JP2002542841A - Method and apparatus for producing a homogeneous cavity that facilitates transdermal movement - Google Patents

Abstract

(57) Summary The present invention relates to an apparatus and a method for forming uniform cavitation. An ultrasonic source is disclosed that includes an ultrasonic transmission member (20) having an axis (5) and a cross-section along a coaxial line. The ultrasonic transmission member also has a first axial end (1) and a second axial end (2) that operates to generate ultrasonic waves. The cross section has an area having a maximum value at a first axial end and a minimum value at a second axial end. A method for forming a uniform cavitation in an area of skin includes forming 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, causing cavitation in the cavitation nucleus.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to transdermal molecular transfer. More particularly, the present invention relates to a method and apparatus for forming a uniform cavity in a transcutaneous transfer device. BACKGROUND OF THE INVENTION Drugs are routinely administered orally or by injection. The effectiveness of most drugs depends on establishing a certain concentration in the blood stream. Although some drugs have inherent side effects that cannot be ruled out in the dosage form, many drugs exhibit undesirable behavior, particularly related to the particular route of administration. For example, a drug may degrade in the G1 tract due to low gastric pH, local enzymes or reactions with food or beverages in the stomach. The drug or the degradation itself may obviate or reduce the absorption of the drug by vomiting or diarrhea.
If the drug remains present after translocation in the G1 tract, the drug will undergo rapid metabolism and a pharmacologically inactive form due to the liver, first-pass effect. Might be. Sometimes the drug itself,
It may have inherent undesirable tendencies such as a short half-life, a narrow blood concentration range with high efficacy or therapeutic effect.

[0002] Recently, efforts to eliminate some of the problems of traditional dosage forms include transdermal drug delivery (TDD). This method has been used for a very long time mainly for the treatment of local skin diseases. However,
Topical treatment requires only that the drug penetrate the outer layers of the skin to treat the disease state with little or no systemic accumulation. Transdermal administration devices are designed, inter alia, to obtain systemic blood levels. For this use, the term "transdermal" is used as a general term to describe the passage of substances into and through the skin.

[0003] TDD offers several advantages over traditional methods of administration, including injection and oral administration. When compared to oral administration, TDD is less than Percutaneu.
s Absorption: Mechanism-Methodology-D
rug Delivery, Bronough, R.A. L. Maibach, H .;
1 (Ed), pp. 1-12, Marcel Dekker, New York
, 1989, avoids gastrointestinal metabolism of the drug, reduces the effects of first pass, and provides sustained release of the drug for up to several days.

[0004] The movement of drugs through the skin is complicated because many factors affect their penetration. These factors include the skin structure and properties of the skin, the molecules that penetrate and its physico-chemical relationship to the skin and the delivery matrix, as well as the combination of skin permeate and delivery device as a whole. In particular, the skin is a complex structure. There are at least four distinct layers on the skin. That is, the degraded layer (stra
tun corneum, SC), living epidermis, living dermis, subcutaneous connective tissue. Within these layers are located appendages including circulatory tissue of the skin, arterial plexus and hair follicles, sebaceous glands and sweat glands. The dermis and subcutaneous tissue include circulating tissue. The capillaries do not actually enter the epidermal tissue, but reach within 150 to 200 microns of the surface of the skin.

[0005] Compared to injection, TDD can reduce or eliminate the associated pain and potential for infection. In theory, the transdermal route of drug administration is that many drugs, including proteins, are susceptible to gastrointestinal weakness and exhibit low gastrointestinal uptake, proteins such as interferons are rapidly cleared from the blood and In order to maintain high blood levels, the drug must be administered at a sustained rate, and transdermal devices are easier to use than injections.

[0006] Despite these advantages, recently, most drugs and proteins or peptides are not administered at all transdermally for medical use because of their low skin permeability to drugs. This low permeability is due to SC, the outermost layer of flat dead cells filled with a phospholipid bilayer (keratinocytes) surrounded by a lipid bilayer. The highly ordered structure of the phospholipid bilayer is described by SC (Flynn, GL.
, In Percutaneous Absorption: Mechanis
m-METHOLOGY-Drug Delivery: Bronaugh, R
. L. , Maibach H .; I. (Ed) pp. 27-53, Marcel
Dekker, New York 1989).
Some methods include the use of chemical enhancers to alter the skin structure or increase the concentration of the drug in the transdermal route, i.e., enhance transdermal drug transport, including the use of chemicals (Developmental Issues and Rese
arch Initiatives; Handgraft J .; , Guy,
R. H. , Eds. , Marcel Dekker: 1989; Burnette, R. C., pp. 247-288. R. Drug Permeatio
n Enhancement; Hsieh, D .; S. , Eds 59-90
Page; Marcel Dekker, Inc. Ju at New York
nginger et al.) and a temporary transfer route [electroporation].
Or increasing the transfer of an administered drug through the skin (iontophoresis) (Prausnitz Proc. Nail Acad. Sci. U
SA90, 10504-10508 (1993); Transdermal D
Rug Delivery: Developmental Issues and Research I
nitiatives, Ed. Hadgraft J.S. Guy, R .;
H. Walters, K., Marcel Dekker, 1989.
. A. ,) Has been proposed. Another method explored is the application of ultrasound.

