U.S. patent application number 16/100651 was filed with the patent office on 2018-12-06 for sweat monitoring and control of drug delivery.
The applicant listed for this patent is University Of Cincinnati. Invention is credited to Jason C. Heikenfeld.
Application Number | 20180344223 16/100651 |
Document ID | / |
Family ID | 54700054 |
Filed Date | 2018-12-06 |
United States Patent
Application |
20180344223 |
Kind Code |
A1 |
Heikenfeld; Jason C. |
December 6, 2018 |
SWEAT MONITORING AND CONTROL OF DRUG DELIVERY
Abstract
The concentration of an administered compound, such as a drug
(D), in an organ or a bodily fluid, such as blood, is determined
directly through detecting the drug (D) or its metabolites (DM) in
sweat. The concentration may be determined indirectly by
administering the drug (D) together with one or more tracer
compounds (T, T2) or metabolites thereof (TM, T2M) or by detecting
concentrations and trends of other analytes present in the body
that react to the presence of the drug (D). By determining tracer
concentration in sweat, the concentration of the drug (D) in blood
or an organ can be determined. The tracer (T, T2) is a compound
selected for ease of detection in sweat, known metabolic and
solubility profiles that correspond to those of the drug (D), and
safety of use. A smart transdermal delivery patch (300) is used to
administer a dosage of drug to a wearer in coordination with at
least one sweat sensor (324) reading conveying information about
the wearer.
Inventors: |
Heikenfeld; Jason C.;
(Cincinnati, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
University Of Cincinnati |
Cincinnati |
OH |
US |
|
|
Family ID: |
54700054 |
Appl. No.: |
16/100651 |
Filed: |
August 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15314414 |
Nov 28, 2016 |
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PCT/US2015/032866 |
May 28, 2015 |
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16100651 |
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62092897 |
Dec 17, 2014 |
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62023233 |
Jul 11, 2014 |
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62003699 |
May 28, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/14546 20130101;
A61M 37/0015 20130101; A61N 1/327 20130101; A61M 2037/0007
20130101; A61M 2037/0023 20130101; A61B 5/4839 20130101; A61B
5/6804 20130101; A61B 5/6831 20130101; A61B 5/0531 20130101; A61M
2230/005 20130101; A61B 5/14517 20130101; A61N 1/0412 20130101;
A61B 5/4266 20130101; A61N 1/0448 20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61N 1/32 20060101 A61N001/32; A61N 1/04 20060101
A61N001/04; A61M 37/00 20060101 A61M037/00; A61B 5/00 20060101
A61B005/00; A61B 5/053 20060101 A61B005/053 |
Claims
1. A method of transdermally delivering a primary drug or a tracer
compound using a smart transdermal delivery device on an
individual's skin, the method comprising: performing at least one
measurement of sweat; and delivering a dosage of said primary drug
or said tracer compound based on said at least one measurement
using said smart transdermal delivery device.
2. The method of claim 1, wherein performing at least one
measurement of sweat includes using a sensing and delivery system
including said smart transdermal delivery device and at least one
sweat sensor.
3. The method of claim 1, wherein performing at least one
measurement includes measuring a sweat rate.
4. The method of claim 1, further comprising: performing at least
one measurement of a twitch of the skin or a muscle.
5. The method of claim 1, wherein performing at least one
measurement includes measuring a concentration of at least one
analyte in sweat, the method further comprising: correlating the
concentration of said analyte in sweat to a concentration of said
primary drug or said tracer compound in the individual's blood.
6. The method of claim 1, wherein delivering a dosage of the solute
includes delivering a dosage of a primary drug.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 15/314,414 entitled "SWEAT MONITORING AND CONTROL OF DRUG
DELIVERY", filed Nov. 28, 2016, which is the U.S. National phase
application of PCT Application No. PCT/US2015/032866, entitled
"SWEAT MONITORING AND CONTROL OF DRUG DELIVERY", filed May 28,
2015, and claims the benefit of U.S. Provisional Applications No.
62/003,699 entitled "SWEAT MONITORING OF PRODUCT DELIVERY AND
DOSAGE", filed May 28, 2014, No. 62/023,233 entitled "SWEAT SENSOR
WITH CHRONOLOGICAL ASSURANCE", filed Jul. 11, 2014, and No.
62/092,897 entitled "SWEAT MONITORING OF PRODUCT DELIVERY AND
DOSAGE", filed Dec. 17, 2014, the disclosures of which are hereby
incorporated by reference herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] Sweat sensing technologies have enormous potential for
applications ranging from athletics, to neonates, to
pharmacological monitoring, to personal digital health, to name a
few applications. Sweat contains many of the same biomarkers,
chemicals, or solutes that are carried in blood and can provide
significant information enabling one to diagnose ailments, health
status, toxins, performance, and other physiological attributes
even in advance of any physical sign. Furthermore, sweat itself,
the action of sweating, and other parameters, attributes, solutes,
or features on, near, or beneath the skin can be measured to
further reveal physiological information.
[0003] If sweat has such significant potential as a sensing
paradigm, then why has it not emerged beyond decades-old usage in
infant chloride assays for Cystic Fibrosis or in illicit drug
monitoring patches? In decades of sweat sensing literature, the
majority of medical literature utilizes the crude, slow, and
inconvenient process of sweat stimulation, collection of a sample,
transport of the sample to a lab, and then analysis of the sample
by a bench-top machine and a trained expert. This process is so
labor intensive, complicated, and costly that in most cases, one
would just as well implement a blood draw since it is the gold
standard for most forms of high performance biomarker sensing.
Hence, sweat sensing has not emerged into its fullest opportunity
and capability for biosensing, especially for continuous or
repeated biosensing or monitoring. Furthermore, attempts at using
sweat to sense "holy grails" such as glucose have not yet succeeded
to produce viable commercial products, reducing the publicly
perceived capability and opportunity space for sweat sensing.
[0004] Of all the other physiological fluids used for bio
monitoring (e.g., blood, urine, saliva, tears), sweat has arguably
the most variable sampling rate as its collection methods and
variable rate of generation both induce large variances in the
effective sampling rate. Sweat is also exposed to numerous
contamination sources, which can distort the effective sampling
rate. The variable sampling rate creates a challenge in providing
chronological assurance, especially so in continuous monitoring
applications.
[0005] Detection of drug compounds, particularly a concentration
over time in bodily fluids, is complex and difficult. Continuous
detection and monitoring by blood draw is undesirable. Saliva is
inconvenient and prone to contamination. Chronologically sensing
urine would require a catheter. Tears are also difficult to access
regularly and ergonomically. Therefore, alternate methods of
detection are needed. Once these methods are in hand, non-invasive
sensing and drug delivery control becomes a possibility with
numerous potential applications.
[0006] Many of the drawbacks stated above can be resolved by
creating novel and advanced interplays of chemicals, materials,
sensors, electronics, microfluidics, algorithms, computing,
software, systems, and other features or designs, in a manner that
affordably, effectively, conveniently, intelligently, or reliably
brings sweat sensing technology into intimate proximity with sweat
as it is generated. With such a new invention, sweat sensing could
become a compelling new paradigm as a biosensing platform.
