept can be applied at any wavelength and one must only choose an appropriate dye or stain and optical wavelength.
  • One such reference is Green, The Sigma-Aldrich Handbook of Stains, Dyes and Indicators, Aldrich Chemical Company, Inc. Milwaukee, Wisconsin (1991).
  • copper phthalocyanine (Pigment Blue 15; CPC) absorbs at about 800 nm; copper phthalocyanine tetrasulfonic acid (Acid Blue 249) absorbs at about 610 nm; and Indocyanine Green absorbs at about 775 nm; and Cryptocyanine absorbs at about 703 nm.
  • CPC copper phthalocyanine
  • Acid Blue 249 copper phthalocyanine tetrasulfonic acid
  • Indocyanine Green absorbs at about 775 nm
  • Cryptocyanine absorbs at about 703 nm.
  • CPC is particularly well suited for this embodiment for the following reasons: it is a very stable and inert compound, already approved by the FDA for use as a dye in implantable sutures; it absorbs very strongly at wavelengths from 750 nm to 950 nm, which coincide well with numerous low cost, solid state emitters such as laser diodes and LEDs, and in addition, this area of optical bandwidth is similarly not absorbed directly by the skin tissues in any significant amount; CPC has a very high vaporization point (>550C in a vacuum) and goes directly from a solid phase to a vapor phase with no liquid phase; CPC has a relatively low thermal diffusivity constant, allowing the light energy focused on it to selectively heat only that area directly in the focal point with very little lateral spreading of the 'hot-spot' into the surrounding CPC thereby assisting in the spatial definition of the contact heat-probe.
  • pu ⁇ ose of this disclosure is not to make an exhaustive listing of suitable dyes or stains because such may be easily ascertained by one skilled in the art from data readily available.
  • this method may be implemented with a mechanically shuttered, focused incandescent lamp as the pulse light source.
  • Various catalogs and sales literature show numerouslasers operating in the near UV, visible and near IR range. Representative lasers are Hammamatsu Photonic Systems Model PLP-02 which operates at a power output of 2xl0 '8 J, at a wavelength of 415 nm;
  • Hammamatsu Photonic Systems Model PLP-05 which operates at a power output of 15 J, at a wavelength of 685 nm
  • SDL, Inc. SDL-3250 Series pulsed laser which operates at a power output of 2x10 6 J at a wavelength of about 800-810 nm
  • SDL, Inc. Model SDL-8630 which operates at a power output of 500 mW at a wavelength of about 670 nm
  • Uniphase Laser Model AR-081-15000 which operates at a power output of 15,000 W at a wavelength of
  • a pulsed laser light source can emit radiation over a wide range of wavelengths ranging from between about 100 nm to 12,000 nm.
  • Excimer lasers typically will emit over a range of between about 100 to 400 nm.
  • Commercial excimer lasers are currently available with wavelengths in the range of about 193 nm to 350 nm.
  • a laser diode will have an emission range of between about 380 to 1550 nm.
  • a frequency doubled laser diode will have an emission range of between about 190 and 775 nm.
  • Longer wavelengths ranging from between about 1300 and 3000 nm may be utilized using a laser diode pumped optical parametric oscillator. It is expected, given the amount of research taking place on laser technology, that these ranges will expand with time.
  • Delivered or absorbed energy need not be obtained from a laser as any source of light, whether it is from a laser, a short arc lamp such as a xenon flashlamp, an incandescent lamp, a light-emitting diode (LED), the sun, or any other source may be used.
  • a short arc lamp such as a xenon flashlamp, an incandescent lamp, a light-emitting diode (LED), the sun, or any other source
  • the particular instrument used for delivering electromagnetic radiation is less important than the wavelength and energy associated therewith.
  • Any suitable instrument capable of delivering the necessary energy at suitable wavelengths, i.e. in the range of about 100 nm to about 12,000 nm, can be considered within the scope of the invention.
  • the essential feature is that the energy must be absorbed by the light-absorbing compound to cause localized heating thereof, followed by conduction of sufficient heat to the tissue to be ablated within the timeframe allowed.
  • the heat probe itself is formed from a thin layer, preferably about 5 to 1000 ⁇ m thick, of a solid, non-biologically active compound, applied topically to a selected area of an individual's skin that is large enough to cover the site where a micropore is to be created.
  • the specific formulation of the chemical compound is chosen such that it exhibits high abso ⁇ tion over the spectral range of a light source selected for providing energy to the light-absorbing compound.
  • the probe can be, for example, a sheet of a solid compound, a film treated with a high melting point absorbing compound, or a direct application of the light-absorbing compound to the skin as a precipitate or as a suspension in a carrier.
  • the light-absorbing heat probe Regardless of the configuration of the light-absorbing heat probe, it must exhibit a low enough lateral thermal diffusion coefficient such that any local elevations of temperature will remain spatially defined and the dominant mode of heat loss will be via direct conduction into the stratum comeum through the point of contact between the skin and the probe.
  • the required temperature modulation of the probe can be achieved by focusing a light source onto the light-absorbing compound and modulating the intensity of this light source. If the energy absorbed within the illuminated area is sufficiently high, it will cause the light absorbing compound to rapidly heat up.
  • the amount of energy delivered, and subsequently both the rate of heating and peak temperature of the light-absorbing compound at the focal point, can be easily modulated by varying the pulse width and peak power of the light source. In this embodiment, it is only the small volume of light-absorbing compound heated up by the focused, incident optical energy that forms the heat probe, additional light absorbing compound which may have been applied over a larger area then the actual poration site is incidental.
  • this embodiment comprises choosing a light source with an emission spectmm where very little energy would normally be absorbed in the skin tissues.
  • the energy density of light at the focal waist and the amount of abso ⁇ tion taking place within the light-absorbing compound are set to be sufficient to bring the temperature of the light-absorbing compound, within the area of the small spot defined by the focus of the light source, to greater than 123°C within a few milliseconds.
  • conduction into the stratum comeum delivers energy into these tissues, elevating the local temperature of the stratum co eum.
  • a flash vaporization of this water takes place, ablating the stratum comeum at this point.
  • the temperature of the heat probe can be rapidly modulated and the selective ablation of these tissues can be achieved, allowing a very precisely dimensioned hole to be created, which selectively penetrates only through the first 10 to 30 ⁇ m of skin.
  • An additional feature of this embodiment is that by choosing a light source that would normally have very little energy absorbed by the skin or underlying tissues, and by designing the focusing and delivery optics to have a sufficiently high numerical aperture, the small amount of delivered light that does not happen to get absorbed in the heat probe itself, quickly diverges as it penetrates deep into the body. Since there is very little abso ⁇ tion at the delivered wavelengths, essentially no energy is delivered to the skin directly from the light source. This three dimensional dilution of coupled energy in the tissues due to beam divergence and the low level of abso ⁇ tion in the untreated tissue results in a completely benign interaction between the light beam and the tissues, with no damage being done thereby.
  • a laser diode is used as the light source with an emission wavelength of 800 ⁇ 30 nm.
  • a heat-probe can be formed by topical application of a transparent adhesive tape that has been treated on the adhesive side with a 0.5 cm spot formed from a deposit of finely ground copper phthalocyanine (CPC).
  • CPC finely ground copper phthalocyanine
  • the CPC exhibits extremely high abso ⁇ tion coefficients in the 800 nm spectral range, typically absorbing more than 95% of the radiant energy from a laser diode.
  • FIG. 1 shows a system 10 for delivering light from such a laser diode to a selected area of an individual's skin and for monitoring the progress of the poration process.
  • the system comprises a laser diode 14 coupled to a controller 18, which controls the intensity, duration, and spacing of the light pulses.
  • the laser diode emits a beam 22 that is directed to a collection lens or lenses 26, which focuses the beam onto a mirror 30.
  • the beam is then reflected by the mirror to an objective lens or lenses 34, which focuses the beam at a preselected point 38.
  • This preselected point corresponds with the plane of an xyz stage 42 and the objective hole 46 thereof, such that a selected area of an individual's skin can be irradiated.
  • the xyz stage is connected to the controller such that the position of the xyz stage can be controlled.
  • the system also comprises a monitoring system comprising a CCD camera 50 coupled to a monitor 54 The CCD camera is confocally aligned with the objective lens such that the progress of the poration process can be monitored visually on the monitor.
  • FIG. 2 shows a sensor system 60 for use in this embodiment.
  • the system comprises a light source 64 for emitting a beam of light 68, which is directed through a delivery optics system 72 that focuses the beam at a preselected point 76, such as the surface of an individual's skin 80. A portion of the light contacting the skin is reflected, and other light is emitted from the irradiated area.
  • a portion of this reflected and emitted light passes through a filter 84 and then through a collection optics system 88, which focuses the light on a phototodiode 92.
