Note: Descriptions are shown in the official language in which they were submitted.
WO 00/69515 CA 02372919 2001-11-16 pCT~S00/13559
REMOTE AND LOCAL CONTROLLED DELIVERY OF
PHARMACEUTICAL COMPOUNDS USING
ELECTROMAGNETIC ENERGY
BACKGROUND OF THE INVENTION
Cross-reference to Related Application
This non-provisional patent application claims benefit
of provisional patent application U.S. Serial number 60/134,486,
filed May 17, 1999, now abandoned.
Field of the Invention
The present invention relates generally to the fields of
medical physics and drug delivery. More specifically, the present
invention relates to methods and devices for controlling the
delivery of pharmaceutical compounds through the skin and other
tissue interfaces.
Description of the Related Art
Drug delivery is a critical aspect of medical treatment.
In many cases, correct administration of drugs is critical to the
overall efficacy of its action, and thus, patient compliance becomes
a significant factor in therapy. For this reason, the physician
should carefully monitor drug delivery.
Drug delivery is particularly important in acute care
3 0 settings. Patients must often endure long hospital stays p o s t-
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surgery or other treatment to ensure that drugs are administered
properly. In this case, and many others, a patient must remain in
close contact with the physician during the course of treatment.
This compliance issue, and the cost of long-term hospital stays, h a s
resulted in significant research and development of devices
capable of delivering controlled, continuous and sustainable
release of therapeutics.
Skin has a very thin layer of dead cells, called the
stratum corneum, which acts as an impermeable layer to matter
on either side of the layer. The stratum corneum is w h a t
primarily provides the skin's barrier function. If the stratum
corneum is removed or somehow altered, then materials within
the body can more easily diffuse out to the surface of the skin,
and materials outside the body can more easily diffuse into the
skin. Alternatively, compounds referred to as permeation
enhancers (e.g. alcohol) or drug carriers (e.g. liposomes) can b a
used, with some success, to penetrate the stratum corneum. I n
any case, the barrier function of the skin presents a very
significant problem to pharmaceutical manufacturers who may b a
interested in topical administration of drugs, or in transcutaneous
collection of bodily fluids.
Mucosa, which is the moist lining of many tubular
structures and cavities (e.g. nasal sinuses and mouth), consists i n
part of an epithelial surface layer. This surface layer, which
consists of sheets of cells with strong intercellular bonds, in single
or multiple layers, and that have a non-keratinized or keratinized
epithelium. On the basolateral side of the epithelium is a thin
layer of collagen, proteoglycans and glucoproteins called the basal
lamina, and which serves to bind the epithelial layer to the
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adjacent cells or matrix. The mucosa acts as a barrier to prevent
the significant absorption of topically applied substances, as well
as the desorption of biomolecules and substances from within the
body. The degree to which mucosa acts as a barrier, and the exact
nature of the materials to which the mucosa is impermeable o r
permeable, depends on the anatomical location. For example, the
epithelium of the bladder is 10,000 times less "leaky'° to ions than
the intestinal epithelium.
The mucosa is substantially different from skin in
many ways. For example, mucosa does not have a stratum
corneum. Despite this difference, permeation of compounds across
mucosa is limited and somewhat selective. The most recent model
of the permeability of mucosa is that the adjacent cells in the
epithelium are tightly bound by occluding junctions, which inhibit
most small molecules from diffusing through the mucosa, while
allowing effusion of mucoid proteins. The molecular structure of
the epithelium consists of strands of proteins that link together
between the cells, as well as focal protein structures such a s
desmosomes. The permeation characteristics of mucosa are not
fully understood, but it is conceivable that the selective
permeability of the mucosa may depend on this epithelial layer,
which may or may not be keratinized, as well as the basal lamina.
While it has been shown that removal or alteration of the stratum
corneum of skin can lead to an increase in skin permeability, there
is no corresponding layer on the mucosa to modify. Thus, it is n o t
obvious that electromagnetic energy irradiation will cause a
modification of the permeability of mucosa.
Various methods have been used for facilitating the
delivery of compounds across the skin and other membranes.