SUMMARY OF THE INVENTION
[0007] The concentration in a bodily fluid of a delivered solute
such as a drug administered to an individual is detected indirectly
by co-administering to the patient a known amount of a tracer
compound that predictably emerges in sweat, and is easily
detectable or has a metabolite that is easily detectible in sweat
and/or is detected indirectly by monitoring the ratios and
concentration trends of the drug, its metabolites, and
naturally-occurring analytes in sweat that are correlated to the
presence of the delivered solute in the body. With the detection
and monitoring of the delivered solute using an individual's sweat,
the drug delivery system can then use sweat sensor data and
algorithms to continuously control the delivery of the solute
through a smart transdermal delivery device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The objects and advantages of the present invention will be
further appreciated in light of the following detailed descriptions
and drawings in which:
[0009] FIG. 1 is a schematic of a sweat sensor device and a smart
transdermal delivery device in communication with each other and
with a reader device.
[0010] FIG. 2 is a cross-sectional view of a smart transdermal
delivery device according to one embodiment of the present
invention.
[0011] FIG. 3 is a cross-sectional view of a smart transdermal
delivery device according to one embodiment of the present
invention having a sweat sensing mechanism.
[0012] FIG. 4 is a flow diagram representing pathways a delivered
solute can take before being excreted in sweat or through skin.
[0013] FIGS. 5-7 are flow diagrams representing pathways a
delivered solute can take before being excreted in sweat or through
skin according to various embodiments of the present invention
[0014] FIG. 8 is a chart showing the relationship of drug
concentration over time using various methods of administering the
drug.
DEFINITIONS
[0015] As used herein, "delivered solute" means any substance that
is at least partially soluble in plasma (blood), tissue or sweat
and that may be delivered into the human body. For example, any
drug, fluid, vitamin, inert substance, salt, sugar, molecule,
grain, or other suitable substance or compound may be a delivered
solute.
[0016] As used herein, "analyte" means any substance can provide
meaningful measurements of physiological importance, and that is
present in sweat.
[0017] As used herein, "sweat sensor data" means all of the
information collected by sweat sensor(s) and communicated via the
device to a user or a data aggregation location.
[0018] As used herein, "correlated aggregated sweat sensor data"
means sweat sensor data that has been collected in a data
aggregation location and correlated with outside information such
as time, temperature, weather, location, user profile, other sweat
sensor data, or any other relevant data.
[0019] As used herein, "tracer compound" or "tracer" means a
compound having a known co-relationship between the tracer
compound's concentration in sweat with the concentration of a
primary drug in blood or an organ. The tracer may be more readily
detectible in sweat than the drug itself, in a lower concentration,
non-toxic, and less or differently bioactive than the primary
drug.
[0020] As used herein, "tracer profile" means the collection of
sweat sensor data on analytes that indicate the concentration and
ratios of a primary drug, one or more tracer compounds, and/or
relevant metabolites over a relevant period after delivery of the
drug and tracer(s).
[0021] As used herein, "indirect detection" means determining the
presence or concentration of a primary drug in the blood or an
organ by detecting in sweat one or more tracer compounds, one or
more tracer metabolites, or one or more other analytes, or through
some combination of these analytes.
[0022] As used herein, "drug response profile" means the collection
of sweat sensor data on sweat rate, temperature, pH, and/or
analytes that indicate the chronological concentration and ratios
of those analytes in the blood stream of a target individual that
is correlated to the presence of a primary drug.
[0023] As used herein, "drug compliance profile" means a known set
of directly detected analytes, a tracer profile and/or a response
profile that is unique to compliance with a particular drug
regimen.
[0024] As used herein, "drug detection threshold" means a
calculated detection level in sweat of a primary drug, tracer(s),
metabolite(s), other analyte(s), or a combination of these analytes
that shows the primary drug is present in the blood or an organ
with reasonable certainty.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The ability to detect the concentration of a drug in sweat
over time requires the use of a chronologically assured sweat
sampling rate. To understand the proper numerical values or
representations of sweat sampling rate, sweat generation rate and
sweat volumes should be understood. Based on the assumption of a
sweat gland density of 100/cm.sup.2, a sensor that is 0.55 cm in
radius (1.1 cm in diameter) would cover about 1 cm.sup.2 area or
approximately 100 sweat glands. Next, assume a sweat volume under a
skin-facing sensor (space between the sensor and the skin) of 50
.mu.m average height or 50.times.10.sup.-4 cm, and that same 1
cm.sup.2 area, which provides a sweat volume of 50.times.10.sup.-4
cm.sup.3 or about 50.times.10.sup.-4 mL or 5 .mu.L of volume. With
the maximum sweat generation rate of 5 nL/min/gland and 100 glands,
it would require a 10 minutes to fully refresh the sweat volume
(using 1st principles/simplest calculation only). With the minimum
sweat generation rate of 0.1 nL/min/gland and 100 glands, it would
require 500 minutes or 8 hours to fully refresh the sweat volume.
If the sweat volume could be reduced by 10.times. to a volume
height of 5 .mu.m roughly, the max and min times would be 1 minute
and 1 hour, respectively, but the min time would also be subject to
diffusion and other contamination issues (and 5 .mu.m dead volume
height would be technically challenging). Times and rates are
inversely proportional (rates having at least partial units of
1/seconds), therefore a short time required to refill the sweat
volume can also be said to have a fast or high sweat sampling
rate.
[0026] The space between the sensor and the skin could be a
microfluidic component. For example, a 25 .mu.m thick piece of
paper or glass fiber covering an area of 1 cm.sup.2 would equate to
a volume of 2.5 .mu.L; if the paper was 50% porous (50% solids),
then the sweat volume would be 1.25 .mu.L. With the maximum sweat
generation rate of 5 nL/min/gland and 100 glands, it would require
2.5 minutes to fully refresh the sweat volume. With the minimum
sweat generation rate of 0.1 nL/min/gland and 100 glands it would
require about 100 minutes to fully refresh the sweat volume. "Fully
refresh" is a term that in some cases should be interpreted loosely
unless further details or calculations are provided. Because of
mixing and diffusion over time, the moment of having a "fresh sweat
volume" must be determined using finer details of the specific
usage and device and situation in question.
[0027] Sweat stimulation, or sweat activation, can be achieved by
known methods. For example, sweat stimulation can be achieved by
simple thermal stimulation, by orally administering a drug, by
intradermal injection of drugs such as methylcholine or
pilocarpine, and by dermal introduction of such drugs using
iontophoresis. A device for iontophoresis may, for example, provide
DC current and use large lead electrodes lined with porous
material, where the positive pole is dampened with 2% pilocarpine
hydrochloride and the negative one with 0.9% NaCl solution. Sweat
can also be controlled or created by asking the subject using the
patch to enact or increase activities or conditions that cause them
to sweat. These techniques may be referred to as active control of
sweat generation rate.
[0028] Sweat generation rate can be measured in real time in
several ways. Both sodium and chloride, which are excreted by the
sweat gland during sweating, can be utilized to measure sweat
generation rate in real time (higher sweat generation rate, higher
concentration). Both sodium and chloride can be measured using
ion-selective electrodes or sealed reference electrodes, for
example placed in the sweat sensor itself and measured real time as
sweat emerges onto the skin. Sato 1989 provides details on sweat
generation rate versus concentration of sodium and chloride.
Electrical impedance can also be utilized to measure sweat
generation rate. Grimnes 2011 and Tronstad 2013 demonstrate skin
electrical impedance and sweat generation rate correlations.
Impedance, sodium concentration, and/or other measurements can be
made and used to determine at least roughly the sweat pore density
and sweat generation rate from individual sweat glands, and, when
coupled with sweat sensing or collection area, can be used to
determine an overall sweat generation rate to a sensor. Common
electronic measurements to also predict sweat generation rate
include those such as pulse, pulse-oxygenation, respiration, heart
rate variability, mental activity, overall body activity level, and
3-axis accelerometry, or other common readings published by Fitbit,
Nike Fuel, Zephyr Technology, and others in the current wearables
field. These techniques can be referred to as measured sweat
generation rate. Techniques for measured sweat rate can also be
used before use of a sweat measuring device to obtain predetermined
sweat generation rates for use with the sweat measuring device.