  • a controller 96 is coupled to both the laser diode and the photodiode for, respectively, controlling the output of the laser diode and detecting the light that reaches the photodiode. Only selected portions of the spectrum emitted from the skin pass through the filter. By analyzing the shifts in the reflected and emitted light from the targeted area, the system has the ability to detect when the stratum comeum has been breached, and this feedback is then used to control the light source, deactivating the pulses of light when the microporation of the stratum co eum is achieved.
  • FIG. 3A shows an illustrative schematic representation thereof.
  • a light source 104 (coupled to a controller 106) emits a beam of light 108, which passes through and is focused by a delivery optics system 112. The beam is focused by the delivery optics system to a preselected point 116, such as a selected area of an individual's skin 120.
  • a cooling device 124 such as a Peltier device or other means of chilling, contacts the skin to cool the surface thereof.
  • the cooling device 124 FIG. 3B
  • a heat sink 132 is also preferably placed in contact with the cooling device.
  • pre-cooling allows a greater safety margin for the system to operate in that the potential sensations to the user and the possibility of any collateral damage to the epidermis directly below the poration site are reduced significantly from non-cooled embodiment.
  • pre-cooling minimizes evaporation of interstitial fluid and can also provide advantageous physical properties, such as decreased surface tension of such interstitial fluid.
  • cooling the tissue is known to cause a localized increase in blood flow in such cooled tissue, thus promoting diffusion of analytes from the blood into the interstitial fluid.
  • the method can also be applied for other micro-surgery techniques wherein the light- absorbing compound/heat-probe is applied to the area to be ablated and then the light source is used to selectively modulate the temperature of the probe at the selected target site, affecting the tissues via the vaporization-ablation process produced.
  • a further feature of the invention is to use the light source to help seal the micropore after its usefulness has passed. Specifically, in the case of monitoring for an intemal analyte, a micropore is created and some amount of interstitial fluid is extracted through this opening. After a sufficient amount of interstitial fluid had been collected, the light source is reactivated at a reduced power level to facilitate rapid clotting or coagulation of the interstitial fluid within the micropore.
  • the use of the light source itself for both the formation of the micropore and the sealing thereof is an inherently sterile procedure, with no physical penetration into the body by any device or apparatus.
  • thermal shock induced by the light energy kills any microbes that may happen to be present at the ablation site.
  • optical sterilization can be extended to include an additional step in the process wherein the light source is first applied in an unfocused manner, covering the target area with an illuminated area that extends 100 ⁇ m or more beyond the actual size of the micropore to be produced.
  • the flux density can be correspondingly reduced to a level well below the ablation threshold but high enough to effectively sterilize the surface of the skin.
  • the system is then configured into the sha ⁇ ly focused ablation mode and the optical microporation process begins.
  • Another illustrative embodiment of the invention is to create the required heat probe from a metallic solid, such as a small diameter wire.
  • the contacting surface of the heat probe must be able to have its temperature modulated from ambient skin temperatures (33°C) to temperatures greater than 123°C, within the required time allowed of, preferably, between about 1 to 50 ms at the high temperature (on-time) and at least about 10 to 50 ms at the low temperature (off-time).
  • ambient skin temperatures 33°C
  • temperatures greater than 123°C within the required time allowed of, preferably, between about 1 to 50 ms at the high temperature (on-time) and at least about 10 to 50 ms at the low temperature (off-time).
  • being able to modulate the temperature up to greater than 150°C for an "on" time of around 5 ms and an off time of 50 ms produces very effective thermal ablation with little or no sensation to the individual.
  • FIG. 4 shows an ohmic heating device 140 with a mechanical actuator.
  • the ohmic heating device comprises an ohmic heat source 144 coupled to a wire heat probe 148.
  • the ohmic heat source is also coupled through an insulating mount 152 to a mechanical modulation device 156, such as a solenoid.
  • a steady state condition can be reached wherein the tip of the wire probe will stabilize at some equilibrium temperature defined by the physical parameters of the stmcture, i.e., the temperature of the ohmic heat source, the length and diameter of the wire, the temperature of the air surrounding the wire, and the material of which the wire is comprised.
  • the modulation of the temperature of the selected area of an individual's skin 160 is effected directly via the mechanical modulation device to altematively place the hot tip of the wire in contact with the skin for, preferably, a 5 ms on-time and then withdraw it into the air for, preferably, a 50 ms off-time.
  • FIG. 5 shows a device 170 comprising a current source 174 coupled to a controller 178.
  • the current source is coupled to a current loop 182 comprising a wire 186 formed into a stmcture such that it presents a high resistance point.
  • the wire is held on a mount 190, and an insulator 194 separates different parts of the current loop.
  • the desired modulation of temperature is then achieved by merely modulating the current through the wire. If the thermal mass of the wire element is appropriately sized and the heat sinking provided by the electrodes connecting it to the current source is sufficient, the warm-up and cool-down times of the wire element can be achieved in a few milliseconds. Contacting the wire with a selected area of skin 198 heats the stratum comeum to achieve the selected ablation.
  • FIG. 6 there is shown still another illustrative example of porating the stratum comeum with a hot wire.
  • the wire 204 can be positioned within a modulatable alternating magnetic field formed by a coil of wire 208, the excitation coil.
  • a controller 212 coupled thereto, eddy currents can be induced in the wire heat probe of sufficient intensity that it will be heated up directly via the intemal ohmic losses.
  • This is essentially a miniature version of an inductive heating system commonly used for heat treating the tips of tools or inducing out- gassing from the electrodes in vacuum or flash tubes.
  • the advantage of the inductive heating method is that the energy delivered into the wire heat probe can be closely controlled and modulated easily via the electronic control of the excitation coil. If the thermal mass of the wire probe itself, and the thermal mass of the stratum comeum in contact with the tip of the probe are known, controlling the inductive energy delivered can produce very precise control of the temperature at the contact point 216 with the skin 220. Because the skin tissue is essentially non-magnetic at the lower frequencies at which inductive heating can be achieved, if appropriately selected frequencies are used in the excitation coil, then this alternating electromagnetic field will have no effect on the skin tissues.
  • an additional feature may be realized by inco ⁇ orating a simple closed loop control system wherein the electrical impedance between the probe tip and the subject's skin is monitored. In this manner, the position of the probe can be brought into contact with the subject's skin, indicated by the step- wise reduction in resistance once contact is made, and then held there for the desired "on- time,” after which it can be withdrawn.
  • a simple closed loop control system wherein the electrical impedance between the probe tip and the subject's skin is monitored. In this manner, the position of the probe can be brought into contact with the subject's skin, indicated by the step- wise reduction in resistance once contact is made, and then held there for the desired "on- time,” after which it can be withdrawn.
  • linear actuators are suitable for this form of closed loop control, such as a voice-coil mechanism, a simple solenoid, a rotary system with a cam or bell-crank, and the like.
  • FIG. 7 shows an illustrative example of such a closed loop impedance monitor.
  • this system 230 there is an ohmic heat source 234 coupled to a wire heat probe 238.
  • the heat source is mounted through an insulating mount 242 on a mechanical modulator 246.
  • a controller 250 is coupled to the wire and to the skin 254, wherein the controller detects changes in impedance in the selected area 258 of skin, and when a predetermined level is obtained the controller stops the poration process.
  • hydraulic poration means are icrolancets adapted to just penetrate the stratum comeum for pu ⁇ oses of administering a permeant, such as a dmg, through the pore formed or to withdraw an analyte through the pore for analysis.
  • a permeant such as a dmg
  • Such a device is considered to be "minimally invasive” as compared to devices and/or techniques which are non-invasive.
  • micro-lancets that penetrate below the stratum comeum for withdrawing blood are well known.
  • Such devices are commercially available from manufacturers such as Becton-Dickinson and Lifescan and can be utilized in the present invention by controlling the depth of penetration.
  • micro-lancet device for collecting body fluids
  • This application shows a device for penetration into the dermal layer of the skin, without penetration into subcutaneous tissues, to collect body fluids for monitoring, such as for blood glucose levels.
  • Poration of stratum comeum can also be accomplished using sonic means.
  • Sonic- poration is a variation of the optical means described above except that, instead of using a light source, a very tightly focused beam of sonic energy is delivered to the area of the stratum comeum to be ablated. The same levels of energy are required, i.e.
  • electroporation or short bursts or pulses of electrical current can be delivered to the stratum comeum with sufficient energy to form micropores.
  • Electroporation is known in the art for producing pores in biological membranes and electroporation instmments are commercially available. Thus, a person of skill in this art can select an instrument and conditions for use thereof without undue experimentation according to the guidelines provided herein.
  • the micropores produced in the stratum comeum by the methods of the present invention allow high flux rates of large molecular weight therapeutic compounds to be delivered transdermally.