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Iontophoresis uses an electric current to increase the permeation
rate of charged molecules. Iontophoresis however is dependent
on charge density of the molecule, and furthermore, has b a a n
known to cause burning in patients. Use of ultrasound has also
been tested whereby application of ultrasonic energy to the skin
results in a transient alteration of the skin, resulting in increased
permeability to substances. Electromagnetic energy produced b y
lasers may be used to ablate stratum corneum in order to make
the skin more permeable to pharmaceutical substances (U.S.
Patent No. 4,775,361), and, impulse transients generated by lasers
or by mechanical means may be used to make alterations i n
epithelial layers that result in improved permeation of compounds
(U.S. Patent No. 5,614,502).
There are many therapeutic and diagnostic procedures
that would benefit from a transmucosal or transendothelial route
of administration or collection. For example, local anesthetics,
such as lidocaine, are delivered to a region prior to a medical
treatment. Such a local administration of lidocaine could b a
efficacious at providing anesthesia, but would minimize any side
effects and eliminate the need for a needle. Local administration
of an antineoplastic drug into the bladder wall could greatly
minimize the time required for a patient to hold a drug in the
bladder during chemotherapy.
Electrosurgery, which is a method whereby tissue
coagulation and/or dissection can be effected. In electrosurgery,
radiofrequency (RF) current is applied to tissue applied by a n
(active) electrode. In a bipolar system, the current is passed
through tissue between two electrodes on the same surgical
instrument, such as a forceps. In a monopolar system, a return
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path (ground) electrode is affixed in intimate electrical contact,
with some part of the patient. Because of the importance of the
ground electrode providing the lowest impedance conductive path
for the electrical current, protection circuits monitoring the contact
of the ground with the patient are often employed whereupon a n
increase in ground electrode-skin impedance results in the
instrument shutting down. Factors involved in electrosurgical
system include treatment electrode shape, electrode position
(contact or non-contact) with respect to the tissue surface,
frequency and modulation of the RF, power of the RF and time for
which it is applied to the tissue surface, peak-to-peak voltage of
the radiofrequency, and tissue type. In typical electrosurgical
systems, radiofrequency frequencies of 300 kHz to 4 MHz are a s a d
since nerve and muscle stimulation cease at frequencies beyond
100 kHz. For example, all else being equal, decreasing electrode
size translates into increased current density in the tissue
proximal to the electrode and so a more invasive tissue effect,
such as dissection, as compared to coagulation. Similarly, all else
being equal, if the electrode is held close to the tissue, but not in
contact, then the area of RF-tissue interaction is small (as
compared to the area when the electrode is in contact with the
tissue), and so the effect on the tissue is more invasive. By
changing the waveform of the applied RF from a continuous
sinusoid to packets of higher peak voltage sinusoids separated b y
dead time (i.e. a duty cycle of, say, 6%), then the tissue effect (all
else being equal) can be changed from dissection to coagulation.
Holding all else equal, increasing the voltage of the waveform
increases the invasiveness of the tissue effect. Of course, the
longer the tissue is exposed to the radiofrequency, the greater the
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tissue effect. Finally, different tissues respond to radiofrequency
differently because of their different electrical conductive
properties, concentration of current carrying ions, and different
thermal properties.
The prior art is deficient in the lack of effective m a a n s
of controlling the rate of pharmaceutical delivery or biomolecule
collection by utilizing electromagnetic energy, wherein controlled
electromagnetic energy driven systems are integrated into patches
and other delivery devices. The present invention fulfills this
long-standing need and desire in the art.
SUMMARY OF THE INVENTION
The present invention provides a microprocessor
which may be controlled, and may be communicated with, over
analog and digital telecommunication links, including the Internet.
Specifically, the present invention describes microprocessor-
controlled transdermal patches that use electromagnetic energy to
enhance the uptake of a pharmaceutical formulation in contact
with a membrane or skin. The devices could also be used to
increase the diffusion of the substances, as well as endogenous
biomolecules, out of tissue. The electromagnetic energy inherent
to the inventions described herein is often referred to a s
microwave (MW) and radiofrequency (RF).
The application of the present invention is not limited
to delivery across oral mucosa or skin. Other anatomical
structures including, for example, vaginal, uterine, intestinal,
buccal, tongue, nasopharyngeal, anal, and bladder walls, as well a s
vascular, lymphatic and urethral vessels are also applicable.
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Importantly, the present invention can be used to breach
compromised or intact stratum corneum and the tissue layers
underneath in order to deliver compounds across skin, and with
many drugs, through intact skin. Furthermore, this method m a y
be used to control systems that drive substances across non-
biological membranes and films.