[0029] Embodiments of the present invention apply at least to any
type of sweat sensor device that measures sweat, sweat generation
rate, sweat chronological assurance, its solutes, solutes that
transfer into sweat from skin, a property of or things on the
surface of skin, or properties or things beneath the skin.
Embodiments of the present invention further apply to sweat sensing
devices that have differing forms including patches, bands, straps,
portions of clothing, wearables, or any suitable mechanism that
reliably brings sweat stimulating, sweat collecting, and/or sweat
sensing technology into intimate proximity with sweat as it is
generated. While certain embodiments of the present invention
utilize adhesives to hold the device near the skin, other
embodiments include devices held by other mechanisms that hold the
device secure against the skin, such as a strap or embedding in a
helmet.
[0030] Certain embodiments of the present invention show sensors as
simple individual elements. It is understood that many sensors
require two or more electrodes, reference electrodes, or additional
supporting technology or features which are not captured in the
description herein. Sensors are preferably electrical in nature,
but may also include optical, chemical, mechanical, or other known
biosensing mechanisms. Sensors can be in duplicate, triplicate, or
more, to provide improved data and readings. Sensors may be
referred to by what the sensor is sensing, for example: a sweat
sensor; an impedance sensor; a sweat volume sensor; a sweat
generation rate sensor; and a solute generation rate sensor.
Certain embodiments of the present invention show sub-components of
what would be sweat sensing devices with more sub-components needed
for use of the device in various applications, which are obvious
(e.g., a battery, adhesive backing, or wireless antenna), and for
purpose of brevity and focus on inventive aspects are not
explicitly shown in the diagrams or described in the embodiments of
the present invention.
[0031] With reference to FIG. 1, a sweat sensor device 100 is
placed on or near skin 12.
[0032] In an alternate embodiment, the sweat sensor device 100 is
simply fluidically connected to skin or regions near skin through
microfluidics or other suitable techniques (not shown). The device
100 is in wired communication 152 or wireless communication 154
with a reader device 150. In one embodiment of the present
invention, the reader device 150 is a portable electronic device,
such as a smart phone. In alternate embodiments, the reader device
is a companion transceiver is, for instance, placed at a bedside or
mounted in a commercial or military vehicle. In one embodiment, the
reader device 150 is a portable electronic device or companion
transceiver capable of secure two-way communication with the sweat
sensor device 100 and secure two-way communication with a computer
network, such as a local area network or the Internet via a
wireless router and/or a cellular data network. In alternate
embodiments, the device 100 and device 150 can be combined.
According to an aspect of the present invention, the presence or
concentration of a primary drug in a bodily fluid or an organ may
be determined by measuring or continuously monitoring sweat through
use of a sweat sensor device and system, such as those disclosed in
PCT/US2013/25092, filed Apr. 3, 2013; PCT/US2014/061083, filed Oct.
17, 2014; and PCT/US2014/061098, filed Oct. 17, 2014, the
disclosures of which are incorporated herein by reference.
Embodiments of the present invention may benefit from chemicals,
materials, sensors, electronics, microfluidics, algorithms,
computing, software, systems, and other features or designs, as
commonly known to those skilled in the art.
[0033] Embodiments of the present invention may include
communication techniques such as, for example, RFID or a wireless
protocol such as Bluetooth, that allow the sweat sensing device to
communicate with a reader device. FIG. 1 shows device 100 having a
thin layer battery 160 that provides a power source for the device
100. One embodiment includes both RFID and Bluetooth used in
conjunction where RFID charges a battery in the sweat sensing
device when provided the proper near field communications. A device
according to one embodiment may include a signal amplification
mechanism to improve signal quality communicated to the reader
device and to improve transmission distance to the reader device.
Those skilled in the art will recognize that other biomarker
sensing methods and sweat transport methods may be included in
embodiments of the present invention that provide the capability of
continuous or semi-continuous monitoring of biomarkers in
sweat.
[0034] Embodiments of the present invention include a computing and
data storage mechanism capable of sufficiently operating the sweat
sensing and drug delivery system. The computing and data storage
mechanism may be configured to conduct communication among system
components, to monitor sweat sensor data, to perform data
aggregation, to execute algorithms capable of controlling drug
delivery timing and amounts, and to issue alerts and advisories
related to detected analyte levels in sweat. By way of example,
this computing mechanism may be fully or partially located on the
sensing device, on the reader device, smart transdermal delivery
device, or on a connected computer network.
[0035] The sensing and delivery system may also include data
aggregation and monitoring capability. Such data aggregation may
include collecting all of the sweat sensor data generated by sweat
sensors and communicated to the system. Such data may also be
correlated with outside information, such as the time, date,
weather conditions, activity performed by the individual, the
individual's mental and physical performance during the data
collection, the proximity to significant health events experienced
by the individual, the individual's age or gender, the individual's
health history, or other relevant information.
[0036] For drug monitoring in particular, detailed information
about the individual's dosage level, the drug delivery method
(e.g., oral, topical, bolus injection, suppository, etc.), the
timing of drug delivery, and drug delivery duration may be
considered. In addition, the individual may respond to the drug
differently depending on their particular genetic makeup. Further,
the emergence of drugs and their metabolites in sweat may vary by
individual depending on variances in how the person absorbs,
distributes, metabolizes, and excretes the drug. Detailed
information about the drug itself, or its metabolites, may be
incorporated as well, including the drug half-life, partition
coefficient (P), the dissociation constant (pK), and other relevant
characteristics. Such information may also be partially supplied by
an appropriately configured sweat sensor.
[0037] The reader device or companion transceiver may also be
configured to correlate speed, location, temperature or other
relevant data with the sweat sensor data. The data collected may be
made accessible via secure website portal to allow sensing and
delivery system users to perform safety, compliance and/or care
monitoring of target individuals. The sweat sensor data monitored
by the user may include real-time data, trend data, or may also
include aggregated sweat sensor data drawn from the system database
and correlated to a particular user, a user profile (such as age,
gender, co-medications, drug sensitivity level, medical condition),
combined analyte profile, or other relevant metric. Trend data,
such as a target individual's hydration level over time, may be
used to predict the likelihood of an impending physiological event.
Such predictive capability can be enhanced by using correlated
aggregated data, which would allow the user to compare an
individual's historical analyte and external data profiles to a
real-time situation as it progresses, or even to compare thousands
of similar analyte and external data profiles from other
individuals to the real-time situation. Sweat sensor data may also
be used to identify wearers that are in need of additional
monitoring or instruction, such as to adhere to a drug regimen or
to avoid contraindicated drugs or behaviors. The disclosed uses of
aggregated data are for illustration purposes only, and do not
limit other potential sources or applications available for such
data, which are within the spirit of the present invention.
[0038] A variety of pathways for delivery of a delivered solute
into the body are useful in embodiments of the present invention.
Delivery methods include, for example, oral ingestion, nasal, anal,
transdermal absorption, and injection. A solute may also be
delivered using devices or engineered products that deliver a
solute into the body in a controlled or designed manner. The
delivered solute may be, for example, any drug, fluid, vitamin,
inert substance, salt, sugar, molecules, grains, or other suitable
substance or compound.
