JP2002532130A - Method and apparatus for improving transdermal transport - Google Patents

Abstract

(57) Summary According to the present invention, a method for improving transdermal transport is disclosed. The method includes the step of increasing the permeability of an area of the membrane using a device for permeation (a permeation device). The membrane can be, inter alia, biological or synthetic skin. The permeabilization device can be an ultrasound generating device. Transporting material into and through the area of the membrane. The substance can be a component of a drug, vaccine, or interstitial fluid.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to transdermal molecular transport.
transportation). More particularly, the present invention relates to methods and devices for adjusting skin permeabilization and analyzing analytes in extracted body fluids.

[0002] 2. 2. Description of the Related Art Drugs are regularly administered orally or by infusion. The effectiveness of most drugs depends on achieving a given concentration in the bloodstream. While some drugs have inherent side effects and may not be eliminated by any dosage form, the undesirable behavior exhibited by many drugs is specifically related to certain routes of administration. For example, due to low gastric juice pH, local enzymes, or interaction with food or drink in the stomach, drugs can be in the gastrointestinal tract (G1
(Tract). The drug or disease itself may interfere with or impair the absorption of the drug due to vomiting or diarrhea. When a drug entity achieves its translocation through the gastrointestinal tract, it has a rapid metabolic, first-pass effect on the pharmacologically inactive form by the liver (f
first-pass effect). Also, the drug itself may have its own undesirable attributes, such as a short half-life or a narrow range of therapeutic blood levels.

Recently, transdermal drug delivery (TDD: transderm)
Efforts have been made to address some of the problems of conventional dosage forms, including al delivery of the drugs. Topical applications have been used for a very long time, most often in the treatment of localized dermatoses. However, with localized treatment, the drug need only penetrate the outer layers of the skin to treat the diseased state, with little or no systemic accumulation. Transdermal delivery systems are designed for, among other things, systemic blood levels and localized drug application. For the purposes of this application, the word "transdermal" is a generic term that describes the passage of a substance into the skin, the passage of a substance from the skin to the outside, the transfer of a substance to the skin, and the penetration of a substance through the skin Shall be used as

[0004] TDD offers several advantages over traditional delivery methods, including injection and oral delivery. Compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects and maintains drug release for up to 7 days. This is "Percutane" by Elias.
ous Absorption: Mechanisms-Methodology
y-Drug Delivery (transdermal absorption: mechanism-methodology-drug delivery)
", Bronaugh, R .; L. Maibach, H .; I. (Ed), p.
1-12, Marcel Dekker, New York, 1989.

[0005] Transport of drugs to the skin, into the skin, outside the skin, and through (through) the skin is complicated because many factors affect its penetration. These include the skin structure and its properties, the penetrating molecules and their physicochemical relationships to the skin and the delivery matrix, and the combination of skin, penetrants, and the entire delivery system. In particular, the skin is a complex structure. Non-growth epidermis (keratin, SC), growing epidermis, growing dermis, subcutaneous connective tissue
There are at least four distinct tissue layers. Within these layers are the circulatory system of the skin, the arterial plexus, and appendages including hair follicles, fat glands, and sweat glands. The circulatory system resides in the dermis and the underlying tissue. Capillaries do not actually penetrate the epidermal tissue,
Located within 150 to 200 microns of the outer surface of the skin.

[0006] Compared to infusion (injection), TDD can reduce or eliminate the associated pain and potential for infection. In theory, the transdermal route of drug administration has advantages in delivering many therapeutic drugs, including proteins. This is because many drugs, including proteins, are prone to gastrointestinal degradation and have low gastrointestinal uptake.
Proteins, such as interferons, are quickly cleared from the blood and must be delivered at a constant rate to keep their blood levels high. Transdermal devices are also easier to use than injections.

[0007] Despite these advantages, due to the low skin permeability of drugs, only a few drugs are currently transdermally administered for clinical use, and no proteins or peptides are present. It is. This low permeability is attributable to SC. SC is the outermost skin layer consisting of flat dead cells filled with keratin fibers (keratinocytes) surrounded by a lipid bilayer. Higher-ordered structure of lipid bilayer
structure) imparts impermeability to SC ((furin) Fl
ynn, G .; L. Percutaneous Absorption: M
echanisms-Methodology-Drug Delivery.
(Transdermal absorption: mechanism-methodology-drug delivery) ", Bronaugh,
R. L. , Maibach, H .; 1. (ED), pages 27-53, Mar
cel Dekker, New York, 1989). Several methods for improving transdermal drug delivery have been proposed, including the use of chemical synergists, ie, drugs that modify the skin structure or increase the drug concentration in transdermal patches (Burnet)
"Developmental by Burnett, RR"
Issues and Research Initiatives, "Hadgraft J. et al. Guy, R .; H. Edit, Marcel Dekker, 1989, pp. 2
47-288, “Drug by Junginger and others
Permeation Enhancement (improvement of drug penetration) "; S. Edit, pp. 59-90, Marcel De
kker, Inc. New York 1994), and the use of the application of an electric field to form a transient transport pathway (electroporation) or to enhance the mobility of a charged drug through the skin (iontophoresis) (Prau).
snitz Proc. Natl. Acad. Sci. USA 90, 105
Walters K. 04-10508 (1993). A. "T
Randommal Drug Delivery: Developmentmenta
I Issues and Research Initiatives (Transdermal Drug Delivery: Developmental Issues and Research Initiatives), "Hadgraft J. et al. , Guy R
. H. Editing, Marcel Dekker, 1989). Another technique being investigated is the application of ultrasound.

[0008] Ultrasound has been shown to improve the transdermal delivery of drugs through human skin, a phenomenon known as sonic transmission (Levy, J. Clin. Inv.).
est. 1989, 83, 2974-2078, Cost and Langer's "Topical drug Bioavailable."
, Bioequivalence, and Penetration ”(
Bioavailability, Bioequivalence, and Penetration of Local Drugs "), pp. 91-1
03, Shah V. P. , Maibach H .; I. Edit (Plenum:
New York, 1993)). For example, U.S. Pat. No. 4,309,989 to Fahim and U.S. Pat.
No. 767,402 both describe the use of ultrasound with transdermal drug delivery. U.S. Pat. No. 4,309,989 discloses the topical application of medication using ultrasound with a binder such as oil. Ultrasound at a frequency of at least 1000 kHz and power of 1 to 3 W / cm ² was used to form selective local intracellular concentrations of zinc-containing compounds for the treatment of herpes simplex virus.

US Pat. No. 4,309,989 describes the transdermal penetration of molecules, including drugs, antigens, vitamins, inorganic and organic compounds, and combinations of these substances, through the skin and into the circulation. Disclosed is the use of ultrasound to improve and control. The contents thereof are hereby incorporated by reference in their entirety. To introduce molecules into the circulatory system through the skin, it has a frequency of about 20 kHz and about 0-3 W / c
it is necessary to use an ultrasonic wave having an intensity of m ^2.

[0010] Various ultrasonic conditions have been used for acoustic transmission methods, but the most commonly used conditions are therapeutic ultrasonic waves (frequency ranging between 1 MHz and 3 MHz, intensity Corresponds to a range between above 0 and 2 W / cm ² (such as those described in Cost and Others). It is commonly observed that the typical improvement induced by therapeutic ultrasound is less than 10-fold. In many cases, no improvement in transdermal drug delivery has been observed upon application of ultrasound. Therefore, a better choice of ultrasound technique is needed to induce further improvements in transdermal drug delivery by sonication.

[0011] Massachusetts Institute of Technology (Massachusetts Institute)
As described in PCT / US96 / 12244 by E. of Technology, the application of low frequency ultrasound (between about 20 and 200 kHz)
Transdermal drug delivery, analyte extraction and measurement can be dramatically improved. The improvement in transdermal transport provided by low frequency ultrasound was found to be 1000 times higher than provided by therapeutic ultrasound. Another advantage of low frequency sonic transmission over therapeutic ultrasound is that the latter can induce transdermal transport of drugs that do not passively penetrate the skin.

For most medical applications of ultrasonic energy, ultrasonic gels can be used as binders. The use of these gels is messy and labor intensive. To overcome the problems associated with applying ultrasound with gels and other binders, patches containing the required components have been developed. The patch adheres to a clean area of the skin, and the drug molecules are continuously absorbed through the skin and into the bloodstream and dispersed systemically. These patches include a drug-containing layer provided near the ultrasonic oscillator. The drug is
It is reliably absorbed by the action of the ultrasonic waves from the oscillator. The amount of drug released is
The control can be performed by changing the ultrasonic wave output from the oscillator. This is described in US Pat. No. 5,007, Tachibana et al.
No. 438. Its contents are hereby incorporated in its entirety by this reference. US Patent 4,821,740 to Tachibana et al.
The article discloses a kit for providing an external medicament, which includes a drug-containing layer and an ultrasonic oscillator for releasing the drug for ingestion through the skin surface. The transducer may be battery powered. By applying ultrasonic waves,
The dosing travels from the device to the skin and then changes the ultrasound energy to control the rate of administration through the skin.

US Pat. No. 5,421,816 to Lipkover,
Ultrasound energy is described that releases stored drug and forces the drug through the skin of the tissue and into the bloodstream. The housing includes a cavity defined by the assembly of the ultrasonic transducer and separated from the skin by a polymer membrane that stores the drug to be delivered. The ultrasonic transducer assembly includes a planar circular ultrasonic transducer, which defines the polarity of the transducer segments that define the top surface of the truncated cone and the wall surface of the truncated cone. The resonance frequency of the planar transducer is lower than the resonance frequency of the transducer segment. The flat planar circular transducer generates an ultrasonic stimulation impulse for a fixed frequency in the range of 5 kHz to 1 MHz, and for a predetermined time period, such as 10 to 20 seconds.

[0014] Between stimulation pulse periods, the transducer segments receive variable frequency ultrasound pumping pulses. Variable frequency ultrasonic pumping pulses are in the 50 MHz to 300 MHz range. Variable frequency ultrasonic pumping pulses are applied to opposing transducer segments. The transducer segments form a beam which is incident on the skin at an oblique angle to form a pulsating wave. In addition, variable frequency ultrasonic pumping pulses are applied in a rotating manner to opposing transducer segments to form pulsating waves in various directions within the skin. With the stimulus pulse, the flat transducer generates ultrasound, which is like a trauma such as heat or force that excites a local nerve.
Excite local nerves. With the variable frequency ultrasonic pumping pulse, the transducer segments generate ultrasonic waves on both the polymer membrane and the skin. Ultrasound pumps the drug into the polymer membrane and then introduces it into the underlying blood vessel through an opening in the skin.

[0015] Thus, ultrasonic energy, in addition to passive diffusion, provides an active source of energy, forcing molecules through pores and channels,
It can act to improve the flow of active osmotic molecules through the skin and other biological membranes.

In addition to the need to deliver drugs through the skin, there is a significant medical need to extract analytes through the skin. For example, for diabetics, it is desirable to measure blood glucose several times a day to optimize insulin treatment, thereby reducing the severe long-term complications of the disease. Currently, diabetics do this by piercing the skin with a lancet through a fingertip with many blood vessels, then squeezing the skin with hand pressure to release a drop of blood, and then using a disposable diagnostic strip and this strip. Glucose is measured using a meter compatible with This glucose measurement method has the major drawback of being painful, so that diabetic patients do not want to take glucose readings as medically indicated.

Thus, non-invasive (non-invasive) for measuring glucose, such as micro lancets, which are very small in diameter, very sharp and penetrate only the interstitium (rather than into the dermal vessels) ), And many groups are studying ways to reduce invasiveness. About 0.1 to 2 μl of a small sample of interstitial fluid is obtained by capillary force and a glucose measurement is made. Other groups use lasers to break the integrity of the stratum corneum, such that blood or interstitial fluid diffuses out of such holes and gains through such holes using pneumatic (suction) or other techniques. To One example of such a laser-based sampling device is Tankovic.
U.S. Patent No. 5,165,418 to Budnik, and Budnik.
) WPI ACC No. 94-167045 / 20 (Venisect, I
nc. (Transferred to).

One of the problems with the method of penetrating the skin to obtain interstitial fluid is that the interstitial fluid occurs in the body in a gel-like form, has little free fluid, is actually negative pressure, and is obtained The amount of free interstitial fluid is limited. If the skin is pierced with very small holes to a depth such that interstitial fluid can be obtained, a large amount of mechanical force (to obtain the required amount of blood or interstitial fluid used in the glucose meter) Milking, vacuum, or other force).

[0019] Geometric ultrasound channeling is one method of applying ultrasound to a small area. Ultrasonic channeling is described in Sontra L. et al. P. "Ultrasound Enhancement of Trans"
PCT entitled "Dermal Transport"
It is disclosed in Patent Application No. PCT / US97 / 11559, the contents of which are hereby incorporated by reference in their entirety. Vibration of a small element near or in contact with the skin surface is another method of applying ultrasound to a small area.
Can generate large forces locally, cavities, mechanical oscillations in the skin itself,
And a large localized shear force near the surface of the skin. Elements can also generate audio streaming. This indicates a large convection generated by the ultrasound. This would help to obtain a sample of blood or interstitial fluid without having to "squeeze" the perforation site. Ultrasonic transducers are known to heat up rapidly under continuous operation, reaching temperatures that can damage the skin. Thermal damage to the skin can be minimized by oscillating small elements near the skin using a transducer located away from the skin. In the case of analyte extraction, compounds present on the skin surface and / or inside the skin may contaminate the extracted sample. The level of contamination increases as the surface area of the skin increases. Surface contamination can be minimized by minimizing the surface area of the ultrasound application. Thus, the use of the methods and devices described herein, whether for drug delivery or assay measurement, can increase skin permeability locally and transiently.

Furthermore, the application of ultrasound is not required for each extraction or delivery, but only once for multiple delivery or extractions over a long period of time. That is, when an ultrasonic wave having a specific frequency and a specific intensity is applied, a large number of extractions of an analysis solution or delivery of a drug can be performed over a long period of time. For example, 20
When applying an ultrasonic wave having a frequency of kHz and an intensity of about 10 W / cm ² ,
The skin remains highly permeable for up to 4 hours. This is January 8, 1999
Mitagotri and other "Sonops" filed on the same day
horetic Enhanced Transdermal Transpo
No. 09/22, entitled "RT (Improving Transdermal Delivery by Sound Transmission)".
7,623, and "Sonophoretic" by Sontra Medical et al., Filed January 8, 1999.
PCT Application No. PCT / US99 / 00377 entitled "Enhanced Transdermal Transport".
It is described more specifically in the issue. The disclosure of which is hereby incorporated by reference in its entirety.