[0007] Ultrasound has been shown to enhance a phenomenon called sonophoresis, which is the transdermal movement of low molecular weight drugs (molecular weight less than 500) across the skin ("Topical"). drug Bioavailability
, Bioequivalence, and Penetration ", pp. 91-103, Shah VP, Maibach HI,
Eds. Levy, (Plenum: New York, 1993).
J. Chim Invest); "Interferons: A Prime
er ", Frideman, RM in Academic Press, New York, 1993. For example, U.S. Patent No. 4,309,989 to Fahim and U.S. Patent No. 4,767, to Kost et al.
No. 402 both describe the use of ultrasound in combination with transdermal drug administration. U.S. Pat. No. 4,309,989 discloses the use of drugs using ultrasound with a binder such as oil. Ultrasound at a frequency of at least 1000 kHz and a power of 1 to 3 W / cm ² was used to produce selective localized intracellular concentrations of zinc-containing compounds for the treatment of herpes simplex virus. .

[0008] US Pat. No. 4,309,989, the disclosure of which is specifically incorporated herein by reference, describes drugs, antigens, vitamins, inorganic and organic compounds, and materials thereof. Discloses the use of ultrasound to promote and control the percutaneous penetration of molecules, including various combinations of, into the circulating tissue through the skin. Having a frequency between about 20 kHz and 30 MHz and about 0 and 3 W / cm ²
Ultrasound with an intensity between and is basically used to drive molecules into the skin and circulating tissue. An important deficiency for this device is that the resulting high permeability only occurs while ultrasound is being applied to the skin.

[0009] Although various ultrasound conditions are used for acoustic wave induction, most of the commonly used conditions correspond to therapeutic ultrasound (ranges between 1 MHz and 3 MHz). Frequency and intensity ranging between about 0 and 2 W / cm ² ) (as described in Kost et al.). It is a general observation that the typical enhancement induced by therapeutic ultrasound is less than 10-fold. In many cases, no enhancement of transdermal drug transfer was observed when ultrasound was applied. Therefore, a better choice of ultrasound technology is needed to provoke greater transdermal drug transport through sonication.

[0010] The application of low frequency (between about 20 and 200 kHz) ultrasound dramatically enhances the transdermal movement of drugs, as described in PCT / US96 / 12244 by the Massachusetts Institute of Technology. be able to. It was found to be about 1000 times higher than that caused by low frequency ultrasound. Another advantage of low frequency sonophoresis over therapeutic ultrasound is that the former can cause transdermal movement of non-penetrating drugs across the skin.

[0011] In addition to the need to administer drugs through the skin, there is an important medical need to withdraw analytes through the skin. For example, idealize the handling of insulin,
It is desirable for diabetics to measure glucose in the blood several times a day, thereby reducing the severe long-term complications of the disease. More recently, diabetics have used a lancet to pierce the tip of a finger that has many blood vessels through it to pierce the skin, and then push it by hand to squeeze out blood from the skin to form blood droplets, which are disposable. A diagnostic strip and a meter to which this strip fits,
Do this by analyzing glucose using. This method of measuring glucose is painful and therefore has the important disadvantage that diabetic patients do not want to measure glucose as frequently as medically indicated.

[0012] Thus, many groups are non-invasive or invasive, such as micro-lancets, that are very small in diameter, extremely sharp, and penetrate only between cells (not into epidermal blood vessels). We are making means to measure low glucose. For glucose measurement, a small sample (about 0.1 to 2 μl) of the intercellular fluid is obtained by capillary action. Another group tears the integrity of the delaminating layer so that blood or intercellular fluids can scatter through such holes or create holes or the like using air pressure (suction) or other techniques. Lasers have been used to allow them to be obtained through. Examples of such laser-based sampling devices are U.S. Pat. No. 5,165,418 to Tankovich and WPI A by Budnik (assigned to Venisect, Inc.).
CC No. 94-167045 / 20.

The problem with the method of puncturing the skin to obtain the intercellular fluid is that the intercellular fluid exists in the body in the form of a gel with almost no free fluid, and in fact, the free intercellular fluid that is obtained It is a negative pressure that limits the amount of fluid. When very small holes are formed in the skin that penetrate to a depth such that intercellular fluids are obtained, large mechanical forces (such as withdrawal, vacuum or other) must be used to obtain the amount of blood used in the glucose meter. Power) is required.

