U.S. patent application number 10/600758 was filed with the patent office on 2004-05-06 for method and apparatus for producing homogenous cavitation to enhance transdermal transport.
This patent application is currently assigned to Sontra Medical, Inc.. Invention is credited to Kellogg, Scott C., Kost, Joseph, Mitragotri, Samir S., Warner, Nicholas F..
Application Number | 20040087879 10/600758 |
Document ID | / |
Family ID | 27805653 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040087879 |
Kind Code |
A1 |
Mitragotri, Samir S. ; et
al. |
May 6, 2004 |
Method and apparatus for producing homogenous cavitation to enhance
transdermal transport
Abstract
The present invention is directed to apparatus and methods for
producing homogenous cavitation. An ultrasound souce comprising an
ultrasound transmitting element having an axis and a cross-section
along the axis is disclosed 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. A method for producing homogenous cavitation at
an area of skin 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.
Inventors: |
Mitragotri, Samir S.;
(Goleta, CA) ; Kost, Joseph; (Cambridge, MA)
; Kellogg, Scott C.; (Boston, MA) ; Warner,
Nicholas F.; (Belmont, MA) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP
INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W.
SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Assignee: |
Sontra Medical, Inc.
|
Family ID: |
27805653 |
Appl. No.: |
10/600758 |
Filed: |
June 23, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10600758 |
Jun 23, 2003 |
|
|
|
09868443 |
Jul 26, 2001 |
|
|
|
6620123 |
|
|
|
|
09868443 |
Jul 26, 2001 |
|
|
|
PCT/US99/30067 |
Dec 17, 1999 |
|
|
|
60112936 |
Dec 18, 1998 |
|
|
|
Current U.S.
Class: |
601/4 ;
604/22 |
Current CPC
Class: |
A61B 2017/22027
20130101; A61B 2017/22008 20130101; A61B 2017/320073 20170801; A61M
37/0092 20130101 |
Class at
Publication: |
601/004 ;
604/022 |
International
Class: |
A61B 017/22 |
Claims
1. An ultrasound source comprising: an ultrasound transmitting
element having an axis and a first cross-section along said axis,
said ultrasound transmitting element having a first axial end and a
second axial end, said first axial end operable to produce
ultrasonic waves; and said first axial end comprising a matrix of
ultrasound producing portions, said matrix having the first
cross-section; wherein said ultrasound producing portions are
formed by making a first series of parallel axial cuts in the
ultrasound transmitting element and a second series of parallel
axial cuts in the ultrasound transmitting element, and wherein said
first series of parallel axial cuts and said second series of
parallel axial cuts are approximately perpendicular.
2. The ultrasound source of claim 1 wherein said ultrasound
transmitting element comprises a cylindrical horn and said first
cross-section is a circle.
3. The ultrasound source of claim 1 wherein said ultrasound
transmitting element comprises a flat horn and said first
cross-section is rectangular.
4. The ultrasound source of claim 3 wherein said matrix of
ultrasound producing portions comprises a row of ultrasound
producing portions.
5. The ultrasound source of claim 1 wherein each one of said
ultrasound producing portions has a first end proximal to the
ultrasound transmitting element, a second end distal to the
ultrasound transmitting element and a cross-section.
6. The ultrasound source of claim 5 wherein at least one of said
ultrasound producing portions comprises a cross-section having an
area with a maximum value at the first end and an area with a
minimum value at the second end.
7. The ultrasound source of claim 6 wherein at least one of said
ultrasound producing portions has a circular cross-section.
8. The ultrasound source of claim 1 wherein the first end radiates
ultrasound toward a skin surface and causes cavitation in the
coupling medium, at the skin surface or in the skin.
9. The ultrasound source of claim 1 wherein said first end
comprises an anodized coating.
10. The ultrasound source of claim 1 wherein said first end
comprises carbide steel.
11. The ultrasound source of claim 10 wherein said carbide steel
fist end is bonded to said ultrasound transmitting element.
12. An ultrasound source comprising: an ultrasound transmitting
element having an axis and a cross-section along said axis, said
ultrasound transmitting element having a first axial end and a
second axial end, said second axial end operable to produce
ultrasonic waves; said cross-section having an area having a
maximum value at the first axial end and a minimum value at the
second axial end; and said first axial end comprising a matrix of
ultrasound producing portions, said matrix having the first
cross-section; wherein said ultrasound producing portions are
formed by malting a first series of parallel axial cuts in the
ultrasound transmitting element and a second series of parallel
axial cuts in the ultrasound transmitting element, and wherein said
first series of parallel axial cuts and said second series of
parallel axial cuts are approximately perpendicular.
