Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
  • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
  • A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
  • A61B2017/22005—Effects, e.g. on tissue
  • A61B2017/22007—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing
  • A61B2017/22008—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing used or promoted
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
  • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
  • A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
  • A61B2017/22027—Features of transducers

Definitions

• This invention relates to transdermal molecular transportation. More specifically, this invention relates to methods and apparatus for producing homogenous cavitation in a transdermal transport system.
• Drugs are routinely administered either orally or by injection. The effectiveness of most drugs relies on achieving a certain concentration in the bloodstream. Although some drugs have inherent side effects which cannot be eliminated in any dosage form, many drugs exhibit undesirable behaviors that are specifically related to a particular route of administration. For example, drugs may be degraded in the GI tract by the low gastric pH, local enzymes or interaction with food or drink within the stomach. The drug or disease itself may forestall or compromise drug absorption because of vomiting or diarrhea. If a drug entity survives its trip through the Gl tract, it may face rapid metabolism to pharmacologically inactive forms by the liver, the first-pass effect. Sometimes the drug itself has inherent undesirable attributes such as a short half-life, high potency or a narrow therapeutic blood level range.
• Transdermal delivery of the drugs Topical application has been used for a very long time, mostly in the treatment of localized skin diseases. Local treatment, however, only require that the drug permeate the outer layers of the skin to treat the diseased state, with little or no systemic accumulation.
• Transdermal delivery systems are designed for, inter alia, obtaining systemic blood levels, and topical drug application.
• the word "transdermal” is used as a generic term to describe the passage of substances to and through the skin.
• TDD offers several advantages over traditional delivery methods including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery, Bronaugh, R L Maibach, H 1 (Ed), pp 1 - 12, Marcel Dekker, New York, 1989
• the transport of drugs through the skin is complex since many factors influence their permeation These include the skin structure and its properties, the penetrating molecule and its physical-chemical relationship to the skin and the delivery matrix, and the combination of the skin, the penetrant, and the delivery system as a whole
• the skin is a complex structure
• the nonviable epidermis stratum corneum, SC
• the viable epidermis the viable dermis
• the subcutaneous connective tissue Located within these layers are the skin's circulatory system, the arterial plexus, and appendages, including hair follicles, sebaceous glands, and sweat glands
• the circulatory system lies in the dermis and tissues below the dermis
• the capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns of the outer surface of the skin
• TDD can reduce or eliminate the associated pain and the possibility of infection
• the transdermal route of drug administration could be advantageous in the delivery of many
• U.S. Patent No. 4,309,989 discloses the use of ultrasound for enhancing and controlling transdermal permeation of a molecule, including drugs, antigens, vitamins, inorganic and organic compounds, and various combinations of these substances, through the skin and into the circulatory system.
• Ultrasound having a frequency between about 20 kHz. and 10 MHz. and having an intensity between about 0 and 3 W/cm 2 is used essentially to drive molecules through the skin and into the circulatory system.
• a significant drawback to this system is that the resultant enhanced permeability only occurs while the ultrasound is being applied to the skin Thus, the skin is often damaged due to over exposure to the ultrasound
• low-frequency ultrasound can dramatically enhance transdermal transport of drugs, as described in PCT/US96/12244 by Massachusetts Institute of Technology Transdermal transport enhancement induced by low-frequency ultrasound was found to be as much as 1000- fold higher than that induced by therapeutic ultrasound
• Another advantage of low- frequency sonophoresis as compared to therapeutic ultrasound is that the former can induce transdermal transport of drugs which do not passively permeate across the skin
• diabetics do this by pricking the highly vascularized fingertips with a lancet to perforate the skin, then milking the skin with manual pressure to produce a drop of blood, which is then assayed for glucose using a disposable diagnostic strip and a meter into which this strip fits This method of
• interstitial fluid occurs in the body in a gel like form with little free fluid and in fact is even negative pressure that limits the amount of free interstitial fluid that can be obtained
• mechanical force milking, vacuum, or other force
• Ultrasound transducers are known to rapidly heat under continuous operation, reaching temperatures that can cause skin damage. Heat damage to the skin can be minimized by using a transducer that is located away from the skin to oscillate a small element near the skin. In the case of analyte extraction, compounds present on the surface of and/or in the skin can contaminate the extracted sample. The level of contamination increases as skin surface area increases. Surface contamination can be minimized by minimizing the surface area of ultrasound application. Thus, skin permeability can be increased locally, and transiently through the use of the methods and devices described herein, for either drug delivery or measurement of analyte.
