U.S. patent application number 09/939506 was filed with the patent office on 2002-08-22 for substance delivery system.
Invention is credited to Redding, Bruce K. JR..
Application Number | 20020115960 09/939506 |
Document ID | / |
Family ID | 27397712 |
Filed Date | 2002-08-22 |
United States Patent
Application |
20020115960 |
Kind Code |
A1 |
Redding, Bruce K. JR. |
August 22, 2002 |
Substance delivery system
Abstract
A system being suitable for being secured substantially adjacent
to a surface of a subject so as to effect delivery of at least one
substance through the surface and into the subject. The system
includes at least one aperture for receiving at least one
ultrasonic transmission. The at least one substance is releasably
secured substantially adjacent to the at least one aperture. A
sonic member is disposed with respect to the at least one aperture
so as to communicate the at least one transmission to the at least
one substance so as to effect the delivery of the at least one
substance through the surface of the subject.
Inventors: |
Redding, Bruce K. JR.;
(Broomall, PA) |
Correspondence
Address: |
Louis M. Heidelberger, Esq.
Reed Smith LLP
2500 One Liberty Place
1650 Market Street
Philadelphia
PA
19103
US
|
Family ID: |
27397712 |
Appl. No.: |
09/939506 |
Filed: |
August 24, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60300343 |
Jun 22, 2001 |
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60300292 |
Jun 22, 2001 |
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60227359 |
Aug 24, 2000 |
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Current U.S.
Class: |
604/22 |
Current CPC
Class: |
A61M 37/0092 20130101;
A61M 2037/0007 20130101; A61M 31/002 20130101 |
Class at
Publication: |
604/22 |
International
Class: |
A61B 017/20 |
Claims
What is claimed is:
1. A system being suitable for being secured substantially adjacent
to a surface of a subject so as to effect delivery of at least one
substance through said surface and into said subject comprising: at
least one aperture for receiving at least one ultrasonic
transmission, said at least one substance being releasably secured
substantially adjacent to said at least one aperture; and, a sonic
member disposed with respect to said at least one aperture so as to
communicate said at least one transmission to said at least one
substance so as to effect said delivery of said at least one
substance through said surface of said subject.
2. A system being suitable for being secured substantially adjacent
to a surface of a subject so as to effect delivery of at least one
substance through said surface and into said subject comprising: a
backing layer; at least one aperture formed in said backing layer
for receiving at least one ultrasonic transmission; a pad
releasably securing said at least one substance substantially
adjacent to said at least one aperture; and, a sonic member
disposed with respect to said at least one aperture so as to
communicate said at least one transmission to said at least one
substance so as to effect said delivery of said at least one
substance through said surface of said subject.
Description
RELATED APPLICATIONS
[0001] This application claims priority of each of: U.S. patent
application Ser. No. 60/300,343, filed Jun. 22, 2001 and entitled
"ULTRASONIC TRANSDUCER APPARATUS AND METHOD OF USE SUITABLE FOR
ULTRASONIC DRUG DELIVERY VIA A SYSTEM WHICH IS PORTABLE AND
WEARABLE BY A SUBJECT"; U.S. patent application Ser. No.
60/300,292, filed Jun. 22, 2001 and entitled "TRANSDERMAL PATCH FOR
USE IN ULTRASONIC DRUG DELIVERY APPLICATIONS"; and, U.S. patent
application Ser. No. 60/227,359, filed Aug. 24, 2000, entitled
"TRANSDERMAL DRUG DELIVERY SYSTEM UTILIZING A WEARABLE, PORTABLE
SONIC APPLICATOR", the entire disclosures of which are each
respectively hereby incorporated by reference herein as if being
set forth in their respective entireties.
FIELD OF THE INVENTION
[0002] The present invention relates generally to substance
delivery systems, and particularly to patches being suitable for
use with an ultrasonically enhanced substance delivery.
BACKGROUND OF THE INVENTION
[0003] Generally, transdermal drug delivery systems employ a
medicated device or patch which is affixed to the skin of a
patient. The patch allows a medicinal compound contained within the
patch to be absorbed through the skin layers and into the patient's
blood stream. Transdermal drug delivery reduces the pain associated
with drug injections and intravenous drug administration, as well
as the risk of infection associated with these techniques.
Transdermal drug delivery also avoids gastrointestinal metabolism
of administered drugs, reduces the elimination of drugs by the
liver, and provides a sustained release of the administered drug.
Transdermal drug delivery also enhances patient compliance with a
drug regimen because of the relative ease of administration and the
sustained release of the drug.
[0004] Many medicinal compounds are not suitable for administration
via known transdermal drug delivery systems since they are absorbed
with difficulty through the skin due to the molecular size of the
drug or to other bioadhesion properties of the drug. In these
cases, when transdermal drug delivery is attempted, the drug may be
found pooling on the outer surface of the skin and not permeating
through the skin into the blood stream. Once such example is
insulin, which has been found difficult to administer by means of
transdermal drug delivery.
[0005] Some of the most critically needed medications are currently
administered either by injection or oral dosage forms, which can
have several drawbacks. In particular, chemotherapeutic agents are
administered in increased dosages because of their need to survive
degradation in the gastrointestinal tract. Many critical treatments
for AIDS require a cocktail of drugs taken orally in solid dosage
forms, several times a day to be effective. These medications are
not suitable for administration via known transdermal drug delivery
system because of the extensive dosing requirement, as well as the
inability of the drug molecule to remain stable in a transdermal
form. Moreover, the unsuitability of many drugs for conventional
transdermal transfer may be due to low bioabsorbance of the drug
across the skin layers.
[0006] Generally, conventional transdermal drug delivery methods
have been found suitable only for low molecular weight medications
such as nitroglycerin for alleviating angina, nicotine for smoking
cessation regimens, and estradiol for estrogen replacement in
post-menopausal women. Larger molecular medications such as insulin
(a polypeptide for the treatment of diabetes), erythropoietin (used
to treat severe anemia) and gamma-interferon (used to boost the
immune systems cancer fighting ability) are all compounds not
normally effective when used with conventional transdermal drug
delivery methods.
[0007] However, the use of energy, such as ultrasonic energy, may
be used to enhance the transdermal delivery of certain drugs. While
these terms "ultrasound" and "ultrasonic" as used herein have their
ordinary meaning, at least one source has defined "ultrasound" as
mechanical pressure waves with frequencies above 20 kHz, H. Lutz et
al., Manual of Ultrasound 3-12 (1984). Ultrasound may be generated
by vibrating a piezoelectric crystal or other electromechanical
element by passing an alternating current through the material. he
use of ultrasound to increase the permeability of the skin to drug
molecules has been termed sonophoresis or phonophoresis.
[0008] Previously described methods for using ultrasound to enhance
transdermal drug delivery required the use in a clinical ultrasonic
delivery setting, such as a physician's office, hospital or clinic.