However, the amount of ultrasound needed to achieve this permeability improvement (eg,
Duration, intensity, duty cycle, etc.) can vary widely. Several factors of the nature of the skin must be considered. For example, the type of skin through which a substance passes varies from species to species and from age to age (eg, the permeability of infant skin is
Higher than that of older adults), depends on local composition and thickness and density, varies as a function of trauma or exposure to drugs such as organic solvents and surfactants, and may cause some Varies as a function of disease or curettage. Further, as discussed above, overexposure to ultrasound and cavitation can cause damage to the skin by heating and pressing. Therefore, there is a need to control the application of ultrasound to enable clinically useful transdermal delivery.

Accordingly, there is a need for a method and apparatus for regulating skin penetration (permeation) through a feedback system.

There is a need for a method and apparatus for controlling improved transdermal delivery. There is also a need for systems and methods for extracting and analyzing at least one analyte in a body fluid.

There is also a need for sonophoretic drug delivery methods and devices. According to the present invention, a method for improving transdermal delivery is disclosed. The method includes increasing the permeability (permeability) of an area of a membrane with a permeation (permeation) device. Next, the permeability of the area of the membrane is monitored. The substance is transported into and through the area of the membrane.

According to one embodiment of the present invention, a method for increasing the permeability of an area of skin is disclosed. The method includes applying ultrasound to the skin area. While applying ultrasound, electricity (eg, an ac current source or an ac voltage source) is applied to the skin area. While applying electricity to the skin area, a first electrical parameter of the skin area is measured. The ultrasonic wave is controlled based on the measured first electrical parameter.

According to another embodiment, the invention comprises an apparatus for improving the permeability of an area of skin. The apparatus measures an ultrasound generating device configured to apply ultrasound to a skin area, a power supply operable to apply electricity to the skin area, and measures a first electrical parameter of the skin area. The circuit includes a controller responsive to the circuit and operable to control the ultrasound generating device.

According to another embodiment, the invention comprises a method for improving the permeability of an area of skin. The method begins by forming a volume of fluid adjacent to the skin area. The fluid has an initial concentration of the first substance. Next, an ultrasonic wave is applied to the skin area. While applying the ultrasonic wave, the change in the concentration of the first substance is monitored. Finally, the method controls the ultrasound based on changes in the concentration of the substance.

According to another embodiment, the invention comprises a method for improving the permeability of an area of skin. The method begins by forming a volume of fluid adjacent to the skin area that improves permeability. A reference value is determined for the electrical parameters of this volume of fluid. The method then applies ultrasound to the skin area and monitors changes in the electrical parameters of the volume of fluid. Finally, the ultrasound is controlled based on changes in the electrical parameters of the volume of fluid.

According to another embodiment of the present invention, a method for adjusting skin permeability is disclosed. The method includes coupling a first electrode to a first skin area in electrical contact. The second electrode is arranged to make electrical contact with the second skin area. The initial conductivity (conductivity) between these sites is measured, and then a skin permeation method such as ultrasound is applied to the first skin area. The conductivity between the first area and the second area is measured again. Perform mathematical analysis and signal processing on the conductivity information. next,
Calculate parameters describing the kinetics of skin conductance. Next, once the desired value of the parameter has been reached, the skin permeation step is terminated.

According to another embodiment, the invention comprises a device for improving the permeability of an area of the skin. The device includes a first skin area that electrically couples to a first skin area.
An electrode and a second electrode arranged to make electrical contact with the second skin area. A skin permeation device, such as an ultrasound generating device, is provided to apply a skin permeation treatment to the first skin area. Means are provided for measuring conductivity between the first area and the second area. It includes a controller that performs mathematical analysis or signal processing on the conductivity information and calculates the kinetics of skin conductance. The controller also controls the skin permeation device.

According to another embodiment of the present invention, a method for extracting and analyzing at least one analyte in a body fluid is disclosed. According to this method, first the permeability level of an area of the skin is increased. Next, the body fluid is extracted from the skin area. Next, the bodily fluid is collected. Next, a determination is made as to the presence of at least one analyte in the body fluid.

[0032] Bodily fluids are characterized by physical, chemical, biological, vacuum, electrical, osmotic, diffusing, electromagnetic, ultrasonic, cavitational, mechanical, and thermal forces. Force, capillary force, skin fluid circulation, electro-acoustic force, magnetic force, magneto-hydrodynamic force, acoustic force, convection dispersion, photo-acoustic force, rinsing bodily fluids from the skin, and any combination thereof Can be extracted by Body fluids absorb, adsorb, phase separate, mechanical, electrical,
It can be collected by collection methods including chemical inductive forces, and combinations thereof. The presence of an analyte can be detected by detection methods including electrochemical, optical, acoustic, biological, enzymatic techniques, and combinations thereof.

According to another embodiment of the present invention, a system for extracting and analyzing at least one analyte in a body fluid is disclosed. The system includes a transducer that increases the permeability of an area of the skin, an extraction device that extracts interstitial fluid from the skin area, a collection device that collects the extracted interstitial fluid, and A sensing device for sensing the presence of at least one analyte.

According to another embodiment of the present invention, a method for determining blood glucose is disclosed. The method includes first increasing the permeability of an area of skin. Next, the interstitial fluid, or a component thereof, is extracted from the skin area. In another embodiment, the interstitial fluid, or a component thereof, diffuses through the skin and collects. Next, the interstitial fluid is collected in the gel. The gel may contain at least one glucose-sensitive reagent that changes at least one property of the gel, such as color, when glucose is present. Finally,
Monitor for changes in gel properties.

According to another embodiment of the present invention, a system for determining blood glucose is disclosed. The system increases the permeability of the skin, the extraction device that extracts interstitial fluid from the skin, the collection device that collects the extracted interstitial fluid, and changes the properties of the gel when glucose is present It comprises a gel having at least one glucose-sensitive reagent, and a monitoring device for monitoring a change in the properties of the gel.

According to another embodiment of the present invention, a drug delivery (delivery) patch device is disclosed. This device includes an ultrasonic transducer that applies ultrasonic waves to a membrane (membrane).
Membrane can include a biological membrane, a synthetic membrane, or a cell culture. Biological membranes can include skin, mucous membranes and oral membranes. Further, the device includes a power supply coupled to the converter.
Further, the device includes a drug molecule between the transducer and the membrane and a mounting device that attaches the device to the membrane. According to another embodiment, the device further comprises drive electronics coupled to the transducer, which allows the transducer to apply ultrasound. According to another embodiment, the device further comprises:
Includes an interface coupled to the drive electronics.

[0037] The drug delivery patch device may also include interfaces, drive electronics, power supplies, transducers, drug molecules, and mounting devices incorporated within the patch for transdermal delivery through the membrane. Alternatively, the transducer and drug molecule and attachment device can be incorporated within the patch. Power supplies and interfaces can be connected to the patch with or without connecting wires. Alternatively, a drug delivery patch can include a power supply, transducer, drug molecules, and a mounting device within the patch. The interface can be located anywhere and communicates with the patch through hardwire, infrared, fiber optic, or telemetry.

According to another embodiment of the present invention, a method of transdermal vaccination by sonic transmission is disclosed. According to this embodiment, the method comprises the steps of improving the permeability of the skin by application of ultrasound, providing a vaccine to the skin that has been rendered transparent, and providing skin cells, e.g., Langerhans cells, Delivering vaccine to dendritic cells and epidermal cells.

In another embodiment of the present invention, ultrasound is used to improve skin permeability. In another embodiment of the present invention, increasing the permeability of the skin and providing the vaccine to the skin that has been rendered permeable occur simultaneously.

In another embodiment of the present invention, ultrasound is used to stimulate or irritate an area of skin. The vaccine is then given to the irritated or inflamed skin. This is more effective in eliciting an immune response in the body.

The features and objects of the present invention, and the manner of achieving them, are described in detail in the following detailed description of the preferred embodiments, taken in conjunction with the accompanying drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, the terms skin permeation method and device include ultrasound, chemicals, electroporation,
Includes mechanical disruption devices, tape stripping, and application of lasers, and devices for these applications. In addition, the term skin includes membranes such as biological and synthetic skin.

Ultrasound is generally defined as a sound whose frequency is higher than about 20 kHz. Therapeutic ultrasound is typically between 20 kHz and 5 MHz.
Sonophoresis is defined as applying ultrasound to the skin to improve transdermal transport of molecules. Low frequency sonication or ultrasound is defined as sonication or ultrasound at a frequency of less than 2.5 MHz, typically less than 1 MHz, and more preferably in the range of 20-100 kHz.

Near-ultrasonic waves are typically about 10 kHz to 20 kHz. It should be understood that near ultrasound, in addition to ultrasound, can be used in embodiments of the present invention.

1. Improving and adjusting skin permeability It is known to facilitate transdermal delivery using ultrasound. The mechanisms that facilitate transdermal delivery using ultrasound are different. In transdermal delivery systems, ultrasound was initially used essentially as a driving force to push drugs through the skin and into the circulatory system. Ultrasound is also used to increase skin permeability. That is, the application of ultrasound having a specific frequency disrupts the structural order of the lipid bilayer in the skin, thereby increasing the permeability of the skin. In this context, the drug can be delivered into the body through the skin, or the analyte (s) can be extracted from the body through the skin. Although some driving force is still required, the required strength of the driving force is decreasing. For example, the concentration gradient
The translation gradient is generally a sufficient driving force for transdermal delivery through skin with improved permeability using ultrasound.

Regardless of which mechanism is used, it is still necessary to control the ultrasound. That is, overexposure to ultrasound can result in skin damage from heating, pressurization, and other factors. Thus, according to various embodiments of the present invention, an improved method and apparatus with controlled skin permeability is disclosed. The method and device according to the invention focus on the use of skin electrical parameters as a proxy for skin permeability. Skin can be modeled using an RC circuit as shown in FIG. The "skin circuit" shown in FIG. 1 comprises a resistor R1 in parallel with a capacitor C, both of which are in series with a resistor R2. Area about 1.7c
In intact normal skin m ^2, the value of R1 is about 100 k.OMEGA, the value of C is about 13
μF and the value of R2 is about 2 kΩ. Of course, these values vary from person to person depending on the type and condition of the skin. By its nature, the behavior of the "skin circuit" (i.e., frequency response) changes in response to excitations having different frequencies. For example, under normal conditions, the impedance of this circuit drops sharply, for example, when the frequency increases from 10 Hz to 1 kHz. That is, at low frequencies, R
The capacitive component to the impedance of the parallel combination of 1 and C is large, thus
The impedance of the whole circuit becomes high. However, the higher the frequency, the less the capacitive component to the impedance of this parallel combination, and therefore the lower the overall impedance of the "skin circuit".

Various electrical parameters of the skin (eg, impedance, conductance,
Inductance and capacitance) have values that correlate with skin permeability. For example, in the circuit of FIG. 1, the value of R1 decreases significantly as the skin becomes permeable. For example, R1 may drop to a value of about 5 kΩ for a skin area of about 1.7 cm ² . Thus, the frequency response of the entire skin circuit becomes flatter at higher frequencies. That is, the difference in circuit impedance between 10 Hz and 1 kHz is not as important as at 10 Hz alone. Accordingly, the method and apparatus of the present invention measures one or more electrical parameters of the skin area exposed to the ultrasound and then adjusts the ultrasound source based on the measured parameters.

According to one embodiment of the present invention, a method of controlled improvement of skin permeability is disclosed,
This will be described with reference to FIG. Typically, when using a skin permeation device, such as an ultrasound device, to improve transdermal transport properties, the skin permeation device is applied to a small patch of skin. You. In step 202, a baseline measurement for an electrical parameter is determined for a patch of skin to which skin permeation is applied to determine a baseline parameter. In one embodiment, the baseline impedance is measured on a skin patch to which the skin permeation device is applied. In another embodiment, baseline conductance, baseline capacitance (capacitance), baseline inductance, or baseline capacitance may be measured.

To perform a baseline measurement, two or more electrodes may be used. As shown in more detail in FIG. 3, an electrode, such as source electrode 310, is coupled to a skin patch to which ultrasound is applied. Source electrode 310 need not directly contact the skin. Rather, it may be electrically coupled to the skin via the medium used to transmit the ultrasound. A second or opposite electrode, such as a conductive band 312, may be located on a second skin area where the skin permeation device is not applied. This second skin area may be adjacent to or separate from the skin patch to which the skin permeation device is applied.

In one embodiment, the ultrasonic transducer and horn for applying ultrasonic waves doubles that of the source electrode, which can measure the electrical parameters of the skin patch, and provides the sarin (salts) used as an ultrasonic medium. Solution) to the skin via a conductive solution. In another embodiment, a separate electrode can be attached to the skin area to which the ultrasound is applied and used as the source electrode. In yet another embodiment, the housing of the device used to apply ultrasound to the skin area can be used as the source electrode. The electrodes can be made of any suitable conductive material, including, for example, metals and conductive polymers.

In order to achieve a precise electrical reading, the counter electrode must be in good contact with the skin. This can be done in many ways. In one embodiment, the counter electrode attaches directly to the epidermis of the skin. That is, a counter electrode is put on the skin area from which the stratum corneum has been removed. The stratum corneum can be removed in a number of ways. In one embodiment, the stratum corneum is removed by tape stripping. In one embodiment,
To make sufficient electrical contact between the skin and the counter electrode, a counter electrode having a large surface area is used. That is, a conductive polymer path or metal foil patch having a much larger area than the skin area exposed to ultrasound is used. The large area of the counter electrode in this embodiment reduces its impedance and allows for accurate measurement of electrical parameters of the skin area exposed to ultrasound. In one specific embodiment, a conductive band is wrapped around the subject's arm and used as a counter electrode. In another embodiment, the counter electrode may be located on the handle of the skin permeation device that the subject grips during operation.

In another embodiment, the counter electrode surrounds the skin permeation device. With the two electrodes properly positioned, a baseline measurement can be made by applying an electrical signal to the skin patch through the electrodes. The electrical signal supplied is strong enough to measure the electrical parameters of the skin, but does not damage the skin and does not affect any important electrophoretic effects of the delivered substance. It is preferable to have an appropriately low strength so as not to cause damage. In one embodiment, a 10 Hz AC power supply is used to create a voltage difference between the source electrode and the counter electrode. In one embodiment, the voltage supplied does not exceed 500 mV, preferably 100 mV, to avoid the danger of permanent damage to the skin.
Do not exceed V. In another embodiment, an AC current source is used. The current source may be similarly limited. Baseline measurements are taken after the source has been applied using the appropriate circuitry. In one embodiment, the impedance of the skin patch at 10 Hz is measured using a resistance sensor. In another embodiment, a 1 kHz power supply is used. Other frequency sources are possible.