Thus, the application of ultrasound and disclosed in US patent application Ser. No. 08 / 885,931, filed Jun. 30, 1997, which is incorporated herein by reference. Methods have been described for the extraction of analytes that rely on techniques known in the art as described. The method described in this specification directs or focuses an ultrasonic beam on a small area of the skin. In some embodiments, the methods and devices utilizing the chambers and ultrasound probes disclosed herein non-invasively squeeze the analyte and move the drug (i.e., translocate widely percutaneously). Substance). This offers a number of advantages, including the ability to form small punctures or localized, sores of skin tissue without the accompanying severe pain. The number of pain receiving organs within the ultrasound application site decreases as the area of application decreases. Thus, the application of ultrasound to very small areas produces less stimulation and may be administered at a higher intensity with less pain or discomfort with less ultrasound and / or its local action. Will be possible. Geometric ultrasound flow is one way to apply ultrasound to a small area. Vibration of a small member near or in contact with the skin surface is another method for applying ultrasound to a small area. Large forces can be formed locally, thereby creating mechanical vibrations within the skin itself within the cavity and large local shear forces near the surface of the skin. This absence can also create an acoustic flow referred to as a large circulating flow created by the ultrasound. Obviously, this will help to obtain a sample of blood or intercellular fluid without having to "exploit" the puncture site. Ultrasonic transducers are known to heat rapidly under continuous operation to reach temperatures that can damage the skin. Damage to the skin can be minimized by using a transducer that is placed away from the skin and vibrates a small member near the skin. In the case of analyte exploitation, compounds present on and / or on the skin may contaminate the exploited sample. The degree of contamination increases as the surface area of the skin increases. Surface contamination can be minimized by minimizing the ultrasound application area. Thus, skin penetration for drug administration or analyte measurement can be locally and temporarily increased using the methods and devices described herein.

Furthermore, the application of ultrasound is only required once for multiple doses or exploitations over a longer period of time rather than prior to each exploitation or dose. That is, when ultrasonic waves having a specific frequency and a specific intensity are applied, multiple times of analyte exploitation or drug administration is performed over a long period of time. For example, a frequency of 20 kHz and 10
When ultrasound with an intensity of W / cm ² is applied, the skin remains highly permeable over a period of up to 4 hours. This is more particularly described in the US Provisional Application filed January 8, 1998, the disclosure of which is incorporated herein by reference.

Nevertheless, the amount of ultrasound (eg, duration, intensity, duty cycle, etc.) required to achieve this enhanced permeability varies widely. Several factors for the properties of the skin must be considered. For example, the type of skin through which a substance can pass varies from species to species and from year to year, with pediatric skin having greater permeability than older adults and depending on the local composition. And changes as a function of wound or exposure to reagents such as organic solvents or surfactants,
It changes as a function of several diseases such as psoriasis or abrasions.

If cavitation is relied upon to enhance transdermal movement, avoid excessive cavitation that can damage the skin via local increase in heat and pressure properties due to the cavitation phenomenon Care must be taken in order to. If the cavities formed are sudden or non-uniform, it is very difficult to prevent local heat and pressure increases.

SUMMARY OF THE INVENTION Accordingly, a need has arisen for a method and apparatus for providing uniform cavitation for use in transdermal transfer devices.

According to one embodiment, the present invention includes an improved ultrasound source.
The ultrasonic source includes an ultrasonic transmission member having an axis and a first cross section along a coaxial line. The ultrasonic transmission member also has a first axial end operable to generate ultrasonic waves, and a second axial end. The first axial end includes a matrix of ultrasound forming portions.

According to another embodiment, the invention includes an ultrasonic source. The ultrasonic source includes an ultrasonic transmission member having an axis and a cross section along a coaxial line. The ultrasonic transmission member also has a first axial end and a second axial end operable to form ultrasonic waves. The cross section has an area having a maximum value at a first axial end and a minimum value at a second axial end.

According to another embodiment, the present invention includes a method for producing uniform cavitation in an area of skin. The method involves forming a volume of fluid having a uniformly dispersed concentration of cavitation nuclei adjacent to an area of skin. Ultrasound is then applied to this volume of fluid, causing cavitation in the cavitation nucleus.

According to another embodiment, the present invention includes a method for forming a homogeneous cavitation in a region of the skin. The method includes forming a volume of fluid having a uniformly dispersed concentration of a first substance adjacent to an area of skin. This first substance is a substance that promotes cavitation. Ultrasound is then applied to this volume of fluid to cause cavitation.

According to another embodiment, the invention includes a method for forming a homogeneous cavitation in a region of the skin. An ultrasound source is provided to apply ultrasound to the area of the skin. A screen with multiple openings is positioned between the area of skin and the source of ultrasound. Finally, ultrasound is applied to the area of the skin through the screen. The openings in the screen nucleate the cavitation and control the size of the cavitation bubbles formed.