Moreover, the time for delivery of measurable amounts into human
skin using these methods ranged from 10 minutes to 24 hours. In
this case, the use of ultrasound-transdermal drug delivery
treatment may be actually less desirable from a patient
administration standpoint than a simple injection. This method is
undesirable because of the need for the patient to visit the
clinical setting and to remain on a treatment table while the
ultrasound treatment is used to deliver the drug.
[0009] While the use of certain ultrasonic frequencies for the
enhancing delivery of certain drugs in certain applications is
known, results in such applications have been largely
disappointing. In many cases the drug delivery pathway utilized
enabled initial quantities of a drug to permeate the skin, but as
longer periods of ultrasound were applied to the same location on
the skin the delivery rate dropped off or was reduced to zero.
[0010] The exposure to ultrasound has been either continuous or
pulsed to reduce heating of biological membranes. The depth of
penetration of ultrasonic energy into living soft tissue is
inversely proportional to the frequency, thus high frequencies have
been suggested to improve drug penetration through the skin by
concentrating the effect in the outermost skin layer, the stratum
corneum. Pharmaceutical agents under sonic transdermal delivery may
require variable frequencies and intensities in order to deliver
therapeutic quantities of drugs to patients. Variables such as fat
content and mass of a particular patient's tissue, through which
the drug will be delivered, may vary the frequency and intensity
requirements to obtain an effective dosing regimen.
[0011] Portable programmable devices and methods for ultrasonically
enhancing substance delivery through a surface of a subject have
not been disclosed. Because of the inefficiencies and lack of
safety of the previous ultrasonic methods, no useful device has
been proposed for the transdermal delivery of drugs with an
ultrasonic assist.
[0012] Little effort has in the past been focused upon the design
of a transdermal patch suitable for ultrasonic drug transport. The
use of an ultrasonic applicator or sonicator applied to skin tissue
has conventionally been employed with a pool of a target drug
laying under the tip of the transducer and laying upon the skin
surface. This method of ultrasonic drug delivery is not believed to
be feasible in a commercial application. Other examples in which
the skin is pre-sonicated and then a patch is placed over the
sonicated skin area employ a passive drug delivery based upon the
concept of induced increased permeability as effected by the
ultrasonic transmission. This also is commercially non-feasible
because of the length of time needed to pre-sonicate the skin and
other factors.
[0013] In view of the foregoing problems and/or deficiencies, the
development of a device for safely enhancing the permeability of
the skin for noninvasive drug delivery in a more rapid time frame
would be a significant advancement in the art. It would be another
significant advancement in the art to provide an ultrasonic
programmable device and method that can be used with a
drug-containing patch. In addition, patient mobility, coupled with
sustained release of a broad range of drugs, until now, has
remained an elusive goal of transdermal drug delivery devices.
Thus, the design of a suitable transdermal patch to accommodate an
active ultrasonic transdermal delivery method is helpful to
achieving a commercial ultrasonic drug delivery device.
SUMMARY OF THE PRESENT INVENTION
[0014] A system being suitable for being secured substantially
adjacent to a surface of a subject so as to effect delivery of at
least one substance through the surface and into the subject
including: at least one aperture for receiving at least one
ultrasonic transmission, the at least one substance being
releasably secured substantially adjacent to the at least one
aperture; and, a sonic member disposed with respect to the at least
one aperture so as to communicate the at least one transmission to
the at least one substance so as to effect the delivery of the at
least one substance through the surface of the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The present invention will be more readily understood in
connection with the non-limiting, attached figures, wherein:
[0016] FIG. 1 is a transdermal patch with an ultrasonic generator,
which is worn by the patient, as it is placed on the arm of a
patient.
[0017] FIG. 2 is an illustration of the structure of human
skin.
[0018] FIG. 3 illustrates for a transdermal patch wherein
transducers are exterior to the patch.
[0019] FIG. 4 illustrates a transdermal patch wherein the patch is
constructed employing a gasket or sealer around the edges of the
patch.
[0020] FIG. 5 illustrates an ultrasonic signal, which alternates
from a sawtooth to a square waveform.
[0021] FIG. 6 illustrates a transdermal patch wherein a transducer
or array of transducers is directly imbedded within the patch.
[0022] FIG. 7 illustrates a transdermal patch wherein a
semi-permeable film placed on the underside of the patch acts to
provide a valving function with the administration of transmitted
ultrasound though the patch.
[0023] FIG. 8 illustrates a patch according to an embodiment of the
present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0024] It is to be understood that the figures and descriptions of
the present invention have been simplified to illustrate elements
that are relevant for a clear understanding of the present
invention, while eliminating, for purposes of clarity, many other
elements found in substance delivery systems. Those of ordinary
skill in the art will recognize that other elements are desirable
and/or required in order to implement the present invention.
However, because such elements are well known in the art, and
because they do not facilitate a better understanding of the
present invention, a discussion of such elements is not provided
herein.
[0025] The present invention relates to patches, which may be
employed with an ultrasonic drug delivery device, which is ideally
worn by the patient.
[0026] According to an embodiment of the present invention, a
transdermal patch is provided for enhancing transdermal drug
delivery by the use of ultrasound. As used herein, the terms "drug"
and "substance" may be used together or interchangeably and may
include, but are not limited to, any substance including, but not
limited to, a medicinal or non-medicinal substance which may be
transported through a surface or membrane, including, but not
limited to, tissue and other types of membranes. Use of ultrasonics
is particularly effective in delivering larger pharmaceutically
active compounds, wherein the transdermal patch is made to
accommodate both the special needs of ultrasonic excitation through
the patch construct and the delivery of medicinal compounds stored
within the patch.
[0027] According to an embodiment of the present invention, a
transdermal delivery device or patch is designed with materials to
enable the transmission of ultrasound through the patch, effecting
the delivery of medications stored within the patch, and to be used
in conjunction with ultrasonic drug delivery processes. The
transdermal patch may contain a substance, such as, for example, a
particular medication or cocktail of medications for treatment of
disease or relief of pain. A sonic applicator may be placed in the
proximity of the patch, such as for example, over the top of the
patch or into a pocket in the patch or may be contained within the
patch construction itself. When the sonic applicator is activated
by means of an external timing circuitry and driver mechanism or
other suitable electronics, the sonic applicator generates an
ultrasonic vibration or ultrasonic transmission through the
transdermal patch. The effects of the energy of the ultrasonic
signal, including, but not necessarily limited to, the vibration
induced within the patient's skin, increase the absorption of the
medication emanating from the transdermal patch through the skin
into the patient's bloodstream.
[0028] According to an embodiment of the present invention,
introduction of an ultrasonic signal to a transdermal patch
increases the type of medications which can be employed in a
transdermal delivery system, including large molecule medications,
nutrient solutions, and proteins which heretofore were not capable
of being delivered through a transdermal system.