  • these non-traumatic microscopic openings into the body allow access to various analytes within the body, which can be assayed to determine their intemal concentrations.
  • skin samples were prepared as follows. Epidermal membrane was separated from human cadaver whole skin by the heat-separation method of Klingman and Christopher, 88 Arch. Dermatol. 702 (1963), involving the exposure of the full thickness skin to a temperature of 60°C for 60 seconds, after which time the stratum comeum and part of the epidermis (epidermal membrane) were gently peeled from the dermis.
  • Example 2 Heat separated stratum comeum samples prepared according to the procedure of Example 1 were cut into 1 cm 2 sections. These small samples were than attached to a glass cover slide by placing them on the slide and applying an pressure sensitive adhesive backed disk with a 6 mm hole in the center over the skin sample. The samples were then ready for experimental testing. In some instances the skin samples were hydrated by allowing them to soak for several hours in a neutral buffered phosphate solution or pure water.
  • the delivery optics were designed to produce a focal waist 25 ⁇ m across with a final objective have a numerical aperture of 0.4.
  • the total power delivered to the focal point was measured to be between 50 and 200 milliwatts for the 810 and 1480 nm laser diodes, which were capable of operating in a continuous wave (CW) fashion.
  • the 905 and 1550 nm laser diodes were designed to produce high peak power pulses roughly 10 to 200 nanoseconds long at repetition rates up to 5000 Hz.
  • the peak power levels were measured to be 45 watts at 905 nm and 3.5 watts at 1550 nm. Under these operating conditions, there was no apparent effect on the skin samples from any of the lasers.
  • the targeted area was illuminated continuously for 60 seconds and then examined microscopically, revealing no visible effects.
  • the sample was placed in a modified Franz cell, typically used to test transdermal delivery systems based on chemical permeation enhancers, and the conductivity from one side of the membrane to the other was measured both before and after the irradiation by the laser and showed no change.
  • Example 2 To evaluate the potential sensation to a living subject when illuminated with optical energy under the conditions of Example 2, six volunteers were used and the output of each laser source was applied to their fingertips, forearms, and the backs of their hands. In the cases of the 810, 905 and 1550 nm lasers, the subject was unable to sense when the laser was turned on or off. In the case of the 1480 nm laser, there was a some sensation during the illumination by the 1480 nm laser operating at 70 mW CW, and a short while later a tiny blister was formed under the skin due to the abso ⁇ tion of the 1480 nm radiation by one of the water abso ⁇ tion bands.
  • the amount of energy absorbed was sufficient to induce the formation of the blister, but was not enough to cause the ablative removal of the stratum comeum. Also, the abso ⁇ tion of the 1480 nm light occurred predominantly in the deeper, fully hydrated (85% to 90% water content) tissues of the epidermis and dermis, not the relatively dry (10% to 15% water content) tissue of the stratum comeum.
  • Example 4 Having demonstrated the lack of effect on the skin in its natural state (Example 3), a series of chemical compounds was evaluated for effectiveness in absorbing the light energy and then transferring this absorbed energy, via conduction, into the targeted tissue of the stratum comeum.
  • Compounds tested included India ink; "SHARPIE” brand indelible black, blue, and red marking pens; methylene blue; fuschian red; epolite #67, an absorbing compound developed for molding into polycarbonate lenses for protected laser goggles; tincture of iodine; iodine-polyvinylpyrrolidone complex ("BETADINE"); copper phthalocyanine; and printers ink.
  • BETADINE tincture of iodine
  • Example 1 when using all of these products, however some performed better than others.
  • the copper phthalocyanine (CPC) and the epolite #67 were some of the most effective.
  • One probable reason for the superior performance of the CPC is its high boiling point of greater the 500°C and the fact that it maintains its solid phase up to this temperature.
  • Example 5 As copper phthalocyanine has already been approved by the FDA for use in implantable sutures, and is listed in the Merck index as a rather benign and stabile molecule in regard to human biocompatability, the next step taken was to combine the topical application of the CPC and the focused light source to the skin of healthy human volunteers.
  • a suspension of finely ground CPC in isopropyl alcohol was prepared.
  • the method of application used was to shake the solution and then apply a small drop at the target site. As the alcohol evaporated, a fine and uniform coating of the solid phase CPC was then left on the surface of the skin.
  • the apparatus show in FIG. 1 was then applied to the site, wherein the CPC had been topically coated onto the skin, by placing the selected area of the individual's skin against a reference plate.
  • the reference plate consists of a thin glass window roughly 3 cm X 3 cm, with a 4 mm hole in the center.
  • the CPC covered area was then positioned such that it was within the central hole.
  • a confocal video microscope (FIG. 1) was then used to bring the surface of the skin into sha ⁇ focus.
  • Positioning the skin to achieve the sha ⁇ est focus on the video system also positioned it such that the focal point of the laser system was coincident with the surface of the skin. The operator then activated the pulses of laser light while watching the effects at the target site on the video monitor.
  • the amount of penetration was estimated visually by the operator by gauging the amount of defocusing of the laser spot in the micropore as the depth of the micropore increased, and this can be dynamically corrected by the operator, essentially following the ablated surface down into the tissues by moving the position of the camera/laser source along the "z" axis, into the skin.
  • the appearance of the base of the hole changed noticeably, becoming much wetter and shinier.
  • the operator deactivated the laser.
  • a dramatic outflow of interstitial fluid occurred in response to the barrier function of the stratum comeum being removed over this small area.
  • the video system was used to record this visual record of the accessibility of interstitial fluid at the poration site.
  • Example 6 The procedure of Example 5 was followed except that the CPC was applied to a transparent adhesive tape, which was then caused to adhere to a selected site on the skin of an individual. The results were substantially similar to those of Example 5.
  • the top surface of the skin sample was treated with a solution of copper phthalocyanine (CPC) in alcohol. After the alcohol evaporated, a topical layer of solid phase CPC was distributed over the skin surface with a mean thickness of 10 to 20 um.
  • FIG. 8A shows a cross-section of full thickness skin prior to the laser application, wherein the CPC layer 270, stratum comeum 274, and underlying epidermal layers 278 are shown.
  • FIG. 8A shows a cross-section of full thickness skin prior to the laser application, wherein the CPC layer 270, stratum comeum 274, and underlying epidermal layers 278 are shown.
  • 8B shows the sample after a single pulse of 810 nm light was applied to an 80 um diameter circle with an energy density of 4000 J/cm2, for a pulse period of 20 ms. It is noteworthy that there was still a significant amount of CPC present on the surface of the stratum comeum even in the middle of the ablated crater 282. It should also be noted that laboratory measurements indicate that only about 10% of the light energy incident on the CPC is actually absorbed, with the other 90% being reflected or backscattered. Thus the effective energy flux being deliverd to the dye layer which could cause the desired heating is only about 400 J/cm2.
  • 8C shows the sample after 5 pulses of 810 nm light were applied, wherein the stratum comeum barrier was removed with no damage to the underlying tissue.
  • FIG. 8D shows the sample after 50 pulses were applied. Damaged tissue 286 was present in the epidermal layers due to carbonization of non ablated tissue and thermal denaturing of the underlying tissue.
  • FIGS. 8A-8C show separations between the stratum comeum and the underlying epidermal layers due to an artifact pf dehydration, freezing, and preparations for imaging.
  • Example 8 To examine the details of the thermal ablation mechanism, a mathematical model of the skin tissues was constructed upon which various different embodiments of the thermal ablation method could be tried. This model computes the temperature distribution in a layered semi-infinite medium with a specified heat flux input locally on the surface and heat removal from the surface some distance away, i.e. convection is applied between the two. The axisymmetric, time-dependent diffusion equation is solved in cylindrical coordinates using the alternating-direction-implicit (ADI) method. (Note: Constant Temp. B.C. is applied on lower boundary to serve as z->inf; and zero radial heat flux is applied on max radial boundary to serve as r->inf).
  • ADI alternating-direction-implicit
  • the layers are parallel to the surface and are defined as: (1) dye; (2) stratum comeum; (3) underlying epidermis; and (4) dermis.
  • the depth into the semi-infinite medium and thermal properties, density (rho), specific heat (c), and conductivity (k) must be specified for each layer.
  • rho density
  • c specific heat
  • k conductivity
  • Each embodiment of the method described herein, for which empirical data have been collected, has been modeled for at least one set of operational parameters, showing how stratum comeum ablation can be achieved in a precise and controllable fashion.
  • the output of the simulations is presented graphically in two different formats: (1) a cross-sectional view of the skin showing the different tissue layers with three isotherms plotted on top of this view which define three critical temperature thresholds, and (2) two different temperature -vs- time plots, one for the point in the middle of the stratum comeum directly beneath the target site, and the second for the point at the boundary of the viable cell layers of the epidermis and the underside of the stratum comeum.