According to another embodiment, the invention includes an ultrasound device. The ultrasonic device includes an ultrasonic projection and a housing for the ultrasonic projection. The housing has a portion having an inner diameter that is smaller than the diameter of the projection. This small inner diameter focuses the ultrasonic energy on a small area of the skin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS It is known to use ultrasound to facilitate transcutaneous movement. The mechanism by which ultrasound is used to facilitate percutaneous movement has been different. In the context of transdermal delivery devices, ultrasound was initially used essentially as a driving force to push the drug through the skin and into the circulating tissue. Ultrasound is also used to increase skin permeability. That is, the application of ultrasound having a particular frequency will destroy the phospholipid bilayer tissue in the skin and thus increase the permeability of the skin. In this condition, any drug can be administered through the skin, or the analyte can be squeezed from the body through the skin. Although certain types of driving force are still required, the required strength of the driving force is reduced. For example, the concentration gradient is almost enough driving force for transcutaneous movement through skin that has been penetrated using ultrasound.

The increase in permeability caused by the application of ultrasound is at least partially due to
Due to cavitation caused by ultrasound. Certain ultrasonic fields, when used to irradiate a liquid medium, such as a binding medium used in conjunction with the present invention, will cause cavitation within the liquid. Broadly defined, cavitation refers to the formation of a vapor or gas filled cavity in a liquid when subjected to mechanical forces. One problem when cavitation can be used effectively to increase skin permeability is that cavitation is not easily predictable or controllable. In transdermal delivery devices, the non-coordinated and non-uniformly dispersed cavitation is more consistent with the co-ordinated and uniformly dispersed cavitation with respect to enhancing skin permeability. Not valid. In addition, extremely localized cavitation may cause skin damage. This application describes various devices and methods that the inventors have discovered to form harmonized and uniformly distributed cavitations.

Ultrasound is formed and transmitted using a combination of transducers and protrusions. The transducer converts the electrical impulse into mechanical vibration, and the protrusion transmits this mechanical vibration to the medium. The shape of the protrusion determines the pattern of the ultrasonic wave being transmitted to the medium. Further, the ultrasound waveform is at least partially responsive to cavitation. Thus, the shape of the protrusions directly affects the amount and dispersion of cavitation caused by ultrasound. The inventor has discovered a number of protrusion shapes that form a waveform that is uniformly dispersed and causes harmonized cavitation.

According to one aspect, the present invention includes an ultrasound projection shape that includes a number of ultrasound-forming portions, ie, “fingers” that form a uniformly dispersed cavitation. As shown in FIG. 1, a cylindrical ultrasonic projection 10 having an axis 5 includes a first axial end 1, a second axial end 2, and a plurality of ultrasonic forming portions 3. Contains. The ultrasound projection 10 is generally coupled to the transducer at a first axial end 1. The transducer transmits a vibration to the projection 10, which is then transmitted to the fluid medium at the twelfth axial end 2 of the projection 10.

The second axial end 2 of the projection 10 is shaped to include a plurality of ultrasound generating parts, ie, fingers 3. Each ultrasound generating part 3 generates a separate ultrasound,
Therefore, individual cavitation sources are formed. Further, during operation, the ultrasound generated by each finger 3 is in phase with and overlaps the ultrasound generated by its adjacent finger. This overlap produces more uniformly dispersed ultrasound, which in turn leads to more uniformly dispersed cavitation.

In devices used to enhance skin permeability, the ultrasound projection 10 may be shaped such that a more evenly distributed cavitation occurs at or near the skin. preferable. This is achieved by controlling the width WF of each finger, the gap WG between the fingers and the distance D between the second axial end of the projection and the skin surface 4.

The ultrasound generating part 3 can be made at the end of the projection 10 in many ways, depending on the material used for the projection 10. For example, if the projection 10 is made of metal, the finger 3 may be provided with a number of cutouts extending through the projection 10 parallel to the axis 5 so that the second axial end of the projection 10 It may be formed on top.
These notches can be made, for example, by an electric discharge manufacturing method.
This can be used to form a matrix of ultrasound generating parts as shown in FIG. In another embodiment, the ultrasound generating part 3 is fixed to the second axial end 2 of the projection 10, for example by pressing a finger into the end of the projection 10. The fingers are preferably made of a hard and durable material such as titanium and carbide steel. Other materials such as stainless steel, aluminum, ceramic and glass can be used.

The protrusion 10 is shown as a cylindrical protrusion having an ultrasound generating portion having a rectangular cross section along the axis of the protrusion. However, the protrusions and ultrasound generating portions can have many different shapes and combinations of many different shapes. For example, the protrusion may be a rod-shaped protrusion having a rectangular cross section, and the finger portion may be a cylindrical shape having a circular cross section. Further, the number of fingers formed on the ends of the protrusions can vary. The number of fingers will determine the required dimensions WG and WF.