Experiments were performed on volunteers to confirm that the electrode arrangement described above provided highly accurate measurements. The first glass chamber (area ~1.5cm ²⁾ placed in the forearm and secured with flexible strap in place. The first chamber was filled with 2 ml of 1% sodium lauryl sulfate (SLS) in saline solution. An ultrasonic horn was placed in this chamber and used to apply ultrasonic waves to the skin. in addition,
The electrodes used to measure the electrical parameters were built into the horn.

A second small chamber (〜1.5 cm ² ) was placed on the subject's arm and skin conductivity (conductivity) was measured. This is called a reference chamber. The skin under the reference chamber was tape stripped using Scotch tape to remove the stratum corneum. This process involves placing a piece of scotch tape (1.5 cm wide and 3 cm long) on the subject's arm.
) And peeling it off. This procedure was repeated up to about 25 times to remove the stratum corneum from the designated area. The electrodes were then placed on the skin under the chamber.

Another electrode is placed on the subject's arm. This electrode consists of a large piece of aluminum foil placed on intact skin. Ultrasonic waves (27 kHz, ~
(10 μm tip displacement, pulsed, 5 seconds on / 5 seconds off) was applied. The conductance of the skin exposed to ultrasound was measured using both counter electrodes (tape stripping and intact). The measured conductances were similar, demonstrating that a large counter electrode placed on intact skin could be used satisfactorily to measure skin conductance during sonication.

Referring again to FIG. 2, in step 204, a skin permeation device, such as an ultrasound delivery device, is applied to the skin patch. Although the exact ultrasound parameters are not the subject of the present invention, according to one embodiment where the ultrasound device is used as a skin permeation device, an ultrasound having a frequency of about 20 kHz and an intensity of about 10 W / cm ² is used. This can improve the permeability of the skin patch used for transdermal delivery.

After turning on the skin permeation device, at step 206, the permeability of the skin patch is monitored. That is, as discussed above, the electrical parameters of the skin patch are used instead of skin permeability. That is, what is actually monitored are the electrical parameters for which the baseline measurement was performed in step 202. The monitoring measurements are performed using the same electrode settings used to make the baseline measurements.

In step 208, the skin permeation device is controlled based on the monitoring measurements performed in step 206. In one embodiment, the monitoring measurements are fed back to a microcontroller used to control the skin permeation device. When ultrasonic waves are used, there is a limit to the improvement in transmittance obtained by supplying ultrasonic waves. That is, once a certain degree of permeability is reached, the permeability of the skin is not improved by further application of ultrasound. Overexposure to ultrasound, or the resulting cavitation, can lead to skin damage due to local pressure, elevated temperature, and shear stress. Thus, in one embodiment, the ultrasound generation device is turned off when the monitored parameter reaches a predetermined value. If the parameter to be monitored has not reached the predetermined value, the measurement is repeated until the parameter reaches the predetermined value.

The predetermined value can depend on a number of factors, including, among other things, the skin properties of the individual, the drug to be delivered, or the analyte (s) to be extracted (the molecular size is not constant) ), And the frequency of the excitation source. As will be apparent to those skilled in the art, the specific correlation between the electrical parameters used and skin permeability can be determined by performing experiments and using experimental data. A predetermined value can then be determined for each subject, taking into account all appropriate factors and experimental data.

[0060] According to another embodiment, the strength of the skin permeation device may also gradually scale back as it approaches the point of maximum permeability improvement. In one embodiment, when the monitored parameter reaches 50% of the predetermined value, the intensity or duty cycle
Any of the cycles can be reduced by a predetermined amount, such as 50%. This is done so that the predetermined value does not "overshoot" and increase the risk of skin damage. Additional controls are also possible. For example, in another embodiment, the intensity can be scaled back when the monitored parameter reaches 25%, 50%, and 75% of the predetermined value.

According to another embodiment, the transparency improvement control can be performed using two power supplies having different frequencies. This method relies on the above observation that the skin's frequency response flattens as the skin's permeability increases. In this embodiment, the first step 202 of measuring a baseline for the parameter is not required. This is because ultrasound control is based on the difference between parameter values at two different frequencies of the stimulus. However, a baseline measurement may still be desirable to determine the range of predicted values. In this embodiment, the arrangement of the electrodes may be the same as described above. Step 20 of starting application of ultrasonic waves
4 is the same as described above. Therefore, the details of these steps will not be repeated.

After initiating skin permeation in step 206, skin permeability is monitored. In this embodiment, electrical parameters measured from the skin are also used in monitoring skin permeability. This embodiment differs from the first embodiment in that electrical parameters are measured at two frequencies. In one embodiment, 10 Hz and 1 kHz
The skin impedance is measured at a frequency of. These measurements are then used to control the skin permeation device.

According to this embodiment, in step 208, the parameter measurement value at the first frequency is compared with the parameter measurement value at the second frequency to determine whether the two measurement values are within a predetermined difference. Do. If the two values are within a predetermined difference, this is an indication that the frequency response of the skin has flattened, and thus the skin has reached an improved level of permeability. At this point, the skin permeation device is turned off. In one particular embodiment, the impedance of the skin is measured at 10 Hz and 1 kHz. Further, the skin permeation device may be turned off if the two impedance measurements are within 20% of each other.

The rate of change of the parameter measurements can also be used to determine the point at which the skin permeation device scales back or interrupts (stops). The rate of change of one or both of the parameters can be used. In another embodiment, the rate of change of the difference between the two parameters may be used. When the rate of change reaches a predetermined value, the strength of the skin permeation device can be gradually scaled back (returned) or interrupted, as discussed above.

As discussed above, the value of a given difference can depend on a number of factors, including, among other things, the skin properties of the individual, the drug to be delivered or the analyte to be extracted (molecular And the frequency of the excitation (stimulus) source. Thus, a predetermined difference is determined for each subject, taking into account all appropriate parameters. Empirical data may be used to determine the exact value for a given difference.

In a variation of this embodiment, the strength of the skin permeation device can gradually scale back as it approaches the point of maximum permeability improvement. For example, when the difference between two parameter measurements approaches 50% of the predetermined difference value, either the intensity or the duty cycle can be reduced by a predetermined amount, such as 50%. Additional controls are also possible. For example, in another embodiment, when the difference between the two monitored parameters reaches 25%, 50% and 75% of the predetermined difference value,
Scale back the intensity.

In order to evaluate the two-source method described above, in vitro experiments were performed. Pig skin was mounted on the diffusion cell. Place the skin on the diffusion cell and
% Sodium lauryl sulphate and saline solution were used as binding media and exposed to ultrasound. Two electrodes were placed across the skin and the conductance of the skin was measured. Impedance was measured at two frequencies, 10 Hz and 1 kHz.
When the skin had no permeability, the impedance was measured at a frequency about 25 times apart before the application of the ultrasonic wave. Upon sonication, the difference between the impedances at the two frequencies decreased. The decrease in impedance difference increased with time. With increased skin permeability, the difference in impedance at the two frequencies was only 〜20%. Thus, using the difference between the impedances measured at the two frequencies,
The level of transmittance can be determined and the sonication stopped.

The method described above used a single electrical parameter to control the ultrasound generating device. However, control of the ultrasound generating device can also be based on more than one electrical parameter.

According to another embodiment of the present invention, an apparatus 30 for improved control of transdermal transport
0 will be described with reference to FIG. The apparatus 300 uses an ultrasonic generation device as a skin permeation device. It should be noted that other devices that increase skin permeability can be used in place of the ultrasound generating device. For example, skin permeability can be enhanced by the application of electric fields, chemicals, mechanical forces, needles, and magnetic forces.

The device 300 comprises an ultrasonic transducer / horn combination 30
2, including a source 304, a bandpass filter 306, a transmission monitoring circuit 308, a source electrode 310, a return electrode 312, and a microcontroller 314. The transparency monitoring circuit 308 includes a current sensor 315, an amplifier 316, and an A / D converter.
(Converter) 318 and the resistor 320.

The ultrasonic transducer / horn combination 302 is used to apply ultrasonic waves to the skin area 322. Transducer 302 may be any known ultrasonic transducer, such as a piezoelectric transducer, a ceramic transducer, or a polymer block transducer. The horn can have any known configuration. In one embodiment, the horn is made of a conductive metal.

As described above, while delivering ultrasound to the skin area, monitor skin permeability,
It is important to control the application of ultrasound so that the skin is not overexposed to ultrasound. Apparatus 300 may include the aforementioned electrical control circuit elements to perform this monitoring and control. Specifically, it includes a source 304 and a band-pass filter 306, and drives an electric control circuit. That is, a small signal is passed through the skin area to obtain electrical parameter measurements that are used to control the source 304. In one embodiment of the present invention, source 304 provides a 10 Hz AC square waveform voltage, which is used to monitor the permeability of the skin area in device 300. A bandpass filter 306 is provided to convert a square wave to a sine wave.

The source electrode 310 and the return electrode 312 form an electrical path so that electrical parameters of the skin area 322 can be measured. The source electrode 310 may be incorporated into the transducer / horn combination 302 and is preferably formed from any suitable conductive material. In one embodiment, the ultrasonic horn is metal and is used as a source electrode. Return electrode 312 is a conductive band and is preferably formed of a conductive polymer pathway or metal foil.

The permeability monitoring circuit 308 includes circuitry designed to measure electrical parameters of the skin as a proxy for skin permeability. More specifically, according to one embodiment of the present invention, the permeability monitoring circuit 308 measures the current passing through an area of the skin 322 and converts the measurement into a form suitable for use by the microcontroller 314. It has a circuit designed to convert. Permeability monitoring circuit 308
Comprises a current sensor 315 operable to measure the impedance of the area of the skin 322. The current sensor 315 may be any sensor capable of measuring current, and in one embodiment, the current sensor 315 is a 1 kΩ current sensing resistor, and the output voltage generated is 1000 times the current passing through the skin. . Current sensor 3
The output of 15 is an analog signal and must be digitized before use by microcontroller 315. Amplifier 316 and resistor 320 act to amplify the output voltage of current sensor 315 so that digitization by A / D converter 318 is possible. The A / D converter 318 may be any suitable A / D converter.

The signal from A / D converter 316 can then be provided to microcontroller 314. Microcontroller 314 may be any suitable microcontroller. Microcontroller 314 is programmed to control transducer drive circuit 324, as described above. In one embodiment, microcontroller 314 determines whether a signal from transparency monitoring circuit 308 is greater than a certain predetermined value. If so, the microcontroller 314 may, for example, shut off DC power to the
Ultrasound can be stopped. Microcontroller 314 can also be configured to perform other controls, such as changing the duty cycle of converter drive circuit 324 with a phase locked loop circuit.

According to one embodiment of the present invention, additional controls and user interfaces may be provided. Fluid controller 330 controls the pumps and fluids of the system. A pump 332 may be provided to seal between the transducer 302 and the surface of the skin 322. Pump 334 can be used with valve 337 to fill and evacuate the chamber of transducer 302. The coupling (coupling) fluid used in the transducer 302 may be provided in a cartridge 338. Other devices and methods can be used to supply the coupling fluid.

A user interface may also be provided. User interface 340 includes a low battery sensor 342, which may include a comparator. A switch 344 can be provided to turn the ultrasound generation device on or off. An input 346 can be provided to allow the user to adjust the ultrasound intensity. The ultrasonic level can be displayed on the display 350. The permeability level of the skin can be displayed on the display 352. Indicators 354 and 356 can be provided to inform the user of the operation of the ultrasound and to warn when the battery is low. Additional controls and displays may also be provided, if necessary, to prevent the user from applying hazardous intensity and duration ultrasonic waves, or before the system is ready (ie, the transducer 302).
Before the coupling fluid is supplied to the other, etc.).

The circuit described above can be replaced with other elements if the measurement of the electrical parameter is performed in another way. More specifically, if a control methodology using sources at two frequencies is employed, the circuit shown in FIG.
4. Can be used in place of bandpass filter 306 and transparency monitoring circuit 308. FIG. 4 schematically illustrates one embodiment of a circuit useful in implementing dual frequency control of skin permeability. This circuit comprises sources F1 and F2 that supply two different AC signals to the skin area where the ultrasound is being applied. In one embodiment, sources F1 and F2 comprise 10 Hz and 1 kHz current sources, respectively. These sources are alternately applied to the skin area via microprocessor controlled switches. In the embodiment shown in FIG. 3, the microcontroller 314 controls the switching so that the sources F1 and F2 alternately stimulate the skin.

After stimulation by one of the sources, the impedance of the skin is measured by measuring the voltage V1. That is, the gain circuit 402, the diode 404, and the capacitor C
1 and V1 via output resistors R01 and R02 to a microprocessor (eg, microcontroller 314 of FIG. 3). Diode 40
4 and the capacitor C1 make it possible to set A1 suitable for input to the A / D converter
Construct a C / DC converter. This converts the analog signal from gain circuit 402 into a digital signal suitable for use by a microprocessor. Output resistance R01
And R02 perform impedance matching and filtering, respectively, for the microprocessor.

In operation, the circuit of FIG. 4, with an appropriately programmed microcontroller, alternately applies 10 Hz and 1 kHz AC power to the skin. This circuit is
In cooperation with the microprocessor, the impedance of the skin is measured at both frequencies. The microcontroller makes appropriate adjustments to the ultrasound generating device based on the difference between the skin impedance at 10 Hz and the skin impedance at 1 kHz.

FIG. 5 schematically illustrates yet another embodiment of a permeability monitoring circuit for use with multiple frequency stimuli. In the circuit of FIG. 5, the sources F1 and F2 are simultaneously applied to the skin area to which the ultrasonic wave is applied via the adding circuit 502. Next, the output signal from the skin is provided to two bandpass filters 504 and 506. The elements C1, C2 and R1 of the bandpass filter 504 are preferably selected to form a passband centered around the frequency of the source F1. Elements C3, C4 and R2 of bandpass filter 506 are connected to source F
It is preferable to select so as to form a pass band centered around the frequency of 2. The output signals from bandpass filters 504 and 506 are then subtracted in comparison circuit 508 to form a difference signal for the microprocessor.
An appropriately configured processor then uses the difference signal to make appropriate adjustments to the ultrasound generating device.

In another embodiment of the present invention, a method for controlled improvement of skin permeability by coupled fluid monitoring is disclosed. When applying a skin permeation device, such as an ultrasound generating device, to the skin, apply it through some binding fluid, which may be a liquid, gel, or solid, to facilitate the transfer of high frequency sound wave energy to the skin . As skin permeability increases, appropriately sized molecules and ions within the binding fluid begin to pass into and out of the skin. The method according to this embodiment takes advantage of the improved skin permeability, a desirable endpoint of the present invention, to control the skin permeation device. This method will be described with reference to the flowchart of FIG.