In one embodiment of the present invention, there is
provided a method for controlling delivery of a pharmaceutical
compound in a subject, comprising the steps of: irradiating the
subject with electromagnetic energy; and applying the
pharmaceutical compound to the subject, wherein the compound is
contained in a patch. Preferably, the electromagnetic energy i s
selected from the group consisting of radiofrequency, microwave
and light. The patch may be implanted in the subject or topically
positioned in relation to the subject, and controlled locally or
remotely by an external controller, such as a microprocessor.
In another embodiment of the present invention, there
is provided a system for controlling the rate of pharmaceutical
delivery or biomolecule collection in a subject, comprising: a
means to generate electromagnetic energy; a means to deliver the
electromagnetic energy to the subject; and a means to administer
the pharmaceutical to or collect the biomolecule from the subject,
wherein the pharmaceutical is contained in a patch controlled
locally or remotely by an external controller. Preferably, the
electromagnetic energy is selected from the group consisting of
radiofrequency, microwave and light, and means to generate
electromagnetic energy include lasers and ultrasound transducers.
Preferably, the controller is a microprocessor, powered by a
battery, a solar cell, an electrochemical generator, a thermal
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energy generator, or an piezeoelectric generator. The patch m a y
be implanted in the subject or topically positioned in relation to
the subject, and furthermore, the patch may be made of material
selected from the group consisting of a dressing material, a gel, a
viscous material, and an adhesive material.
In a preferred embodiment, the patch contains one o r
more reservoirs separated by a rupturable membrane(s). In the
case of multiple reservoir-containing patch, lyophilized crystal
portion of an unstable pharmaceutical compound is stored in one
reservoir, while liquid portion of the compound is stored i n
another reservoir. An example of such compound is prostaglandin
E1.
The above disclosed system can further comprise a n
electrode, wherein the electrode is in contact with both the patch
and controller, and transmits an electrical current or
electromagnetic radiant energy. Or the same system can further
comprises a computer monitor connected to the Internet, wherein
a signal is sent over the Internet, through the computer monitor,
and into the patch.
In still another embodiment of the present invention,
there is provided a drug delivery or biomolecule collection patch,
wherein the patch is electronically monitored by global positioning
system.
Other and further aspects, features, and advantages of
the present invention will be apparent from the following
description of the presently preferred embodiments of the
invention given for the purpose of disclosure.
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BRIEF DESCRIPTION OF THE DRAWINGS
So that the matter in which the above-recited features,
advantages and objects of the invention, as well as others which
will become clear, are attained and can be understood in detail,
more particular descriptions of the invention briefly summarized
above may be had by reference to certain embodiments thereof
which are illustrated in the appended drawings. These drawings
form a part of the specification. It is to be noted, however, that
the appended drawings illustrate preferred embodiments of the
invention and therefore are not to be considered limiting in their
scope.
Figure 1 shows a transdermal patch with
electromagnetic energy controller, electrode for transmitting
energy, drug reservoir containing the formulation and adhesive
backing for attachment to skin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods/devices for
remote and local controlled delivery of pharmaceutical compounds
using electromagnetic energy. Electromagnetic devices described
herein, including laser systems, are used to effect drug delivery
and may be controlled locally or remotely by microprocessors
integrated into the devices, which are in turn programmed to
receive or transmit data over telecommunication networks.
Controlled electromagnetic energy driven systems may b a
integrated into patches and other delivery devices that may b a
worn on the skin, or may be implanted.
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The presently disclosed devices contain
microprocessors or other electronically controlled elements that
can be interrogated remotely or locally using integrated or remote
transmitters. The transmitters in turn may be communicated with
via telecommunication networks. Equipment used in paging
systems is built into a transdermal patch that receives a signal, o r
code, sent by the operator over telecommunication networks.
Control may also be exerted by coding systems, including bar a n d
magnetic coding, communicated by devices that generate and read
such code. Code may also be communicated via the Internet,
either directly in the case of visible code, or through the use of
dedicated communications devices that receive and process code.