13. The ultrasound source of claim 12 wherein said cross-section
has a uniform shape and an area that decreases from a maximum value
at the first axial end to a minimum value at the second axial
end.
14. The ultrasound source of claim 12 wherein said ultrasound
transmitting element has a circular cross-section along said
axis.
15. The ultrasound source of claim 12 wherein the ultrasound
transmitting element produces an ultrasound wave pattern that
produces uniformly distributed cavitation.
16. The ultrasound source of claim 12 wherein the first axial end
radiates ultrasound toward a skin surface and causes uniformly
distributed cavitation in the coupling medium, at the skin surface
or in the skin.
17. The ultrasound source of claim 12 wherein said first end
comprises an anodized coating.
18. The ultrasound source of claim 12 wherein said first end
comprises carbide steel.
19. The ultrasound source of claim 18 wherein said carbide steel
first end is bonded to said ultrasound transmitting element.
20. A method for producing homogenous cavitation at an area of skin
comprising: creating a volume of fluid adjacent the area of skin,
said fluid having a uniformly dispersed concentration of cavitation
nuclei therein; and applying ultrasound to the volume of fluid from
an ultrasound transmitting element having an axis and a
cross-section along said axis, said ultrasound transmitting element
having a first axial end and a second axial end, said second axial
end operable to produce ultrasonic waves, said first axial end
comprising a matrix of ultrasound producing portions, said matrix
having the first cross-section, wherein said ultrasound producing
portions are formed by making a first series of parallel axial cuts
in the ultrasound transmitting element and a second series of
parallel axial cuts in the ultrasound transmitting element, and
wherein said first series of parallel axial cuts and said second
series of parallel axial cuts are approximately perpendicular;
wherein the ultrasound causes cavitation to begin at or around the
cavitation nuclei.
21. The method of claim 20 wherein the cavitation nuclei comprise
appropriately sized ceramic particles.
22. The method of claim 20 wherein the cavitation nuclei comprise
appropriately sized polymer particles.
23. The method of claim 20 wherein the cavitation nuclei comprise
appropriately sized titanium dioxide particles.
24. The method of claim 20 wherein the cavitation nuclei comprises
gas bubbles.
25. The method of claim 20 further comprising delivering a
substance through the area of skin.
26. The method of claim 20 further comprising extracting analyte
through the area of skin.
27. A method for producing homogenous cavitation at an area of skin
comprising: creating a volume of fluid adjacent the area of skin,
said fluid having a uniformly dispersed concentration of a
fluorocarbon therein, said fluorocarbon facilitating the production
of cavitation; and applying ultrasound to the volume of fluid;
wherein the ultrasound causes cavitation in the fluid, evaporation
of the fluorocarbon and the creation of gas bubbles in the coupling
medium.
28. The method of claim 27 further comprising delivering a
substance through the area of skin.
29. The method of claim 27 further comprising extracting analyte
through the area of skin.
30. A method for producing homogenous cavitation at an area of skin
comprising: creating a volume of fluid adjacent the area of skin,
said fluid having a uniformly dispersed concentration of a first
substance therein, said first substance facilitating the production
of cavitation; applying ultrasound to the volume of fluid; wherein
the ultrasound causes cavitation in the fluid; and wherein the
first substance is a surfactant that facilitates the occurrence of
cavitation when the coupling fluid is exposed to ultrasound.
32. The method of claim 30 further comprising delivering a
substance through the area of skin.
33. The method of claim 30 further comprising extracting analyte
through the area of skin.
34. A method for producing homogenous cavitation at an area of skin
comprising: providing an ultrasound source to apply an ultrasonic
wave to the area of skin; positioning a screen between the area of
skin and the ultrasound source, the screen having a number of
openings therein; and, applying ultrasound to the area of skin
through the screen; wherein the openings in the screen nucleate
cavitation and filter cavitation bubbles by size thereby producing
a homogenous bubble population.
35. The method of claim 34 further comprising delivering a
substance through the area of skin.
36. The method of claim 34 further comprising extracting
analyte-through the area of skin.