[0029] According to an embodiment of the present invention, the use
of an ultrasonic applicator with a transdermal patch provides full
portability in the drug delivery system, as opposed to systems
employing ultrasound to enhance drug delivery wherein the patient
requires the assistance of a health professional, typically at a
hospital, doctor's office or clinic.
[0030] According to an embodiment of the present invention, the
system can be programmed to provide steady drug delivery or pulsed
timed delivery at certain medication quantities, providing more
flexibility and control over a particular patients dosing needs.
Conventional transdermal drug delivery systems are generally steady
state release devices providing a-one-size-fits-all regimen, which
is not suited for all patient medication regimes.
[0031] According to an embodiment of the present invention, a
transdermal patch may be employed with an ultrasonic drug delivery
device which is ideally wearable by the patient, and/or is a
programmable device using ultrasound for controlling transdermal
and/or transmucosal flux rates of drugs and other molecules into
the body.
[0032] According to an embodiment of the present invention, a
method is provided for non-invasive delivery of molecules,
including, but not necessarily limited to, biologically active
molecules, through the skin or mucosal membranes using ultrasound
and a transdermal patch.
[0033] According to an embodiment of the present invention, various
ultrasound frequencies, intensities, amplitudes and/or phase
modulations may be applied to control the magnitude of the
transdermal flux from the patch to achieve a therapeutic or
nutritional level.
[0034] According to an embodiment of the present invention, the
design of the transdermal patch is such that the ultrasound energy
is transmitted at a sufficiently high efficiency to permit drug
permeation and contains an absorbent material, which holds the drug
within the patch until liberated by ultrasound.
[0035] According to an embodiment of the present invention, a
transducer or an array of transducers may be built into the patch.
According to an aspect of the present invention, the transducers
can be removably inserted into the patch.
[0036] According to an embodiment of the present invention,
ultrasound may be combined with iontophoresis, electroporation,
depilatories, and/or chemical enhancers such as surfactants to
facilitate transdermal permeation. Other advantages and novel
features of the invention will be evident from the description
which follows, and in part will become apparent to those skilled in
the art upon examination of the foregoing and/or the following.
[0037] FIG. 1 illustrates one embodiment of this transdermal drug
(or other desirable substance) delivery system 100 of this
invention. Transdermal drug delivery system 100 comprises an
ultrasonic applicator 1, placed within functional proximity with a
transdermal delivery device or patch 2. Patch 2, which contains the
substance to be delivered, is placed in functional proximity to
typically contact with the exterior of the patient's skin 3 by
means of a strap or other suitable stabilizing device 4, which
strap 4 holds the ultrasonic applicator 1 and patch 2 in desired
proximity. Power for the ultrasonic applicator 1 is provided by
power cells or other suitable power supply (not shown) which power
supply is ideally rechargeable, and which may be located within
strap 4 itself or other convenient location which provides for a
fixed portable transdermal drug delivery system 100. For example,
the power supply may be contained within the ultrasonic applicator
device 1 itself or provided by an external source.
[0038] Reference is hereby made to commonly assigned and copending
U.S. patent applications Ser. No. Not Yet Assigned, entitled
"ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY METHOD", and Ser. No.
Not Yet Assigned, entitled "ULTRASONICALLY ENHANCED SUBSTANCE
DELIVERY SYSTEM AND DEVICE", both filed on even date herewith, the
entire disclosures of which are respectively hereby incorporated by
reference herein.
[0039] FIG. 1 illustrates usage on the arm of the patient,
according to an aspect of the present invention. Alternatively, the
system may be placed in contact with some other part of the
patient's body as determined by the medical personnel or other
person administering the drug or other substance treatment regimen.
Such locations may include, but are not necessarily limited to, the
patient's chest (as in the case of nitroglycerin drug delivery, for
example), abdomen, neck, back and legs.
[0040] FIG. 2 illustrates the structure of human skin, showing the
various structures comprising the skin. According to an aspect of
the present invention, drug or other substance delivery may be
accomplished by inducing a substance to travel down one or more
hair follicles. In such an embodiment, the rate of delivery of a
large molecule drug or other substance may be increased
significantly, when such transmission is effected at the hair
follicle of the skin. This effect may be achieved through the use
of ultrasound, altered to a combination transmission incorporating
both sawtooth and square waveforms. More specifically, in this
embodiment, the pilosebaceous pores surrounding the hair follicle
may become expanded with this method of substance delivery and a
penetrating drug substance travels down the hair follicle to the
hair root, whereupon it is absorbed into the blood stream located
within the vascular network directly under the hair root. This
substance pathway enables a greater quantity of the substance to be
delivered ultrasonically than can be achieved simply by the use of
cavitation effects upon the surface of the skin leading to
microporation of the skin tissue or by simply enabling the drug to
pool on the skin and travel through open skin pores.
[0041] In an embodiment, patch 2 may be subjected to ultrasound for
the purpose of enhancing the penetration of substances, for
example, medicinal compounds (drugs) contained within the patch,
through tissue such as the skin or a mucous or other membrane, and
into the patient's bloodstream. The ultrasonic drug delivery system
100 may be programmed to deliver a medicinal compound to the
patient continuously (hereafter referred to as "sustained release")
or intermittently (hereinafter referred to as "pulsed release"),
whichever may be deemed more appropriate to a drug maintenance or
other treatment regimen for a particular patient.
[0042] FIG. 5 illustrates one embodiment of an ultrasonic signal
which generates the enhanced substance delivery of this invention.
The signal of FIG. 5 employs a combination of a sawtooth and a
square waveform. In this embodiment, the sawtooth wave front
effects homogenization of the drug contained within the patch, and
the square waveform which follows delivers ultrasonic energy to the
surface of the skin to effect skin transport.
[0043] As referred to above, FIG. 2 generally illustrates the
typical structure of human skin. Examples of pathways through the
skin into the bloodstream include:
[0044] 1. Breaching the Stratum Corneum.
[0045] 2. Passing a pharmaceutical agent through sweat pores in the
skin.
[0046] 3. Passing a pharmaceutical agent through the skin by
following the pilosebaceous pore to the hair root, and from there
into the vascular network located at the base of the hair root.