In one embodiment of the present invention, there is
provided a method for controlling delivery of a pharmaceutical
compound in a subject, comprising the steps of: irradiating the
subject with electromagnetic energy; and applying the
pharmaceutical compound to the subject, wherein the compound is
contained in a patch. Preferably, the electromagnetic energy is
selected from the group consisting of radiofrequency, microwave
and light. Still preferably, the patch is implanted in the subject or
topically positioned in relation to the subject, and controlled
locally or remotely by an external controller, such as a
microprocessor.
In a preferred embodiment, the patch is made of
material selected from the group consisting of a dressing material,
a gel, a viscous material, and an adhesive material.
In another preferred embodiment, the pharmaceutical
compound is selected from the group consisting of an anesthetic
drug, an anti-neoplastic drug, a photodynamic therapeutical drug,
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an anti-infection drug, and an anti-inflammatory drug. More
preferably, the anesthetic drug is lidocaine.
In another embodiment of the present invention, there
is provided a system for controlling the rate of pharmaceutical
delivery or biomolecule collection in a subject, comprising: a
means to generate electromagnetic energy; a means to deliver the
electromagnetic energy to the subject; and a means to administer
the pharmaceutical to or collect the biomolecule from the subject,
wherein the pharmaceutical is contained in a patch controlled
locally or remotely by an external controller. Preferably, the
electromagnetic energy is selected from the group consisting of
radiofrequency, microwave and light, and means to generate
electromagnetic energy include lasers and ultrasound transducers.
Still preferably, the controller is a microprocessor, powered by a
battery, a solar cell, an electrochemical generator, a thermal
energy generator, or an piezeoelectric generator. Yet still
preferably, the patch is implanted in the subject or topically
positioned in relation to the subject, and made of material selected
from the group consisting of a dressing material, a gel, a viscous
material, and an adhesive material.
In a preferred embodiment, the patch contains one o r
more reservoirs separated by a rupturable membrane(s). In the
case of multiple reservoir-containing patch, lyophilized crystal
portion of an unstable pharmaceutical compound is stored in one
reservoir, while liquid portion of the compound is stored i n
another reservoir. An example of such compound is prostaglandin
E1.
The above disclosed system can further comprise a n
electrode, wherein the electrode is in contact with both the patch
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and controller, and transmits an electrical current or
electromagnetic radiant energy. Or the same system can further
comprises a computer monitor connected to the Internet, wherein
a signal is sent over the Internet, through the computer monitor,
and into the patch.
In still another embodiment of the present invention,
there is provided a drug delivery or biomolecule collection patch,
wherein the patch is electronically monitored by global positioning
system. Preferably, the global positioning system is a global
positioning satellite receiver.
The following examples are given for the purpose of
illustrating various embodiments of the invention and are not
meant to limit the present invention in any fashion.
EXAMPLE 1
Pressure Waves for Driving Compounds Through Skin o r
Membranes
Pressure waves created through the interaction of
electromagnetic energy with tissue or non-biological matter m a y
be used to drive molecules in a medium across tissue interfaces or
between cellular junctions such as those found in membranes,
between cells, or even through cellular membranes. The
interaction of radiofrequency or microwave irradiation with tissue
or another absorber and various pharmaceutical formulations can
lead to the generation of propagating pressure waves (generated
from a rapid volumetric change in the medium by heating, or b y
the generation of plasma) which are in the form of low pressure
acoustic waves propagating at the speed of sound or high pressure
shock waves propagating at supersonic speeds. These waves c an
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also be a consequence of a generation of waves in a non-biological
target which is in intimate acoustic contact with the biological
media. Continuously pulsing electromagnetic energy delivered in
discrete short duration pulses propagates the pressure waves
which thereby physically move the molecules between cellular
junctions or across membranes. The "pumping" effect may occur
through the creation of increased pressure, including osmotic or
atmospheric pressure. A separation results, which is due to the
differential resistance of the tissues or membranes relative to the
fluid medium, which is the mobile phase. The degree of pumping
will be related to the shape, duty cycle, and power of the driving
RF.
Pumping may at times be inefficient if the energy is
deposited directly on a tissue due to its large surface area. To
compensate for this inefficiency, a target material which
preferentially absorbs energy at these radiofrequency
frequencies, may be placed adjacent to the tissue, in order to
transfer energy effectively. This target could effectively act as a n
antenna and may optionally be composed of metals or metal
containing compounds.