37. An ultrasound device comprising: an ultrasound horn; and a
housing for said ultrasound horn, a portion of said housing having
a reduced inside diameter relative to a diameter of said horn; a
screen positioned between an area of skin and the ultrasound horn,
the screen having a number of openings therein; wherein the reduced
inside diameter focuses ultrasonic energy on a small area of skin;
and
38. The ultrasound device of claim 37, wherein said reduced inside
diameter is located near the skin.
39. The ultrasound device of claim 37, further comprising a
coupling medium contained in said housing.
Description
FIELD OF THE INVENTION
[0001] 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.
BACKGROUND OF THE INVENTION
[0002] 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 GI 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.
[0003] Recently, efforts aimed at eliminating some of the problems
of traditional dosage forms involve transdermal delivery of the
drugs (TDD). 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. For purposes of this application, the word
"transdermal" is used as a generic term to describe the passage of
substances to and through the skin.
[0004] 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:
Mechanism-Methodology-Drug Delivery, Bronaugh, R. L. Maibach, H. I.
(Ed), pp 1-12, Marcel Dekker, New York, 1989.
[0005] 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. Particularly, the skin is a complex structure.
There are at least four distinct layers of tissue: 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.
[0006] In comparison to injections, TDD can reduce or eliminate the
associated pain and the possibility of infection. Theoretically,
the transdermal route of drug administration could be advantageous
in the delivery of many therapeutic drugs, including proteins,
because many drugs, including proteins, are susceptible to
gastrointestinal degradation and exhibit poor gastrointestinal
uptake, proteins such as interferon are cleared rapidly from the
blood and need to be delivered at a sustained rate in order to
maintain their blood concentration at a high value, and transdermal
devices are easier to use than injections.
[0007] In spite of these advantages, very few drugs and no proteins
or peptides are currently administered transdermally for clinical
applications because of the low skin permeability to drugs. This
low permeability is attributed to the SC, the outermost skin layer
which consists of flat, dead cells filled with keratin fibers
(keratinocytes) surrounded by lipid bilayers. The highly-ordered
structure of the lipid bilayers confers an impermeable character to
the SC (Flynn, G. L., in Percutaneous Absorption:
Mechanisms-Methodology-Drug Delivery.; Bronaugh, R. L., Maibach, H.
I. (Ed), pages 27-53, Marcel Dekker, New York 1989). Several
methods have been proposed to enhance transdermal drug transport,
including the use of chemical enhancers, i.e. the use of chemicals
to either modify the skin structure or to increase the drug
concentration in a transdermal patch (Burnette, R. R., in
Developmental Issues and Research Initiatives; Hadgraft J., Guy, R.
H., Eds., Marcel Dekker: 1989; pp. 247-288; Junginger, et al. in
Drug Permeation Enhancement; Hsieh, D. S., Eds., pp.59-90; Marcel
Dekker, Inc. New York 1994) and the use of applications of electric
fields to create transient transport pathways [electroporation] or
to increase the mobility of charged drugs through the skin
(iontophoresis) (Prausnitz Proc. Natl. Acad. Sci. USA 90,
10504-10508 (1993); Walters, K. A., in Transdermal Drug Delivery:
Developmental Issues and Research Initiatives, Ed. Hadgraft J.,
Guy, R. H., Marcel Dekker, 1989). Another approach that has been
explored is the application of ultrasound.
[0008] Ultrasound has been shown to enhance transdermal transport
of low-molecular weight drugs (molecular weight less than 500)
across human skin, a phenomenon referred to as sonophoresis (Levy,
J. Clin. Invest. 1989, 83, 2974-2078; Kost and Langer in "Topical
drug Bioavailability, Bioequivalence, and Penetration"; pp: 91-103,
Shah V. P., Maibach H. I. Eds. (Plenum: New York, 1993); Frideman,
R. M., "Interferons: A Primer", Academic Press, New York, 1981) For
example, U.S. Pat. No. 4,309,989 to Fahim and U.S. Pat. No.
4,767,402 issued to Kost et al. both describe the use of ultrasound
in conjunction with transdermal drug delivery. U.S. Pat. No.
4,309,989 discloses the topical application of a medication using
ultrasound with a coupling agent such as oil. Ultrasound at a
frequency of at least 1000 kHz and a power of one to three
W/cm.sup.2 was used to cause selective localized intracellular
concentration of a zinc containing compound for the treatment of
herpes simplex virus.