  • the model provides a good approximation of the thermal gradients present in the actual tissues.
  • the dimensions used in this, and all subsequent simulations, for the thicknesses of the CPC dye layer and the various skin layers are as follows: dye, 10 ⁇ m; stratum comeum, 30 ⁇ m; underlying epidermis, 70 ⁇ m; and dermis, 100 ⁇ m.
  • stratum co eum may be shown as having a temperature already exceeded the ablation threshold for thermal vaporization of the water content, this event is not modeled, and the subsequent loss of heat energy in the tissues due to this vaporization is not factored into the simulation. This will cause a slight elevation in the temperatures shown in the underlying tissues from that point on in the simulation mn.
  • the basic information presented by the simulation is that if one keeps the "on-time" of the heat pulse to less than 20 milliseconds with the flux density of 400 Joules/cm 2 , then no damage to the living cells in the underlying epidermis will be sustained, even though the ablation threshold isotherm has been moved well into the stratum comeum.
  • ablation of the stratum comeum can be achieved without any damage to the adjacent cells in the underlying epidermis (see FIG. 8C). This is possible in large part due to the significantly different thermal diffusivities of these two tissues layers. That is, the stratum comeum, containing only about 10% to 20% water content, has a much lower thermal conductivity constant, 0.00123
  • the same simulation scenario started in the damage threshold critical point mn illustrated in FIG. 9 is carried out farther in time.
  • the pain sensory isotherm at 45°C just enters the enervated layer of skin comprised by the dermis.
  • the damage threshold isotherm moves significantly farther into the epidermal layer than where it was shown to be in FIG. 9. Relating this simulation to the numerous clinical studies conducted with this method, an excellent verification of the model's accuracy is obtained in that the model shows almost exactly the duration of 'on-time' that the heat probe can be applied to the skin before the individual feels it.
  • a controllable pulse generator was used to set the "on-time”and “off-time” of a series of light pulses applied to the topical layer of copper phthalocyanine (CPC) dye on the skin. While maintaining a constant "off-time” of 80 milliseconds, the "on-time” was gradually increased until the subject reported a mild "pain” sensation. Without exception, all of the subjects involved in these studies, reported the first "pain” at an "on-time” of between 45 and 60 milliseconds, very close to that predicted by the model. In addition, the site-to-site variability mentioned previously as regards the sensation of "pain” was noted in these clinical studies. Accordingly, what is reported as "pain” is the point at which the first unambiguous sensation is noticeable. At one site this may be reported as pain, whereas at an adjacent site the same subject may report this as merely “noticeable.”
  • Example 9 An object of this invention is to achieve a painless, micro-poration of the stratum comeum without causing any significant damage to the adjacent viable tissues.
  • a boundary appears to exist for any given flux density of thermal energy within the ablation target spot within which the micro ⁇ poration can be achieved in just such a painless and non-traumatic manner.
  • Both the in vivo and in vitro studies have shown that this is the case, and this has permitted development through empirical methods of some operational parameters that appear to work very well. The following set of simulations shows how the method works when these specific parameters are used.
  • FIG. 11 shows the final temperature distribution in the skin tissues immediately after this pulse train has ended.
  • the isotherms representing the three critical temperature thresholds show that stratum comeum ablation has been achieved, with no sensation present in the dermal layer nerves and very little cross-over of the damage threshold into the viable cells of the underlying epidermis.
  • the epidermal cells must not only be heated up to a certain point, but they also must be held at this temperature for some period of time, generally thought to be about five seconds.
  • Example 11 Once the basic thermal conduction mechanism of delivering the energy into the skin tissues underlying the effective painless ablation and micro-poration of the stratum comeum is understood, several different specific methods to achieve the required rapid temperature modulations of the contact point can be conceived, such as the hot wire embodiments illustrated in FIGS. 4-7.
  • the heater When electricity is applied with a constant current source, the heater will come up to some temperature and within a few seconds, achieve a steady state with the convection losses to the surrounding air.
  • the wire which is a part of this thermal system, will reach a steady state such that the very tip of the wire can be raised to almost any arbitrary temperature, up to roughly 1000°C with these types of components.
  • the tip can be sized to give exactly the dimension micropore desired.
  • tungsten wires with a diameter of 80 ⁇ m attached to the replaceable tip of a "WAHL" cordless soldering iron with approximately 2 mm of wire protruding from the tip have been utilized.
  • the temperature of the tip has been measured at its steady state, and it has been noted that by varying the constant current settings, steady state temperatures of greater than 700°C can easily be reached.
  • a low mass, fast response electromechanical actuator was coupled to the tip such that the position of the wire could be translated linearly more than 2 mm at up to a 200 Hz rate.
  • this vibrating tip could very controllably be brought into contact with the skin surface in a manner where it was only in contact for less than 10 milliseconds at a time, the "on-time,” while an “off-time” of arbitratily long periods could be acheived by setting the pulse generator accordingly.
  • the hot wire embodiment can be n with the identical simulation code. Because the contact with the wire occurs essentially instantly, there is no time dependent build-up of heat in the CPC dye layer and when the wire is physically removed from contact with the skin, there is a no residual heat still left on the surface as there is with the heated CPC dye layer. Also, as the wire itself defines the area targeted for ablation/micro-poration, there should be no lateral diffusion of thermal energy prior to its application to the stratum comeum. The comparative performances of the "hot ⁇ wire" embodiment are shown in FIGS. 17-19.
  • Example 12 In this example, the procedure of Example 11 was followed except that the skin was pre-cooled according to the procedure of Example 10. Similarly, pre-cooling the target site yields similarly positive results with the "hot-wire" embodiment. The results of the pre-cooled simulation of the "hot-wire" approach are shown in FIGS. 20-22.
  • Tankovich '803 patent appears at first glance to be similar to the presently claimed invention.
  • the simulation model was set up with the operating parameters specified in Tankovich '803, i.e. a pulse width of 1 ⁇ s and a power level of 40,000,000 W/cm 2 .
  • FIGS. 23 and 24 show that under these conditions no portion of the stratum comeum reaches the threshold for flash vaporization of water, 123°C, and thus no ablation/microporation of the stratum comeum occurs.
  • applying this type of high peak power, short duration pulse to the topical dye layer merely vaporizes the dye off of the surface of the skin with no effect on the skin.
  • This example thus, demonstrates that the conditions specified by Tankovich '803 are inoperative in the presently claimed invention.
  • interstitial fluid obtained after porating the skin according to the procedure of Example 6 was collected and analyzed to determine the glucose concentration thereof.
  • Data were obtained on four non-diabetic subjects and six type I diabetic subjects undergoing a glucose load test. Subject's ages ranged from 27 to 43. The goal of the study was to examine the utility of the method for painlessly harvesting enough interstitial fluid
  • ISF insulin receptor presenting in the subject's whole blood
  • the basic design of the study was to recruit a modest number of volunteers, some with diabetes and some without diabetes, from which a series of sample pairs of ISF and whole blood were drawn every 3 to 5 minutes throughout the 3 to 4 hour duration of the study period. Both the blood and the ISF samples were assayed for glucose and the statistical relationship between the blood glucose levels and the interstitial fluid determined. To examine the hypothesized temporal lag of the ISF glucose levels as compared to the whole blood glucose levels, the study subjects were induced to exhibit a significant and dynamic change in their glucose levels. This was accomplished by having each subject fast for 12 hours prior to beginning the test and then giving the subject a glucose load after his or her baseline glucose levels have been established via a set of three fasting blood and ISF glucose levels.
  • the subjects were given a glucose load in the form of sweet juice based on the following guidelines: i.
  • the glucose load was calculated based on a .75 gram glucose per pound of body weight.
  • the glucose load was calculated based on a .75 gram glucose per pound of body weight.
  • the diabetic subjects will self inject their normal morning dose of fast acting insulin.
  • the diabetic subject presents with fasting glucose levels above 300 mg/dL, they were asked to give themselves their insulin injection first, and the glucose load was provided after their blood glucose levels have dropped to below 120 mg/dL.
  • This attachment allowed a convenient method by which a small suction hose could be connected, applying a mild vacuum (10 to 12 inches of Hg) to the porated area to induce the ISF to flow out of the body through the micropores.
  • a mild vacuum (10 to 12 inches of Hg)
  • the top of the teflon disk was fitted with a clear glass window allowing the operator to directly view the micro-porated skin beneath it.
  • This level of vacuum created a nominal pressure gradient of around 5 pounds/square inch (PSI). Without the micropores, no ISF whatsoever could be drawn from the subject's body using only the mild vacuum.
  • the subject was given a glucose load in the form of highly sweetened orange juice.