[0047] In an embodiment of the invention, transdermal drug delivery
may be achieved by utilizing drug pathways associated with the
sweat pore and the hair follicle system on the patient's skin. In
an embodiment, the ultrasonic frequency, intensity level and
waveform dynamics may be adjusted to maximize drug delivery through
the hair follicle pathway primarily and through the sweat pores in
the skin surface secondarily, but not necessarily directly through
the stratum corneum. It is believed that the amount of energy
needed for piercing the stratum corneum is excessive and is also
damaging to the fatty tissue. This transport through the patch and
through the skin hair follicles and sweat pores in the embodiment
of the invention may be enhanced by employing either or both of the
following forces which may be exerted upon the skin surface:
[0048] 1. First, in an embodiment, application of compression or
tensile force to the surface of the skin may constrict the skin to
allow the drug pathways to become more pronounced. Referring to
FIG. 1 it can be seen that a strap holds the device to a patient's
arm. In addition to securing the device to the patient's body, the
strap also exerts a pressure upon the surface of the skin,
constricting the skin. It is believed that the constriction offered
by a tight strap may affect the permeability of the skin by: 1)
exerting downward pressure upon the skin, perpendicular to the skin
surface, 2) stretching the skin such that skin pores, such as the
sweat pores and/or pilosebaceous pores, are more readily accessible
to a drug; and/or 3) altering the location of the fat or other
tissue underlying the outer skin layers such that transdermal
delivery is enhanced, thus providing a more substantial pathway for
drug delivery than was available by methods of the previous art
which employed excessive cavitation energies to the skin surface in
hope of breaching the stratum corneum.
[0049] 2. Second, application of force on skin which force is the
pressure generated by an ultrasonic signal. It is believed that
through the use of alternating waveforms the amount of energy
transmitted to the surface of the skin can be minimized, while also
providing a pressure wave effect upon the skin, enhancing drug
delivery through the hair follicle and sweat pore system. Referring
to FIG. 5, an embodiment employs a waveform, which alternates from
sawtooth to square wave. The amplitude of and intensity of the wave
shaping is believed to aid in both the homogenization of the drug
contained within the transdermal patch (as seen in FIGS. 3 and 4),
helping to miniaturize the beadlet size of the active
pharmaceutical substance within the patch, and in drug transport
through the skin. It is believed that the short, peaked portion of
the ultrasonic waveform in a sawtooth shape helps with drug
homogenization, without imparting destructive frequencies and
cavitation to the drug substance. Upon conversion to the square
waveform the ultrasonic transmission acts to massage and open the
fatty tissue surrounding the hair follicles and sweat pores. Drugs
permeating from the transdermal patch are in monomer form and/or
reduced in droplet size, making them more suitable in dimension to
pass through the skin. In an embodiment, the droplet size may be
reduced to below approximately 50 Angstroms. The square waveform
helps to "push" the drug through the pores and alongside the hair
follicles, where the drug makes it way to the hair root, and
directly into the bloodstream through the vascular network.
[0050] The parameters of ultrasound that can be changed to improve
or control penetration include, but are not necessarily limited to:
(1) frequency, (2) intensity, (3) time of exposure and/or (4)
ultrasonic waveform. All of these parameters may be modulated
simultaneously in a complex fashion to increase the effect or
efficiency of the ultrasound as it relates to enhancing the
transdermal molecular flux rate either into or out of the human
body.
[0051] Since ultrasound is rapidly attenuated in air, a coupling
agent, for example one having lowest realizable absorption
coefficient that is non-staining, non-irritating, and slow drying,
may be used to efficiently transfer the ultrasonic energy from the
ultrasound transducer into the skin. When a chemical enhancer fluid
or anti-irritant or both are employed, they may function as the
coupling agent. For example, glycerin used as an anti-irritant may
also function as a coupling agent. If needed, additional components
may be added to the enhancer fluid to increase the efficiency of
ultrasonic transduction. In an aspect of the present invention,
resonance responsive gels may be used to further enhance the
transport of drugs through the skin. In addition, maintaining the
drug in a sterile and non-degradable form may be used to increase
bioactivity.
[0052] In an embodiment of this invention, transdermal patch 2 may
operate in conjunction with sonic applicator 1 to achieve
ultrasonically promoted transdermal delivery of a desired
substance. In particular, the contact between applicator 1 and
patch 2 may be adjusted to insure efficient energy transmission.
The materials used to construct the patch may be selected to
maintain the intensity and power output of the ultrasonic
transmission from the transducers through the transdermal patch.
The present invention is particularly suited to deliver large
molecule substances. For example, insulin has a large molecular
size, and forms hexamers generally over 50 Angstroms, making it
difficult to permeate through the pores of the skin. Insulin
molecules tend to agglomerate when stored. Insulin therefore stored
within a pocket of the patch may tend to agglomerate into even
larger drug clump sizes, reducing skin transport potential.
[0053] To help alleviate this problem and to keep the drug at a
size sufficiently small enough for skin transport, the waveform of
the ultrasonic signal delivered by applicator 1 may be altered from
time to time, using a sawtooth to a square waveform. FIG. 5
illustrates the alternating waveform concept wherein a sawtooth
waveform is more efficient at homogenization of a drug within the
patch, leading to increased skin transport as the ultrasonic
waveform switches to a square wave shape. Under the sawtooth
waveform the short period leads to high energy, with short duration
of pressure amplitude, leading to a vibration effect with the
targeted pharmaceutical substance. This vibration is with low heat
and has the effect of mixing or homogenizing the drug within the
patch. Smaller beadlet sizes are made possible by the sawtooth
waveform.
[0054] Referring now to FIGS. 3 and 5, when the sonic transmission
converts to square waveform induced, more energy is released
through the patch, forcing the homogenized drug through the
semi-permeable membrane 13 which may be made part of the patch
secured to the surface of the skin. There the intensity of the
sonic transmission acts upon the pores directly alongside the hair
follicles as shown in FIG. 2. The square waveform enables the pores
directly alongside the hair follicle to "open" and become more
receptive to drug transport. The deposited drug follows the hair
follicle down through the epidermis to the base root of the
follicle and is deposited directly into the blood stream within the
skin's vascular network. From there the deposited drug is
circulated through the body.
[0055] Referring now to FIG. 1, it can be seen a transdermal patch
2, is first placed within functional proximity, such as for
example, in contact with skin 3 of the patient. In one embodiment
of the invention, patch 2 may be affixed to skin 3 by adhesive or
other appropriate means. Sonic applicator 1 may be placed in
functional proximity to patch 2, such as, for example, in contact
with patch 2, such that applicator 1 generates an energy signal,
for example, an ultrasonic signal which signal transverses
transdermal patch 2 underneath sonic applicator 1. The substance
contained within transdermal patch 2 may be homogenized into
smaller droplet sizes, which may tend to more readily diffuse the
substance into and through the skin. The ultrasonic signal may also
affect the skin lipids by disrupting and/or disorganizing them to
permit the substance to be delivered. Alternatively, the hair
follicle channels may serve as substance delivery channels.
Regardless of the mechanism, the substance under the influence of
ultrasonic signals penetrates the surface of the skin, travels
through the various layers of the skin and fatty tissue and finally
is absorbed into the bloodstream and/or tissue of the patient.