In step 602, an initial concentration of the known substance is determined for the binding medium. In practice, the binding medium may have a known initial concentration of a known substance. That is, step 602 does not require any additional measurements. The known substance can be any substance (molecule or ion) as long as its concentration in the binding medium is known. However, if the substance is sent into the body, the substance must not be harmful to the body. Here, a benign (
benign) is used. Glucose and calcium are examples of substances that can be used in this embodiment.

In step 604, a skin permeation device is applied to the skin patch. In one embodiment, the ultrasound generating device is used as a skin permeation device. The exact parameters of the ultrasound are not the subject of the present invention, but according to one embodiment, about 20k
The use of ultrasound having a frequency of Hz and an intensity of about 10 W / cm ² improves the permeability of the skin patch and allows it to be used for transdermal delivery.

After turning on the skin permeation device, at step 606, the permeability of the skin patch is monitored. According to this embodiment, when performing the permeability monitoring, a change in the concentration of a known substance in the binding medium is monitored. That is, when the skin permeation device is applied to the skin area, it becomes permeable. As the skin area becomes permeable, molecules and ions begin to move into the binding medium from inside the body and from the binding medium into the body, depending on the concentration gradient of the substance between the body and the binding medium. This concentration monitoring can be performed in real time using an online sensor specifically programmed to detect and measure the concentration of a known substance.

In one embodiment, glucose is used as a known substance. The concentration of glucose is usually higher in the body than in the binding medium, unless the concentration in the binding medium is artificially increased. Thus, as the skin becomes permeable, glucose molecules begin to migrate into the binding medium. In step 606, the change in glucose concentration in the binding medium is monitored to determine when the skin becomes permeable.

In another embodiment, mannitol is used as a known substance. Mannitol, in the context of the present application, is a benign substance. The concentration of mannitol in the binding medium is adjusted to be higher than the mannitol concentration in the body. As the skin becomes permeable, mannitol molecules begin to migrate from the binding medium into the body and the mannitol concentration in the binding medium decreases. In step 606, the decrease in mannitol concentration in the binding medium is monitored to determine when the skin becomes permeable.

In step 608, the skin permeation device is controlled based on the density measurement performed in step 606. In one embodiment, the concentration measurements from the chemical analyzer are fed back to the microcontroller used to control the skin permeation device. According to another embodiment, when the concentration of the substance to be monitored reaches a predetermined value, the skin permeation device is turned off. If the concentration of the substance to be monitored has not reached the predetermined value, the measurement is repeated until the concentration reaches the predetermined value.

The predetermined value depends on a number of factors, including, among other things, the skin properties of the individual, known substances, and the frequency of the stimulus. As will be apparent to those skilled in the art, the specific correlation between changes in the concentration of a known substance used and skin permeability can be determined by performing experiments and using experimental data. A predetermined value is then determined for each subject, taking into account all appropriate factors and any empirical data.

According to another embodiment, the strength of the skin permeation device can gradually scale back as it approaches the point of maximum permeability improvement. In one embodiment using an ultrasound generating device, when the concentration of the monitored substance approaches 50% of the predetermined value, either the intensity or the duty cycle of the ultrasound is reduced by a predetermined amount, such as 50%. be able to. This is done so that the predetermined value does not "overshoot" and increase the risk of skin damage. Additional control is possible. For example, in another embodiment, the concentration of the monitoring target is 25% of a predetermined value, 50%.
When the% and 75% are reached, the intensity can be scaled back.

It is also possible to use the rate of change of the concentration of a substance to determine the point at which the skin permeation device is scaled back or interrupted. When the rate of change of concentration reaches a predetermined value, the strength of the skin permeation device can be gradually scaled back or interrupted, as discussed above.

In another embodiment, skin permeability can be monitored by detecting electrical parameters of the binding fluid. More specifically, increased skin permeability allows ions to move into and out of the binding medium. As the ion concentration in the coupling medium increases or decreases, the electrical properties of the coupling medium change. Thus, the electrical properties of the coupling medium can be used to monitor skin permeability using a methodology that is a hybrid of the methods shown in FIGS. This is illustrated in FIG.

In a first step 702, a reference value of an electrical parameter is determined for the coupling medium. In practice, since the binding medium has a known ionic composition, its electrical parameters should be known. In one embodiment, the binding fluid is a known concentration of calcium ions. Therefore, this step does not of course require an actual measurement. In another embodiment, the electrical parameter to be determined is conductivity (conductivity), and in step 702, the conductivity of the coupling medium is determined.

After determining the reference values for the electrical parameters, in step 704, the skin permeation device is turned on. Then, in step 706, skin permeability is determined by monitoring changes in the electrical parameters of the binding medium. This monitoring may be performed using a simple measuring device. As the skin becomes permeable, depending on the composition of the binding medium, ions can migrate into or out of the binding medium, increasing or decreasing the electrical parameters of the binding medium. In one embodiment, the binding medium is a known concentration of calcium ions, which is lower than the concentration of calcium ions in the body. Thus, as skin permeability increases, calcium ions begin to migrate from the body into the binding medium.

At step 708, the skin permeation device is controlled based on the monitoring measurements. In one embodiment, the monitoring measurements are fed back to a microcontroller used to control the skin permeation device. In one embodiment, the skin permeation device is turned off when the monitored electrical parameter reaches a predetermined value.
If the parameter to be monitored has not reached the predetermined value, the measurement is repeated until the parameter reaches the predetermined value.

The rate of change of the monitored parameter can also be used to determine the point at which the skin permeation device scales back or interrupts. When the rate of change reaches a predetermined value, the strength of the skin permeation device can be gradually scaled back or interrupted, as discussed above.

The predetermined value depends on a number of factors, including, inter alia, the composition of the binding medium, the surface area of the skin patch to which the skin permeation device is applied, and the concentration of certain ions used in the body. included. Given all appropriate factors and empirical data, a predetermined value is determined for each subject.

According to another embodiment, the strength of the skin permeation device can gradually scale back as it approaches the point of maximum permeability improvement. In one embodiment using ultrasound, when the monitored parameter approaches 50% of the predetermined value, either the intensity or the duty cycle can be reduced by a predetermined amount, such as 50%. This is done so that the predetermined value does not "overshoot" and increase the risk of skin damage. Additional control is possible. For example, in another embodiment, the intensity can be scaled back when the monitored parameter reaches 25%, 50%, and 75% of the predetermined value.

According to another embodiment of the present invention, there is provided an apparatus and method for adjusting the degree of skin permeability (permeability) by a feedback system. This device and method are similar to those described above, with the addition of a degree of skin permeability adjustment. However, in this embodiment, the application of the skin permeation device is terminated when the desired value of the parameter describing the skin conductance is obtained. As the discussion proceeds with respect to FIG. 8, it will be noted that the preceding description is relevant to this description.

Referring to FIG. 8, a flowchart of the method is shown. In step 802,
A first or source electrode is coupled in electrical contact with a first area of skin requiring permeation. As discussed above, the source electrode need not be in direct contact with the skin. Rather, it may be electrically coupled to the skin via the medium used to transmit the ultrasound. In one embodiment using an ultrasound generating device as a skin permeation device, the ultrasound transducer and horn used to apply the ultrasound are:
Doubling that of the source electrode capable of measuring the electrical parameters of the first skin area,
It is bound to the skin via a saline solution used as an ultrasonic medium. In another embodiment, a separate electrode is attached to the first skin area and used as a source electrode. In yet another embodiment, the housing of the device used to apply ultrasound to the first skin area is used as the source electrode. The source electrode can be made of any suitable conductive material, including, for example, metals and conductive polymers.

Next, in step 804, a second or counter electrode is coupled in electrical contact with a second skin area at another selected location. This second skin area
It can be adjacent to the first skin area or it can be remote from the first skin area. The counter electrode can be made of any suitable conductive material, including, for example, metals and conductive polymers.

In order to achieve a precise electrical reading, the counter electrode must be in good contact with the skin. This can be done in many ways. In one embodiment, the counter electrode attaches directly to the epidermis of the skin. That is, a counter electrode is applied to the skin area from which the stratum corneum has been removed. The stratum corneum can be removed in a number of ways. According to one embodiment, the stratum corneum is removed by tape stripping. In another embodiment, a counter electrode having a large surface area is used to make sufficient electrical contact between the skin and the counter electrode. More specifically, a conductive polymer path or metal foil patch having a much larger area than the skin area exposed to the skin permeation device is used. The large area of the counter electrode in this embodiment reduces its impedance and allows for accurate measurement of electrical parameters of the skin area exposed to the skin permeation device. In one specific embodiment, a conductive band is wrapped around the subject's arm and used as a counter electrode. In another embodiment, the counter electrode may be located on the handle of the skin permeation device that the subject grips during operation.

[0103] In another embodiment, the counter electrode surrounds the skin permeation device. Once the two electrodes have been properly positioned, step 806 measures the initial conductivity between the two electrodes. This can be done by applying an electrical signal to the patch on the skin via the electrodes. In one embodiment, the electrical signal provided is of sufficient strength to allow the measurement of electrical parameters of the skin, but the electrical signal may cause permanent damage to the skin or any important electrophoresis for substances to be delivered. It has a suitably low strength so as not to damage the effect. In one embodiment, a 10 Hz AC power supply is used to create a voltage difference between the source electrode and the counter electrode. The voltage supplied does not exceed 500 mV, preferably it should not exceed 100 mV. Otherwise, there is a risk of damaging the skin. In another embodiment, A
A C current source is used. The current source may be appropriately limited. The initial conductivity measurement is taken after the source has been applied using the appropriate circuitry. In one embodiment, the impedance of the skin patch at 10 Hz is measured using a resistance sensor.
In another embodiment, a 1 kHz power supply is used. Other frequency sources are possible.

At step 808, a skin permeation device is applied to the first part of the skin. Any suitable device that enhances skin permeability can be used. In one embodiment, the ultrasound is applied to a first portion of the skin. In one embodiment, 20 kHz
Ultrasound having a frequency of z and an intensity of about 10 W / cm ² is used to improve the permeability of skin patches and used for transdermal delivery.

At step 810, the conductivity between the two sites is measured. The conductivity may be measured periodically or connected continuously. When performing monitoring measurements, use the same electrode settings that were used when performing the initial conductivity measurement.

At step 812, mathematical analysis and / or signal processing may be performed on the time variation of the skin conductance data. Experiments were performed on volunteers using ultrasound as a method of permeabilization according to the procedure described above. Ultrasound was applied until the subject reported pain. The skin conductivity was measured once per second during the ultrasonic exposure. After plotting the conductance data, the graph resembled a sigmoidal curve. The conductance data was a general S-shaped curve equation.

[0107]

(Equation 2)

Here, C is a current, Ci is a current at t = 0, Cf is a final current, S is a sensitivity constant, t * is an exposure time required to obtain an inflection point, and t is an exposure time. is there.

FIG. 9 shows the temporal variation of skin conductance during exposure to ultrasound. The curve is an S-shaped curve and can be fitted into the above equation. The line shown in FIG. 9 corresponds to the fit to the above equation. Obtain and plot the values of the fitted parameters. The value of t * is the inflection point (the point where the slope of the curve shown changes the sign)
Corresponds to the exposure time required to obtain The inflection time approximately indicates the time required to reach half of the total exposure.

FIG. 10 shows the relationship between inflection time and pain time for various volunteers. This data shows that for human volunteers, the time to distress is proportional to the time to inflection point. In this figure, R2 is a correlation coefficient,
R2 = 1 indicates a 100% correlation with the predicted value of the experimental data. Based on this data, a method for estimating the required ultrasonic exposure time can be configured.

Referring to FIGS. 11 and 12, there are shown a flowchart illustrating a method of determining when to stop applying ultrasonic waves, and an example of a corresponding graph. Step 1
At 102, A / D conversion is performed on the conductivity data. As a result, FIG.
A graph similar to the graph in a is obtained. Next, in step 1104, the digital data is filtered. As shown in FIG. 12b, the filtered data has a smoother curve than the unfiltered data of FIG. 12a. Next, in step 1106, the slope of the curve is calculated. In step 1108, the maximum value of the slope is saved. If the current value of the slope is greater than the saved maximum value, replace the maximum value with the current value. Next, step 1110
At, if the slope is not less than or equal to the maximum value, the process returns to step 1102 and
Wait for the peak. If the slope is less than or equal to the maximum, the process detects the peak or inflection point shown in FIG. 12c in step 1112, and then ends the application of the ultrasound to the skin in step 1114.

In one embodiment, the effectiveness of peak detection may be checked. This can be provided to confirm that the “peak” detected in step 1112 is not a noise but an actual peak.

In another embodiment, the ultrasound may be applied even after reaching the inflection point. In one embodiment, an ultrasonic wave is applied for a predetermined time. This predetermined time can be based on the percentage of time to reach the inflection point. For example, once the inflection point is reached, ultrasonic waves are continuously applied for 50% of the time required to reach the inflection point. Therefore, if it takes 14 seconds to reach the inflection point, ultrasonic waves are applied for another 7 seconds. Other percentages may be used, and may be based on factors including pain threshold and skin characteristics.

[0114] In another embodiment, ultrasound is applied until the slope drops to a certain value. Figure 1 again
Referring to FIG. 1, after reaching the inflection point, the inclination decreases as ultrasonic waves are applied. Thus, ultrasound can be applied by a percentage, such as 50%, or until the slope decreases to some predetermined value. As mentioned earlier, this decision is flexible,
It may be changed for each individual.

In another embodiment, the current at the inflection point is measured and then a percentage of this current is still applied. For example, if the inflection point is reached at 40 μA,
Can be further reached, ie a total of 44 μA. Also in this case, this determination is flexible and may be changed one by one.

Referring to FIG. 8 again. In step 814, parameters describing the dynamics of the skin conductance change are calculated. These parameters include, among other things, skin impedance, skin impedance variation over time, final skin impedance, skin impedance at inflection, final current, exposure time to inflection, and the like.

In step 816, when the desired value of the parameter describing the skin conductance is obtained, the skin permeation device applied in step 808 is stopped.