  • the amount of glucose given was 0.75 grams per pound of body weight for the nondiabetic subjects and 50 grams for the diabetic subjects.
  • the diabetic subjects also self administered a shot of fast acting insulin, (regular) with the dosage appropriately calculated, based on this 50 gram level of glucose concurrent with the ingestion of the glucose load.
  • the diabetic subjects were expected to exhibit an upwards excursion of their blood glucose levels ranging up to 300 mg/dL and then dropping rapidly back into the normal range as the insulin takes effect.
  • the nondiabetic subjects were expected to exhibit the standard glucose tolerance test profiles, typically showing a peak in blood glucose levels between 150 mg/dL and 220 mg/dL from 45 minutes to 90 minutes after administering the glucose load, and then a rapid drop back to their normal baseline levels over the next hour or so.
  • This scaling of the output of the ELITE glucometer when used to measure ISF glucose levels allows one to examine, over the entire data set, the error terms associated with using ISF to estimate blood glucose levels.
  • the correlations between the ISF glucose values and the blood glucose levels are the same as the scaled version.
  • the graph shown in FIG. 25 presents all ten of the glucose load tests, concatenated one after another on an extended time scale.
  • the blood based measurement already contains an error term.
  • the manufacturer's published performance data indicates that the ELITE system has a nominal Coefficient of Variance (CV) of between 5% and 7%, depending on the glucose levels and the amount of hematocrit in the blood.
  • CV Coefficient of Variance
  • ISF ⁇ [(ISF devialion ) 2 - (Blood actual ) 2 p.
  • a histogram of the relative deviation of the ISF to the blood glucose levels is shown in FIG. 27.
  • the present invention also includes a method for the delivery of dmgs, including dmgs currently delivered transdermally, through micro-pores in the stratum comeum.
  • the delivery is achieved by placing the solution in a reservoir over the poration site.
  • a pressure gradient is used to further enhance the delivery.
  • sonic energy is used with or without a pressure gradient to further enhance the delivery.
  • the sonic energy can be operated according to traditional transdermal parameters or by utilizing acoustic streaming effects, which will be described momentarily, to push the delivery solution through the porated stratum comeum.
  • Example 15 This example shows the use of stratum comeum poration for the delivery of lidocaine, a topical analgesic.
  • the lidocaine solution also contained a chemical permeation enhancer formulation designed to enhance its passive diffusion across the stratum comeum.
  • a drawing of an illustrative delivery apparatus 300 is shown in FIG. 28, wherein the apparatus comprises a housing 304 enclosing a reservoir 308 for holding a dmg-containing solution 312.
  • the top portion of the housing comprises an ultrasonic transducer 316 for providing sonic energy to aid in transporting the dmg-containing solution through micropores 320 in the stratum comeum 324.
  • a port 328 in the ultrasonic transducer permits application of pressure thereto for further aiding in transporting the dmg-containing solution through the micropores in the stratum comeum.
  • the delivery apparatus is applied to a selected area of an individual's skin such that it is positioned over at least one, and preferably a plurality, of micropores.
  • An adhesive layer 332 attached to a lower portion of the housing permits the apparatus to adhere to the skin such that the dmg- containing solution in the reservoir is in liquid communication with the micropores. Delivery of the dmg through the micropores results in transport into the underlying epidermis 336 and dermis 340. Five subjects were tested for the effectiveness of drug delivery using poration together with ultrasound.
  • site 1 The site near the thumb will be referred to as site 1
  • site furthest from the thumb will be referred to as site 2.
  • Site 1 was used as a control where the lidocaine and enhancersolution was applied using an identical delivery apparatus 300, but without any micro-poration of the stratum comeum or sonic energy.
  • Site 2 was porated with 24 holes spaced 0.8 millimeters apart in a grid contained within a 1 cm diameter circle. The micropores in Site 2 were generated according to the procedure of Example 6. Lidocaine and low level ultrasound were applied.
  • Ultrasound applications were made with a custom manufactured Zevex ultrasonic transducer assembly set in burst mode with 0.4 Volts peak to peak input with 1000 count bursts occurring at 10 Hz with a 65.4 kHz fundamental frequency, i.e., a pulse modulated signal with the transducer energized for 15 millisecond bursts, and then turned off for the next 85 milliseconds.
  • the measured output ofthe amplifier to the transducer was 0.090 watts
  • the control site, site 1 presented little to no numbness (scale 7 to 10) at 10 to 12 minutes. At approximately 20 minutes some numbness (scale 3) was observed at site 1 as the solution completely permeated the stratum comeum. Site 1 was cleaned at the completion of the lidocaine application. Site 2 presented nearly complete numbness (scale 0 to 1) in the 1 cm circle containing the porations. Outside the 1 cm diameter circle the numbness fell off almost linearly to 1 at a 2.5 cm diameter circle with no numbness outside the 2.5 cm diameter circle.
  • FIGS. 29A-C A graphic representation of illustrative results obtained on a typical subject is shown in FIGS. 29A-C.
  • FIGS. 29A and 29B show the results obtained at Site 2 (porated) after 5 and 10 minutes, respectively.
  • FIG. 29C shows the results obtained at Site 1 (control with no poration).
  • the physics of sonic energy fields created by sonic transducers can be utilized in a method by which sonic frequency can be modulated to improve on flux rates achieved by other methods.
  • the energy distribution of an sonic transducer can be divided into near and far fields.
  • the near field characterized by length N, is the zone from the first energy minimum to the last energy maximum.
  • the zone distal to the last maximum is the far field.
  • the near (N) field patte is dominated by a large number of closely spaced local pressure peaks and nulls.
  • the length of the near field zone, N is a function of the frequency, size, and shape of the transducer face, and the speed of sound in the medium through which the ultrasound travels.
  • intensity variations within its normal operating range do not affect the nature of the sonic energy distribution other than in a linear fashion.
  • the relative intensities of separate transducers do affect the energy distribution in the sonic medium, regardless of whether it is skin or another medium.
  • a frequency modulation from high to low drives the pressure peaks into the body, whereas a frequency modulation from low to high pulls the pressure peaks from within the body toward the surface and through the skin to the outside of the body.
  • a frequency modulation of 1 MHz produces a movement of about 2.5 mm ofthe peaks and nulls of the near field energy patte in the vicinity ofthe stratum comeum.
  • this degree of action provides access to the area well below the stratum comeum and even the epidermis, dermis, and other tissues beneath it.
  • the flux of a dmg or analyte across the skin can also be increased by changing either the resistance (the diffusion coefficient) or the driving force (the gradient for diffusion). Flux can be enhanced by the use of so-called penetration or chemical enhancers.
  • Chemical enhancers are comprised of two primary categories of components, i.e., cell- envelope disordering compounds and solvents or binary systems containing both cell-envelope disordering compounds and solvents.
  • Cell envelope disordering compounds are known in the art as being useful in topical pharmaceutical preparations and function also in analyte withdrawal through the skin. These compounds are thought to assist in skin penetration by disordering the lipid stmcture ofthe stratum comeum cell-envelopes. A comprehensive list of these compounds is described in European Patent Application 43,738, published June 13, 1982, which is inco ⁇ orated herein by reference. It is believed that any cell envelope disordering compound is useful for pu ⁇ oses of this invention.
  • Suitable solvents include water; diols, such as propylene glycol and glycerol; mono- alcohols, such as ethanol, propanol, and higher alcohols; DMSO; dimethylformamide; N,N- dimethylacetamide; 2-pyrrolidone; N-(2-hydroxyethyl) pyrroiidone, N-methylpyrrolidone, 1- dodecylazacycloheptan-2-oneand other n-substituted-a!kyl-azacycloalkyl-2-ones(azones) and the like.
  • a dual enhancer consisting of glycerol monolaurate and ethanol for the transdermal delivery of dmgs is shown in U.S. Patent 4,820,720.
  • U.S. Patent 5,006,342 lists numerous enhancers for transdermal drug administration consisting of fatty acid esters or fatty alcohol ethers of C 2 to C 4 alkanediols, where each fatty acid/alcohol portion of the ester/ether is of about 8 to 22 carbon atoms.
  • Patent 4,863,970 shows penetration-enhancing compositions for topical application comprising an active permeant contained in a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C 2 or C 3 alkanol and an inert diluent such as water.
  • cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid
  • C 2 or C 3 alkanol such as water.
  • Other chemical enhancers, not necessarily associated with binary systems include DMSO or aqueous solutions of DMSO such as taught in Herschler, U.S. Patent 3,551,554; Herschler, U.S. Patent 3,711,602; and Herschler, U.S. Patent 3,711,606, and the azones (n-substituted-alkyl- azacyclo
  • U.S. Patent 4,855,298 discloses compositions for reducing skin irritation caused by chemical enhancer containing compositions having skin irritation properties with an amount of glycerin sufficient to provide an anti-irritating effect.