[0056] FIG. 3 illustrates an embodiment of the transdermal patch 2
of the present invention, referred to here as "patch A".
Transdermal patch 2 is constructed with a backbone or backing
material 10 into which a section, or aperture, has been created
incorporating a sonic membrane 11 at the top of the patch 2. A
peel-away film 12 seals patch 2 until use. Peel-away film 12 may be
constructed by any suitable material, including, but not limited
to, UV-resistant, anti-static polyethylene film (50 micrometer
thickness) available from Crystal-X Corp., Sharon Hill, Pa. At the
bottom of patch 2 is a semi-permeable member, such as a membrane or
film, 13, which comes into functional proximity with the skin, such
as within direct contact with the skin when in use. In the interior
of patch 2 an absorbent pad 14 holds the desired drug or medication
compound 15. Ultrasonic signals are transmitted through sonic
membrane 11 and pass through the patch 2 by first traveling through
the absorbent pad 14. Drug or other substance 15, is contained
within the absorbent pad 14 until it is released by the ultrasonic
signal, or by other means. The substance then passes through
semi-permeable membrane 13 and is deposited on or through the
surface of the patient's skin.
[0057] FIG. 4 illustrates yet another embodiment of transdermal
patch 2 of the present invention referred to here as "patch B".
Gasket 16 is placed between backbone 10 and absorbent pad 14.
Gasket 16 may be composed of any suitable material, such as, for
example, synthetic rubber. Gasket 16 forms a reservoir or well over
which absorbent pad 14 is placed. When pressed upon the skin gasket
16 forms a barrier, which tends to restrict moisture and air from
traveling under the patch and interfering with the ultrasonic
signal intensity. Alternatively, a sealant compound, ultrasonic gel
or other suitable material may be used for or in place of the
gasket 16 to provide a sealing action around the borders of patch 2
to provide moisture protection, prevent leakage of substance or the
drug from the patch and prevent air from entering under the
patch.
[0058] Referring now to FIG. 6, transducers 18 may be incorporated
directly within patch 2 or in any other suitable location. In such
construction a single transducer may be employed or an array of
ultrasonic transducers may be desired.
[0059] FIG. 7 illustrates the underside of patch 2 showing well 17
together with semi-permeable membrane 13 over absorbent pad 14.
Alternatively or in addition, sealing gasket or compound 16 may be
placed in well 17 of the underside of patch 2.
[0060] Referring now to FIG. 8, according to an embodiment of the
present invention, a patch, or system, 2 being suitable for being
secured substantially adjacent to a surface of a subject so as to
effect delivery of at least one substance through the surface and
into the subject is provided. The system 2 may include a backing
layer, backing material, backbone, or backbone material, 10 and at
least one aperture 19 formed in the backing layer 10 for receiving
at least one ultrasonic transmission. The system 2 may further
include a pad, such as an absorbent pad, 14 releasably securing the
at least one substance substantially adjacent to the at least one
aperture 19. A sonic member, such as a sonic membrane or film, 11
may be disposed with respect to the at least one aperture 19 so as
to communicate the at least one transmission to the at least one
substance so as to effect said delivery of the at least one
substance through the surface of the subject. Optionally, a
semi-permeable member, such as a membrane or film, or valving
layer, 13 may be provided.
[0061] In an embodiment of the present invention, ultrasonic
signals are transmitted using a combination frequency of a saw
tooth and square waveforms as depicted in FIG. 5, which is believed
to first homogenize substance 15 within the patch 2 and then to
effect skin transport once the substance 15 has been deposited onto
or through the surface of the skin. It may not be necessary for a
coupling agent to be used between the skin and the semi-permeable
membrane.
[0062] Referring again to FIGS. 3 and 4, sonic membrane 11 may be
constructed of any suitable resonance compatible material which
will enable the sonic transmission emanating from transducer(s) 18
to pass through sonic membrane 11, and then the absorbent pad 14
and thereafter through patch 2 and onto and/or through the
patient's skin. Sonic membrane 11 may be composed of any suitable
resonance compatible material which will conduct the ultrasonic
transmission without unduly decreasing the effect generated by the
transmission of frequency or intensity potential. Suitable
resonance compatible materials used for sonic membrane 11 may
include, without limitation, polyvinylidene chloride plastic film,
such as, for example, the film sold as Saran.RTM., including, but
not necessarily limited to, Model Numbers Dow BLF-2014, Dow
BLF-2015, Dow BLF-2023, Dow BLF-2050, Dow BLF-2052, Dow BLF-2057,
and Dow BLF-2080, available from Dow Chemical Company, Midland,
Mich.; and polyester film, for example, Mylar.RTM. film, including,
but not necessarily limited to, Model Numbers M30, M33, M34, D887,
MC2, and SBL-300, available from DuPont Teijin Films Div.,
Wilmington, Del. Polyvinylidene chloride film has been found to be
effective as a sonic membrane material, however many other
materials may also provide a similar function. The materials of
patch 2 may be chosen or fabricated for resonance compatibility
with a desired frequency and intensity of ultrasound to be used for
a particular substances or drug's skin transport dynamics.
[0063] In an embodiment of the invention, sonic membrane 11 may be
affixed to absorbent pad 14 with a suitable resonance compatible
material, including, but not limited to, a flat layer of polymer
epoxy. One suitable material is a polyurethane material, such as
Uralite.RTM., available from H. B. Fuller Company, St. Paul,
Minn.
[0064] Absorbent pad 14 may be composed of any suitable material,
such as a non-woven cellulose fiber or any similarly acting
material which will absorb or otherwise hold drug 15 during storage
within patch 2, but also release drug 15 upon transmission of the
ultrasonic signal through patch 2. Other possible materials may be
used, including, but not limited to, natural sponges, fused silica,
and various woven and non-woven materials. Examples of suitable
materials include, without limitation, CoTran 9729, a non-woven
polypropylene material available from 3M, St. Paul, Minn.; Pop-Up
Compressed Sponge (comprising 76% cellulose, 7.7% polyol, and 15.5%
NaCl), available from Clipper Mill, San Francisco, Calif.; Microdon
Web, Model Number M-261420025, a non-woven polyester fiber blend,
available from 3M, St. Paul, Minn.; Vizorb #3010, a cellulose pad
comprising wood pulp and ethylene vinyl acetate based synthetic
latex, available from Buckeye Absorbent Products, Memphis, Tenn.;
and Vicell #6009, a cellulose pad comprising wood pulp and ethylene
vinyl acetate based synthetic latex, available from Buckeye
Absorbent Products, Memphis, Tenn.