[0039] In one aspect of the present invention, a smart transdermal
delivery device communicates with a sweat sensor device such that
the smart transdermal delivery device is capable of feedback
control. FIG. 1 schematically shows one embodiment where the sweat
sensor device 100 and a smart transdermal delivery device 200
communicate. Like the sweat sensor device 100, the smart
transdermal delivery device 200 is configured with a power source
260 and a communication mechanism to enable operation. Through the
communication mechanism, the device 200 is in wired communication
252 or wireless communication 254 with the reader device 150.
Further, the devices 100, 200 may be configured to communicate with
each other directly (line 256). The communication mechanism in
particular is configured to enable communication with the sweat
sensor device 100 directly, through a control device or companion
transceiver, or through a computer network.
[0040] With reference to FIG. 2, a smart transdermal delivery patch
or device 200 is placed on skin 12. The device 200 includes at
least one reservoir 240 containing a substance, such as a drug and
a tracer compound that are available for iontophoretic delivery, or
other transdermal delivery (e.g., diffusion). The device 200
further includes electrode 220, a breathable skin adhesive layer
210, a substrate 212, and an optional microfluidic component 230.
Electrode 220 may be, for example, an iontophoresis and/or
electro-osmosis electrode. For example, control of electrodes 220,
222 could be computationally controlled, or controlled using simple
analog electronic controls, or other suitable methods. All such
control methods can be referred to as a control mechanism for
controlling the dosage of one or more substances into the body.
Dosage includes total amount of substance dosed into the body, the
periodicity or rate, or other time or amount or other delivery
factors which are important to delivery of a substance in a manner
which is recommended or effective. The device 200 may also include
electronics that limit activating current or total dosage to ensure
harmful or toxic dosages are never reached.
[0041] In one aspect of the invention, a smart transdermal delivery
device is capable of feedback control. For example, a sweat
stimulating drug, such as pilocarpine or methacholine, could be
iontophoretically dosed using the smart transdermal delivery device
200. The sweat sensor 100 could detect generated sweat rate by
measurement of sodium concentration and/or by measurement of
electrical impedance of the skin 12 and communicate that
information to the smart transdermal delivery device 200. The
device 200 could respond to the sweat rate information by adjusting
the sweat stimulating drug delivery through a dosing electrode.
This sensing and delivery system 290 could thereby control the
delivery of the sweat stimulant so that it is dosed optimally to
create a particular sweat rate. In another exemplary application of
the smart transdermal delivery device 200, control of skin
hydration could be provided. A skin hydrating cream is
traditionally applied by hand, and the skin absorbs the hydrating
substances by diffusion. In the present invention, the hydrating
substances may be added to the microfluidic component 230 and
delivered iontophoretically to the skin 12 by control with
electrode 224. The hydration level of skin would be measured by the
sweat sensor device 100, which could be co-located with the device
such that delivery and sensing are from the same area of skin or
adequately close to represent the same general area of skin. Due to
the communication between the devices 100, 200, the dosing of the
hydrating substance would stop once the required dose for the
desired hydration level had been delivered. In another exemplary
application, the smart transdermal delivery device 200 may also be
used to treat inflammation. An anti-inflammatory agent such as
hydrocortisone may be administered using electrode 220 from inside
gel 240 into skin 12 and into muscle tissue (not shown) beneath the
skin 12. The system 290 would administer the hydrocortisone based
on a threshold reading from sensor 100 that indicates that muscle
tissue is inflamed, for example, by detecting higher cytokine
biomarker levels, which are caused by the muscle inflammation. The
system 290 could then stop the anti-inflammatory dosing from device
200 once measured levels of cytokines reach a threshold level
indicating less inflamed tissue.
[0042] With reference to FIG. 3, a smart transdermal delivery patch
or device 300 combines the drug delivery function and the sweat
sensor function in one device. The device 300 is placed on skin 12
and includes iontophoresis and/or electro-osmosis electrode 320,
impedance sensor electrode 322 for measuring sweat rate, and a
breathable skin adhesive layer 310. The device 300 includes at
least one sweat sensing mechanism able to perform at least one
measurement of a marker for a physiological condition or response,
the at least one measurement being that which would change in
response to iontophoretic delivery, or other transdermal delivery
(e.g., diffusion), of a substance contained in reservoir 340. The
sweat sensing mechanism includes a sweat sensor 324 and electronics
350 that are carried on the substrate 312. The sweat flows from the
microfluidic component 330 to the sensor 324, which is in
communication with the electronics 350.
[0043] FIGS. 4-7 show flow diagrams representing pathways a
delivered solute can take before being excreted in sweat or through
skin in various embodiments of the present invention. With
reference to FIGS. 4-7, in one embodiment, a smart transdermal
delivery device capable of sensing sweat has been applied to an
individual's skin. In other embodiments, a smart transdermal
delivery device that is not capable of sensing sweat has been
applied to an individual's skin. In such embodiments, techniques of
sensing the sweat and communicating with the smart transdermal
delivery device are utilized. By way of example, a sweat sensor
device may also be applied to the individual's skin or a bench-top
measurement system may be used to analyze the sweat. FIGS. 4-7
include the blocks `delivery,` `effect,` `metabolize,` and
`excrete.` `Delivery` represents techniques like those listed
above. `Effect` represents some biological response to the solute
that is delivered. `Metabolize` represents the body's ability to
alter the delivered solute, commonly in a fashion that makes it
more water soluble (but not so limited). `Excrete` represents the
delivered solute, the metabolized solute, or other analytes altered
by or by effect from the original delivered solute that are
excreted as sweat or through skin.
[0044] With reference to FIG. 5, an active solute is delivered,
where the active solute is a drug (D). In one path, D could be
directly excreted (e.g., in sweat) and sensed or measured by the
sweat sensor (not shown) in its original un-metabolized form. This
would allow the sensing and delivery system to detect and monitor D
in sweat and utilize that to determine relevant information about
the concentration of D in blood, plasma or an organ. D could also
be metabolized, excreted, and then measured as a metabolite (DM).
Further, since D is an active component, it has an effect on the
body, and the effect could cause a change in sweat or analytes in
sweat that could be measured as an effect (DE). D may also be
directly detected in sweat by monitoring some combination of the
un-metabolized form, the metabolized form, or the physiological
effect of D, which could cause changes in other sweat or skin
biomarkers or measurable aspects of sweat. Such combined monitoring
may provide relevant information beyond that which can be obtained
by measuring such analytes alone or independently of each
other.
[0045] The ability and usefulness of directly detecting a drug in
sweat will depend on the particular application, the delay between
when a drug is delivered and the emergence of the drug or its
metabolite in sweat, the concentration of such analytes in sweat,
how the drug or the drug metabolite may become more dilute at high
sweat rates, and the nature of those analytes, among other factors.
The emergence of a drug or its metabolites depends primarily on the
compound's partition coefficient (P) and secondarily on its
dissociation constant (pK). Therefore, a compound with a high P
value (high lipid solubility) will diffuse more readily from blood
plasma into sweat. Similarly, a compound with a pK value close to
the pH of sweat (typically about 5.0) will tend to partition into
sweat more readily.
[0046] The nature of the delivered solute (e.g., the drug) or its
metabolites may lend also itself more or less readily to detection
by a sweat sensor. Smaller molecules, such as Na+, K+, Cl-, and
other ions, are relatively easy to detect using straightforward
potentiometric electrode sensors. Non-electroactive molecules often
require the use of amperometric type sensors, impedance type
sensors, or enzymatic type sensors, such as those based on
cytochrome P450-related enzymes. Drugs with non-electroactive
molecules include, for example, verapamil and benzphetamine Larger
molecules, such as proteins, are relatively more difficult to
detect since they typically require the use of physical (rather
than electrical) capture coatings composed of antibodies or other
customized assays, which then must be read by electro-impedance
spectroscopy, aptamer, optical or other methods. Other drugs simply
partition into sweat in very low concentrations, requiring the use
of highly sensitive and carefully-calibrated sensors. In addition,
the availability of easily detected proxy molecules may also
influence the decision to detect a drug directly. Consider an
example involving Cystic Fibrosis treatments. When the current
state-of-the art Cystic Fibrosis drugs are effectively working, the
patient's sweat chloride levels will decrease to normal levels.