EXAMPLE 2
Pressure Waves for Altering the Barrier Function of Skin or
Membranes
Pressure waves can be used to alter the skin o r
membrane itself thereby reducing its barrier function. This
barrier function alteration will be transient; the integrity of the
barrier function will reestablish itself soon after the
radiofrequency energy ceases to impinge on the tissue. The
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degree to which the barrier function is reduced will be d a p a n d a n t
on the frequency and intensity of the radiofrequency radiation.
The pharmaceutical to be applied to the tissue is preferentially in
place during irradiation.
EXAMPLE 3
Dipole Tray i~ng
The force arising from a coherent interaction with light
is also called the dipole force. A laser field polarizes the atom, and
the polarized atom experiences a force in the gradient of a n
electromagnetic filed. The strong electric filed of a laser beam can
be used to induce a dipole moment in a process called optical
trapping. As long as the frequency of the laser field is below the
natural resonance of the particle being trapped (e.g. below the
atomic transition of an atom or the absorption edge of a
polystyrene sphere), the dipole moment is in phase with the
driving electrical field. Because the energy of the induced dipole p
in the laser field E is given by W = -pE; the particle achieves a
lower energy state by moving into the high-intensity focal spot of
the laser beam. There have been numerous reports of optical
traps being used to manipulate particles, or even cells. These
traps are used to move these tiny particle around under a
microscope lens for manipulation. Optical tweezers have also b a a n
described whereby a focal spot of a single beam optical trap i s
moved with mirrors or lenses.
In the present study, a dipole is formed using
radiofrequency or microwave energy, rather than laser energy.
The trap is formed at the interface between molecules in a
formulation and a tissue or membrane interface. This trap is then
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moved vectorially in the desired direction of movement. In the
case of drug delivery, the desired direction is into the tissues.
Thus, the focal point of the trap is moved along a vector that
penetrates the tissue of interest, while a formulation containing
the drug is applied to the surface of the tissue. The focal point of
a single beam or multiple beam trap would then be m o v a d
progressively into the tissue, which could occur cyclically so as to
ensure the maximum pumping effect.
EXAMPLE 4
Creation of Pores in Skin or Membranes
Small pores are made in the skin or membrane b y
applying the electromagnetic energy with needle-like probes. For
example, a patch-like device with thousands of tiny, needle-like
probes which conduct electomagnetic energy can deliver th a
energy to create pores. These probes can be made of silicon with
a metallic conducting material.
EXAMPLE 5
Ablation or Alteration of Membranes and Tissues
Radiofrequency or microwave energy is applied
directly to the surface of the tissue, or to a target the
adjacent to
tissue, in are
such a way
that the
epithelial
layers of
the tissue
altered to make the layers "leaky" to substances such a
s
pharmaceuticals. b
In the case a
of skin,
the stratum
corneum
may
ablated through the application of electromagnetic energyto
generate heat. Alternatively, shear forces may be createdb
y
targeting this energy on an absorber adjacent to the skin,
which
transfers energy to create stress waves that alter or ablatethe
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stratum corneum. Specifically, radiofrequencies producing a
desired rapid heating effect on stratum corneum result in a n
ablative event, while minimizing coagulation. The removal of the
stratum corneum in this way will result in increased permeability
of compounds across the compromised tissue interface. For
example, application of 4% lidocaine to a section of skin with
stratum corneum ablated in this way will result in a rapid
(minutes to onset) anesthesthetic effect.
Alternatively, delivery of electromagnetic energy a t
these wavelengths may be optimized, by adjusting pulse duration,
dwell time between pulses, and peak-power to result in a rapid,
intermittent excitation of molecules in the tissues of interest, such
that there is no net coagulation effect from heating, but molecules
are altered transiently to effect a transient change in membrane
conformation that results in greater "leakiness" to substances such
as pharmaceuticals. Furthermore, energy with the appropriate
pulse mode characteristics is continuously applied that these
transient alterations are maintained during the energy cycle, thus
creating a means for maintaining increased membrane
permeability over time. This method allows substances to b a
continually delivered over a desired period of time.