[0065] A semi-permeable membrane 13 may be placed at the bottom of
patch 2, such that it comes into direct contact with the patient's
skin. Such a semi-permeable membrane 13 may function like a valve,
enabling drug 15 released from absorbent pad 14 to pass through
semi-permeable membrane 13 only with the active generation of
ultrasound. When no ultrasonic signal is present, semi-permeable
membrane 13 prevents a significant amount of the drug from
permeating the membrane onto or through the surface of the
patient's skin. The valving action of semi-permeable membrane 13
may provide a means of controlling the dose delivered to the
patient. It is believed that a sonicated skin section may remain
permeable to a delivered substance such as a drug, for some amount
of time after the ultrasonic signal has been terminated. If drug 15
were to reach the skin in this case, the skin might continue to
absorb the drug even after the cessation of the ultrasonic signal.
Assuming that a steady rate of delivery can be achieved with an
active ultrasonic signal, the delivery of the proper dose would be
proportional to the number of seconds or minutes that an active
ultrasonic signal was present upon the skin surface. In such a
manner the delivered drug dose levels would be comparable to the
timing of active ultrasonic signal.
[0066] If continued skin permeation follows the cessation of active
ultrasonic signal, it may be difficult to ascertain the exact
amount of dose actually delivered to the patient. Hence a valving
patch, which effectively shuts down drug delivery when the
ultrasonic signal is terminated, may be provided. A sonically
reactive semi-permeable membrane 13 may be used at the base of
patch 2 in order to insure that patch 2 delivers the drug only with
the presence of a ultrasonic signal, timed to deliver the proper
dose by a timing circuit in sonic applicator device 1 depicted in
FIG. 1, for example.
[0067] Suitable elastomeric materials that change properties when
exposed to changes in pressure and/or temperature may be used to
construct semi-permeable membrane 13. In an embodiment of the
invention, any suitable material, including, but not limited to,
natural sponge and perforated polymer films may be used as a
semi-permeable membrane 13. Ultrasonic signals are believed to
generate a cavitation effect in polymer films, expanding the
diameter of the perforations of the film, thereby enabling the film
to become more permeable. When an ultrasonic signal is not present,
the elasticity of the film may enable it to return to its original
structure and reduce the diameter of any perforation, thereby
blocking a large molecule substance contained within patch 2 from
further transport from patch 2 to the skin.
[0068] According to an embodiment of the invention, semi-permeable
membrane 13 may be constructed of any suitable semi-permeable
material that, in the absence of an ultrasonic signal, does not
permit diffusion of a solution containing a drug across the
membrane, but permits diffusion of a drug solution through the
membrane upon being subjected to an ultrasonic signal.
[0069] According to an embodiment of the invention, semi-permeable
membrane 13 may be constructed of any suitable thermoplastic
material. Such a material may change properties upon being
subjected to an increase in temperature as a result of a ultrasonic
vibrations, and return to its original state upon cessation of the
ultrasonic signal. According to an embodiment of the invention,
semi-permeable membrane 13 may be constructed of any suitable
thermoplastic elastomer that changes its permeability properties
upon being subjected to an ultrasonic signal, allowing movement of
the drug across the membrane, and substantially returns to its
original permeability state upon cessation of the ultrasonic
signal.
[0070] According to an embodiment of the invention, semi-permeable
membrane 13 may be constructed of any suitable ionomer
(ion-containing polymer), including, but not necessarily limited
to, those ionomers that function as thermoplastic elastomers.
According to an embodiment of the invention, suitable ionomers
include, but are not necessarily limited to,
ethylene-co-methacrylic acid copolymers (such as, for example, the
film sold as Surlyn.RTM., available from DuPont, Wilmington,
Del.).
[0071] As the transdermal patch 2 releases the contents of drug 15,
patch 2 may be replaced by a new patch 2. New patch 2 may then be
employed for another drug delivery period. Alternatively,
additional quantities of a substance or pharmaceutical agent may be
inserted into patch 2 by appropriate means to effectively "re-load"
the patch. In an embodiment, when patch 2 is replaced, it may be
uncoupled from transducer assembly 18 or other source of the
ultrasonic signal.
[0072] According to an embodiment of the invention, patch 2 is
attached to one or more transducers 18 by a sonic adhesive or
coupling agent. The sonic adhesive may be any suitable material,
including, but not limited to, a mineral oil. An example of a
suitable mineral oil is Draecol 9, available form Eastern Chemical,
Philadelphia, Pa.
[0073] Alternatively, a fold at the top of transdermal patch 2 may
be used to enable the transducer(s) 18 to slide into the topmost
section of the patch, for example.
[0074] Transducers 18 may be built directly into the structure of
the patch as shown in FIG. 6.
[0075] Backbone 10 of patch 2 may be made from any suitable
material, including, but not limited to, polyolefin film or
polyvinyl chloride. An example of suitable materials are Polyvinyl
Chloride Foam Tape 9772-L available from 3M, St. Paul, Minn. and
Model Number 3M 9773 Foam Tape, a polyolefin foam tape with
adhesive backing, available from 3M, St. Paul, Minn. Backbone
material 10 may also possess adhesives, such as, for example, the
pressure-sensitive acrylate adhesive used on 3M 9772-LFoam Tape,
available from 3M, St. Paul, Minn., which will enable the patch 2
to adhere to the surface of the patient's skin.
[0076] According to an embodiment of the invention, backing member
10, comprising Model Number 9772-L Foam Tape (3M, St. Paul, Minn.)
includes at least one aperture that is covered by sonic membrane 11
comprising Saran.RTM. film, Model Number Dow BLF-2014 (Dow chemical
Co., Midland, Mich.) or Mylar.RTM. film, Model Number M34, DuPont
Teijin Films, Wilmington, Del. At least one absorbent pad 14
comprising cellulose material (Model Number Vicell.RTM. #6009,
Buckeye Absorbent Products, Memphis, Tenn.) may be placed such that
ultrasonic energy is transmitted through sonic membrane 11 to
absorbent pad 14. In the presence of an ultrasonic signal, insulin
solution (Humulin.RTM.R, Eli Lilly, Indianapolis, Ind.) contained
on or within absorbent pad 14 may move through semi-permeable
membrane 13, comprising Surlyn.RTM. film (DuPont, Wilmington,
Del.), and be delivered to a subject. Peel-away film 12 comprising
UV-resistant anti-static polyethylene film (50 micrometer
thickness) (Crystal-X Corp., Sharon Hill, Pa.) may be utilized.
[0077] According to an embodiment of the invention, patch 2 may
enable ultrasonic signal transmission completely therethrough.
Therefore, it may be desirable to minimize attenuation of the
ultrasonic signal as it travels through the materials in patch 2.
Of particular concern are pockets containing, for example, air,
gas, or moisture located within the absorbent materials used in
patch 2, which may act to later the frequency and/or intensity of
the transmitted ultrasonic signal.