• the amount (e.g., duration, intensity, duty cycle etc.) of ultrasound necessary to achieve this permeability enhancement varies widely.
• the type of skin which the substance is to pass through varies from species to species, varies according to age, with the skin of an infant having a greater permeability than that of an older adult, varies according to local composition, thickness and density, varies as a function of injury or exposure to agents such as organic solvents or surfactants, and varies as a function of some diseases such as psoriasis or abrasion
• the present invention comprises an improved ultrasound source
• the ultrasound source comprises an ultrasound transmitting element having an axis and a first cross-section along said axis
• the ultrasound transmitting element also has a first axial end operable to produce ultrasonic waves and a second axial end
• the first axial end comprises a matrix of ultrasound producing portions
• the present invention comprises an ultrasound source
• the ultrasound souce comprises an ultrasound transmitting element having an axis and a cross-section along the axis
• the ultrasound transmitting element also has a first axial end and a second axial end operable to produce ultrasonic waves
• the cross-section has an area having a maximum value at the first axial end and a minimum value at the second axial end
• the present invention comprises a method for producing homogenous cavitation at an area of skin
• the method comprises creating a volume of fluid having a uniformly dispersed concentration of cavitation nuclei adjacent the area of skin Ultrasound is then applied to the volume of fluid and causes cavitation at the cavitation nuclei
• the present invention comprises a method for producing homogenous cavitation at an area of skin
• the method comprises creating a volume of fluid having a uniformly dispersed concentration of a first substance adjacent the area of skin
• the first substance is a substance that facilitates the production of cavitation
• Ultrasound is then applied to the volume of fluid to cause cavitation
• the present invention comprises a method for producing homogenous cavitation at an area of skin
• An ultrasound source is provided to apply an ultrasonic wave to the area of skin
• a screen having a number of opening therein is positioned between the area of skin and the ultrasound source
• ultrasound is applied to the area of skin through the screen
• the openings in the screen nucleate cavitation and control the size of cavitation bubbles produced
• the present invention comprises an ultrasound device
• the ultrasound device includes an ultrasound horn and a housing for the ultrasound horn
• the housing has a portion with a reduced inside diameter relative to a diameter of the horn
• the reduced inside diameter focuses ultrasonic energy on a small area of skin
• FIGS 1 a and 1 b depict an ultrasonic horn configuration according to one embodiment of the present invention
• Figures 2a-2d depict an ultrasonic horn configuration according to another embodiment of the present invention
• Figures 3a and 3b depict an ultrasonic horn configuration according to another embodiment of the present invention
• Figure 4 depicts an ultrasound configuration according to another embodiment of the present invention DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
• ultrasound was initially used as a driving force that essentially pushed drugs through the skin and into the circulatory system.
• Ultrasound is also used to increase the permeability of the skin. That is, application of ultrasound having a particular frequency will disorganize the lipid bilayer in the skin and thus increase the permeability of the skin.
• drugs can be delivered through the skin to the body or analyte can be extracted through the skin from the body.
• a driving force of some type is still required, but the required intensity of the driving force is decreased.
• a concentration gradient is generally sufficient driving force for transdermal transport through skin whose permeability has been enhanced using ultrasound.
• the permeability enhancement that results from the application of ultrasound is due, at least in part, to cavitation that is caused by the ultrasound.
• cavitation is the formation of vapor- or gas-filled cavities in liquids when subjected to mechanical forces.
• cavitation is not readily predictable or controllable.
• cavitation that is inconsistent and unevenly dispersed is not as effective at enhancing skin permeability as cavitation that is consistent and evenly dispersed.
• cavitation that is highly localized may cause skin damage.
• Ultrasound is created and transmitted using a combination of a transducer and horn.
• the transducer converts an electrical impulse into a mechanical vibration and the horn transmits that mechanical vibration to a medium.
• the configuration of the horn determines the wave pattern of the ultrasound being transmitted to the medium.