EXAMPLE 6
Combinations of Techniques to Effect Molecular Delivery o r
Collection: A.pplying Pressure to Permeabilized Membranes
A "leaky" membrane or ablation site in skin is created
by first applying electromagnetic energy, including light,
microwave or radiofrequency, such that membrane o r
intramembrane structures are realigned, or the membrane is
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compromised otherwise, so as to improve permeation. This step is
followed by application of electromagnetic energy induced
pressure to drive molecules across tissue interfaces and between
cellular junctions at a greater rate than can be achieved by either
method alone. The laser energy may be delivered continuously o r
in discrete pulses to prevent closure of the pore. Optionally, a
different wavelength laser may be used in tandem to pump
molecules through the pore than is used to create the pore.
Alternatively, a single laser may be modulated such that pulse
width and energy vary and alternate over time to alternately
create a pore through which the subsequent pulse drives the
molecule.
Alternatively, intact skin is treated such that the
stratum corneum is compromised leading to a decrease i n
resistance and increased permeability to molecules in general.
This step is followed by application of a electromagnetic energy
generated pressure wave to drive molecules across membranes
and between cellular junctions at a greater rate than can b a
achieved by either method alone.
Laser energy is directed through optical fibers or
guided through a series of optics such that pressure waves are
generated to come in contact with or create a gradient across the
membrane surface. These pressure waves may be optionally used
to create a pressure gradient such that the pressure waves move
through a liquid or semi-solid medium thereby "pumping"
compounds through the medium, into and across the membrane.
This technology may optionally be used to deliver
laser energy for the purpose of drug delivery across, for example,
buccal, uterine, intestinal, urethral, vaginal, bladder and ocular
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membranes. Pharmaceutical compounds may be delivered into
cellular spaces beyond these membranes or into chambers
encompassed by these membranes. Compromised or intact
stratum corneum may also be breached by applying appropriate
optical pressure.
EXAMPLE 7
Formulations
Specific formulations are chosen such that
electromagnetic energy absorption is maximized relative to the
surrounding medium. Further, many pharmaceutical or diagnostic
compounds can be modified by the addition of such energy
absorbing groups (or selecting those that minimize absorption) so
as to maximize the effects of the electromagnetic energy on a
particular formulation relative to the surrounding medium o r
tissue. A new class of compounds is therefore defined that have
unique permeability and migration characteristics in the presence
of, or following a treatment of electromagnetic energy a s
described here. These molecules possess different characteristics
by virtue of the addition of groups or structures that absorb
energy in a characteristic way that may impart momentum to the
molecule causing it to move relative to the medium which contains
it, or may result in excitation of the molecule to result in a desired
alteration of that molecule. For example, rapid heating of a
molecule, which preferentially absorbs energy relative to its
environment, by radiofrequency or microwave energy could result
in cleavage of a heat-sensitive linkage or activation of a specific
activity. These compounds are designed to include both
physiologically active groups and molecular groups which
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maximize the absorbance or reflectance of energy to achieve the
desired effect. In these examples, an analogy is drawn to
photodynamic therapy whereby molecules absorb photons a n d
make interstate transition from ground to excited singlet state
whereupon they transfer energy to ground sate oxygen thus
exciting it to a excited singlet state which is toxic.
Similarly, pharmaceutically active compounds may b a
modified by the addition of groups that readily form a dipole
when exposed to appropriate electromagnetic energy, such a s
radiofrequencies or microwaves. The addition of such groups
would result in enhanced ability to use optical trapping methods
for the delivery of these types of compounds as described herein.
Further, any compound which may interact with electromagnetic
energy in such a way that it is propelled through a medium can b a
used. Thus, the present study defines a means by which
molecules may be propelled through a medium at differential
rates relative to the medium and other molecules in the medium,
and a means by which molecules may be separated from one
another based on their optical characteristics.
The application is not limited to delivering
pharmaceuticals. Other separations of molecules may be achieved
by the methods described herein, such as separating protein
species in polyacrylamide gels, or separating oligonucleotides on
microarray devices. These examples also include using magnetic
fields alone to propel molecules through a medium or tissue based
on intrinsic magnetic properties or by the addition of magnetic
groups, metals, etc. Such methods may also be enhanced by using
them in combination with methods to alter membranes and
tissues to work synergistically.