According to another embodiment, the present invention includes an ultrasonic projection having a “bullet” shape that creates a cavitation effect that spreads over the surface of the skin 24. As shown in FIG. 2, a bullet-shaped ultrasound projection 20 having an axis 25 has a first axial end 21 and a beveled or bullet-shaped second axial end. 22 and
Contains. The ultrasonic projection 20 is generally coupled to the transducer at a first axial end 21 thereof. The transducer transmits vibration to the projection 20, which in turn is transmitted to the fluid medium at a second axial end 22 of the projection 20.

The second axial end 22 of the projection 20 is shaped to include a bullet shape. That is, the cross section of the projection 20 along the axis 25 is formed by the first axial end and the
The size changes with the end portion 22 in the axial direction. More specifically, the axial section has an area with a maximum value at the first axial end 21 and a minimum value at the second axial end 22. With particular reference to FIGS. 2b, 2c and 2d, various cross sections of the protrusion 20 are shown. As is readily apparent, the area A
Is larger than the area A1, and the area A1 is larger than the area A2. Here, A2 is
The cross-sectional area closest to the second axial end of the projection 20, wherein A is the first area of the projection 20.
Is the cross-sectional area closest to the axial end. In operation, the ultrasound waves created by this bullet shape gradually spread as the distance from the second axial end 22 increased, leading to cavitation extending over the skin surface 24.

The extent of this spreading action can be somewhat idealized by controlling the rate of reduction of the cross-sectional area of the projection 20. Generally, the area reduction rate increases, ie, the protrusion 20
As is more inclined, the spreading effect becomes greater to the point where the second axial end 22 has a spherical shape.

[0036] The protrusions 20 can be made of any suitable material. This bullet shape can be formed at the second axial end of the projection 20 using any suitable machining method. For example, the second axial end 22 can be rotated on a lathe into a bullet shape.

The protrusion 20 is shown as a cylindrical protrusion. Otherwise, a similar spreading action can be obtained by machining the bullet shape at the second axial end of any projection. For example, a rod-shaped projection having a rectangular cross section along the axis of the projection can be in the shape of a bullet end.

According to another embodiment, the present invention includes an ultrasound projection that combines the beneficial features of finger and bullet projections described in connection with FIGS. 1 and 2. In. As shown in FIG. 3, the ultrasonic projection 30 having the axis 35 includes a first axial end 31, a second axial end 32, and a plurality of ultrasonic generating portions 33. . The ultrasound projection 30 is generally coupled to the transducer at a first axial end 31 thereof. The transducer transmits the vibration to the projection 30, which in turn is transmitted to the fluid medium at the second axial end 32 of the projection 30.

The second axial end 32 of the projection 30 is connected to a plurality of ultrasonic generators or fingers 33.
Is included. Each ultrasound generating portion 33 has a beveled or bullet-like shape and generates individual ultrasound waves that form a cavitation effect that spreads over the surface of the skin 34. In operation, the ultrasound generated by each finger 33 is synchronized and overlaps with the ultrasound generated by its adjacent finger. This overlap results in more evenly distributed ultrasound, which in turn leads to more uniformly 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 monopoly end 332. More specifically,
The axial section has an area with a maximum value at a first axial end 331 and a minimum value at a second axial end 332. The protrusion 30 is illustrated as having eighteen fingers for ease of illustration only. In a preferred embodiment, projections 30 have as many fingers as necessary to form the desired cavitation pattern. According to one embodiment, the protrusion 30 is shaped with about 60 fingers.

In the environment of the device used to enhance skin penetration, the ultrasound projections 30 are shaped and shaped such that more evenly distributed cavitation occurs at or near the surface of the skin. Preferably. This is achieved by controlling the width WF of each finger, the gap WG between the fingers, and the distance D between the second axial end of the protrusion and the skin surface 34.

The protrusion 30 is shown as a cylindrical protrusion. Otherwise, the projection 30
May have many different shapes. For example, a bullet-shaped finger can incorporate a rod-shaped finger having a rectangular cross-section into a rod-shaped protrusion having a rectangular cross-section. Further, the number of fingers formed on the ends of the protrusions 30 can vary. The number of fingers will determine the required dimensions, WG and WF.

Ultrasonic transducers withstand stress in normal operation. For example, cavitation can cause localized hot spots and high pressure gradients. Prolonged exposure to ultrasonic waves and cavitation can cause ultrasonic dents. The depression due to the ultrasonic projection is
This leads to a rapidly accelerated collapse. Because, the inhomogeneities within the protrusions act as nuclei for cavitation and thus lead to cavitation occurring at the surface of the protrusion. Furthermore, when cavitation occurs at the surface of the protrusion, it hinders further transmission of the ultrasound, and thus
Reduces the amount of cavitation that occurs elsewhere. In the case of devices for increasing the penetration of the skin, this is disadvantageous as it reduces the effect of the ultrasound. In order to increase the permeability, it is necessary to increase the number of exposures, and therefore, to increase the exposure to ultrasonic waves.