  • the specific carrier vehicle and particularly the chemical enhancer utilized can be selected from a long list of prior art vehicles some of which are mentioned above and inco ⁇ orated herein by reference. To specifically detail or enumerate that which is readily available in the art is not thought necessary.
  • the invention is not drawn to the use of chemical enhancers per se and it is believed that all chemical enhancers, useful in the delivery of drugs through the skin, will function with dyes in optical microporation and also with sonic energy in effecting measurable withdrawal of analytes from beneath and through the skin surface or the delivery of permeants or dmgs through the skin surface.
  • Modulated sonic energy and chemical enhancers were tested for their ability to control transdermal flux on human cadaver skin samples.
  • the epidermal membrane had been separated from the human cadaver whole skin by the heat-separation method of Example 1.
  • the epidermal membrane was cut and placed between two halves of the permeation cell with the stratum comeum facing either the upper (donor) compartment or lower (receiver) compartment.
  • Modified Franz cells were used to hold the epidermis, as shown in FIG. 2 of U.S. Patent No. 5,445,611.
  • Each Franz cell consists of an upper chamber and a lower chamber held together with one or more clamps.
  • the lower chamber has a sampling port through which materials can be added or removed.
  • a sample of stratum comeum is held between the upper and lower chambers when they are clamped together.
  • the upper chamber of each Franz cell is modified to allow an ultrasound transducer to be positioned within 1 cm ofthe stratum comeum membrane.
  • Methylene blue solution was used as an indicator molecule to assess the permeation ofthe stratum co eum.
  • a visual record of the process and results of each experiment was obtained in a time stamped magnetic tape format with a video camera and video cassette recorder (not shown).
  • the system for producing and controlling the sonic energy included a programmable 0-30 MHz arbitrary waveform generator (Stanford Reserach Systems Model DS345), a 20 watt 0-30 MHz amplifier, and two unfocused ultrasound immersion transducers having peak resonances at 15 and
  • Example 16 the heat-separated epidermis was placed in the Franz cells with the epidermal side facing up, and the stratum comeum side facing down, unless noted otherwise.
  • the lower chambers were filled with distilled water, whereas the upper chambers were filled with concentrated methylene blue solution in distilled water.
  • Heat Separated Epidermis Immediately after filling the upper chambers with methylene blue solution, sonic energy was applied to one of the cells with the transducer fully immersed. This orientation would correspond, for example, to having the transducer on the opposite side of a fold of skin, or causing the sonic energy to be reflected off a reflector plate similarly positioned and being used to "push" analyte out of the other side of the fold into a collection device.
  • the sonic energy setting was initially set at the nominal operating frequency of 25 MHz with an intensity equivalent to a 20 volt peak-to-peak (P-P) input wave form.
  • the frequency was set to modulate or sweep from 30 MHz to 10 MHz. This 20 MHz sweep was performed ten times per second, i.e., a sweep rate of 10 Hz.
  • a contact thermocouple was applied to the body ofthe transducer and power was cycled on and off to maintain maximum temperature of the transducer under 42°C. After about 30 minutes of cycling maximum power at about a 50% duty cycle of 1 minute on and 1 minute off, there was still no visually detectable permeation of the stratum comeum by the methylene blue dye.
  • Perforated Stratum Comeum Six cells were prepared as described above in Example 16. The clamps holding the upper and lower chambers of the Franz cells were tightened greater than the extent required to normally seal the upper compartment from the lower compartment, and to the extent to artificially introduce perforations and "pinholes" into the heat-separated epidermal samples. When dye solution was added to the upper chamber of each cell, there were immediate visual indications of leakage of dye into the lower chambers through the perforations formed in the stratum comeum. Upon application of sonic energy to cells in which the stratum comeum was so perforated with small "pinholes," a rapid increase in the transport of fluid through a pinhole in the stratum comeum was observed.
  • the rate of transport of the indicator dye molecules was directly related to whether the sonic energy was applied or not. That is, application of the sonic energy caused an immediate (lag time approximately ⁇ 0.1 second) pulse ofthe indicator molecules through the pinholes in the stratum comeum. This pulse of indicator molecules ceased immediately upon turning off of the sonic energy (a shutoff lag of approximately ⁇ 0.1 second). The pulse could be repeated as described.
  • Chemical Enhancer One or CE1 was an admixture of ethanol/glycerol/water/glycerol monooleate/methyl laurate in a 50/30/15/2.5/2.5 volume ratio. These are components generally regarded as safe, i.e. GRAS, by the FDA for use as pharmaceutical excipients.
  • Chemical Enhancer Two or CE2 is an experimental formulation shown to be very effective in enhancing transdermal dmg delivery, but generally considered too irritating for long term transdermal delivery applications.
  • CE2 contained ethanol/glycerol/water/lauradone/methyllaurate in the volume ratios 50/30/15/2.5/2.5.
  • Lauradone is the lauryl (dodecyl) ester of 2-pyrrolidone-5- carboxylic acid (“PCA”) and is also referred to as lauryl PCA.
  • Example 16 Six Franz cells were set up as before (Example 16) except that the heat separated epidermis was installed with the epidermal layer down, i.e., stratum co eum side facing up. Hydration was established by exposing each sample to distilled water ovemight. To begin the experiment, the distilled water in the lower chambers was replaced with methylene blue dye solution in all six cells. The upper chambers were filled with distilled water and the cells were observed for about 30 minutes confirming no passage of dye to ensure that no pinhole perforations were present in any ofthe cells. When none were found, the distilled water in the upper chambers was removed from four of the cells. The other two cells served as distilled water controls. The upper chambers of two of the experimental cells were then filled with CE1 and the other two experimental cells were filled with CE2.
  • Sonic energy was immediately applied to one of the two CE2 cells.
  • dye flux was visually detected. No dye flux was detected in the other five cells.
  • Sonic energy was then applied to one of the two cells containing CE1 at the same settings. Dye began to appear in the upper chamber within 5 minutes. Thus, sonic energy together with a chemical enhancer significantly increased the transdermal flux rate of a marker dye through the stratum comeum, as well as reduced the lag time.
  • Formulations of the two chemical enhancers, CE1 and CE2 were prepared minus the glycerin and these new formulations, designated CE1MG and CE2MG, were tested as before.
  • the cells were then drained of all fluids and flushed with distilled water on both sides of the stratum comeum.
  • the lower chambers were then immediately filled with distilled water and the upper chambers were refilled with dye solution.
  • the cells were observed for 30 minutes. No holes in the stratum comeum samples were observed and no large amount of dye was detected in the lower chambers. A small amount of dye became visible in the lower chambers, probably due to the dye and enhancer trapped in the skin samples from their previous exposures. After an additional 12 hours, the amount of dye detected was still very small.
  • Perforated Stratum Co eum Three cells were prepared with heat-separated epidermis samples with the epidermal side facing toward the upper side of the chamber from the same donor as in Example 16. The samples were hydrated for 8 hours and then the distilled water in the lower chambers was replaced with either CE1MG or CE2MG. The upper chambers were then filled with dye solution. Pinhole perforations in the stratum comeum samples permitted dye to leak through the stratum comeum samples into the underlying enhancer containing chambers. Sonic energy was applied. Immediately upon application of the sonic energy, the dye molecules were rapidly pushed through the pores. As shown above, the rapid flux of the dye through the pores was directly and immediately correlated with the application of the sonic energy.
  • Example 22 Effects of Sonic Energy and Chemical Enhancers
  • TDK #NB-58S-01 (TDK Co ⁇ .) was tested for its capability to enhance transdermal flux rates.
  • the peak response of this transducer was determined to be about 5.4 MHz with other local peaks occurring at about 7 MHz, 9 MHz, 12.4 MHz, and 16 MHz.
  • This TDK transducer was then tested at 5.4 MHz for its ability to enhance transdermal flux rate in conjunction with CE1MG.
  • Three cells were set up with the epidermal side facing the lower chamber, then the skin samples were hydrated for 8 hrs. The dye solution was placed in the lower chamber.
  • the transducer was placed in the upper chamber immersed in CE IMG. Using swept frequencies from 5.3 to 5.6 MHz as the sonic energy excitation, significant quantities of dye moved through the stratum comeum and were detected in the collection well of the cell in 5 minutes. Local heating occurred, with the transducer reaching a temperature of 48°C. In a control using CE1MG without sonic energy, a 24 hour exposure yielded less dye in the collection well than the 5 minute exposure with sonic energy.
  • FIGS. 3 A and 3B of U.S. Patent No. 5,445,611 show plots of data obtained from three separate cells with the trandermal flux rate measured in the monitoring direction. Even at the 5 minute time point, readily measurable quantities of the dye were present in the chemical enhancer on the outside of the stratum comeum, indicating transport from the epidermal side through the stratum comeum to the "outside" area of the skin sample.