• the present invention comprises an ultrasonic horn configuration including a number of ultrasound producing portions or "fingers" that produce evenly dispersed cavitation
• cylindrical shaped ultrasound horn 10 having an axis 5 comprises a first axial end 1 , a second axial end 2 and a plurality of ultrasound producing portions 3
• Ultrasound horn 10 is generally connected to a transducer at its first axial end 1 The transducer transmits a vibration to horn 10 and the vibration is, in turn, transmitted to a fluid medium at second axial end 2 of horn 10
• Second axial end 2 of horn 10 is configured to include a plurality of ultrasound producing portions or fingers 3
• Each ultrasound producing portion 3 produces a separate ultrasonic wave and therefore a separate cavitation source
• the ultrasonic wave produced by each finger 3 is in phase with and overlaps with the ultrasonic waves produced by its neighboring fingers This overlap results in more evenly distributed ultrasound that in turn leads to more evenly distributed cavitation
• ultrasound horn 10 is preferably configured so that the more evenly distributed cavitation occurs at or near the surface of the skin This is accomplished by controlling the width of each finger, WF, the width of the gaps between the fingers, WG, and the distance, D, between the second axial end of the horn and the skin surface 4
• Ultrasound producing portions 3 can be fabricated on the end of horn 10 in a number of ways depending on the material used for horn 10 For example, if horn 10 is made of metal, fingers 3 may be configured on the second axial end of horn 10 by making a number of cuts
• Horn 10 is shown as a cylindrical horn having ultrasound producing portions having a square cross-section along the horn axis
• the horn and ultrasound producing portions could have many different shapes and many different combinations of shapes
• the horn could be a bar shaped horn having a square cross- section and the fingers could be cylindrical with a circular cross-section
• the number of fingers configured on the end of the horn can vary The number of fingers will determine the necessary dimensions WG and WF
• the present invention comprises an ultrasonic horn having a "bullet" configuration that produces a cavitation effect that spreads out over the surface of the skin 24
• bullet shaped ultrasound horn 20 having an axis 25 comprises a first axial end 21 , a second axial end 22 having a tapered or bullet shaped configuration
• Ultrasound horn 20 is generally connected to a transducer at its first axial end 21 The transducer transmits a vibration to horn 20 and the vibration is, in turn, transmitted to a fluid medium at second axial end 22 of horn 20
• Second axial end 22 of horn 20 is configured to include a bullet shape That is, the cross-section along axis 25 of horn 20 varies in size between first axial end 21 and second axial end 22 More specifically, the axial cross-section has an area having a maximum value at first axial end 21 and a minimum value at second axial end 22 Referring particularly to Figures 2b, 2c and 2d, various cross sections of horn 20 are shown As is readily apparent, the area A is greater than the area Al , and the area Al is greater than the area A2, A2 being the area of the cross-section nearest the second axial end of horn 20 and A being the area of the cross-section nearest the first axial end of horn 20 In operation, the ultrasonic wave produced by this bullet shaped configuration gradually spreads out as the distance from second axial end 22 increases and leads to cavitation that spreads out over skin surface 24.
• This extent of the spreading out effect can be optimized somewhat by controlling the rate of decrease of the cross-sectional area of horn 20.
• the rate of area reduction increases, that is, horn 20 becomes more tapered, the spreading effect becomes greater up to the point where second axial end 22 has a spherical configuration.
• Horn 20 can be fabricated from any suitable material.
• the bullet configuration can be formed at second axial end of horn 20 using any suitable machining process.
• second axial end 22 can be turned on a lathe to the bullet configuration.
• Horn 20 is shown as a cylindrical horn. Nevertheless, a similar spreading effect can be obtained by machining the bullet configuration at the second axial end of any horn.
• a bar shaped horn having a square cross-section along the horn axis could be configured with a bullet shaped end.
• the present invention comprises an ultrasonic horn that combines the beneficial features of the finger horn and bullet horn described in conjunction with Figures 1 and 2.
• ultrasound horn 30 having an axis 35 comprises a first axial end 31 , a second axial end 32, and a plurality of ultrasound producing portions 33.
• Ultrasound horn 30 is generally connected to a transducer at its first axial end 31. The transducer transmits a vibration to horn 30 and the vibration is, in turn, transmitted to a fluid medium at second axial end 32 of horn 30.
• Second axial end 32 of horn 30 is configured to include a plurality of ultrasound producing portions or fingers 33.
• Each ultrasound producing portion 33 has a tapered or bullet shaped configuration and generates a separate ultrasonic wave that produces a cavitation effect that spreads out over the surface of the skin 34.