[0009] U.S. Pat. No. 4,309,989, the disclosure of which is
specifically incorporated by reference, 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.sup.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.
[0010] Although a variety of ultrasound conditions have been used
for sonophoresis, the most commonly used conditions correspond to
therapeutic ultrasound (frequency in the range of between one MHz
and three MHz, and intensity in the range of between above zero and
two W/cm.sup.2) (such as that described in the Kost et al. patent).
It is a common observation that the typical enhancement induced by
therapeutic ultrasound is less than ten-fold. In many cases, no
enhancement of transdermal drug transport has been observed upon
ultrasound application. Accordingly, a better selection of
ultrasound techniques is needed to induce a higher enhancement of
transdermal drug transport by sonophoresis.
[0011] Application of low-frequency (between approximately 20 and
200 kHz) 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.
[0012] In addition to there being a need to deliver drugs through
the skin, there is a major medical need to extract analytes through
the skin. For example, it is desirable for diabetics to measure
blood glucose several times per day in order to optimize insulin
treatment and thereby reduce the severe long-term complications, of
the disease. Currently, 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
glucose measurement has the major disadvantage that it is painful,
so diabetics do not like to obtain a glucose measurement as often
as is medically indicated.
[0013] Therefore, many groups are working on non-invasive and less
invasive means to measure glucose, such as micro lancets that are
very small in diameter, very sharp, and penetrate only to the
interstitium (not to the blood vessels of the dermis). A small
sample, from about 0.1 to two .mu.l, of interstitial fluid is
obtained through capillary forces for glucose measurements. Other
groups have used a laser to breach the integrity of the stratum
corneum and thereby make it possible for blood or interstitial
fluid to diffuse out of such a hole or to be obtained through such
a hole using pneumatic force (suction) or other techniques. An
example of such a laser based sampling device is disclosed in U.S.
Pat. No. 5,165,418 to Tankovich and WPI ACC No: 94-167045/20 by
Budnik (assigned to Venisect, Inc.).
[0014] A problem with methods that penetrate the skin to obtain
interstitial fluid is that 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. When a very small hole is made in the skin,
penetrating to a depth such that interstitial fluid is available,
it takes a great deal of mechanical force (milking, vacuum, or
other force) to obtain the quantity of blood used in a glucose
meter.
[0015] Thus, there has been described methods for application of
ultrasound and extraction of analyte that rely on techniques known
in the art such as are disclosed in U.S. patent application Ser.
No. 08/885,931 filed Jun. 30, 1997, the disclosure of which is
hereby incorporated by reference. The methods described therein
channel or focus an ultrasound beam onto a small area of skin. In
some embodiments, methods and devices utilizing a chamber and
ultrasound probe disclosed can be used to non-invasively extract
analyte and deliver drugs (i.e, broadly transdermally transport
substances). This provides many advantages, including the ability
to create a small puncture or localized erosion of the skin tissue,
without a large degree of concomitant pain. The number of pain
receptors within the ultrasound application site decreases as the
application area decreases. Thus, the application of ultrasound to
a very small area will produce less sensation and allow ultrasound
and/or its local effects to be administered at higher intensities
with little pain or discomfort. Channeling of ultrasound
geometrically is one way to apply ultrasound to a small area. The
oscillation of a small element near or in contact with the surface
of the skin is another way to apply ultrasound to a small area.
Large forces can be produced locally, resulting in cavitation,
mechanical oscillations in the skin itself, and large localized
shearing forces near the surface of the skin. The element can also
produce acoustic streaming, which refers to the large convective
flows produced by ultrasound. This appears to aid in obtaining a
sample of blood or interstitial fluid without having to "milk" the
puncture site. 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.
[0016] Moreover, it has been disclosed that the application of
ultrasound is only required once for multiple deliveries or
extractions over an extended period of time rather than prior to
each extraction or delivery. That is, it has been shown that if
ultrasound having a particular frequency and a particular intensity
of is applied, multiple analyte extractions or drug deliveries
maybe performed over an extended period of time. For example, if
ultrasound having a frequency of 20 kHz. and an intensity of 10
W/cm.sup.2 is applied, the skin retains an increased permeability
for a period of up to four hours. This is described more
particularly in United States Provisional Patent Application No.