EXAMPLES In vitro experiments were performed according to a method according to one embodiment of the present invention. Porcine skin was mounted on a diffusion cell and exposed to ultrasound using water containing 1% sodium lauryl sulfate as the binding medium. Two electrodes were placed across the skin and the conductance of the skin was measured. The impedance was measured at two frequencies, 10 Hz and 1 kHz, which are close to the ultrasonic range. About 25 when the skin is not permeable
The impedance was measured at twice the frequency. Upon sonication, the difference between the impedance at the two frequencies decreased. The impedance difference between the two frequencies decreased with time. With increased skin permeability, the difference in impedance at the two frequencies was only about 20%. The SLS was removed from the chamber and the chamber was dried. The gel was placed in the chamber in contact with the skin. The gel was prepared by mixing glucose reagent (10% by weight) from Sigma ™ (Sigma (trademark)) kit 315 with a polyvinyl alcohol solution (20% by weight) in PBS. The gel was kept in the freezer to allow crosslinking. The gel was initially clear and turned red when exposed to glucose.

[0119] 2. Extraction and Analysis of At least One Analyte in Body Fluid According to another embodiment of the present invention, ultrasound can be used to extract a body fluid through the skin that has become more permeable, ie, outside the skin. Referring to FIG.
A flowchart illustrating a method for extracting and analyzing at least one analyte in a body fluid according to one embodiment of the present invention is disclosed. In step 1302, skin permeability is increased. This can be done by any suitable method for increasing skin permeability, such as iontophoresis. In one embodiment, the application of ultrasound can increase the permeability of the skin.

As used herein, the term “interstitial fluid” can include lymph, interstitial fluid, and serum extractable from the body. It is also used when describing the components of interstitial fluid.

In step 1304, interstitial fluid is extracted percutaneously from the surface of the skin. Extraction can be performed after sonication or other methods of transmission using a wide variety of different forces. These forces are physical, chemical, biological, vacuum, electric, osmotic, diffusion, electromagnetic, ultrasonic, cavitation
n), including mechanical, thermal, capillary forces, skin fluid circulation, electroacoustics, magnetism, magnetohydrodynamics, acoustics, convective dispersion, photoacoustics, rinsing bodily fluids from the skin, or any combination of these forces Can be.

[0122] Spatial and / or temporal positive and / or negative pressure modulation can also be used. In spatial modulation, a positive pressure is applied to the skin area, a vacuum is applied to another area,
Helps extract body fluids. In temporal modulation, vacuum and positive pressure are alternately applied to approximately the same skin area to assist in the extraction of bodily fluids. Any application of spatial or temporal modulation may be continuous or discontinuous, and they may be applied separately or in combination.

In one embodiment, a body pressure can be extracted by applying a vacuum pressure. The vacuum pressure can be applied continuously, or it can be applied discontinuously. When applying discontinuously, the vacuum may be applied in a pulsed manner. Substances that maintain the surface shape (eg, planar, convex, or concave) of the skin, such as meshes, membranes, perforated metals, or other porous materials, while applying vacuum pressure, are subjected to vacuum pressure and skin It is good to arrange between. Vacuum can act through these structures, and the vacuum can be generated mechanically, electromechanically, chemically, or electrochemically. In other embodiments, a vacuum can be applied to maintain the skin topography only with the vacuum.

In another embodiment, the skin-depositing chamber can have a design (configuration and material properties) that localizes the high pressure gradient in the skin and / or other tissues.

In another embodiment, an electrical force can be applied. The electrical force can be ion osmosis, electro osmosis, or electroporation. It is also possible to apply a charged gel to facilitate the absorption and elimination of body fluids and their components.

[0126] In another embodiment, osmotic power can be used. A gel or solution is applied to the skin surface to promote penetration. In another embodiment, ultrasound is used to wick and levitate bodily fluids and fluid components, activate a gas body, create circulating impulse mechanical stress in the skin, and form microstreaming. , Increasing the temperature, or setting a standing wave. Using one or multiple ultrasonic sources with various ultrasonic properties, such as different frequencies, intensities, or coupling media,
It can also facilitate the extraction of bodily fluids.

[0127] In another embodiment, bodily fluids can be extracted using mechanical force. These forces are obtained, inter alia, by rollers, squeezers, stretchers, iris compressor / tensioner devices, etc., and can increase the amount of bodily fluids extracted.

In one embodiment, a bodily fluid is extracted using a tensioner. FIG.
Referring to, one embodiment of a tensioner is shown, wherein the tensioner 1402 comprises a convex geometry that is held against the skin 1404. Tensioner 1
By pressing 402 against skin 1404, cavity 1 of tensioner 1402 is
Body fluid can be collected in 406.

In another embodiment, bodily fluids can be extracted using thermal power. The temperature of the skin can be raised using an electrical, chemical, ultrasonic, or light energy source or method, and / or utilize a temperature sensitive polymer to swell or shrink the gel, membrane and / or solid In this way, the absorption and elimination of body fluids and their components can be promoted. The piston or membrane may be moved using a temperature sensitive polymer to extrude or aspirate fluid. Examples of such polymers include poloximers, among others.

[0130] In another embodiment, chemical forces are used. Chemicals can be used to increase convective and / or diffusive forces as a means to extract additional bodily fluids and / or to enhance transport and / or accumulation of bodily fluids at specific body sites. . Hydrogels that incorporate, incorporate, or immobilize bioactive molecules such as enzymes allow for osmotic extraction into a sensing scafford.

[0131] In another embodiment, pH / ionic force can be used. These forces can be used to change the properties or characteristics of a material. For example, a hydrophilic material can be changed to a hydrophobic material. pH / ion sensitive membrane and / or
Alternatively, it swells or shrinks the gel to promote absorption and elimination of bodily fluids and their components.

In another embodiment, capillary forces can be used. These forces can be used to assist fluid transport through pores in the skin. Referring again to FIG. 13, in step 1306, a bodily fluid and its components are collected. This collection can be obtained by absorption, adsorption, phase separation, mechanical, electrical, chemically induced, or a combination thereof. Preferably, a humid environment is created and maintained to control analyte evaporation during extraction. The volume of bodily fluid collected may be the same as the volume extracted, but may be a fixed, fixed volume.

In one embodiment, absorption or adsorption can be used. In this embodiment,
The body fluid is collected in a gel containing the restriction enzyme. This can be done using a polymer, metal, or ceramic screen, scaffold, mesh, or membrane, or a combination. These materials can also be components of the sensor.

In one embodiment, phase separation can be used. Body fluids can be separated by combining them with an immiscible fluid of appropriate density. Body fluid can be collected in a conical chamber.

In another use of phase separation, a hydrophobic coating is first applied on the skin prior to the extraction step. After extraction, the bodily fluid is present in the form of drops on the hydrophobic coating.

In another embodiment, bodily fluids can be collected using mechanical force. this is,
Including forces such as vacuum, pressure, and acoustic power. The dispersed body fluid can be collected from a larger area to a smaller area using microfluidic channels on the skin. Means for effecting drainage of the fluid path may include the introduction of a liquid and / or gas. This discharge means can be applied to all collection processes, not just mechanical collection.

[0137] In another embodiment, electrical collection can be used. In this embodiment, a solid, liquid droplet, or gas is charged and transported (transferred) from the skin to the sensor or collection compartment using electrical force.

In another embodiment, chemical collection can be used. The body fluid can be collected using a hydrophilic gel. Material properties and characteristics can be varied, for example, from a hydrophilic material to a hydrophobic material, to facilitate absorption and elimination of bodily fluids and their components.

[0139] In another embodiment, capillary collection can be used. Fluid can be collected in a capillary tube or a plurality of capillaries. This allows the quantitative volume (quantit
active volume) or a method of moving fluid to the sensor. A single capillary or multiple capillaries can be filled with a large number of fibers to increase the surface area over which the adhesive force of the fluid can act. This method can be used in combination with chemicals and / or other driving forces.

In step 1308, the concentration of the analyte in the body fluid is detected. Sensing the concentration of an analyte present in a body fluid can be performed by employing electrochemical, light, acoustic, biological, and enzymatic techniques in combination or alone. The sensor or sensors may be disposable, refillable, single or continuous.

According to one embodiment, the sensing device is one that can detect more than one analyte.
It can have one or more sensors. When one or more or a combination of several analytes is present at a stable and / or predictable physiological concentration, the ratio of one analyte to the other allows concentration detection and self-calibration Becomes
Neither the volume of the body fluid nor the dilute volume needs to be known.

If the sensing device is presented with a known volume of bodily fluid (undiluted) and a known volume of diluent, it is not necessary to calibrate frequently. In one embodiment, the body fluid is extracted and an optical analysis is performed on the body fluid.

In another embodiment, a bodily fluid is extracted and an electrochemical analysis is performed on the bodily fluid. In another embodiment, a bodily fluid is extracted to detect and analyze the acoustic emission of an analyte undergoing a chemical reaction.

In another embodiment, a bodily fluid can be extracted and the concentration of the analyte in the bodily fluid detected using the living cells. In another embodiment, the bodily fluid is extracted and a thermal analysis is performed on the bodily fluid.

At step 1310, information is provided to a user interface. The user interface may include features for both day and night monitoring. In one embodiment, this can include high / low analyte concentration alarms, provide trends and history, and allow for prediction of future concentration values. The user interface may include a function for downloading the history. Other useful features, such as a low battery indicator, may also be included in the user interface. The batteries are solar cells, nickel
It can be a cadmium battery, a standard alkaline battery, or a lithium ion battery.

In another embodiment, the presence of an analyte can be detected without extracting it after increasing skin permeability. For example, using infrared light to detect the presence of an analyte can reduce H ₂ O interference.

In another embodiment, after increasing the permeability of the skin, at least one analyte can be passively diffused through the skin. The analyte can be collected in a gel used as a collection device, and the presence of the analyte can be detected using a sensing device attached to the gel.

In another embodiment, a further method of generating cavitation and convection is provided before, after and after the step of sonication and / or extraction and / or collection for skin permeation.
Or it can be applied instead. These methods include the use of propellers, flywheels, transverse needles, and local shear induced permeation.

In another embodiment, blood glucose levels can be determined using the non-invasive methods disclosed herein. Referring to FIG. 15, in step 1502, skin permeability is increased. This can be done in any suitable way. Preferably,
Ultrasound is applied as discussed above.

At step 1504, interstitial fluid is extracted from the skin. This can be done in any suitable way, including those discussed above. Preferably, a vacuum is applied to extract interstitial fluid from the skin.

In step 1506, interstitial fluid is collected. This can be done in any suitable way, including those discussed above. Preferably, the interstitial fluid is collected on a gel containing a glucose-sensitive reagent. The gel changes color upon contact with glucose.

At step 1508, the change in gel color is monitored to determine the glucose concentration in the interstitial fluid. In another embodiment, the detection (evaluation, follow-up treatment) of skin and / or other subcutaneous abnormalities represented by a pathological concentration of a particular analyte, or a particular administration administered to a site Detection of components and their elimination or conversion (psoriasis,
Ultrasound can be used to detect skin malignancies, etc.). This technique is
For example, it can be used when extracting an analyte or a reagent from an affected skin (lesion spot), tumor or the like.

[0153] In another embodiment, the delivery and / or removal of endogenous and non-endogenous components from the skin by applying force is disclosed. Force such as ultrasound, electricity, magnetism, capillary, mechanical, chemical, electromagnetic, osmotic, concentration gradient, or a combination thereof
Among others, it can be used in applications such as removal of residual surfactant, enhanced cavitation, tattoo decolorization, and botox (removal from frontal and neck muscles, reduced perspiration).

In another embodiment, the sensing component is introduced into the skin and is in situ
Can be used to analyze the components of the interstitial fluid. The sensing component can be delivered into the skin and the released products or reagents of any sensing reaction (chemical or enzymatic) measured.

[0155] 3. Sonophoretic Drug Delivery A drug is defined as a therapeutic, prophylactic, or diagnostic molecule or substance, in a form dissolved in or suspended in a liquid, solid, or micro or nanoparticle, emulsion, liposome, or It can be in a form encapsulated and / or dispersed within lipid vesicles. Delivery of a drug is defined as delivering the drug to blood, lymph, interstitial fluid, cells, tissues, and / or organs, or any combination thereof.

Referring to FIG. 16, an active patch drug delivery device 1602 attached to the skin 1600 is shown. The drug delivery device 1602 includes the patch 1
604. Patch 1604 includes adhesive 1610, drug molecules 1612, and transducer 1614. Patch 1604 is active
Patch. Adhesive 1610 acts as a mounting device. Alternatively, the attachment device may be a vacuum, band, or strap. Converter 16
Oscillation 14 causes skin 1600 to become more permeable in accordance with the present invention, and drug molecules 1612 are delivered to and / or through skin 1600, and / or after skin 1600 is permeabilized, drug molecules 1612 16
00 to the capillaries and blood vessels beneath the skin 1600. Skin 1
Between 600 and the drug molecule 1612, there is a limiting stage membrane (limitings).
(stage membrane) 1613 may be provided.

Transducer 1614 preferably operates at a frequency in the range between 20 kHz and 2.5 MHz and uses a suitable electrical signal generator and amplifier. Converter 16
14 operates more preferably at a frequency in the range between 20 and 200 kHz. Other ultrasonic parameters include, but are not limited to, amplitude, duty cycle, distance from the skin, binder composition, and time of application, and are varied to provide a sufficient improvement in transdermal delivery be able to. The intensity is from 0 to 20 W /
It is preferable to change up to cm ² . Further, the transducer 1614 can be configured as a cylinder, a hollow cylinder, a hemisphere, a cone, a plane, or a rectangle. Transducer 1614 can also be comprised of an array of acoustic elements that are swept in time. Transducer 1614 can be composed of ceramics, including quartz, PVDF, PZT, and composites including screen-printed ceramics, magnetoresistors, or molded ceramics and vendors. Transducer 1614 can be used alone or with other forces or triggers to improve drug delivery. These other forces or triggers include, but are not limited to, magnetic fields, including electromagnetic forces, current or iontophoresis, mechanical skin manipulation, chemical modification, heat, and osmotic forces.

Transducer 1614 preferably has a frequency of about 2.5 MHz or less, preferably
The ultrasound is administered at a frequency below MHz, and more typically in the range of about 20-100 kHz. Exposure to ultrasound from the transducer 1614 is typically continuous for about 5 seconds to about 10 minutes, but may be shorter, and / or
Pulses may be pulsed for a time sufficient to permeabilize the skin, for example, 100 to 500 milliseconds per second. The intensity of the ultrasound is preferably
The temperature of 600 is not raised by more than about 1-2 ° C. and is at a level that does not cause permanent damage to the skin. The strength is typically less than 20 W / cm ² , preferably less than 10 W / cm ² . Since the intensity at the time of application is inversely proportional to the exposure time, in order to avoid damage to the skin, the higher the intensity, the shorter the time period of application. Incidentally, the ultrasonic wave in the normal low range is 20 kHz, but even if the frequency is changed to less than 20 kHz or to the sound range, comparable results can be obtained.