• the ultrasonic wave produced by each finger 33 is in phase with and overlaps with the ultrasonic waves produced by its neighboring fingers. This overlap results in more evenly distributed ultrasound that in turn leads to more evenly distributed cavitation.
• Each bullet shaped finger 33 has an axis 335 and a cross-section that varies in size between a first axial end 331 and a second axial end 332.
• the axial cross-section has an area having a maximum value at first axial end 331 and a minimum value at second axial end 332.
• Horn 30 is depicted as having eighteen fingers only for ease of illustration. In a preferred embodiment, horn 30 has a number of figures necessary to produce a desired cavitation pattern. According to one embodiment, horn 30 is configured to have about 60 fingers.
• ultrasound horn 30 is preferably configured so that the more evenly distributed cavitation occurs at or near the surface of the skin. This is accomplished by controlling the width of each finger, WF, the width of the gaps between the fingers, WG, and the distance, D, between the second axial end of the horn and the skin surface 34.
• Horn 30 is shown as a cylindrical horn. Nevertheless, horn 30 may have many different configurations. For example, bullet shaped fingers could be a incorporated into a bar shaped horn having a square cross-section. Further, the number of fingers configured on the end of horn 30 can vary. The number of fingers will determine the necessary dimensions WG and WF.
• Ultrasound transducers endure a great stress in normal operation. For example, cavitation can cause localized hot spots and high pressure gradients. Extended exposure to ultrasound and cavitation can cause pitting of the ultrasound. Pitting of an ultrasound horn quickly leads to accelerated decay, because the nonuniformities in the horn act as cavitation nuclei and therefore lead to cavitation occurring at the surface of the horn. Moreover, when cavitation occurs at the surface of the horn, it interrupts further transmission of the ultrasonic wave and therefore diminishes the amount of cavitation occurring elsewhere. In the context of an apparatus for enhancing skin permeability, this is disadvantageous because it reduces the effectiveness of the ultrasound. Exposure times need to be increased to enhance permeability, thus increasing the chance of over exposure to ultrasound.
• the present invention comprises a highly durable ultrasound horn.
• the present invention comprises an ultrasound horn comprised of a carbide steel tip
• the present invention comprises an ultrasound horn that has an anodized hard coating
• carbide steel is generally limited to the tip of the horn to minimize losses
• An anodized coating can be used on the entire horn or simply the ultrasound radiating portion
• the teachings of this embodiment of the present invention could be applied to any configuration of ultrasound horn including any of the horns shown and described in Figures 1 -4
• an improved ultrasound horn 10 is formed by fabricating ultrasound radiating portions 3 from carbide steel
• an improved ultrasound horn 10 is formed by anodizing the entire horn to after fabrication Both the use of an anodized coating or carbide steel provide an ultrasound horn having enhanced durability and resistance to pitting
• the present invention comprises a highly polished ultrasound horn
• a highly polished ultrasound horn produces more consistent and homogenous cavitation
• nonuniformities are removed from the surface of the horn This, in turn, limits the chance of sporadic cavitation at the horn surface
• the present invention comprises a method of producing consistent and evenly dispersed cavitation using a cavitation screen Structurally, the cavitation screen is a screen as that term is conventionally used That is, a cavitation screen according to embodiments of the present invention is a flat, planar object having a matrix of openings therein
• the cavitation screen is preferably formed from a durable and non-corrosive material such as metal
• the cavitation screen may also be treated or coated with durable coating so that it is more resistant to the effects of ultrasound
• the screen may be anodized
• the cavitation screen is positioned between an ultrasound horn and the object to which ultrasound is to be applied
• the cavitation screen enables transmission and growth of consistent bubbles
• the openings in the screen nucleate cavitation and filter the bubbles produced by cavitation That is, cavitation bubbles may still be produced throughout the liquid, but the screen acts to break the bubbles that are larger than the size of the openings in the screen
• the size of the openings can be adjusted to produce the cavitation desired
• the screen may be positioned anywhere between the horn and the skin If the screen is positioned close to the horn, the cavitation will be somewhat separated from the skin surface and have a lesser effect If the screen is moved closer to the skin, the cavitation also occurs closer to the skin and therefore will have a more pronounced effect on skin permeability