[0078] To facilitate an improved ultrasonic transmission through
the patch, absorbent material may be treated using vacuum freeze
drying to remove trapped air from within the absorbent material. In
this method the material is frozen by freeze drying and then vacuum
dried. One effect of freeze-drying is the reduction of the amount
of trapped air within the weave of the absorbent material, thus
making the absorbent material more resonance compatible with the
frequency and intensity of the ultrasonic transmission and
improving its attenuation properties.
[0079] According to an embodiment of the invention, the absorbent
pad material may be soaked in an aqueous solution of 0.9% NaCl
prior to the freeze-drying treatment. The pre-treatment with the
saline solution provides that a residue of NaCl remains in the
absorbent material. The salt residue acts as a humectant,
attracting water and thus maintaining some moisture within the
absorbent pad. Preventing the absorbent pad from drying out allows
the drug stored in the pad to remain in solution, preventing loss
of moisture that may cause the drug solution to become increasingly
concentrated. Concentration of the drug solution may be avoided, as
it may lead to aggregation or precipitation of the active drug from
the solution, impeding drug transport.
[0080] Suitable material for an absorbent pad may possess one or
more of the following characteristics:
[0081] 1) High absorbency for the selected drug presented in an
emulsion or solution form.
[0082] 2) The absorbent material is inert with respect to the
select drug, or its excipient or preservatives used in the solution
form of the drug, over a protracted period of storage time.
[0083] 3) The absorbent material is resistant to degradation under
exposure to ultrasound, and to releasing contaminants into the
stored drug.
[0084] 4) The absorbent material is essentially free of metallic,
organic or inorganic contaminants.
[0085] 5) The absorbent material is non-irritating to human skin
and remains stable upon interaction with human sweat.
[0086] 6) The absorbent material remains stable in a stored form
for one year or more and is resistant to degradation with time when
soaked with the drug.
[0087] 7) The absorbent material may be composed of natural or
synthetic materials.
[0088] According to an embodiment of the invention, the absorbent
material is superabsorbent, defined as a material capable of
absorbing about fourteen (14) or more times its weight in liquid.
Such a superabsorbent material provides the pad with the capacity
to store the drug in a dilute solution or suspension. This may be
of particular importance for polypeptides such as insulin, which is
believed to form multimeric structures when concentrated in
solution. Preventing the absorbent pad from drying out, and thus
maintaining insulin in dilute solution, maintains the insulin in
monomeric form, which is most easily transported out of the patch
and through the skin.
[0089] According to an embodiment of the invention, the absorbent
material contains functional groups capable of cross-linking with
the drug. Such cross-linking may act to stabilize the drug for
storage while in patch 2. When an ultrasonic signal is applied
through patch 2, upon reaching the absorbent material the
ultrasonic signal may cause disruption of the cross-linking such
that the drug is released from the absorbent material and is free
to be delivered to the subject.
[0090] According to an embodiment of the invention, the absorbent
material may be formed from material that contains moderate amount
of crosslinking points, such that the absorbent material forms
cross-linkages with the drug, but does not form cross-linkages that
disrupt the native structure of the drug, and such that, upon
exposure to ultrasonic signals, releases the cross-linking such
that the drug is no longer bound to absorbent pad 14 and is free to
be delivered to the tissue of the subject.
[0091] According to an embodiment of the invention, the absorbent
material and the drug are cross-linked through hydrogen bonding.
According to an embodiment of the invention, the absorbent material
contains functional groups able to form hydrogen bonds with
functional groups of a polypeptide drug, such as, for example,
insulin. In this case, the hydrogen bonding acts to stabilize the
structure of the drug. Upon exposure to an ultrasonic signals, the
hydrogen bonding that cross-links the drug to the absorbent
material is disrupted without breaking the hydrogen bonds that form
the native secondary structure or other aspects of the structure of
the polypeptide.
[0092] Table 1 lists at least some of the materials, which may be
utilized in the construction of absorbent pad 14:
1TABLE 1 EXAMPLE OF MATERIALS SUITABLE FOR ABSORBENT PAD 14
Cellulose Fiber Pad Cotton Natural Sponge Woven Cloth Fabrics
Polyurethane foams Polyisocynurate Foams Non-Woven Cloths Fused
Silica Starch Corn Meal Wood Pulp fibers Collagen Pads Poly methyl
methacrylate Polyvinyl alcohol Poly vinyl pyrrolidine Poly acrylic
acid Poly (2-hydroxy ethyl methacrylate Polyacrylamide Poly
ethylene glycol Polylactides (PLA) Polyglycolides (PGA)
Poly(lactide-Co-glycolides) Polycarbonate Chitosan Poly
(N-isopropylacrylamide) Co-Polymer formulations of Poly methacrylic
acid and Poly ethylene glycol Co-Polymer formulations of Poly
acrylic acid and Poly (N-isopropylacrylamide) Hyrdogels, e.g.
Polyacrylamide, poly(propylene oxide Pluronic polyols family of gel
materials, e.g. Pluronic-chitosan hydrogels Silica gels
[0093] Any other natural or synthetic materials, which may act to
absorb the drug compound and be able to release the drug upon
ultrasonic excitation.
[0094] According to an embodiment of the invention, the absorbent
compound may be a non-woven material having a moderate amount of
functional groups available for cross-linking. When the absorbent
material contacts a drug, the functional groups of the absorbent
material form cross-links with the drug such that the structure of
the drug is stabilized in the absence of an ultrasonic signal. When
an ultrasonic signal is transmitted through the patch to the
absorbent material, the cross-linking may be disrupted such that
the drug is released from the absorbent material without
contamination of or disruption of the native structure of the
drug.
[0095] According to an embodiment of the invention, the absorbent
material is treated by freezing, followed by vacuum drying. Such
freeze-drying of the absorbent material acts to reduce the amount
of contaminants such as air or moisture that may be trapped in the
absorbent material. Such contaminants may react with functional
groups of the absorbent material, thus preventing these functional
groups from forming cross-links with the drug. Upon freeze-drying,
such contaminants are removed, thus freeing the cross-linking sites
of the absorbent material such that the sites are free to form
cross-linkages with the substance to be delivered. In addition, the
freeze-drying may remove contaminants that otherwise might react
with or contaminate the drug.
[0096] According to an embodiment of the invention, the absorbent
material may be capable of retaining the drug in the absence of an
ultrasonic signal, of releasing the drug upon excitation by an
ultrasonic signal, and has absorbent properties such that any
excess drug left upon the skin surface after the ultrasonic signal
is terminated is reabsorbed into the absorbent pad and is not
released until another ultrasonic signal is transmitted to the
absorbent material. This function of the absorbent material enables
the accurate control of the delivered drug dose by parameters of
the ultrasonic signal and may eliminate the need for a
semi-permeable "valving" membrane to control the dose. According to
an aspect of the invention, a material having a capacity to absorb
from between about one and about four times its weight in drug
solution may provide the appropriate
absorption/release/reabsorption properties that would enable
controlled dosage release via ultrasound. The rate of absorption
may be adjusted by utilizing different types and combinations of
fibers to produce the absorbent material. For example, cellulose
material may be produced from fibers originating from various types
of wood (for example, "hard" versus "soft" woods) having different
absorbent properties.