Thus, according to another embodiment, the present invention includes a durable ultrasonic projection. According to one embodiment, the present invention includes an ultrasonic projection comprising a carbide billet. In another embodiment, the invention includes an ultrasonic projection having an anodized hard coating. The use of carbide steel is limited to the tip of the projection to minimize losses. The anodized coating can be used on the entire protrusion or just on the ultrasound emitting part.
The teachings of this embodiment of the present invention can be applied to any shape of ultrasonic projection including any of the projections shown and described in FIGS.
For example, in FIG. 1, an improved ultrasonic projection 10 is formed by manufacturing the ultrasonic radiating section 3 from carbide steel. According to another example, an improved ultrasonic projection 10 is formed by anodizing the projection after manufacture. By the use of anodized coatings or carbide steel
Provided is an ultrasonic projection having high durability and resistance to dents.

Similarly, in accordance with another embodiment, the present invention includes a highly polished ultrasonic projection. For the reasons mentioned above, the highly polished ultrasonic projections
Form more stable and uniform cavitation. By polishing the ultrasonic projection, non-uniformities are removed from the surface of the projection. This, in turn, limits the sporadic opportunity for cavitation at the projection surface.

According to another embodiment, the invention includes a method of forming a stable and uniformly distributed cavitation using a cavitation screen. Structurally,
Hollowing screen is a screen whose term is commonly used.
That is, the hollowing screen according to the embodiment of the present invention is a flat and planar shape having a matrix of openings therein. The hollow screen is preferably made of a durable and non-corrosive material such as metal. Hollowing screens may also be treated to have greater resistance to the effects of ultrasound or coated with a durable coating. For example, the screen may be anodized.

[0047] Operatively, the hollowing screen is positioned between the ultrasound projection and the object to which the ultrasound is to be applied. Hollowing screens allow for stable air bubble transmission and growth. The openings in the screen serve as nuclei for cavitation and filter the air bubbles formed by the cavitation. That is, cavitation bubbles may still be created in the fluid, but the screen acts to break bubbles that are larger than the size of the openings in the screen. The size of the opening can be adjusted to form the desired cavitation. Further, in the case of a device for increasing skin permeability, the screen may be located anywhere between the projection and the skin. If the screen is located close to the projections, cavitation is somewhat separated from the skin surface and less effective. As the screen is moved closer to the skin, cavitation also occurs closer to the skin, and thus has a more pronounced effect on skin permeability.

According to another embodiment, the present invention provides a method for “dispersing” cavitation nuclei in a binding medium.
And thereby forming a stable and uniformly dispersed cavitation. Furthermore, it has been discovered that, in particular, the addition of particles to the binding medium used in the device for increasing skin permeability leads to more stable cavitation. Each particle dispersed in the binding medium acts as a core for cavitation. Therefore,
If the particles are uniformly dispersed throughout the binding medium, more stable and evenly dispersed cavitation occurs. The particles can be made of ceramic, polystyrene, titanium dioxide or any other metal or polymer. The particles are appropriately sized for dispersion in the binding medium. In one embodiment, the particles are between 1 and 20 μm in diameter. Smaller or larger sizes are possible. The concentration of particles used must be suitable for dispersion in the binding medium. In one embodiment, 5 to 10
mg / ml particles are used. The concentration of the particles used will vary depending on the type of particles used and the type of binding medium.

In a related embodiment, the decomposed gas, such as O ₂ , causes cavitation to “
Used in the binding medium to "disperse". When the decomposed gases are in the form of bubbles, these bubbles act as nuclei for cavitation. When the decomposed gas is present at the molecular level In the meantime, this gas disperses into the cavitation bubbles and promotes the growth.The increase in cavitation is directly proportional to the amount of decomposed gas in the medium, so that By controlling the concentration, the amount of cavitation formed by the ultrasound can be controlled.To enhance cavitation, any suitable gas can be used, such as, for example, , Oxygen, Zenon,
Includes neon, argon, krypton and helium. If oxygen is used as the gas, a concentration of about 5 mg / ml is provided in the binding medium. Other concentrations are possible and are within the scope of the present invention.

In another embodiment, the present invention includes a method for forming stable and uniformly dispersed cavitations by decomposing chemicals in a binding medium. I have. Certain chemicals have properties that help create stable cavitation. In one embodiment, in one attempt, a fluorocarbon is added into the binding medium to form a more stable cavitation. Fluorocarbons have very low boiling points. Thus, when fluorocarbons are exposed to ultrasound, they tend to vaporize. This vaporization creates bubbles in the binding medium. These bubbles then act as nucleation nuclei to form stable cavitation. The amount of fluorocarbon added to the binding medium can be adjusted based on the desired amount of cavitation. Suitable fluorocarbons include, for example, perfluoropentane, perfluorohexane, and similar molecules. In one embodiment, the fluorocarbon is used at a concentration of 5 to 10 mg / ml. Other concentrations are possible and are within the scope of the present invention.