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Thermal or electronic disruption of a molecule may b a
a problem, however, appropriate carriers may be selected to solve
this problem. The carriers selected act as "sinks" for the energy,
while functional groups are selected that are stable. Attaching
these "sinks" to functional groups results in the energy being
absorbed preferentially to the sink, thereby limiting exposure to
the functional groups. Alternatively, molecules may be developed
that have functional groups attached to a backbone molecule that
is susceptible to cleavage when exposed to electromagnetic energy
described herein. Specifically, radiofrequency waves may result
in excess vibration of groups as they absorb the energy. Using a
linker that is susceptible to cleavage when its atoms vibrate in
this way will result in the release of the functional group of
interest, which could be a pharmaceutically active substance.
EXAMPLE 8
Transdermal Patches
Patches, such as transdermal drug delivery patches,
are controlled by remote or local operation through
microprocessors. Such patches are designed and used together
with electromagnetic energy driven delivery systems.
Patches used herein include a dressing material which
contains a gel or adhesive that in turn contains the drug
formulation to be delivered. The dressing is in contact with a n
electrode, which is, in turn, in contact with the controller (see
Figure 1). The controller regulates the flow of electromagnetic
energy that contacts the electrode. The electrode distributes the
energy to the formulation, and further into the tissue of interest.
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Besides a dressing, the patch may be a gel, viscous material, or
other patch material that covers the site of treatment.
The patch may contain one or more reservoirs. In the
case of multiple reservoirs, a rupturable membrane may separate
different chambers, thus preventing mixing of components until
the membrane is ruptured. In the case of an unstable compound
such as prostaglandin E1 (e.g. Caverject, UpJohn), lyophilized
crystals could be stored in one reservoir while the liquid
components to be mixed with the drug could be stored in another
reservoir. The two reservoirs are separated by a membrane that
may be ruptured by crushing or other physical means, thereby
allowing the components to mix freely to make available for
dosing. This mufti-reservoir concept may be further extended to
include mixing of chemicals that will generate an electrical
current, for the purpose of iontophoresis or electroporation.
Healing at the site of ablation will ultimately reduce
the amount of drug that permeates over time. A substance m a y
be included in the drug formulation or patch and applied to the
site of permeation/ablation whereby this substance slows the
healing process or reduces the rate of scab formation thereby
limiting the rate of closure of the permeation site and having the
effect of extending the enhanced permeability characteristics of
the irradiated site.
EXAMPLE 9
Communication s, s
The controller may be comprised of a current
generator driven by a transportable battery, a solar powered
generator, an electrochemical generator, a thermal energy
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generator, a piezoelectric generator, a radiofrequency generator, a
microwave generator, etc. The electrode of the patch may b a
replaced by a laser, multiple lasers, or optical fibers which conduct
and transmit light at a desired wavelength, pulse length, pulse
energy, pulse number and pulse repetition rate to ablate or alter
the tissue directly beneath the patch. Alternatively, continuous
wave lasers may be used to effect alterations in the tissues that
would lead to a permeabilizing effect. Lasers and other
electromagnetic energy generators, as well as ultrasound
transducers, may be used in controller-electrode combinations
that will result in the desired effects. Also inherent in the design
of these patches is the ability to deliver the drugs simultaneously
with the energy, or at any time before or after a n a r g y
administration.
Telecommunication networks transmit data between
the operator and the remotely sited controller (on the patch). The
device includes a telemetry transceiver for communicating data
and operating instructions between the device and an external
patient communications control device that is either worn by,
located in proximity to the patient, or at a remote location within
the device transceiving range. The control device preferably
includes a communication link with a remote medical support
network through telecommunication networks) and may include
a global positioning satellite receiver for receiving positioning d a t a
identifying the global position of the control device.
The device may also contain a patient activated link
for permitting patient initiated personal communication with the
medical support network. A system controller in the control
device controls data and digital communications for selectively
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transmitting patient initiated personal communications and global
positioning data to the medical support network, for receiving
telemetry out of data and operating commands from the medical
support network, and for receiving and initiating re-programming
of the device operating modes and parameters in response to
instructions received from the medical support network. The
communication link between the medical support network and the
patient communications control device may comprise a world wide
satellite network, hard-wired telephone network, a cellular
telephone network or other personal communication system.