The time required for permeabilization (making it transparent) depends on the frequency and intensity of the ultrasound from transducer 1614 and the condition of skin 1600. 20 kh
At z, for example, at a strength of 10 / cm ² and a duty cycle of 50 percent, if the skin 1600 is a human forearm, the skin 1600 will fully permeate in about 5 minutes.

The ultrasonic waves to be transmitted can be applied for a predetermined amount of time, or may be applied until transmission is achieved. As the characteristics or properties of skin 1600 change over time, permeability is measured based on aging, diet, stress, and other factors to minimize the risk of skin 1600 damage when ultrasound is applied. It may be preferable to do so. Several methods are available to determine when sufficient permeability has been reached. One method measures the relative skin conductivity at the permeation site relative to a reference point. To make these measurements, a small AC or DC electrical potential is applied between two electrically separate electrodes in contact with skin 1600. The current passing through these electrodes is measured using an ammeter, and the resistance of the skin 1600 is measured using the potential and the value of the current. The drug delivery patch device 1602 can function as one of the electrically isolated electrodes that contact the skin 1600. Preferably, drug delivery patch device 1602 permeabilizes skin 1600 prior to conductivity testing.

Another way to determine when sufficient permeability has been reached is to measure conductivity. The resistance of the maximally permeated skin is less than about 5 kΩ when measured over about 1.7 cm ² . Another method is to detect and / or quantify the transdermal movement of an analyte such as creatinine, calcium or total ions. The analyte is present in the interstitial fluid in an approximately constant amount and can be used to calibrate the concentration of the analyte to be extracted and quantified, or as a measure of permeation. The higher the constant analyte flux, the greater the degree of permeability. The degree of permeability can also be monitored using a sensor attached to the drug delivery patch device 1602 that determines the concentration of drug molecules 1612 to be delivered or the analyte to be extracted. As the permeability increases, the drug concentration in the drug delivery patch 1602 decreases.

[0162] The drug delivery and patch device 1602 is also applicable to previously treated skin 1600. In other words, permeation of skin 1600 has already been achieved. The drug delivery patch device 1602 is placed on the previously treated skin 1600 to deliver the drug molecules 1612. Any known device can be used to pre-treat the skin 1600, including, but not limited to, physical, chemical, biological, vacuum, electrical, osmotic, and diffusional forces. Force, electromagnetic force, ultrasonic force,
Cavitation, mechanical, thermal, capillary, fluid circulation through the skin, electroacoustic, magnetic, magnetohydrodynamic, acoustic, convective diffusion, photoacoustic, skin to body fluids Rinsing, and any combination thereof.

[0163] Drug molecules 1612 include various bioactive agents, including proteins and peptides. Other substances include nucleic acid molecules such as vaccines containing therapeutic proteins, synthetic organic and inorganic molecules including anti-inflammatory, antiviral, antifungal, antibiotics, and local anesthetics, and saccharides and polysaccharides Is included. The drug molecule 1612 can be administered in a suitable pharmaceutically acceptable carrier having a water-like absorption coefficient, such as an aqueous gel, ointment, lotion, or suspension. In addition, drug molecule 16
12 can also be included with an adhesive 1610 that adheres to the skin 1600. Further, drug molecules 1612 can be encapsulated or suspended within a liquid, gel, or solid matrix within patch 1604.

The drug delivery patch device 1602 also includes a battery 1616. Battery 1616 acts as a power source for converter 1614. Battery 1616 provides a relatively high energy burst. In addition, the drug delivery / patch device 16
02 functions as a driving electronic component of the drug delivery / patch device 1602,
Also includes an electronic coupling 1618. The drug delivery patch device 1602 also includes a user interface 1620.

In one embodiment, patch 1604 includes a transducer 1614, a drug molecule 1610, and an adhesive 1610. In another embodiment, the patch 1604 includes the converter 16
14, including drug molecule 1612, adhesive 1610, battery 1616, electronic coupling 1618, and user interface 1620. In another embodiment, the patch 1604 includes a transducer 1614, a drug molecule 1612, an adhesive 1610,
And a battery 1616. In another embodiment, the adhesive 1610 is on the side of the transducer 1614 and the drug molecule 1612.

The battery 1616, electronic coupling 1618, and user interface 1620 may be located anywhere on the user and communicate with the patch 1604 via hard wire or telemetry. In another embodiment, the user interface 1620 may be located anywhere on the user and communicates with the patch 1604 via hard wire, telemetry, infrared, or fiber optic means. Accordingly, the elements of the drug delivery device 1602 can be detachable and portable from each other. Further, any of the components of the drug delivery device 1602 can be disposable or reusable. For example, the converter 161
4. A patch 1604 containing drug molecules 1612 and adhesive 1610
After removal from 00, it can be discarded. However, the battery 16
16, electronic coupling 1618, and user interface 1620 may be reusable with another patch 1604.

In one embodiment, the transducer 1614 operates alone and applies the drug molecule 1612 to the skin 1
Press through 600 and into skin 1600. Alternatively, the drug delivery patch device 1602 and the transducer 1614, when operated with a driving force, can further facilitate transdermal delivery of the drug molecule 1612. These forces include, but are not limited to, physical, chemical, biological, vacuum, electrical, osmotic,
Diffusion, electromagnetic, ultrasonic, cavitation, mechanical, thermal, capillary, fluid circulation through the skin, electro-acoustic, magnetic, magneto-hydrodynamic, acoustic, convection Includes diffusion, photoacoustic power, rinsing bodily fluids from the skin, and any combination thereof.

Referring to FIG. 17, an embodiment of the converter 1614 is shown. Converter 16
14 shows that ultrasound is applied to the drug molecules 1612 and to the skin 16 via an adhesive 1610.
When applied to 00, it can be an array of acoustic elements that are swept in time. The acoustic element 1700 includes a transducer 1614. Element 1700 is represented as a square within a large square. The element is
The present invention is not limited to this configuration, and it is also possible to form a cylinder, a hollow cylinder, a hemisphere, a cone, a plane, and a rectangle. Each acoustic element of the 1700 elements can be swept separately or in groups when the transducer 1614 is activated. For example, element A is activated, followed by elements B and E, followed by elements C, F and I, and so on. Element P is
The converter 1614 activates at the end of the sweep. Further, the acoustic element 17
00 can also have fingers. Referring to FIG. 17, the fingers are illustrated as elements A, E, I, M. Each finger can be activated or swept on a time basis. The acoustic element 1700 transmits ultrasonic energy,
It can be configured to lead from the converter 1614 to a designated area that is 100 smaller than the area of the converter 1614.

Referring to FIG. 18, the patch 1604 and the user interface 162
0 is coupled to feedback mechanism 1802. Feedback mechanism 180
2 may be removable from the user interface 1620. Alternatively, the feedback mechanism 1802 may be built into the user interface 1620. That is, the feedback mechanism 1802 is connected to the drug delivery / patch device 1
602 can be built in. Feedback mechanism 1802 can program a drug delivery rate or a preset dose of drug molecule 1612. Also, the feedback mechanism 1802 may include a memory for recording or displaying historical delivery data on the user interface 1620. Feedback mechanism 1802 communicates the on-time of transducer 1614 to user interface 1620 for display to the user. Feedback mechanism 1802 may also provide an alarm for low drug molecule 1612 and / or low battery 1616 power. Thus, the feedback mechanism 18
02 alerts the user via the user interface 1620 that the drug molecules 1612 and patches 1604 need to be refilled, or that the drug delivery and patch device 1602 is powered down.

The feedback mechanism 1802 can also monitor the amount of drug molecule 1612 delivered by transdermal delivery. Also, a feedback mechanism 1802
Can also monitor the amount of ultrasonic energy applied to the skin 1600 by the transducer 1614, or other driving forces listed above. A limit may be set in feedback mechanism 1802 to limit the ultrasonic energy from transducer 1614 so as not to irritate or damage skin 1600. The feedback mechanism 1802 can also monitor the concentration of the drug molecule 1612 remaining in the patch 1604. Feedback mechanism 1802 can also monitor the concentration of drug molecules or analytes in interstitial fluid, blood, and other body fluids. Feedback mechanism 1802 can also monitor the amount of cavitation created by the application of ultrasonic energy. Feedback mechanism 1802 can also monitor the magnitude of physiological effects, such as blood pressure, EMG, EEG, and ECT feedback, and measure drug molecule 1612 delivery. Feedback mechanism 1820 can also be connected to additional patches or testing devices to perform conductivity testing.

[0171] 4. Transdermal vaccination by sonication In general, vaccines are administered for the prevention, amelioration or treatment of infectious diseases. Vaccines are commonly used to confer immunity from diseases such as influenza, poliomyelitis, varicella-zoster (varicella), measles, and several other diseases.

In general, vaccines are made from antigens isolated or produced from pathogenic microorganisms.
An antigen is defined as "anything that can be bound by an antibody." It can be a vast range of substances, from simple chemicals, sugars, small peptides to complex protein complexes such as viruses. Small antigens, however, are not themselves immunogens and need to bind a carrier to elicit an immune response.

Typically, vaccines are delivered to the bloodstream by invasive methods, such as injection. B cells in the bloodstream respond to antigens and produce antibodies. These antibodies bind to the antigen and "neutralize" or inactivate it. Memory cells are also generated and remain ready to form a rapid protective immune response against subsequent infection by the same virulence factor.

Immunization is the process of obtaining immunity by injecting antibodies or by stimulating the body to make its own antibodies against specific microorganisms.
Immunization may be the result of vaccination.

As discussed above, it is known to facilitate transdermal delivery using ultrasound. The mechanisms that facilitate transdermal delivery using ultrasound are different. Transdermal delivery
In the system, ultrasound was used initially as a driving force, essentially pushing the drug through the skin and into the circulatory system. Ultrasound is also used to increase skin permeability. In other words, the application of ultrasound having a particular frequency disrupts the order of the lipid bilayer in the skin, thereby increasing the permeability of the skin. In this context, the drug can be delivered into the body through the skin, or the analyte can be extracted from the body through the skin. Systems and methods for improving skin permeability by the application of ultrasound and body fluid extraction systems and methods have been discussed above.

Although the permeability of the skin is increased by the application of ultrasound, transdermal delivery still requires a driving force. However, the required strength of the driving force decreases. For example, a concentration gradient is generally a sufficient driving force for transdermal delivery through skin whose permeability has been improved using ultrasound. The improvement in transmission obtained by the application of ultrasound is due at least in part to the cavitation caused by ultrasound.

FIG. 19 shows a method of transcutaneous vaccination by a sound wave transmission method according to an embodiment of the present invention. Referring to FIG. 19, in step 1902, skin permeability is increased. This may be done in several ways, including the methods discussed above.

In one embodiment, the ultrasound may be applied at about 10 W / cm ² with a duty cycle of about 50%. The ultrasonic wave may be applied from a distance of about 0.5 mm to 1 cm from the skin, and the application time may be about 30 seconds to about 5 minutes.

A coupling medium between the transducer and the skin may be used, and the coupling medium may include aqueous or non-aqueous chemicals, including but not limited to water, saline , Ethanol and isopropanol (1-100 with saline)
% Alcohol), surfactants, linoleic acid (ethanol-water (50%
: 50) fatty acids such as 0.1-2% mixture in the mixture), azone (azone
) (0.1-10% mixture in an ethanol-water (50:50) mixture), 0
. Salt solution containing 1 to 50% polyethylene glycol, 1 to 100 mM ED
Includes TA, EGTA, or 1% SLS and silica particles. The binding medium is
Provides effective transfer of ultrasonic energy from the transducer to the skin. Proper mixing of these binding media also promotes cavitation activity inside, on the surface, or near the skin, thus inducing more efficient transport of molecules through the skin.

In step 1904, after increasing the permeability of the skin, the ultrasonic treatment is terminated,
The vaccine is given to the permeated skin. In one embodiment, the vaccine may be contained within a transdermal patch. Other forms of the vaccine can be used, such as gels and liquids.

The vaccines will comprise as active ingredient a peptide, protein, allergen or other antigen, or DNA encoding any of the foregoing, and may also include other commonly employed adjuvants. These vaccines can be used as cancer vaccines, tetanus vaccines and the like.

At step 1906, the vaccine is delivered to skin cells. In one embodiment, the vaccine is delivered to skin cells, including Langerhans cells, dendritic cells, and epidermal cells.

In one embodiment, the vaccine is delivered to Langerhans cells. Langerhans cells are cells that play a role in capturing a vaccine and presenting it to the lymphatic system, eliciting an immune response. The vaccine may be delivered to other cells to elicit an immune response.

In one embodiment, the vaccine can spread to skin cells, including Langerhans cells, dendritic cells, and epidermal cells. Once the vaccine is received by the skin cells, the vaccine is efficiently transported to the lymph nodes, increasing the efficiency of the vaccination.

In another embodiment, the vaccine is delivered transdermally, through the skin, into the skin and into the bloodstream, and the vaccine acts as if injected in a conventional manner. In another embodiment of the invention, the vaccine is given simultaneously with the application of the ultrasound. Ultrasound in this embodiment is used both to permeabilize the skin and to deliver the vaccine transdermally to Langerhans cells. Ultrasound acts as a driving force. Examples of delivering a drug from a patch using ultrasound have been discussed above.

In another embodiment of the present invention, ultrasound is applied to the skin to increase skin permeability. Once the vaccine has been given, an additional driving force is provided to deliver the vaccine into the body. Examples of driving forces include, among others, physical, chemical, biological, vacuum, electrical, penetrating, diffusing, electromagnetic, ultrasonic, cavitational, mechanical, Thermal, capillary, fluid circulation through the skin, electro-acoustic, magnetic, magneto-hydrodynamic, acoustic, convective dispersion, photo-acoustic, and any combination thereof.

In another embodiment, ultrasound can be used to induce skin irritation and inflammation. Induction of irritation and inflammation can cause a vaccine placed on the skin to more effectively elicit an immune response. In another embodiment, chemical synergists can be used to increase skin permeability.

While the invention has been described in detail, it will be understood that various changes, substitutions, and alterations are possible without departing from the intended scope defined by the appended claims.

[Brief description of the drawings]

FIG. 1 is a diagram showing an outline of an electric model of skin.

FIG. 2 is a flow chart illustrating a controlled and improved method of transdermal delivery according to one embodiment of the present invention.

FIG. 3 illustrates a circuit for improving skin permeability and monitoring the improvement of skin permeability in accordance with one embodiment of the present invention.

FIG. 4 illustrates a transparency monitoring circuit according to another embodiment of the present invention.

FIG. 5 is a diagram illustrating a transparency monitoring circuit according to an embodiment of the present invention.