Similarly, surfactants can be added to the binding medium by different mechanisms to form more stable cavitation. The use of a surfactant in the binding medium does not "disperse" the cavitation when the above method is performed. Rather, adding a surfactant to the binding medium reduces the surface tension of the binding medium. By making it easier to form bubbles in the medium, this reduced surface tension is more likely to cause cavitation. Suitable surfactants include sodium lauryl sulfate and fatty alcohols, such as dodecanol.

In another embodiment, the invention includes a method of forming a stable and uniformly dispersed cavitation by puncturing a skin with a chemical or cavitation nucleus. I have. In one embodiment, the skin receiving the ultrasound comprises:
Wipe off from the skin surface with a chemical cleaner that eliminates unevenness. The removal of inhomogeneities from the skin surface results in a more stable cavitation by removing substances that act as nucleation nuclei and cause sporadic localized cavitation that can damage the skin. Connect. Ethanol and isopropyl alcohol are suitable for use to pre-treat the skin.

In another embodiment, to form a more stable cavitation, the skin to be treated by ultrasound is presoaked in the cavitation nucleus. The cavitation nucleus may have any of the forms described above. According to one embodiment, the skin is pre-soaked in a solution that is uniformly dispersed and has very fine particles. The particles are evenly distributed on the surface of the skin. This results in a stable and evenly dispersed cavitation when subjected to ultrasound. In another embodiment, it is pre-soaked in a liquid having a highly decomposed gas component. As described above, when ultrasonic waves are applied, the decomposed gas acts as a nucleus for cavitation, and stable cavitation is formed.

Referring to FIG. 4, an ultrasonic shape according to another embodiment of the present invention is provided. The ultrasonic projection 40 may be used in combination with the transducer housing 42 having a smaller inner diameter than the projection 40 where the housing 42 is in contact with the skin 44. The ultrasonic projection is applied to the skin 4 via the coupling medium 46.
4 may be combined. The small diameter wall of the housing 42 covers most of the skin 44 and exposes only a portion of the skin 44 to ultrasound.

The effect of cavitation on the skin is generally most pronounced at the center. Therefore,
With this shape, the level of permeation enhancement achieved is concentrated in the center of the skin to be treated.

Other methods such as pin projections and acoustic channel rings may be used to create similar effects on the skin. The above embodiments focus on methods and apparatus used to form stable and uniform cavitation. As will be apparent to those skilled in the art, these methods are not mutually exclusive. The method and apparatus can be combined to provide uniform and greater control of cavitation. For example, any of the protrusions shown in FIGS. 1-4 can be used in combination with the addition of a cavitation nucleus to the binding medium. Similarly, both the chemical and the cavitation nucleus can be pre-processed in connection with any of the devices and methods described above.

While the present invention has been described in detail, it should be understood that various changes, substitutions and alterations can be made without departing from the scope defined by the claims.

[Brief description of the drawings]

FIGS. 1a and 1b show an ultrasonic projection shape according to one embodiment of the present invention.

2a to 2d show an ultrasonic projection shape according to another embodiment of the present invention.

3a and 3b show an ultrasonic projection shape according to another embodiment of the present invention.

FIG. 4 shows an ultrasonic projection shape according to another embodiment of the present invention.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN , IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Cost, Joseph USA Massachusetts State 02141, Cambridge, Mass. Avenue 931, Apartment number 303 (72) Inventor Kellogg, Scott Sea, Massachusetts, USA 02169, Quincy, Kendrick Avenue 155 (72) Inventor Warner, Nick 02178, Massachusetts, Belmont, Belmont , Concord Avenue 296 F term (reference) 4C060 JJ23 MM01 4C077 AA08 FF10 KK30 4C167 AA71 BB 45 CC01 GG22 GG23 GG26 HH19

Claims (39)