[0097] In accordance with an embodiment of the invention, as
ultrasonic signals are transmitted through the patch 2 the signal
massages the pores directly surrounding the hair follicle,
increasing the permeability of the pore. Ultrasonic signals enhance
the transport of drug 15 stored within absorbent pad 14 within
patch 2, across semi-permeable membrane 13 and deposits drug 15
onto the skin surface, where drug 15 is absorbed into the body by
traveling down the hair follicle to the hair root and into the
vascular network.
[0098] In accordance with an embodiment of the invention, the
ultrasonic transmission may have a frequency in the range of about
20 kHz to about 10 MHz. The intensity of said ultrasonic
transmission may be in the range of about 0.01 W/cm.sup.2 to about
5.0 W/cm.sup.2. Changes in frequency and intensity levels may
require alteration of the materials used in the construction of
transdermal patch 2 to accommodate optimum performance in both drug
delivery and in the valving function effected by semi-permeable
film 13.
[0099] In accordance with an embodiment of the invention, while a
waveform converting from sawtooth to square has been described, a
traditional sinusoidal waveform may also be effective as a drug
delivery waveform for the ultrasonic transmission.
[0100] Apparatus and methods according to the present invention are
useful for delivering a wide variety of substances to a patient. As
described in greater detail herein, the substances may be
delivered, for example, transdermally, transcutaneously,
intralumenally, and within solid tissue sites, where in all cases
absorption of the substance or a pharmacologically active portion
thereof into the underlying or surrounding tissue is
phonophoretically enhanced by the application of ultrasonic or
sonic energy. The substance may take any suitable form, including,
but not limited to, liquids, gels, porous reservoirs, inserts, or
the like, and the substance or pharmacologically active portion
thereof may, for example, treat or alleviate an existing condition
or prophylactically prevent or inhibit another condition of the
patient. The effect of the substance may be local, such as
providing for anti-tumor treatment, or may be systemic. Suitable
medicaments include, but are not limited to, broad classes of
compounds normally delivered through the skin and other body
surfaces or into solid tissues.
[0101] In general, such medication may include or incorporate
substances including, but not limited to, the following:
anti-infectives such as antibiotics and antiviral agents;
analgesics and analgesic combinations; anorexics; antihelminthics;
antiarthritics; antiasthmatic agents; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
antihistamines; antuinflammatory agents; antimigraine preparations;
antinauseants; antineoplastics; antiparkinsonism drugs;
antipruritics; antipsychotics; antipyretics; antispasmodics;
anticholinergics; sympathomimatics; xanthine derivatives;
cardiovascular preparations including, but not limited to,
potassium and calcium channel blockers, beta-blockers, and
antiarrhythmics; antihypertensives; diuretics; vasodilators
including general coronary, peripheral and cerebral; central
nervous system stimulants; cough and cold preparations, including
decongestants; hormones, including, but not limited to steroids,
including, without limitation, estradiol, and corticosteroids;
hypnotics; immunosuppressives; muscle relaxants;
parasympatholytics; psychostimulants; sedatives; and tranquilizers.
By the method of the present invention, ionized and nonionized
drugs may be delivered, as can drugs of high or low molecular
weight.
[0102] Proteinaceous and polypeptide drugs represent one class of
drugs suitable for use in conjunction with the presently disclosed
invention. Such drugs cannot generally be administered orally in
that they are often destroyed in the gastrointestinal tract or
metabolized in the liver. Further, due to the high molecular weight
of most polypeptide drugs, conventional transdermal delivery
systems are not generally effective.
[0103] Common examples of pharmaceutical or nutritional compounds
which may be contained within transdermal patch 2 of this invention
include, but are not limited to: acetaminophen, antibiotics,
aspirin, corticosterone, erythromycin, ibuprofen, insulin,
nitroglycerin, nicotine, steroids, including without limitation,
progesterones, estrogens, for example, estradiol, and vitamins.
Suitable forms of insulin include, but are not necessarily limited
to, Humulin .RTM.R and Humulog.RTM., both available from Eli Lilly
and Company, Indianapolis, Ind. Any other substance, including, but
not limited to, pharmaceutical and/or nutritional compounds used
for nutraceutical, medicinal or pharmaceutical purposes, and any
combinations thereof, may also be utilized. It may also desirable
to use the method of the invention in conjunction with drugs to
which the permeability of the skin is relatively low, or which give
rise to a long lag-time. Application of ultrasonic signals as
described herein has been found to significantly reduce the
lag-time involved with the transdermal administration of most
drugs.
[0104] The use of ultrasonic signals coupled with iontophoresis,
the application of electric currents applied to the skin, has been
attempted in various forms of drug delivery. In some instances
ultrasonic signals was used together with iontophoresis while in
others ultrasound was a pre-treatment to the application of
iontophoresis. Applicants have noted the method of iontophoresis in
combination with the apparatus of this invention can be used to
enhance molecular transport through the skin.
[0105] The use of chemical substances, often referred to as
chemical enhancers, can enhance drug transport in this invention as
well.
[0106] According to an embodiment of the invention, a safety
feature, which indicates that the patch is empty or has been used,
may be incorporated. The use of a ultrasonic contrast agent or
color forming label within the patch which will turn color, for
example from green to red, when exposed to ultrasound, may be
provided as a means of indicating that the patch has been used.
[0107] According to an embodiment of the present invention,
transdermal patch 2 may be fitted with a bio-sensor which detects
the glucose level of the patient, either through invasive or
non-invasive means, with the data from the sensor being used to
control the application of medication from the patch and the timing
of the drug delivery.
[0108] According to an embodiment of the invention, transdermal
patch 2 may be fitted with a bio-sensor, which would detect the
amount of medication actually delivered to the patient. Such a
sensor may measure the electrical resistance of the patient's skin.
Delivery of a drug through the skin causes a readable change in the
electrical conductivity of the skin tissue surrounding the
transport site. The data from such a bio-sensor could be used to
record the actual quantity of the drug delivered from the patch to
the patient.
[0109] Having described the invention in the above detail, those
skilled in the art will recognize that there are a number of
variations to the design and functionality for the device, but such
variations of the design and functionality are intended to fall
within the present disclosure. Further, although the invention has
been disclosed with a certain degree of particularity, it is
understood that the present disclosure of the preferred forms has
been made by way of example, and that numerous changes in the
details of construction and combination and arrangement of parts
and steps may be made without departing from the spirit and scope
of the invention as hereinafter claimed.
* * * * *