  • One method involves the use of a pair of optical fibers that are positioned close together in an approximately parallel manner.
  • One ofthe fibers is a source fiber, through which light energy is conducted.
  • the other fiber is a detection fiber connected to a photosensitive diode.
  • a portion of the light energy, the evanescent wave is present at the surface ofthe fiber and a portion of this light energy is collected by the detection fiber.
  • the detection fiber conducts the captured evanescent wave energy to the photosensitive diode which measures it.
  • the fibers are treated with a binder to attract and bind the analyte that is to be measured.
  • analyte molecules bind to the surface (such as the analyte glucose binding to immobilized lectins such as concanavalin A, or to immobilized anti-glucose antibodies) the amount of evanescent wave coupling between the two fibers is changed and the amount of energy captured by the detection fiber and measured by the diode is changed as well.
  • Several measurements of detected evanescent wave energy over short periods of time support a rapid determination of the parameters describing the equilibrium curve, thus making possible calculation ofthe concentration ofthe analyte within the body.
  • the experimental results showing measurable flux within 5 minutes (FIGS. 3A and 3B of U.S. Patent No. 5,445,611) with this system suggest sufficient data for an accurate final reading are collected within 5 minutes.
  • a device that can be utilized for the application of sonic energy and collection of analyte comprises an absorbent pad, either of natural or synthetic material, which serves as a reservoir for the chemical enhancer, if used, and for receiving the analyte from the skin surface.
  • the pad or reservoir is held in place, either passively or aided by appropriate fastening means, such as a strap or adhesive tape, on the selected area of skin surface.
  • An sonic energy transducer is positioned such that the pad or reservoir is between the skin surface and the transducer, and held in place by appropriate means.
  • a power supply is coupled to the transducer and activated by switch means or any other suitable mechanism.
  • the transducer is activated to deliver sonic energy modulated in frequency, phase or intensity, as desired, to deliver the chemical enhancer, if used, from the reservoir through the skin surface followed by collection of the analyte from the skin surface into the reservoir. After the desired fixed or variable time period, the transducer is deactivated.
  • the pad or reservoir, now containing the analyte of interest can be removed to quantitate the analyte, for example, by a laboratory utilizing any number of conventional chemical analyses, or by a portable device.
  • the mechanism for quantitating the analyte can be build into the device used for collection of the analyte, either as an integral portion of the device or as an attachment.
  • Devices for monitoring an analyte are described in U.S. Patent No. 5,458,140, which is inco ⁇ orated herein by reference.
  • An altemate method for detection of an analyte, such as glucose, following the sample collection through the porated skin surface as described above, can be achieved through the use of enzymatic means.
  • enzymatic methods exist for the measurement of glucose in a biological sample.
  • One method involves oxidizing glucose in the sample with glucose oxidase to generate gluconolactone and hydrogen peroxide.
  • the hydrogen peroxide is then converted by peroxidase to water and a colored product.
  • the intensity of the colored product will be proportional to the amount of glucose in the fluid.
  • This color can be determined through the use of conventional absorbance or reflectance methods. By calibration with known concentrations of glucose, the amount of color can be used to determine the concentration of glucose in the collected analyte. By testing to determine the relationship, one can calculate the concentration of glucose in the blood of the subject. This information can then be used in the same way that the information obtained from a blood glucose test from a finger puncture is used. Results can be available within five to ten minutes.
  • Example 25 Any system using a visual display or readout of glucose concentration will indicate to a diagnostician or patient the need for administration of insulin or other appropriate medication.
  • the display may be connected with appropriate signal means which triggers the administration of insulin or other medication in an appropriate manner.
  • appropriate signal means which triggers the administration of insulin or other medication in an appropriate manner.
  • insulin pumps which are implanted into the peritoneum or other body cavity which can be activated in response to extemal or intemal stimuli.
  • an insulin delivery system could be implemented transdermal ly, with control of the flux rates modulated by the signal from the glucose sensing system. In this manner a complete biomedical control system can be available which not only monitors and/or diagnoses a medical need but simultaneously provides corrective action.
  • Biomedical control systems of a similar nature could be provided in other situations such as maintaining correct electrolyte balances or administering analgesics in response to a measured analyte parameter such as prostaglandins.
  • Example 26 Similar to audible sound, sonic waves can undergo reflection, refraction, and abso ⁇ tion when they encounter another medium with dissimilar properties [D. Bommannan et al., 9 Pharm. Res. 559 (1992)]. Reflectors or lenses may be used to focus or otherwise control the distribution of sonic energy in a tissue of interest. For many locations on the human body, a fold of flesh can be found to support this system. For example, an earlobe is a convenient location which would allow use of a reflector or lens to assist in exerting directional control (e.g., "pushing" of analytes or permeants through the porated stratum comeum) similar to what is realized by changing sonic frequency and intensity.
  • directional control e.g., "pushing" of analytes or permeants through the porated stratum comeum
  • Example 27 Multiple sonic energy transducers may be used to selectively direct the direction of transdermal flux through porated stratum comeum either into the body or from the body.
  • a fold of skin such as an earlobe allow transducers to be located on either side of the fold.
  • the transducers may be energized selectively or in a phased fashion to enhance transdermal flux in the desired direction.
  • An array of transducers or an acoustic circuit may be constmcted to use phased array concepts, similar to those developed for radar and microwave communications systems, to direct and focus the sonic energy into the area of interest.
  • Example 28 In this example, the procedure of Example 19 is followed with the exception that the heat-separated epidermis samples are first treated with an excimer laser (e.g. model EMG/200 of
  • Lambda Physik 193 nm wavelength, 14 ns pulsewidth
  • Lambda Physik 193 nm wavelength, 14 ns pulsewidth
  • 70 mJ/cm 2 /50 ms a total of 70 mJ/cm 2 /50 ms is delivered to the dye-treated sample with a model TOLD9150 diode laser (Toshiba America Electronic, 30 mW at 690 nm
  • Example 31 In this example, the procedure of Example 29 is followed with the exception that the dye is methylene blue and the laser is a model SDL-8630 (SDL Inc.; 500 mW at 670 nm).
  • Example 33 the procedure of Example 29 is followed with the exception that the dye is contained in a solution comprising a permeation enhancer, e.g. CE1.
  • a permeation enhancer e.g. CE1.
  • Example 29 the procedure of Example 29 is followed with the exception that the dye and enhancer-containing solution are delivered to the stratum comeum with the aid of exposure to ultrasound.
  • Example 31 the procedure of Example 31 is followed with the exception that the pulsed light source is a short arc lamp emitting over the broad range of 400 to 1100 nm but having a bandpass filter placed in the system to limit the output to the wavelength region of about 650 to 700 nm.
  • the pulsed light source is a short arc lamp emitting over the broad range of 400 to 1100 nm but having a bandpass filter placed in the system to limit the output to the wavelength region of about 650 to 700 nm.
  • Example 35 In this example, the procedure of Example 19 is followed with the exception that the heat-separated epidermis samples are first punctured with a microlancet (Becton Dickinson) calibrated to produce a micropore in the stratum co eum without reaching the underlying tissue.
  • a microlancet Becton Dickinson
  • Example 36 In this example, the procedure of Example 19 is followed with the exception that the heat-separated epidermis samples are first treated with focused sonic energy in the range of 70-480 mJ/cm 2 /50 ms to ablate the stratum comeum.
  • Example 37 In this example, the procedure of Example 19 is followed with the exception that the stratum comeum is first punctured hydraulically with a high pressure jet of fluid to form a micropore of up to about 100 ⁇ m diameter.
  • Example 38
  • Example 19 the procedure of Example 19 is followed with the exception that the stratum comeum is first punctured with short pulses of electricity to form a micropore of up to about 100 ⁇ m diameter.
  • An additional aspect of this invention is the utilization of sonic energy to create an acoustic streaming effect on the fluids flowing around and between the intact cells in the epidermis and dermis ofthe human skin.
  • Acoustic streaming is a well documented mode by which sonic energy can interact with a fluid medium. Nyborg, Physical Acoustics Principles and Methods, p.265-331, Vol II-Part B, Academic Press, 1965. The first theoretical analysis of acoustic streaming phenomenon was given by Rayleigh (1884, 1945). In an extensive treatment of the subject, Longuet-Higgins
  • the design ofthe sonic systems for the enhancement of transdermal flux rates has been based on the early realization that the application of an existing therapeutic ultrasound unit designed to produce a "deep-heating" effect on the subject, when used in conjunction with a topical application of a gelled or liquid preparation containing the drug to be delivered into the body, could produce a quantifiable increase in the flux rate ofthe dmg into the body, in the context of the method taught herein to create micro-pores in this barrier layer, the use of sonic energy may now be thought of in a totally new and different sense than the classically defined concepts of sonophoresis. Based on the experimental discovery mentioned in U.S.