Thus, a sweat sensor could be configured to measure sweat chloride
levels to indirectly monitor the Cystic Fibrosis drug levels in the
body. By this technique, the relatively more development-intensive
route of detecting the drug directly may not be necessary where an
easy-to-detect proxy analyte is available.
[0047] There are several drug candidates for which direct detection
is recommended. For example, there are numerous diseases caused by
the body's inability to regulate cortisol levels, or to generate
sufficient cortisol. Therefore, cortisol supplementation in the
body could be directly measured by monitoring cortisol levels in
sweat. Similarly, lithium is /regularly administered to control
manic-depressive symptoms, yet it has a very narrow range in which
it is both effective and non-toxic. Careful monitoring of plasma
lithium levels is therefore required for such patients, and
detection of lithium in sweat can readily be accomplished by
devices according to embodiments of the present invention. In
addition, certain applications, such as illicit drug or alcohol
screening, might benefit from a direct detection technique.
[0048] Typically, however, drugs or their metabolites require
specialized sensors to be detected. Such drugs and their
metabolites emerge in sweat after a considerable lag time, such as
a matter of several minutes, tens of minutes, or even longer. In
these cases, the concentration of the primary drug in the body may
be determined by indirect detection. One way to measure the
concentration of a primary drug is by measuring the concentrations
or ratios of biomarkers that are known to be affected by the
primary drug. For example, rather than attempting to detect sweat
insulin, which would require a specialized sensor, it might be
advisable to detect sweat glucose as an indirect method of
measuring the level of primary drug taken. As another example,
cortisol supplementation may be revisited from an indirect
monitoring method. Rather than detecting the sweat cortisol levels
directly, the sweat sensor could be configured to monitor another
biomarker that is regulated by cortisol and can be found in sweat,
such as a cytokine biomarker. Thus, even if the concentration of a
drug or its metabolites is difficult to detect directly via sweat,
the drug may produce a strong and timely physiological response
that may be detected indirectly in sweat.
[0049] Another method of indirect drug monitoring is enabled by
administering to the patient the primary drug in combination with a
known concentration of a tracer compound. The tracer compound would
possess two primary desirable characteristics: 1) it ideally would
be more easily detectable in sweat than the primary drug and 2)
there must be a known co-relationship between the concentration of
the tracer compound in sweat and the concentration of the primary
drug or its metabolite in either an organ or in a bodily fluid
(e.g., blood, plasma, or serum). The tracer compound may also be a)
useful for detection by the sweat sensor, even at low
concentrations, b) non-toxic, and c) relatively inactive in the
body.
[0050] With reference to FIG. 6, an inactive delivered solute, a
solute less active than the primary delivered solute, a solute that
is differently active from the primary delivered solute, or a
tracer compound (T) is delivered along with D. T has the purpose of
helping track or measure the body response to D, or the
concentration of D in the body, or the concentration of the
metabolites DM of D in the body. T could be a molecule that is
soluble at the same or predictable levels to D, or which
metabolizes similarly or predictably to that of D. T can therefore
be used to predict effects, concentration, circulation, and other
aspects of D by measuring T or its metabolites (TM) instead of D. A
particular advantage of the use of a tracer compound is that T may
be specifically selected to enable a strong or otherwise
informative reading by a sweat sensor, for example, T may partition
more predictably or rapidly from the body into sweat, or it may be
safely administered at higher concentrations, such that it appears
at a high concentration in sweat. Furthermore, T could be
specifically molecularly designed to work well with a particular
sweat sensing modality. In addition, D and T and/or their
metabolites DM, TM could also be measured to increase the value of
data or measurements obtained by the sweat sensor. In a further
embodiment, D may represent a placebo. In this manner, the tracer
compound T may be used in a clinical trial setting. Measuring T or
its metabolites TM may be useful to monitor a participant's
compliance with the placebo regimen and to ensure uniform
conditions for the clinical trial.
[0051] In one embodiment, T is a compound that would be metabolized
in the body in generally the same manner as D or metabolized at a
known correlated rate as D. For example, if D is metabolized
through the liver, then T would also be a compound that is
metabolized through the liver. Precisely determining the
chronological concentrations of D and T in a relevant fluid (e.g.,
sweat, blood, or plasma) or a relevant organ (e.g., the kidneys or
liver) or the chronological ratios of the compounds D, T or their
metabolites DM, TM to each other, allows the use of a tracer
compound to further enable or enhance the detection of D via the
sweat sensor.
[0052] In one aspect of the present invention, the use of a tracer
compound to enhance the detection of the primary drug may be
further enhanced by prior testing to determine a tracer profile or
chronological relationship between tracer compound(s) and a
particular primary drug as they proceed from delivery into the body
to excretion in a relevant fluid, such as sweat or plasma. The drug
tracer profile could include a process to determine the
relationship between the primary drug and the tracer candidate The
primary drug and a tracer candidate are delivered into the body,
and a sweat sensor (either via sweat sensor device or by lab
instrument) is used to monitor the individual's sweat over the
half-life of the drug or other suitable interval. The sweat sensor
may be configured to monitor the chronological profiles of a number
of relevant substances, to include the primary drug, one or more
tracer molecules, and/or metabolites of these substances. By
monitoring the selected substances in sweat over time, the tracer
profile would be developed to contain detailed information about
the concentrations and ratios of the various analytes over time as
they are processed in the body. Alternative, less costly, processes
could also be employed by limiting the number of analytes monitored
during the testing process. For example, after administering the
primary drug and the tracer candidate, only the tracer's
chronological profile in sweat might be monitored. In this way, a
precise chronological profile of the tracer in sweat as affected by
the primary drug may be developed, which, with sweat sensor
algorithms, can then be used to enhance the use of the tracer
compound to indirectly monitor the primary drug.
[0053] With reference to FIG. 7 a second tracer solute T2 is added,
which can provide benefits similar to those gained by using T.
Further, additional tracers may also be administered (i.e., T3, T4
. . . T.sub.n) to enhance the capabilities of the sensing and
delivery system to indirectly detect and monitor D. The additional
tracer compounds can be active or inactive, as long as they are
compounds that are deemed adequately safe and which provide
advantages over attempting to sense D alone. As with D and T, these
additional tracer compounds may have their one-time or
chronological concentrations in sweat monitored individually, or
the ratios among the various tracers and the primary drug, or
metabolites thereof, could be monitored chronologically.
[0054] In a further embodiment of the invention, the individual may
be administered one or more tracers, which metabolize in the body
at different rates. Solutes that are highly water-soluble are
typically excreted in sweat relatively quickly after delivery
compared to less soluble compounds. Further, as solutes metabolize,
their metabolites may become predictably more water-soluble.
Therefore, tracer compounds may be selected that have known and
predictable post-delivery excretion periods. In this way, a tracer
that metabolizes very slowly or which has low water solubility, may
be measured to represent the amount of D appearing in blood
initially after delivery. A tracer that metabolizes very quickly or
which is already highly water-soluble may be used instead to show
the rate at which a metabolite (DM) of D is excreted through urine,
or the rate at which D reaches the bloodstream if D and the tracer
have similar partition rates into blood. Such use of tracer
compounds could therefore allow the determination of (1) initial D
dosage in plasma; (2) rate of D passage into sweat, kidneys or
other organs; and (3) active remainder of D in plasma over time,
among other things.