[Claims] 1. An ultrasonic transmission member having an axis and a first cross section along a coaxial line, the member having a first axial end and a second axial end. An ultrasonic transmission member operable to generate ultrasonic waves, wherein the first axial end includes an ultrasonic generating portion. An ultrasonic source, comprising: a matrix having the first cross section. 2. The ultrasonic source according to claim 1, wherein the ultrasonic transmission member includes a cylindrical projection, and the first cross section is circular. 3. The ultrasonic source according to claim 1, wherein the ultrasonic generating portion creates a first series of parallel axial cutouts in the ultrasonic transmission member. Creating a second series of parallel axial cutouts in the ultrasound transmission member. 4. The ultrasonic source according to claim 1, wherein the first series of parallel axial cutouts and the second series of parallel axial cutouts. But an ultrasound source that is nearly perpendicular. 5. The ultrasonic source according to claim 1, wherein the ultrasonic transmission member includes a flat protrusion, and the first cross section is rectangular. 6. The ultrasonic source according to claim 5, wherein the matrix of the ultrasonic generating portions includes a row of the ultrasonic generating portions. 7. The ultrasonic generating source according to claim 1, wherein each of the ultrasonic generating portions has a first end of a base of the ultrasonic transmitting member and a distal end of the ultrasonic transmitting member. An ultrasonic source having a second end of the portion and a cross section. 8. The ultrasound source according to claim 7, wherein at least one of the ultrasound generating portions has a maximum value at the first end and a minimum value at the second end. An ultrasonic source having a cross section having a value. 9. The ultrasonic generator according to claim 8, wherein at least one of the ultrasonic generators has a circular cross section. 10. The ultrasound source according to claim 1, wherein the first end emits ultrasound toward a skin surface and the coupling is at or near the skin. An ultrasonic source that causes cavitation in the medium. 11. The ultrasonic source according to claim 1, wherein the first end includes an anodized coating. 12. The ultrasonic source according to claim 1, wherein the first end is made of carbide steel. 13. The ultrasonic source according to claim 12, wherein a first end of the carbide steel is coupled to the ultrasonic transmission member. 14. An ultrasonic transmission member having an axis and a first cross section along a coaxial line, the ultrasonic transmission member comprising a first axial end and a second axial direction. An ultrasonic transmission member operable to generate ultrasonic waves, the cross-section having a maximum value at the first end. An ultrasonic source having an area having a minimum value at said second end. 15. The ultrasonic source according to claim 14, wherein the cross section has a uniform shape and a minimum value at the second axial end from a maximum value at the first axial end. An ultrasonic source having an area that reduces to a value. 16. The ultrasonic source according to claim 14, wherein the ultrasonic transmission member has a circular cross section along the axis. 17. The ultrasonic source according to claim 14, wherein the ultrasonic transmission member forms an ultrasonic pattern that forms uniformly distributed cavities. 18. The ultrasound source of claim 14, wherein the first axial end emits ultrasound toward a skin surface and at or near the skin. An ultrasonic source that causes uniformly distributed cavitation in the coupling medium. 19. The ultrasonic source according to claim 14, wherein the first end includes an anodized coating. 20. The ultrasonic source according to claim 14, wherein said first end comprises carbide steel. 21. The ultrasonic source according to claim 20, wherein a first end of the carbide steel is coupled to the ultrasonic transmission member. 22. A method of forming uniform cavitation in an area of skin, the method comprising forming, adjacent to the area of skin, a volume of fluid having a concentration of cavitation nuclei of evenly distributed concentration therein. And applying ultrasonic waves to the large volume of fluid, wherein the ultrasonic waves cause cavitation at or near the location of the cavitation,
Method. 23. The method of claim 22, wherein the cavitation nuclei comprise approximately the same size ceramic particles. 24. The method of claim 22, wherein the cavitation nuclei comprise particles of approximately the same size polymer. 25. The method of claim 22, wherein the cavitation nuclei comprise titanium dioxide particles of about the same size. 26. The method according to claim 22, wherein the cavitation nuclei comprise gas bubbles. 27. The method of claim 22, further comprising administering a substance through the area of the skin. 28. The method of claim 22, further comprising collecting an analyte through the area of skin. 29. A method of forming uniform cavitation in an area of skin, comprising: adhering to the area of skin, a first substance that aids in forming cavitation in a concentration uniformly distributed therein. A method, comprising: forming a volume of fluid having; and sonicating the volume of fluid, wherein the ultrasound causes cavitation in the fluid. 30. The method of claim 29, wherein the first substance is a fluorocarbon, and applying ultrasonic waves results in vaporization of the fluorocarbon and formation of gas bubbles in the coupling medium. Method. 31. The method of claim 29, wherein the first substance is a surfactant that assists in generating cavitation when the bonding fluid is exposed to ultrasound. 32. The method of claim 29, further comprising administering a substance through the area of the skin. 33. The method of claim 29, comprising extracting an analyte through the area of skin. 34. A method for forming uniform cavitation in a skin area, comprising: providing an ultrasound source for applying ultrasound to the skin area; Positioning a screen with a number of openings between the source and sonicating the area of the skin through the screen, wherein the openings in the screen are hollowed out. A method wherein the cavitation bubbles are filtered by their size and their size, thereby forming a uniform group of bubbles. 35. The method of claim 34, further comprising administering a substance through the area of the skin. 36. The method of claim 34, further comprising extracting an analyte through the area of skin. 37. An ultrasonic device, comprising: an ultrasonic projection; and a housing for the ultrasonic projection, wherein a part of the housing has an inner diameter smaller than a diameter of the ultrasonic projection. An ultrasonic device, wherein the small inner diameter is adapted to focus ultrasonic energy on a narrow area of the skin. 38. The ultrasonic device according to claim 37, wherein the small inner diameter is located near the skin. 39. The ultrasonic device according to claim 37, further comprising a coupling medium contained within the housing.