FIG. 6 is a flow chart illustrating a controlled and improved method of transdermal delivery according to one embodiment of the present invention.

FIG. 7 is a flow chart illustrating a controlled and improved method of transdermal delivery according to one embodiment of the present invention.

FIG. 8 is a flow chart illustrating a controlled and improved method of transdermal delivery according to one embodiment of the present invention.

FIG. 9 illustrates the time variation of skin conductance during exposure to ultrasound, according to one example.

FIG. 10 illustrates the relationship between inflection time and time to pain in various volunteers, according to an example.

FIG. 11 is a flowchart illustrating a method of determining when to stop applying ultrasonic waves.

FIG. 12 is a diagram showing an example of a graph of the method of FIG. 11;

FIG. 13 is a flowchart illustrating a method of extracting and analyzing at least one analyte in a bodily fluid, according to one embodiment of the present invention.

FIG. 14 is a diagram illustrating a tensioner according to an embodiment of the present invention.

FIG. 15 is a flowchart illustrating a method for determining blood glucose according to an embodiment of the present invention.

FIG. 16 illustrates a drug delivery patch device according to one embodiment of the present invention.

FIG. 17 shows a cross-sectional view of a transducer according to one embodiment of the present invention.

FIG. 18 illustrates a drug delivery patch device having a feedback mechanism according to one embodiment of the present invention.

FIG. 19 is a flowchart illustrating a method of ingesting a transdermal vaccine by a sound wave transmission method according to an embodiment of the present invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61N 1/30 A61B 17/36 350 4C167 G01N 33/66 5/14 310 (31) Priority claim number 60 / 142,975 (32) Priority date July 12, 1999 (July 12, 1999) (33) Priority claiming country United States (US) (31) Priority claim number 60 / 142,941 (32) Priority date July 12, 1999 (July 12, 1999) (33) Priority claim country United States (US) (31) Priority claim number 60 / 142,951 (32) Priority date July 12, 1999 ( (July 12, 1999) (33) Priority country United States (US) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT , LU, MC, NL, PT, SE), OA ( F, 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 02141, Massachusetts, United States 02141, Cambridge, Massachusetts Avenue 931, Apartment No. 303 (72) Inventor Kellogg, Scott Sea, 02169, Massachusetts, United States 02169, Quincy, Kendrick Avenue 155 ( 72) Inventor Warner, Nick 02178, Massachusetts, USA, Concord Avenue, Belmont, 296 (72) Inventor Elstrom, Chuan Ay 60044, Illinois, United States, Lake Bluff, West Sanctuary Lane 12780 F-term (reference) 2G045 CA25 DA31 4C026 AA01 DD05 4C027 AA07 CC00 CC04 EE01 FF01 FF02 GG00 GG07 KK00 4C038 KK10 KL00 KL01 KL05 KL07 KL09 KM00 KX01 KY03 KY04 4C053 HH02 4C167 AA72 BB42 BB42 BB42 BB42 BB42 BB42 BB42

Claims (157)