  • frequencies of sonic energy can be determined for which the skin tissues are virtually transparent, that is at the very low frequency region of 1 kHz to 500 KHz. Even at some ofthe lowest frequencies tested, significant acoustic streaming effects could be observed by using a micro-scope to watch an in vivo test wherein the subject's skin was micro-porated and ISF was induced to exit the body an pool on the surface of the skin. Energizing the sonic transducer showed dramatic visual indications of the amount of acoustic streaming as small pieces of particulate matter were carried along with the ISF as it swirled about.
  • Typical magnitude of motion exhibited can be described as follows: for a 3 mm diameter circular pool of ISF on the surface of the skin, a single visual particle could be seen to be completing roughly 3 complete orbits per second. This equates to a linear fluid velocity of more than 2.5 mm/second. All of this action was demonstrated with sonic power levels into the tissues of less than 100 mW/cm2.
  • 31-33 is comprised of a thich walled cylinder of piezo-electric material, with an intemal diameter of roughly 8 mm and a wall thickness of 4 mm.
  • the cylinder has been polarized such that when an electrical field is applied across the metalized surfaces ofthe outer diameter and inner diameter, the thickness ofthe wall ofthe cylinder expands or contracts in response to the field polarity.
  • this configuration results in a device which rapidly squeezes the tissue which has been suctioned into the central hole, causing an inward radial acoustic streaming effect on those fluids present in these tissues. This inward acoustic streaming is responsible for bringing more ISF to the location of the micro-porations in the center of the hole, where it can leave the body for extemal collection.
  • FIG. 34A-B A similar device shown in FIG. 34A-B was built and tested and produced similar initial results.
  • an ultrasonic transducer built by Zevex, Inc. Salt Lake City, Utah was modified by having a spatulate extension added to the sonic hom.
  • a 4 mm hole was placed in the 0.5 mm thick spatulate end of this extension.
  • the physical perturbation of the metalic spatula casued by the placement of the 4 mm hole results in a very active, but chaotic, large displacement behavior at this point.
  • the skin ofthe subject was suctioned up into this hole, and the sonic energy was then cunductined into the skin in a fashion similar to that illustrated in FIG. 33.
  • a much lower frequency system can be utilized which has very little abso ⁇ tion in the skin tissues, yet can still create the fluidic streaming phenomenon desired within the intercellular passageways between the epidermal cells which contain the interstitial fluid.
  • the mode of interaction with the tissues and fluids therein is the so-called "streaming" mode, recognized in the sonic literature as a unique and different mode than the classical vibrational interactions capable of shearing cell membranes and accelerating the passive diffusion process.
  • the above examples are but representative of systems which may be employed in the utilization of ultrasound or ultrasound and chemical enhancers in the collection and quantification of analytes for diagnostic pu ⁇ oses and for the transdermal delivery of permeants.
  • the invention is directed to the discovery that the poration of the stratum comeum followed by the proper use of ultrasound, particularly when accompanied with the use of chemical enhancers, enables the noninvasive or minimally invasive transdermal determination of analytes or delivery of permeants.
  • the invention is not limited only to the specific illustrations. There are numerous poration techniques and enhancer systems, some of which may function better than another, for detection and withdrawn of certain analytes or delivery of permeants through the stratum comeum.

Abstract

L'invention concerne un procédé qui consiste à améliorer la perméabilité de la peau (120) (274) à un analysat dans un but diagnostique ou à un médicament dans un but thérapeutique. On utilise pour cela la technique des micropores et, à titre facultatif, l'énergie sonique et un activateur chimique. Si elle est utilisée, l'énergie sonique peut être modulée par modulation de fréquence, modulation d'amplitude, modulation de phase et/ou modulation combinée. On réalise des micropores en (a) procédant à une ablation de la couche cornée (274) par chauffage rapide localisé d'eau jusqu'à vaporiser celle-ci afin d'engendrer une érosion cellulaire par la vapeur; (b) perforant la couche cornée (274) avec une micro-lancette calibrée en vue de former un micropore dont le diamètre mesure jusqu'à 1000 νm environ; (c) en effectuant une ablation de la couche cornée (274) par application d'un faisceau très focalisé d'énergie sonique sur ladite couche cornée (274); (d) en procédant à une perforation hydraulique de la couche cornée (274) au moyen d'un jet de liquide à haute pression en vue de former un micropore dont le diamètre mesure jusqu'à 1000 νm environ; ou (e) en perforant la couche cornée (274) au moyen de brèves impulsions électriques en vue de former un micropore dont le diamètre mesure jusqu'à 1000 νm environ.
PCT/US1996/013865 1993-11-15 1996-08-29 Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage WO1997007734A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP51055297A JP3899427B2 (ja) 1995-08-29 1996-08-29 薬物送達および鑑視適用のためのヒト皮膚の微細穿孔
GB9702766A GB2307414B (en) 1995-08-29 1996-08-29 Microporation of human skin for drug delivery and monitoring applications
EP96929098A EP0858285A4 (fr) 1995-08-29 1996-08-29 Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage
BR9610012-5A BR9610012A (pt) 1995-08-29 1996-08-29 Processos para monitorar a concentração de um analisado e intensificar o índice de fluxo transdérmico de um permeante ativo em uma área selecionada no corpo de um indivíduo, para aplicar uma tatuagem a uma área selecionada da pele e para reduzir um retardamento temporal na difusão de um analisado do sangue de um indivíduo e a evaporação do fluido intersticial e a sua pressão de vapor
IL12337996A IL123379A (en) 1995-08-29 1996-08-29 Microporation of human skin for drug delivery and monitoring applications
AU68631/96A AU707065B2 (en) 1995-08-29 1996-08-29 Microporation of human skin for drug delivery and monitoring applications
US08/776,863 US5885211A (en) 1993-11-15 1996-08-29 Microporation of human skin for monitoring the concentration of an analyte
NO19980878A NO334437B1 (no) 1995-08-29 1998-02-27 Mikroporering av menneskehud for medikamentavlevering og overvåkningsanvendelser
HK98110113A HK1009321A1 (en) 1995-08-29 1998-08-24 Microporation of human skin for drug delivery and monitoring applications

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US52054795A 1995-08-29 1995-08-29
US08/520,547 1995-08-29
US804395P 1995-10-30 1995-10-30
US60/008,043 1995-10-30

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BR (1) BR9610012A (fr)
CA (1) CA2199002C (fr)
ES (1) ES2536459T3 (fr)
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HK (1) HK1009321A1 (fr)
IL (1) IL123379A (fr)
NO (1) NO334437B1 (fr)
PT (1) PT1563788E (fr)
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KR101540761B1 (ko) 2011-04-19 2015-07-30 우니베르시다드 드 코임브라 흡광 박막을 이용하여 피부나 생물 장벽의 표면이나 내부에 화합물을 효율적으로 전달하기 위한 장치
US10702328B2 (en) 2013-12-18 2020-07-07 Novoxel Ltd. Devices and methods for tissue vaporization
US11083515B2 (en) 2013-12-18 2021-08-10 Novoxel Ltd. Methods and devices for thermal tissue vaporization and compression
US11291498B2 (en) 2013-12-18 2022-04-05 Novoxel Ltd. Methods and devices for thermal tissue vaporization and compression
WO2016042547A1 (fr) * 2014-09-15 2016-03-24 Novoxel Ltd. Procédés et dispositifs pour la vaporisation et l'incision de tissus par chirurgie thermique
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CA2199002C (fr) 1999-02-23
AU6863196A (en) 1997-03-19
TR199800347T1 (xx) 1998-05-21
PT1563788E (pt) 2015-06-02
NO334437B1 (no) 2014-03-03
ES2536459T3 (es) 2015-05-25
JP2006192285A (ja) 2006-07-27
JP3899427B2 (ja) 2007-03-28
EP0858285A4 (fr) 2000-05-17
EP0858285A1 (fr) 1998-08-19
BR9610012A (pt) 1999-12-21
NO980878L (no) 1998-04-27
NO980878D0 (no) 1998-02-27
CA2199002A1 (fr) 1997-03-01
AU707065B2 (en) 1999-07-01
IL123379A0 (en) 1998-09-24
CN1195276A (zh) 1998-10-07
HK1009321A1 (en) 1999-05-28
IL123379A (en) 2002-04-21
GB9702766D0 (en) 1997-04-02
JPH11511360A (ja) 1999-10-05
CN1174713C (zh) 2004-11-10
GB2307414A (en) 1997-05-28
GB2307414B (en) 1998-03-11

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