[0055] Co-administration of a tracer compound necessitates that
this tracer compound also be FDA approved, generally regarded as
safe ("GRAS"), or monographed (e.g., aspirin). Accurate knowledge
of the tracer compound's pharmacokinetic profile will allow it to
be correlated with appropriate drugs of interest. Chiefly, this
will involve matching the two substances' metabolic pathway and/or
the time profile between delivery and excretion. One potential
limitation for FDA-approved tracer compounds is that such compounds
likely have some degree of pharmacological activity to be
classified by the FDA. As a result, the tracer compound's active
property must be one that is rather inconsequential or
non-interfering with the drug of interest (e.g., does not block CYP
activity).
[0056] One such candidate tracer compound is the well-known drug
ibuprofen, which has an active and an inactive stereoisomer. The
active stereoisomer, S-ibuprofen, is frequently used as a primary
drug for treatment of pain or inflammation. Like S-ibuprofen, the
inactive stereoisomer R-ibuprofen possesses a similar metabolic
path through the liver and has similar water solubility. Ibuprofen
has a relatively short half-life in the body of 1.3 to 3 hours. It
is also safe for use in the body and causes no known serious side
effects. It can therefore be co-administered with the active
S-ibuprofen as a tracer compound. The system could then be used to
determine the concentration of S-ibuprofen indirectly by monitoring
the concentration of R-ibuprofen metabolites, such as 1- and
2-hydroxyibuprofen, or 1- and 2-hydroxyibuprofen glucuronide, in
sweat. The system may also enhance its direct detection of
S-ibuprofen by detecting and analyzing the concentration ratio of
R-ibuprofen to S-ibuprofen, which may provide a more accurate
measure than measuring S-ibuprofen metabolites alone. Similarly,
R-ibuprofen may be used as a tracer compound for other active
drugs, such as opiates, antibiotics, lidocaine, glucocorticoids,
and other compounds that are also hepatically metabolized. Other
NSAID compounds with similar P and pK values (e.g., indoprofen,
diclofenac, naproxen, and sulindac), may also prove to be effective
tracer compounds. Para-aminobenzoic acid (PABA) may also be a
suitable tracer compound. Similarly, S-ibuprofen could be used as a
tracer compound for other active drugs.
[0057] None of the cases discussed above are necessarily perfect
matches between drug and tracer metabolic profiles. The cases are
given as examples to further illustrate aspects of the present
invention. Further examples are listed as adopted from Chhabra et
al., 2013, "A review of drug isomerism and its significance."
Pharmacodynamic differences resulting out of stereoisomerism can
affect pharmacological activity and potency. For instance,
1-Propranolol has beta-adrenoceptors blocking action while
d-propranolol is inactive. Carvedilol is a racemic mixture, where
the S(-) isomer is a nonselective beta-adrenoceptor blocker, while
both S(-) and R(+) isomers have approximately equally
alpha-blocking potency. S-Timolol is more a potent alpha-blocker
than R-timolol but both are equipotent ocular hypotensive agents.
Labetalol is formulated as a racemic mixture of four isomers, two
of these isomers--the (S, S) and (R, S) isomers--are relatively
inactive, while the (S, R) isomer is a potent alpha-blocker and the
(R, R) isomer is a potent beta-blocker. Labetalol has a 3:1 ratio
of beta to alpha antagonism after oral administration. Sotalol is
formulated as a racemic mixture of D- and L-isomers where the
L-isomer has beta-blocking activity, while the D-isomer has no
beta-blocking activity. Nebivolol has highly selectively
beta-1-blocking effects, while the L-isomers causes vasodilatation.
Most beta-2-selective agonist drugs are formulated as a racemic
mixture of R- and S-isomers. Only the R-isomer of the
beta-2-selective agonist drug has the beta-2-agonistic activity,
while S-isomer has no beta-2-agonistic activity and even promotes
inflammation. Salbutamol is available as a single isomeric
preparation of R-isomer as levalbuterol. Halothane, enflurane, and
isoflurane are chiral drugs with different anesthetic potencies.
D-(+) 2R,3S propoxyphene is analgesic while (-) 2S,3R propoxyphene
has antitussive action.
[0058] Dextromethorphan (DXM or DM), an antitussive (cough
suppressant) drug, is another possible tracer compound. It is one
of the active ingredients in many over-the-counter cold and cough
medicines, including brands such as Benylin DM, Mucinex DM,
Robitussin, NyQuil, and related generic labels. While at high
doses, Dextromethorphan may cause dissociative hallucinogenic
effects, it is a well-studied compound that, at the doses useful in
embodiments of the present invention, is regarded as safe and has
relatively mild active properties. DM has a half-life comparable to
that of ibuprofen at about 2-4 hours.
[0059] Antimicrobials represent another class of candidate tracer
compounds that are safe and possess useful properties for sweat
monitoring. For example, quinolone antimicrobials may be
transferred into sweat. This is a well-studied group of molecules
with known pharmacokinetics and excellent existing analytical
methods for determining levels in biological fluids. Quinolones
generally have low metabolism rates and, hence, longer half-lives
in the body. Exemplary candidates from this class include
Ciprofloxacin, Levofloxacin, Gatifloxacin, Ofloxacin, or
Moxifloxacin. Similarly, Beta Lactam antimicrobials, such as
Ceftriaxone, ceftazidime, and cefuroxime, have been studied in
sweat, and also tend to have long plasma half lives with modest
metabolism rates.
[0060] Anti-fungal medications, such as Ketoconazole and
Fluconazole, represent another class of drugs that contains
candidate tracer compounds. These drugs are known to be excreted
into sweat, are well studied, have established analytical methods
for determining their concentrations in biofluids. These compounds
have modest metabolic rates and relatively innocuous side effect
profiles.
[0061] Nicotine has also been measured in sweat of smokers and
non-smokers and has also been well studied in dermal indications
through its use in transdermal delivery patches. Nicotine has a
short half-life of about 1 to 2 hours, and its metabolite cotinine
has a much longer half-life of about 20 hours. Nicotine and
cotinine therefore may be useful tracer compounds for numerous drug
monitoring applications across a broad time range.
[0062] Finally, tocotrienols, which are members of the Vitamin E
family of compounds, form another class of candidate tracer
molecules. This class of tracer compound presents some challenges
that may be typical in the selection of tracer compounds for sweat
sensor applications. Vitamin E is made up of four tocopherols
(.alpha.-, .beta.-, .gamma.-, .delta.-) and four tocotrienols
(.alpha.-, .beta.-, .gamma.-, .delta.-). Tocotrienols and
tocopherols are very similar in structure and are featured in many
natural substances, including rice bran oil, palm oil, wheat germ,
barley, saw palmetto, annatto, and certain other types of seeds,
nuts, grains, and derivative oils. Of the two sets of compounds,
tocotrienols are better candidates for tracer molecules, since they
typically are found in low concentrations in nature. Since natural
food sources are light in tocotrienols (e.g., an individual would
have to consume 1 kg (2.2 lbs) of olive oil to ingest just 93 mg of
tocotrienols) few foods would spike tocotrienol levels at the same
rate as a pill administered orally. Further, unlike a pill, foods
must be digested, so the absorption rate of tocotrienol into the
bloodstream from food is lower. Tocotrienol concentrations in sweat
are therefore less likely than tocopherols to be skewed by an
individual's diet if they are delivered as a tracer compound.