[Claims] 1. A method for improving transdermal transport comprising: increasing the permeability of an area of a membrane using a permeation device; and monitoring the permeability of an area of the membrane. Transporting material to and through the area of the membrane. 2. The method of claim 1, wherein increasing the permeability of an area of the membrane using a permeabilizing device comprises: applying electricity to the area of the membrane; Measuring at least one electrical parameter of an area of the device, and controlling the permeation device based on the at least one electrical parameter. 3. The method of claim 1, wherein the step of using a permeation device to increase the permeability of an area of a membrane comprises forming a volume of fluid adjacent to the area of the membrane. Applying the permeation device to an area of the membrane, wherein the fluid has an initial concentration of the first substance. 4. The method of claim 3, wherein monitoring the permeability of the area of the membrane comprises: monitoring a change in concentration of the first substance; and the change in concentration of the substance. Controlling the permeabilization device based on the method. 5. The method of claim 1, wherein the step of using a permeation device to increase the permeability of an area of a membrane comprises forming a volume of fluid adjacent to the area of the membrane. Determining a reference value for an electrical parameter of the volume of fluid; and applying the permeation device to an area of the membrane. 6. The method of claim 5, wherein said volume of fluid formed is selected from the group comprising liquids, gels, and solids. 7. The method of claim 5, wherein monitoring the permeability of an area of the membrane comprises: monitoring a change in the electrical parameter of the volume of fluid; Controlling the permeation device based on a change in the electrical parameter. 8. The method of claim 1, wherein the step of using a permeabilizing device to increase the permeability of an area of a membrane comprises: forming a first electrode in electrical contact with the first area of the membrane. Providing; providing a second electrode in electrical contact with a second area of the membrane; measuring an initial conductivity between the electrodes; and providing the first area of the membrane with a first area. Applying a permeabilization device. 9. The method of claim 8, wherein monitoring the permeability of an area of the membrane comprises: measuring a second conductivity between the first electrode and the second electrode. Processing the initial conductivity and the second conductivity to establish information about the temporal variation of the conductance of the membrane; and at least one describing the kinetics of the change in conductance of the membrane in response to the information. Calculating one parameter and ending the application of the permeabilization device in response to a desired value for the at least one parameter. 10. The method of claim 1, wherein transporting a substance through an outer surface of the area of the membrane comprises: extracting a body fluid from or through the area of the membrane; and collecting the body fluid. And detecting the presence of the at least one analyte in the bodily fluid. 11. The method according to claim 1, wherein said substance is a drug. 12. The method according to claim 1, wherein the substance is a vaccine. 13. The method of claim 1, wherein said substance comprises at least one
A method comprising two interstitial fluid components. 14. The method of claim 1, wherein said permeabilizing device is an ultrasound generating device. 15. The method of claim 1, wherein the permeation device is a device that generates a force selected from the group including chemistry, electroporation, mechanical, fracturing, tape stripping, and laser power. Yes, the way. 16. The method of claim 1, wherein said membrane is selected from a group comprising biological skin and artificial skin. 17. A method for improving the permeability of an area of skin, the method comprising: increasing the permeability of the area of skin using a skin permeation device; and applying electricity to the area of skin. Measuring at least one electrical parameter of the area of skin; and controlling the skin permeation device based on the at least one electrical parameter. 18. The method of claim 17, further comprising applying electricity to the skin area before increasing the permeability of the skin area with a skin permeation device. 19. The method of claim 17, wherein applying electricity to the area of skin comprises applying a first source having a first frequency to the area of skin, and having a second frequency. Applying a second source to the area of skin. 20. The method of claim 19, wherein measuring a first electrical parameter comprises: measuring the at least one electrical parameter at the first frequency; and measuring the at least one electrical parameter at the second frequency. Measuring at least one electrical parameter. 21. The method of claim 17, further comprising: coupling a first electrode to the skin area; coupling a second electrode to the skin; Measuring the at least one electrical parameter using two electrodes. 22. The method according to claim 21, wherein the first electrode is coupled to a portion of the stratum corneum in the area of the skin. 23. The method of claim 22, wherein the second electrode is coupled to a portion of the outer skin from which the stratum corneum has been removed. 24. The method of claim 22, wherein the second electrode is coupled to a portion of the stratum corneum of the skin. 25. The method of claim 21, wherein at least one of said first electrode and said second electrode are coupled through a conductive medium. 26. The method of claim 25, wherein the conductive medium is a gel. 27. The method of claim 25, wherein said conductive medium is a liquid. 28. The method according to claim 21, wherein the second electrode is disposed on the skin. 29. The method of claim 17, further comprising comparing the at least one electrical parameter to a baseline, wherein controlling the skin permeation device is based on the comparison. Stopping the application of the skin permeation device. 30. The method of claim 19, wherein the first source is about 10
A method comprising a voltage source having a frequency of 1 Hz. 31. The method of claim 19, wherein said second source is about 1k.
A method comprising a voltage source having a frequency of 1 Hz. 32. The method of claim 17, wherein the parameter is selected from a group including impedance, conductance, capacitance, current, and voltage. 33. The method of claim 17, wherein said skin permeation device comprises an ultrasound generating device. 34. The method of claim 20, wherein controlling the skin permeation device comprises measuring the at least one electrical parameter at the first frequency and the at least one electrical parameter at the second frequency. If the difference between the measured values of the electrical parameters is less than a predetermined amount, the method comprises reducing a property of the skin permeation device, wherein the property is selected from a group including intensity and duty cycle. 35. The method of claim 19, wherein the step of controlling the skin permeation device comprises the step of controlling the skin permeation device when a rate of change between the one electrical parameter reaches a predetermined value. A method comprising the step of reducing a characteristic, wherein said characteristic is selected from a group comprising intensity and duty cycle. 36. An apparatus for improving the permeability of an area of skin, comprising: a skin permeation device configured to increase the permeability of the area of skin; and applying electricity to the area of skin. An apparatus operable to control at least one electrical parameter of the skin area; and a controller responsive to the circuit and operable to control the skin permeation device. . 37. The apparatus of claim 36, wherein the power supply comprises: a first source having a first frequency; and a second source having a second frequency. 38. The apparatus according to claim 37, wherein the circuit measures the at least one electrical parameter of the skin area at the first frequency and the at least one of the skin areas at the second frequency. A device that measures one electrical parameter. 39. The apparatus of claim 36, further comprising: a first electrode coupled to the skin area; and a second electrode disposed on the skin, wherein the circuit comprises the first electrode and the second electrode. The apparatus for measuring the first parameter of the area of the skin between a second electrode. 40. The device according to claim 39, wherein the first electrode comprises an electrode that couples to a portion of the stratum corneum in the area of the skin. 41. The device of claim 40, wherein the second electrode comprises an electrode disposed on a portion of the outer skin from which the stratum corneum has been removed. 42. The method of claim 39, wherein the first electrode comprises an electrode having a first surface area and coupled to a portion of the stratum corneum in the area of the skin. 43. The device of claim 42, wherein the second electrode comprises an electrode having a second surface area disposed on a portion of the stratum corneum of the skin, wherein the second surface area is the first surface. A device that is substantially larger than the area. 44. The apparatus of claim 40, wherein the controller determines a measurement of the at least one electrical parameter at the first frequency and a measurement of the at least one electrical parameter at the second frequency. Compare,
An apparatus for turning off the skin permeation device when these differences are less than a predetermined amount. 45. The apparatus of claim 37, wherein said first source is about 10
A device comprising a voltage source having a frequency of Hz. 46. The apparatus of claim 37, wherein said second source is about 1k.
A device comprising a voltage source having a frequency of Hz. 47. The apparatus according to claim 38, wherein said parameter is selected from the group comprising impedance, conductance, capacitance, current, and voltage. 48. The apparatus of claim 37, wherein the controller determines a measurement of the at least one electrical parameter at the first frequency and a measurement of the at least one electrical parameter at the second frequency. Compare,
An apparatus that reduces the strength of the skin permeation device when these differences are less than about a predetermined amount. 49. The apparatus of claim 38, wherein the controller determines a measurement of the at least one electrical parameter at the first frequency and a measurement of the at least one electrical parameter at the second frequency. Compare,
An apparatus for reducing the duty cycle of the skin permeation device when these differences are less than a predetermined amount. 50. A method for improving the permeability of an area of skin, comprising forming a volume of fluid adjacent to the area of skin, wherein the fluid has an initial concentration of fluid. Applying a skin permeation device to the area of the skin; monitoring a change in the concentration of the first substance; and, based on the change in the concentration of the substance, Controlling the skin permeation device. 51. The method of claim 50, wherein the volume of fluid is a liquid,
A method selected from the group comprising gels and solids. 52. The method of claim 50, wherein said first substance comprises an analyte. 53. The method of claim 52, wherein controlling the skin permeation device comprises applying the skin permeation device when the concentration of the analyte in the volume of fluid increases to a predetermined concentration. Comprising the step of stopping
Method. 54. The method of claim 50, wherein the step of controlling the skin permeation device comprises the step of controlling the skin permeation device when the rate of increase of analyte in the volume of fluid reaches a predetermined concentration. Stopping the application.
Method. 55. The method of claim 50, wherein the step of controlling the skin permeation device comprises the step of: modifying the properties of the skin permeation device when the concentration of the analyte in the volume of fluid increases to a predetermined concentration. A method comprising the step of reducing, wherein said characteristic is selected from a group comprising intensity and duty cycle. 56. The method of claim 50, wherein the first substance is a benign substance and the initial concentration is higher than that found in the body. 57. The method of claim 56, wherein controlling the skin permeation device comprises applying the skin permeation device when the concentration of benign molecules in the volume of fluid drops to a predetermined concentration. C. Stopping the method. 58. The method of claim 56, wherein the step of controlling the skin permeation device comprises the step of controlling the skin permeation when the rate of change in the concentration of benign molecules in the volume of fluid reaches a predetermined value. Stopping the application of the device.
Method. 59. The method of claim 56, wherein the step of controlling the skin permeation device comprises increasing the strength of the skin permeation device when the concentration of benign molecules in the volume of fluid drops to a predetermined concentration. A method comprising the step of lowering. 60. The method of claim 56, wherein the step of controlling the skin permeation device comprises the step of controlling the skin permeation when the rate of change of the concentration of benign molecules in the volume of fluid reaches a predetermined value. A method comprising reducing the strength of a device. 61. The method of claim 56, wherein the step of controlling the skin permeation device comprises the step of controlling the duty cycle of the skin permeation device when the concentration of benign molecules in the volume of fluid drops to a predetermined concentration. A method comprising reducing the intensity of the cycle. 62. A method for improving the permeability of an area of skin, comprising: forming a volume of fluid adjacent to the area of skin; Determining a reference value; applying a skin permeation device to the skin area; monitoring a change in the electrical parameter of the volume of fluid; and Controlling the skin permeation device based on a change in a parameter. 63. The method of claim 62, wherein the volume of fluid is a liquid,
A method selected from the group comprising gels and solids. 64. The method of claim 62, wherein said electrical parameter is electrical conductivity. 65. A method of adjusting the permeability of an area of skin, comprising: providing a first electrode in electrical contact with a first skin area; and electrically contacting a second skin area. Providing a second electrode; measuring an initial conductivity between the electrodes; applying a skin permeation device to the first skin area; and between the first electrode and the second electrode. Measuring a second electrical conductivity of; processing said initial electrical conductivity and said second electrical conductivity to establish information regarding a time variation of skin conductance; and responsive to said information, Calculating at least one parameter describing the kinetics of the change in conductance; and responsive to a desired value for the at least one parameter, the skin permeation device. The method comprising the steps of terminating the application of the scan, the. 66. The method of claim 65, wherein the application of the skin permeation device is continuous. 67. The method of claim 65, wherein the application of the skin permeation device is discontinuous. 68. The method of claim 65, wherein the skin permeation device comprises an ultrasound generating device. 69. The method of claim 65, wherein calculating at least one parameter describing a kinetics of a change in skin conductance in response to the information comprises: the information relating to a time variation in skin conductance. Determining the slope of the skin of the skin, and determining the inflection point of the information regarding the temporal variation of skin conductance. 70. The method of claim 67, further comprising: performing an analog-to-digital conversion on the information relating to the time variation of skin conductance; and filtering the digital data. . 71. The method of claim 65, wherein processing the initial conductivity and the second conductivity to establish information about a time variation of skin conductance comprises the step of: , [Equation 1] Where C is the current, Ci is the current at t = 0, Cf is the final current, S is the sensitivity constant, t * is the exposure time required to reach the inflection point, and t is Exposure time is the method. 72. A method of extracting and analyzing at least one analyte in a bodily fluid, comprising: increasing a permeability level of an area of skin; and extracting a bodily fluid from or through the area of skin. Collecting the bodily fluid; and detecting the presence of the at least one analyte in the bodily fluid. 73. The method of claim 72, wherein increasing the permeability level of an area of skin comprises applying ultrasound to a portion of the skin. 74. The method of claim 72, wherein the step of extracting bodily fluids from or through the area of skin comprises physical, chemical, biological, vacuum, electrical, osmotic. , Diffusion force, electromagnetic force, ultrasonic force, cavitation force, mechanical force, thermal force, capillary force, fluid circulation through the skin, electroacoustic force, magnetic force, magnetohydrodynamic force, acoustic force, A method comprising applying a force selected from the group comprising convective dispersion, photoacoustic forces, rinsing bodily fluids from the skin, and any combination of these forces. 75. The method of claim 74, wherein the vacuum force is applied continuously. 76. The method of claim 74, wherein said vacuum force is applied discontinuously. 77. The method of claim 74, wherein a substance is placed between the vacuum force and the skin to maintain a topography of the skin. 78. The method of claim 77, wherein said substance is selected from the group comprising a mesh, a membrane, and a perforated metal. 79. The method according to claim 77, wherein the vacuum force is mechanical,
The method occurs on a device selected from the group comprising electromechanical, chemical, or electrochemical devices. 80. The method of claim 74, wherein said electrical force is selected from the group comprising iontophoresis, electroosmosis, and electroporation.
Method. 81. The method of claim 74, wherein the gel is applied to the skin to enhance penetration. 82. The method of claim 74, wherein said ultrasonic force is applied to obtain a result, said result wicking, levitating, and activating a gas body. Selecting from the group comprising: generating cyclic impulse mechanical stress in the skin, forming micro-streaming, increasing temperature, and setting a standing wave. 83. The method of claim 74, wherein the ultrasonic force is generated using a plurality of ultrasonic generating devices. 84. The method of claim 83, wherein the plurality of ultrasound generating devices have at least one different operating characteristic. 85. The method of claim 84, wherein said operating characteristic is selected from the group comprising frequency, intensity, and coupling medium. 86. The method of claim 74, wherein the mechanical force is applied by a device selected from the group including a roller, a press, a stretcher, a compressor, and a tensioner. 87. The method of claim 86, wherein the tensioner collects the bodily fluid in a cavity formed therein. 88. The method of claim 74, wherein the thermal force is generated by a source selected from the group including electrical, chemical, ultrasonic, and optical energy sources. 89. The method of claim 74, wherein the body fluid is extracted using a temperature sensitive polymer. 90. The method of claim 72, wherein the step of collecting the bodily fluid comprises a group comprising absorption, adsorption, phase separation, mechanical, electrical, chemically inductive, capillary, and combinations thereof. Using the selected collection method. 91. The method of claim 90, wherein the method of collecting absorption comprises:
Collecting the bodily fluid in a gel. 92. The method of claim 91, wherein said gel contains a capture enzyme. 93. The method of claim 90, wherein the method of phase separation comprises separating the bodily fluid using a suitable concentration of an immiscible fluid. 94. The method of claim 93, further comprising collecting the bodily fluid in a conical chamber. 95. The method of claim 90, wherein a hydrophobic coating is applied to the skin prior to the step of extracting a bodily fluid from the area of the skin. 96. The method of claim 75, wherein the bodily fluid is collected from the hydrophobic coating. 97. The method of claim 90, wherein the mechanical collection method comprises applying a force selected from the group comprising vacuum, pressure, and acoustic forces. 98. The method of claim 90, wherein the electrical collection method comprises using an electrical force to move a charged object from the skin to a collection compartment. 99. The method of claim 90, wherein the chemical collection method comprises applying a hydrophilic gel to collect a bodily fluid. 100. The method of claim 90, wherein the capillary force collecting method comprises: filling at least one capillary with a plurality of fibers; and collecting the bodily fluid in the at least one capillary. And a method comprising: 101. The method of claim 72, wherein detecting the presence of at least one analyte comprises electrochemical, optical, acoustic, biological, enzymatic techniques.
And applying a detection method selected from a group comprising the combination thereof. 102. The method of claim 72, wherein the concentration of the analyte in the body fluid is detected using living cells. 103. The method of claim 72, further comprising providing an output for a user interface, comprising providing an alarm indicating an abnormal analyte concentration. 104. The method of claim 72, wherein providing an output for a user interface comprises providing trend information. 105. The method of claim 72, further comprising providing historical information. 106. The method of claim 72, wherein the user output is downloadable. 107. A system for extracting and analyzing at least one analyte in a bodily fluid, comprising: a transducer for increasing the permeability of an area of skin; an extraction device for extracting interstitial fluid from the area of skin; A system comprising: a collection device that collects the extracted interstitial fluid; and a detection device that detects the presence of at least one analyte in the extracted bodily fluid. 108. The system of claim 107, further comprising a microcontroller controlling at least one of the transducer, the extraction device, the collection device, and the sensing device. 109. The system of claim 107, further comprising a user output device. 110. The system of claim 108, further comprising a microcontroller controlling the user output device. 111. The system of claim 107, wherein said transducer comprises an ultrasonic transducer. 112. The system of claim 107, wherein the extraction device comprises a physical, chemical, biological, vacuum, electrical, osmotic, diffusive, electromagnetic, ultrasonic. Force, cavitation, mechanical, thermal, capillary, fluid circulation through the skin, electroacoustic, magnetic, magnetohydrodynamic, acoustic, convective dispersion, photoacoustic, skin to body fluid System that is a device that rinses off and generates a force selected from a group that includes any combination of these forces. 113. The system of claim 107, wherein the collection device comprises a collection method selected from the group including absorption, adsorption, phase separation, mechanical, electrical, chemical inductive, and combinations thereof. The system that is the device used. 114. The system of claim 107, wherein the sensing device senses the presence of an analyte by a sensing method selected from the group including electrochemical, optical, acoustic, biological, enzymatic techniques, and combinations thereof. Is,
system. 115. The system of claim 109, wherein the user output device provides information selected from a group including trend information, history information, operation information, and combinations thereof. 116. The system of claim 115, wherein the information from the user output device is downloadable to a computer. 117. A method for determining blood glucose, comprising the steps of: increasing the permeability of a certain skin area; extracting interstitial fluid from the skin area; and collecting the interstitial fluid in a gel. Monitoring the gel for changes in the at least one property of the gel, wherein the gel contains at least one glucose-sensitive reagent that changes at least one property of the gel in the presence of glucose. Performing the steps of: 118. A blood glucose determination system, comprising: a transducer for increasing permeability in an area of skin; an extraction device for extracting interstitial fluid from the area of skin; and collecting the extracted interstitial fluid. A collection device, a gel within the collection device, at least one glucose-sensitive reagent that changes at least one property of the gel when glucose is present, and monitoring a change in the at least one property of the gel. And a monitoring device. 119. The system of claim 118, wherein said at least one glucose sensitive reagent is in said gel. 120. A drug delivery patch device, comprising: a transducer for applying ultrasound to a membrane; a power supply coupled to the transducer; and a plurality of transducers between the transducer and the biological membrane. A drug delivery patch device comprising: a drug molecule; a mounting device for attaching the drug molecule and the transducer to the membrane; and a user interface for interfacing with the transducer, the power supply, and the drug molecule. 121. The drug delivery patch device of claim 120, further comprising drive electronics coupled to the transducer, wherein the drive electronics enable the transducer to apply ultrasound. Drug delivery patch device. 122. The drug delivery patch device according to claim 120, wherein the membrane is skin. 123. The drug delivery patch device according to claim 120, wherein the drug molecule and the attachment device are combined. 124. The drug delivery patch device of claim 120, wherein the drug molecules are suspended in a group comprising a liquid, a gel, and a solid substrate. 125. The drug delivery patch device according to claim 120, wherein the power source is coupled to the transducer via hard wires. 126. The drug delivery patch device according to claim 120, wherein the power source is coupled to the transducer via telemetry. 127. The drug delivery patch device according to claim 120, wherein the transducer comprises an acoustic element, the acoustic element being swept based on temporal properties when the transducer applies ultrasound. , Drug delivery patch device. 128. The drug delivery patch device according to claim 120, wherein the attachment device comprises a band attached to the membrane. 129. The drug delivery patch device of claim 120, further comprising a feedback mechanism coupled to the drug molecule and the user interface for monitoring an amount of the drug molecule. 130. The drug delivery patch device of claim 120, further comprising a feedback mechanism coupled to the transducer and the user interface for monitoring an amount of ultrasound applied to the membrane. Drug delivery patch device. 131. The drug delivery patch device according to claim 120, wherein the user interface is coupled to the transducer, the power source and the drug molecule by telemetry. 132. The drug delivery patch device of claim 120, wherein the user interface is coupled to the transducer, the power source and the drug molecule by an infrared device. 133. The drug delivery patch device of claim 120, wherein the user interface is coupled to the transducer, the power source and the drug molecule by an optical fiber. 134. The drug delivery patch device of claim 120, wherein the transducer is configured as a cylinder. 135. The drug delivery patch device of claim 120, wherein the transducer is configured as a hollow cylinder. 136. The drug delivery patch device according to claim 120, wherein the transducer has a hemispherical configuration. 137. The drug delivery patch device according to claim 120, wherein the transducer has a conical configuration. 138. The drug delivery patch device according to claim 120, wherein the transducer has a planar configuration. 139. The drug delivery patch device according to claim 120, wherein the transducer has a rectangular configuration. 140. The drug delivery patch device of claim 120, further comprising a driving force generating device operative with the transducer, wherein the driving force comprises:
Physical, chemical, biological, vacuum, electrical, penetrating, diffusing, electromagnetic, ultrasonic, cavitational, mechanical, thermal, capillary, skin Fluid circulation, electroacoustic, magnetic, magnetohydrodynamic, acoustic, convective dispersion, photoacoustic,
A drug delivery patch device selected from the group comprising rinsing bodily fluids from the skin and any combination of these forces. 141. The drug delivery patch device of claim 120, further comprising a restriction step membrane between the membrane and the drug molecule. 142. The drug delivery patch device according to claim 120, wherein the membrane is pre-treated with force. 143. The drug delivery patch device of claim 142, wherein the force is a physical force, a chemical force, a biological force, a vacuum pressure, an electrical force, a penetrating force, a diffusing force, an electromagnetic force, Ultrasonic force, cavitation force, mechanical force, thermal force, capillary force, fluid circulation through skin, electroacoustic force, magnetic force, magnetohydrodynamic force, acoustic force, convection dispersion, photoacoustic force, skin A drug delivery patch device selected from the group comprising rinsing bodily fluids from and any combination of these forces. 144. A method of delivering a drug through a membrane, comprising: supplying power to a transducer that applies ultrasound; applying ultrasound to a drug molecule to couple at least the drug molecule and the transducer. Delivering the drug molecule through the membrane by having an attachment device that attaches to the membrane. 145. The method of claim 144, further comprising the step of pre-treating said membrane by applying a force prior to said delivering step, wherein said force is a physical force, a chemical force. , Biological force, vacuum pressure, electrical force, permeability force, penetration force, diffusion force, electromagnetic force, ultrasonic force, cavitation force, mechanical force, thermal force, capillary force, fluid circulation through skin A method selected from the group comprising: electroacoustic, magnetic, magnetohydrodynamic, acoustic, convective dispersion, photoacoustic, rinsing bodily fluids from the skin, and any combination of these forces. . 146. The method of claim 144, wherein said delivering comprises applying a driving force with said ultrasonic waves from said transducer, wherein said driving force is a physical force, a chemical force, a living thing. Force, vacuum pressure, electrical force, penetrating force, diffusing force, electromagnetic force, ultrasonic force, cavitation force, mechanical force, thermal force, capillary force, fluid circulation through skin, electroacoustic force, Magnetic force, magnetohydrodynamic force, acoustic force, convection dispersion,
A method selected from the group comprising photoacoustic forces, rinsing bodily fluids from the skin, and any combination of these forces. 147. A transdermal vaccination method, comprising: increasing the permeability of an area of skin; providing a vaccine to the area of skin; and delivering the vaccine to at least one skin cell. And a method comprising: 148. The method of claim 147, wherein increasing the permeability of an area of skin comprises applying ultrasound to the area of skin. 149. The method of claim 147, wherein applying a vaccine to the area of skin comprises applying a patch containing the vaccine to the area of skin. 150. The method of claim 147, wherein applying a vaccine to the area of skin comprises applying a gel containing the vaccine to the area of skin. 151. The method of claim 147, wherein applying a vaccine to the area of skin comprises applying a liquid containing the vaccine to the area of skin. 152. The method of claim 147, wherein delivering the vaccine to at least one skin cell comprises spreading the vaccine to the at least one skin cell. 153. The method of claim 147, wherein the step of increasing the permeability of an area of skin and the step of providing a vaccine to the area of skin are performed simultaneously. 154. The method of claim 147, wherein said vaccine is selected from the group comprising peptides, proteins, DNA, allergens and other antigens. 155. The method of claim 147, wherein said at least one skin cell is selected from the group comprising Langerhans cells, dendritic cells, epidermal cells. 156. The method of claim 147, wherein said step of delivering said vaccine to said immune cells comprises the steps of physical force, chemical force, biological force, vacuum,
Electric, penetrating, diffusing, electromagnetic, ultrasonic, cavitation, mechanical, thermal, capillary, fluid circulation through the skin, electroacoustic, magnetic, magnetohydrodynamic Applying a driving force selected from the group comprising: a dynamic force, an acoustic force, a convective dispersion, a photoacoustic force, and any combination of these forces. 157. A method of transdermal vaccination and immunization, comprising the steps of: applying ultrasound to stimulate an area of skin, and applying the vaccine to the area of skin.