• the present invention comprises a method of producing consistent and evenly dispersed cavitation by "seeding" the coupling medium with cavitation nuclei More, specifically, it has been found that the addition of particles to the coupling medium used in an apparatus for enhancing skin permeability leads to more consistent cavitation Each particle dispersed within the coupling medium acts as a cavitation nuclei Therefore, if particles are evenly dispersed throughout the coupling medium, more consistent and evenly dispersed cavitation results
• the particles may be formed from ceramics, polystyrene, titanium dioxide or any other metal or polymer
• the particles are sized appropriately for dispersion in the coupling medium In one embodiment, the particles are 1 -20 ⁇ m in diameter Smaller or larger sizes are possible
• the concentration of particles used should be appropriate for dispersion in the coupling medium In one embodiment 5-10 mg/ml of particles are used The concentration of particles used varies depending on the type of particles used and the coupling medium
• dissolved gas such as O 2 is used in the coupling medium to "seed" cavitation If the dissolved gas is in the form of bubbles, these bubbles act as cavitation nuclei If the dissolved gas exists at the molecular level, it diffuses into cavitation bubbles and enhances growth
• the cavitation enhancement is directly proportional to the amount of dissolved gas in the medium Therefore, by controlling the dissolved gas concentration in the medium, the amount of cavitation produced by ultrasound can be controlled Any suitable gas may be used to enhance cavitation Suitable gasses include, for example, oxygen, zenon, neon, argon, krypton and helium If oxygen is used as the gas, a concentration of about 5 mg/dl is provided in the coupling medium Other concentrations are possible and within the scope of the present invention
• the present invention comprises a method for producing consistent and evenly dispersed cavitation by dissolving chemicals in the coupling medium Certain chemicals have properties that are helpful for producing consistent cavitation
• fluorocarbons are added to the coupling medium in an attempt to produce more consistent cavitation
• Fluorocarbons have a very low boiling point Therefore, when fluorocarbons are subjected to ultrasound they tend to evaporate This evaporation causes gas bubbles in the coupling medium These gas bubbles, in turn, act as cavitation nuclei and thus produce consistent cavitation
• the amount of fluorocarbon added to the coupling medium can be adjusted based on the desired amount of cavitation Suitable fluorocarbons include, for example, perfluoropentane, perfluorohexane and similar molecules
• the fluorocarbons are used at a concentration of 5-10 mg/ml Other concentrations are possible and within the scope of the present invention.
• surfactants can be added to the coupling medium to produce more consistent cavitation by a different mechanism
• the use of surfactants in the coupling medium does not "seed" cavitation as the above methods do Rather, by adding surfactant to the coupling medium, the surface tension of the coupling medium is reduced This reduced surface tension makes it easier for cavitation to occur by making it easier for bubbles to form in the medium
• Suitable surfactants include sodium lauryl sulfate and fatty alcohols, for example, dodecanol
• the present invention comprises a method for producing consistent and evenly dispersed cavitation by pretreating the skin with chemicals or cavitation nuclei
• the skin surface to be subjected to ultrasound is wiped with a chemical cleansing agent that removes inhomogeneities from the skin surface
• the removal of inhomogeneities from the skin surface leads to more consistent cavitation by removing substances that could act as cavitation nuclei and cause sporadic, localized cavitation that could damage the skin Alhocols such as ethanol and isopropyl alcohol are suitable for use to pretreat the skin
• the skin to be treated with ultrasound is presoaked with cavitation nuclei to produce more consistent cavitation
• the cavitation nuclei could be in any of the forms discussed above
• the skin is presoaked with solution having evenly dispersed and very fine particles The particles evenly distribute themselves on the surface of the skin This results in consistent and evenly dispersed cavitation when ultrasound is applied
• the skin is presoaked with a liquid having

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• Health & Medical Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
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• 1999
  • 1999-12-17 AU AU21921/00A patent/AU768190B2/en not_active Ceased
  • 1999-12-17 JP JP2000587673A patent/JP2002542841A/ja not_active Withdrawn
  • 1999-12-17 EP EP99966360A patent/EP1139880A4/de not_active Withdrawn
  • 1999-12-17 WO PCT/US1999/030067 patent/WO2000035351A1/en not_active Application Discontinuation
  • 1999-12-17 CA CA002355187A patent/CA2355187A1/en not_active Abandoned

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