60/070,813 filed on Jan. 8, 1998, the disclosure of which is
specifically incorporated by reference herein.
[0017] Nevertheless, the amount (e.g., duration, intensity, duty
cycle etc.) of ultrasound necessary to achieve this permeability
enhancement varies widely. Several factors on the nature of skin
must be considered. For example, 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.
[0018] When cavitation is relied upon to enhance transdermal
transport, care must be taken to avoid excessive cavitation which
can do damage to the skin through the localized increases of heat
and pressure characteristic with cavitation phenomena. If the
cavitation produced is sporadic or nonuniform, it very difficult to
prevent the localized heat and pressure increases.
SUMMARY OF THE INVENTION
[0019] Therefore, a need has arisen for a method and apparatus that
provides homogenous cavitation for use in a transdermal transport
system.
[0020] According to one embodiment, 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.
[0021] According to another embodiment, the present invention
comprises an ultrasound source. The ultrasound source 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.
[0022] According to another embodiment, 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.
[0023] According to another embodiment, 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.
[0024] According to another embodiment, 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. Finally, 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.
[0025] According to another embodiment, 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
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The features and objects of the present invention, and the
manner of attaining them is explained in detail in the following
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS of the invention
when taken in conjunction with the accompanying drawings
wherein:
[0027] FIGS. 1a and 1b depict an ultrasonic horn configuration
according to one embodiment of the present invention.
[0028] FIGS. 2a-2d depict an ultrasonic horn configuration
according to another embodiment of the present invention.
[0029] FIGS. 3a and 3b depict an ultrasonic horn configuration
according to another embodiment of the present invention.
[0030] FIG. 4 depicts an ultrasound configuration according to
another embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] The use of ultrasound to facilitate transdermal transport is
known. The mechanism by which ultrasound is used to facilitate
transdermal transport has differed. In the context of transdermal
delivery systems, 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. In this
context, either 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. For example, a
concentration gradient is generally sufficient driving force for
transdermal transport through skin whose permeability, as been
enhanced using ultrasound.
[0032] The permeability enhancement that results from the
application of ultrasound is due, at least in part, to cavitation
that is caused by the ultrasound. When used to irradiate liquid
medium such as the coupling medium used in conjunction with the
present invention, certain ultrasonic fields will cause cavitation
in the liquid. Broadly defined, cavitation is the formation of
vapor or gas filled cavities in liquids when subjected to
mechanical forces. One problem with being able to effectively use
cavitation to enhance skin permeability is that cavitation is not
readily predictable or controllable. In the context of a
transdermal delivery system, cavitation that is inconsistent and
unevenly dispersed is not as effective at enhancing skin
permeability as cavitation that is consistent and evenly dispersed.
Moreover, cavitation that is highly localized may cause skin
damage. This application describes various apparatus and methods
the inventors have found to produce consistent, evenly dispersed
cavitation.
[0033] 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. Moreover, the wave pattern of the ultrasound is, at
least in part, responsible for the cavitation. Therefore, the horn
configuration directly affects the amount and dispersement of the
cavitation caused by an ultrasonic wave. The inventors have found a
number of horn configurations that produce a wave pattern that
causes evenly dispersed and consistent cavitation.
[0034] According to one embodiment, the present invention comprises
an ultrasonic horn configuration including a number of ultrasound
producing portions or "fingers" that produce evenly dispersed
cavitation. As shown in FIG. 1, 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.
[0035] 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. Moreover, in operation
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.
[0036] In the environment of an apparatus used to enhance the
permeability of the skin, 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.
[0037] 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 through horn 10 in parallel with axis 5. These cuts can be
made, for example, by and electrical discharge manufacturing
process. This can be used to produce a matrix of ultrasound
producing portions such as is shown in FIG. 1. In other
embodiments, ultrasound producing portions 3 are affixed to second
axial end 2 of horn 10 by for example by press fitting the fingers
into the end of horn 10. The fingers are preferably made from a
hard and durable material such as titanium, and carbide steel.
Other materials such as, stainless steel, aluminum, ceramic and
glass could be used.
[0038] Horn 10 is shown as a cylindrical horn having ultrasound
producing portions having a square cross-section along the horn
axis. But, the horn and ultrasound producing portions could have
many different shapes and many different combinations of shapes.