An objective of the device is to provide the patient
greater mobility. The patient is allowed to be ambulatory while
his medical condition is monitored and/or treated by the medical
device. Programming devices may be controlled by the physician
or pharmacy, and code or data transmitted o v er
telecommunication networks to the site of the device. This can
happen remotely or locally. Currently, telemetry systems used to
communicate with medical devices are positioned within a short
distance of the device. Furthermore, transdermal patch systems
are currently regulated only by passive controls, built into the
patch, which regulate the dosage. These controls are typically n o t
electronic, but rather based on membrane and diffusion
characteristics of the patch and formulation. The present device
provides a means for a remote operator to adjust the dosage and
timing of drug delivery, while the patient is ambulatory.
Another object of the device is to provide a patient
data communication system for world wide patient r a -
programming telemetry with a medical device worn by the
patient. The device described herein is a transdermally worn
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patch containing a drug formulation which may or may not
include electromagnetic energy permeation enhancement.
However, the invention is not limited to transdermal drug
delivery and may include communication with implanted drug
delivery devices using the aforementioned electromagnetic energy
based delivery technology.
The presently disclosed device transmits and receives
coded information from a remote or local source. The operator a t
the device is positioned at a location, and can transmit information
from the medical support network. The device incorporates a
wireless interface including a control device telemetry transceiver
for receiving and transmitting coded communications between the
system controller and the device telemetry transceiver, a global
positioning system coupled to the system controller for providing
positioning data identifying the global position of the patient to
the system controller; communication means for communicating
with the remote medical support network; and communication
network interface means coupled to the system controller and the
communication means for selectively enabling the communication
means for transmitting the positioning data to the medical support
network and for selectively receiving commands from the medical
support network. The communication interface may include
capabilities for transfer of data between the patient and the
operator by cellular telephone network, paging networks, satellite
communication network, land-based telephone communication
system, or modem-based communication network, including the
Internet. Communications may include but not be limited to
microwave, radiofrequency and digital communication via optical
means.
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The communication and monitoring systems provide a
means for exchanging information with and exercising control
over one or more medical devices attached to the body of a
patient. The devices are intended to function no matter h o w
geographically remote the patient may be relative to the
monitoring site or medical support network. The operator, usually
a physician, types in a code, which is transmitted over the medical
support network to the patient, who may be located by a
geopositioning satellite or in relation to other telecommunication
network. The code contains information which activates the
device and controls dosage.
Data transmission to and from the operator to the
device is accomplished by means of a control device that transmits
data over the communication network. A telemetry antenna a n d
associated transmitter/receiver can both download and upload
data. The antenna may function on radiofrequencies. Control of
dosage in the device itself is provided by a digital controller/timer
circuit with associated logic circuits connected with a
microcomputer. The microcomputer controls the operational
functions of a digital controller and a timer. It specifies activation,
timing and duration of events. The microcomputer contains a
microprocessor and associated RAM and ROM chips, depending on
the need for additional memory and programmable functions.
A base station may exist at the operator's location.
The base station may be comprised of a microprocessor-controlled
computer with hardware and software, and associated modem for
transmission of information that is relayed through the
appropriate communication network. The system controller m a y
also be coupled to a GPS receiver for receiving positioning d a t a
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from an earth satellite. The GPS receiver may use currently
available systems.
EXAMPLE 10
Bar-coded Prescriptions
Dosage schedules for certain medications can be p r a -
encoded by the manufacturer or pharmacy, using bar code
symbols. The encoded bar code symbols can be compiled on one
or more menu sheets accessible at the physician office or
pharmacy counter where the controller is installed. In such
applications, a bar code symbol reading device can be linked to a
data communication port of the medical support network and
located on the patch, which can then be used to program the
proper dosage into the device. The code could be transmitted over
the Internet, or via other telecommunication networks into a
device in the possession of the patient, who can then read the bar
code into the patch.
Any patents or publications mentioned in this
specification are indicative of the levels of those skilled in the art
to which the invention pertains. These patents and publications
are herein incorporated by reference to the same extent as if each
individual publication was specifically and individually indicated
to be incorporated by reference.
One skilled in the art will readily appreciate that the
present invention is well adapted to carry out the objects and
obtain the ends and advantages mentioned, as well as those
inherent therein. The present examples along with the methods,
procedures, treatments, molecules, and specific compounds
described herein are presently representative of preferred
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embodiments, are exemplary, and are not intended as limitations
on the scope of the invention. Changes therein and other uses will
occur to those skilled in the art which are encompassed within the
spirit of the invention as defined by the scope of the claims.
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