[0063] The selection and use of tocotrienol as a tracer molecule
also depends on whether a useful amount of the tracer molecule for
sweat sensing can be delivered without causing unwanted side
effects. Vitamin E, in high concentrations, can act as an
anticoagulant, increasing the risk of bleeding problems. As a
result, many agencies have set a tolerable upper intake levels (UL)
at 1,000 mg (1,500 IU) per day. Currently, the U.S. Food and Drug
Administration has set standards only for intake of
.alpha.-tocopherol, but not the other Vitamin E family compounds.
Nevertheless, the 15 mg adult Recommended Daily Allowance (RDA) of
.alpha.-tocopherol may be taken as a benchmark. For example, a dose
of 500 mg would be sufficient to allow tocotrienol to function as a
tracer molecule for most sweat sensor applications. Therefore,
delivering 500 mg of tocotrienol would present the body with
concentrations not likely to be seen in daily life, and the amount
would not be high enough to cause serious side effects. Tocotrienol
is therefore a strong candidate for an effective tracer
compound.
[0064] The Vitamin E family of compounds also metabolizes into
potentially useful tracer molecules such as, for example,
carboxyethyl-hydroxychroman (CEHC). Many of the candidate
metabolites can arise from any form of Vitamin E, so more careful
attention must be paid to the Vitamin E concentration of foods in
general to successfully do so. However, most foods have only about
10 to about 100 mg/kg of Vitamin E, so administering 500 mg of
Vitamin E would result in higher metabolite concentrations than
would normally be seen in daily life, again without causing serious
side-effects.
[0065] Metabolites of Vitamin E show up in body fluids such as
urine at about 1% to about 10% of the orally administered Vitamin
E, which is an easily detectible concentration. Unfortunately,
measuring metabolites in urine lags the levels found in blood by
several hours. Additionally, the chronological monitoring
capability of urine is poor without the use of a painful catheter.
Unlike urine, however, metabolites of Vitamin E, like CEHC, emerge
relatively rapidly in sweat after ingestion. Dye clearance tests
show that CEHC, and other highly water soluble molecules, are
excreted in sweat with a resolution of about 2-3 minutes.
Therefore, CEHC would also be a superior tracer compound for use in
sweat.
[0066] The half-lives of Vitamin E family compounds are in the
ranges of about 2-4 hours, and more specific half-lives can be
achieved if a particular form of Vitamin E is delivered in
isolation from other types of Vitamin E (such as .alpha.- or
.beta.-tocotrienol). Further, the sweat sensor could be configured
to monitor combinations of the Vitamin E compounds and their
metabolites as tracer molecules to improve the system's ability to
indirectly mimic and trace the similar kinetics of a primary
drug.
[0067] PEGylated drugs may also present several candidates for
tracer compounds. PEGylated drugs are altered by bonding various
polyethylene glycol (PEG) polymer chains to improve water
solubility and decrease the rate of metabolic processing by the
kidneys. As these PEGs are metabolized, they emerge in sweat to be
detected by the system. A particular advantage of such compounds is
their GRAS status, and the pharmacological profiles of these
substances are well-known. Numerous drugs could therefore be
monitored by the use of tracer compounds, as the half-lives of
several drugs and drug types are well known in the art.
[0068] CEHC, for example, may be detected by use of electrochemical
immunosensor. An initial requirement for this type of sensor is a
protein, such as an antibody, capable of binding with the molecule.
Neither the antibody or aptamer (BRE) for .gamma.-CEHC is
commercially available, but one could be developed if required. The
immunosensor signal originates from enlarged and positively charged
gold nanoparticle (AunP)-mediated electron transfer between an
insulating self-assemble monolayer (SAM) modified electrode and a
K.sub.3Fe(CN).sub.6 solution. The AunP electrode is first modified
with SAM to block the electron transfer between the electrode and
K.sub.3Fe(CN).sub.6 solution. After the preparation of the
immunosensor, the AunPs attached to the electrode are enlarged and
positively charged by treating them in a solution containing
HAuCl.sub.4, ascorbic acid, and acetyltrimethylammonium bromide
(CTAB). The enlarged and positively charged AunPs then mediate
electron transfer between the electrode and K.sub.3Fe(CN).sub.6
solution, creating a redox current that is proportional to the
concentration of .gamma.-CEHC detected. This immunosensor can be
highly sensitive and have a wide linear range for this type of
analyte.
[0069] In addition to using tracer molecules to indirectly monitor
a primary drug, devices according to embodiments of the present
invention can also use correlated aggregated sweat sensor data to
indirectly monitor the presence of a primary drug in the body by
detecting and monitoring biological responses to the drug, such as
changes in sweat rate, or concentration trends and ratios of
analytes correlated with the presence of the drug.
[0070] Similar to the use of a tracer profile, as detailed above, a
device according to an embodiment of the present invention could
also be configured to monitor a drug response profile, or the
physiological responses to a primary drug in the form of analyte
concentrations, analyte ratios, or trend data. For example, a smart
transdermal delivery device and/or a sweat sensor may have access
to aggregated data on a particular individual or other individuals
of similar age that have taken a particular primary drug. Through
this aggregated data, the sweat sensor would develop a response
profile that typifies the physiological response to the presence of
a primary drug. This response profile may be customized to various
levels for a particular individual, to include relevant criteria
such as age, liver function, kidney function, fitness level, and
etc. It also may be customized to include other factors, such as
hydration level, activity level, or environmental conditions. The
sensing and delivery system could use the aggregated data to
determine whether the detected analytes from a sweat sensor match
the response profile that corresponds to adherence to a drug
regimen. Such a response profile may be developed through prior
testing.
[0071] Embodiments of the present invention include and can benefit
from the employment of various combinations of direct and indirect
detection of a primary drug, the effect of a primary drug on
existing biomarkers, the use of tracer compounds, and various
combinations thereof. In one embodiment, therefore, a sweat sensor
device may be internally configured to detect the primary drug and
its metabolites, a tracer profile and/or a response profile in a
combined drug compliance profile. The drug compliance profile would
consist of analytes that, when taken together, indicate with high
probability that a test subject has taken the drug or is, or is
not, following a drug regimen. A compliance profile for a
particular drug may be predicted using correlated aggregated sweat
sensor data, or it may need to be developed by prior testing.
[0072] In one embodiment, the sensing and delivery system could be
configured to use a drug detection threshold, or calculated
detection level of a primary drug, a tracer compound, a metabolite,
or a combination of these analytes, that shows that the primary
drug is present with reasonable certainty. The drug detection
threshold may be used in single-use scenarios, or may be calculated
for continuous use scenarios. In an exemplary embodiment, a process
could be implemented to determine the relationship between the
primary drug and the tracer candidate. Known amounts of the primary
drug and a tracer candidate are delivered into the body, and a
sweat sensor is used to measure the individual's sweat over an
interval sufficient to take a meaningful reading. The sweat sensor
may be configured to detect the presence of the primary drug, one
or more tracer molecules, and/or metabolites of these substances.
The drug detection threshold may be calculated using aggregated
sweat sensor data correlated with relevant external data. In this
way, a precise threshold for detecting the primary drug may be
developed that considers the patient's individual characteristics,
details about their drug regimen, such as the amount of time they
have taken the drug, and other relevant information. By using sweat
sensor algorithms, these thresholds can then be used to enhance the
ability of the system to detect the presence of the primary
drug.