For example, the horn could be a bar shaped horn having a square
cross-section and the fingers could be cylindrical with a circular
cross-section. Further, 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.
[0039] According to another embodiment, 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. As shown in FIG. 2, 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.
[0040] 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 FIGS. 2b, 2c and 2d,
various cross sections of horn 20 are shown. As is readily
apparent, the area A is greater than the area A1, and the area A1
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.
[0041] 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. In general, as 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.
[0042] 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. For example, second axial end
22 can be turned on a lathe to the bullet configuration.
[0043] 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 horns. For example, a
bar shaped horn having a square cross-section along the horn axis
could be configured with a bullet shaped end.
[0044] According to another embodiment, the present invention
comprises an ultrasonic-horn that combines the beneficial features
of the finger horn and bullet horn described in conjunction with
FIGS. 1 and 2. As shown in FIG. 3, 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.
[0045] 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. In operation 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.
[0046] 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. More specifically, 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.
[0047] In the environment of an apparatus used to enhance the
permeability of the skin, 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.
[0048] 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 oft fingers
will determine the necessary dimensions WG and WF.
[0049] 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.
[0050] Therefore, according to another embodiment, the present
invention comprises a highly durable ultrasound horn. According to
one embodiment the present invention comprises an ultrasound horn
comprised of a carbide steel tip. In another embodiment, the
present invention comprises an ultrasound horn that has an anodized
hard coating. The use of 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 FIGS. 1-4. For example, in the
context of FIG. 1, an improved ultrasound horn 10 is formed by
fabricating ultrasound radiating portions 3 from carbide steel.
According to another example, 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.
[0051] Similarly, according to another embodiment, the present
invention comprises a highly polished ultrasound horn. For reasons
discussed above, a highly polished ultrasound horn produces more
consistent and homogenous cavitation. By polishing the ultrasound
horn, nonuniformities are removed from the surface of the horn.
This, in turn, limits the chance of sporadic cavitation at the horn
surface.
[0052] According to another embodiment, 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. For example, the screen may
be anodized.
[0053] Operationally, 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. Further, in the context of an
apparatus for enhancing skin permeability, 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.
[0054] According to another embodiment, 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 .mu.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.
[0055] In a related embodiment, dissolved gas, such as O.sub.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.
[0056] In another embodiment, 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. In one embodiment, 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. In one
embodiment, the fluorocarbons are used at a concentration of 5-10
mg/ml. Other concentrations are possible and within the scope of
the present invention.
[0057] Similarly, 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.
[0058] In another embodiment, the present invention comprises a
method for producing consistent and evenly dispersed cavitation by
pretreating the skin with chemicals or cavitation nuclei. In one
embodiment, 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.
[0059] In another embodiment, 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. According to one embodiment, 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. In another
embodiment, the skin is presoaked with a liquid having a high
dissolved gas content. Similar to above, when ultrasound is
applied, the dissolved gas acts as cavitation nuclei and thus
produces consistent cavitation.
[0060] Referring to FIG. 4, an ultrasound configuration according
to another embodiment of the present invention is provided.
Ultrasonic horn 40 may be used in conjunction with transducer
housing 42 that has a reduced inside diameter, relative to horn 40,
where housing 42 is in contact with skin 44. Ultrasonic horn may be
coupled with skin 44 through coupling medium 46. The walls of
reduced diameter housing 42 mask a significant portion of skin 44,
and expose only a fraction of skin 44 to ultrasound.
[0061] The cavitation effect on the skin is generally most
pronounced in the center. Therefore, through this configuration,
the level of permeability enhancement achieved is centralized of
the treated skin.
[0062] Other methods, such as a pin horn and accoustic channeling,
may be used to produce a similar effect on the skin.
[0063] The above embodiments focus on methods and apparatus used to
produce consistent and homogenous cavitation. As will be apparent
to one of ordinary skill in the art, these methods are not mutually
exclusive. The methods and apparatus can be combined to provide
even greater control of cavitation. For example, any of the horns
shown in FIGS. 1-4 can be used in conjunction with the addition of
cavitation nuclei to the coupling medium. Similarly, both chemicals
and cavitation nuclei could be added to the coupling medium for an
enhanced effect. The area of skin can be pretreated in conjunction
with any of the above apparatus and methods.
[0064] Although 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 intended scope
as defined by the appended claims.
* * * * *