[0073] The ability to detect and/or chronologically monitor the
concentration of a drug in the body with the sensing and delivery
system described herein has several potentially useful
applications. It can be used, first of all, to determine whether a
patient has taken his or her medication, or has taken it according
to the required regimen. Embodiments of the present invention as
described may also be used to provide individualized measurement of
toxicity response to particular medications by comparing an
individual's detected response to known variances across various
health populations through correlated aggregated sweat sensor data.
Such drug monitoring may also be used to manage organ transplant
rejection by carefully monitoring the levels of anti-rejection
medication along with detected indications of organ rejection, such
as increased levels of inflammatory response molecules, like
interleukin 10, for instance. The invention as described may also
be used to enhance cardiac stress tests by using a delivered solute
to track a targeted or system-level response to the stress test.
Multiple applications are possible, and are contemplated within the
present invention.
[0074] Utilizing the ability to determine the concentration of a
primary drug in an individual's body, the system can use feedback,
perhaps in combination with correlated aggregated sweat sensor
data, to control the delivery and dosage for the primary drug
through a smart transdermal delivery device described above. The
smart transdermal delivery device may be situated on the same patch
as the sweat sensor, or may be on its own wearable patch. Feedback
control may be accomplished by various mechanisms via the smart
transdermal delivery patch, including controllable microfluidic
gates, iontophoretic electrodes, and heat assisted diffusion, among
others.
[0075] In one embodiment, the feedback control capability of the
sweat sensor working in conjunction with such a transdermal
delivery device could ensure a drug was administered only when
needed. A transdermal drug compound containing lithium could be
delivered into the body by diffusion to control schizophrenia. In
one embodiment, the introduction of the drug to skin and therefore
diffusion and delivery is regulated by microfluidic gates or
another type of gate controlled by the sensing and delivery system.
In one embodiment, the gate could be controlled by electrowetting
using techniques known by those skilled in the art. The gate could
also be an electro-active polymer which swells in response to
electricity and which closes off a microfluidic channel as known by
those skilled in the art of microfluidics. In one embodiment where
the drug is charged, the drug could be electrically introduced near
the skin surface through a track-etch membrane since the porosity
of the membrane is very low, which substantially blocks diffusion
of the drug, but through which current driven transport of the drug
could be very high. The system measures and interprets biomarkers
for increased risk of a schizophrenic episode and releases the drug
accordingly. In another example, the transdermal patch alone might
be used to apply the correct dosage of a numbing agent. A numbing
drug, such as lidocaine, could be loaded into a smart transdermal
delivery device and placed on the skin. The device would administer
the drug by iontophoresis and could also apply an electrical
stimulus to the skin and muscle to determine numbness. The device
would also include a strain sensor or other mechanisms to determine
when the skin or muscle no longer twitches in response to the
stimulus. Once the skin or muscle no longer responds, the device
would determine that the lidocaine has been correctly dosed. The
device could then periodically monitor for skin response, and if
muscle twitches are later detected, numbing agent could again be
administered.
[0076] The device could also benefit from various methods known to
those skilled in the art to control, facilitate, or improve the
delivery of substances into the skin by the smart transdermal
patch. In various embodiments, the patch may employ the following
delivery enhancement methods that can be tuned in response to sweat
sensor feedback, such as: iontophoretic delivery, electroporation,
microneedle arrays, or dispensing solvents, such as glycols or
oils, that increase or decrease skin permeability to the drug.
Solvents that increase skin permeability could be stored in a
reservoir or other fluid storing material until dispensed onto the
area of skin for transdermal delivery. In other embodiments, a
smart transdermal patch may include a drug reservoir that is gated
using microfluidic gates known by those skilled in the art. The
device may also vary the concentration of drug delivered to the
skin's surface, since a higher concentration of available drug
generally results in a higher concentration of the drug diffusing
into the body. Other embodiments of the transdermal patch may use
heat, which can change capillary flow or swelling at the site to
change skin permeation or drug permeation rate. At higher
temperatures, the diffusion rate of any substance typically
increases. Components used to provide heat can include, for
example, those found in commercial chemical heat packs (e.g. hand
warmers), thin film printed electrical resistor heaters, or other
suitable methods that provide heat on demand as needed to control
transdermal delivery. Other suitable methods known by those skilled
in the art are also available and are contemplated in the present
invention. Embodiments of the present invention also include a drug
delivery component that could be in the mouth, implanted in the
body, suppository, or other suitable method for controlled drug
delivery.
[0077] In an advantageous aspect of the present invention, the
measured biomarkers or analytes could also be electro-osmotically
extracted for some applications or simply allowed to diffuse out of
skin, sometimes directly to a detector, sometimes into sweat. In
addition to measuring drug or substance metabolites, biomarkers, or
other analytes in sweat, skin or other properties known in the art
may be measured using mechanical, chemical, optical, or other
suitable methods to provide the data to enable feedback control in
the smart transdermal delivery patch.
[0078] With reference to FIG. 8, generally the smart transdermal
patch would have advantages compared to standard oral dosing. Lines
400, 402 represent a regulated dosing of a drug using embodiments
of the present invention. The standard oral dosing line 404 shows
two dosing events. The `effective` and `toxic` levels of the drug
concentration in blood are also labeled. Embodiments of the present
invention could regulate the maximum safe or maximum needed dosage
(400). Compared to standard oral dosing (404), a regulated dose
based on continuous feedback from a sweat sensor device has a
reduced chance of causing an overdose. For example, patients
frequently overdose on oral painkillers because they experience a
decrease in effectiveness, which would not occur with a
system-regulated dosing schedule. The smart transdermal patch could
be used to dose a primary drug only as needed (402), for instance,
in an application where a patient experiences heart arrhythmia and
rapid dosing of a medication is needed, but the medication's side
effects make it undesirable for frequent or continuous use. In an
aspect of the present invention, compliance monitoring and
automatic dosing may also provide superior adherence with a drug
regimen.
[0079] In addition to the above, devices according to the present
invention as described above may be found beneficial in other
industrial applications. Exemplary applications are discussed
below. Those of ordinary skill in the art will recognize how to
modify or configure a device according to an embodiment of the
present invention so as to effectively operate in these other
applications. Thus, the various features of the invention may be
used alone or in numerous combinations depending on the needs and
preferences of the user.
[0080] In one embodiment, a sweat sensor device may be used to
improve a physician's ability to distinguish between viral and
bacterial pneumonia. A patient may present to the doctor with
pneumonia, but the proper course of treatment would depend on the
nature of the infection. The physician could deliver a particular
solute to the patient's lungs via inhalation. The solute would be
selected, for example, because it is readily metabolized by
bacteria. When the solute partitions into the blood through the
lungs and is detected by the sweat sensor, the detected
metabolite(s) would indicate whether the infection is bacterial.
When the physician interprets the sweat sensor data, it shows
levels of the metabolite exceeding a calculated threshold,
indicating a bacterial infection. The doctor therefore concludes
that the infection is likely bacterial and prescribes a suitable
course of antibiotics.
[0081] A patient experiencing chronic pain is prescribed an opiate
painkiller. The opiate is administered orally along with an S- or
R-ibuprofen tracer or a mixture thereof. When the drug is
administered, a sweat sensor device according to an embodiment of
the present invention configured to monitor ibuprofen and its
metabolites is placed on the patient. The sweat sensor activates,
conducts initialization and establishes communication through the
Internet with the delivery system. The system conducts a baseline
reading for ibuprofen and one or more metabolites in sweat, and
then begins to continuously monitor for those analytes. Based on a
calculated tracer profile, and correlated patient information, the
system determines that a specific concentration of ibuprofen and
the metabolite(s) corresponds to an adequate dosage of the opiate.
After several hours of monitoring, the system determines that the
opiate dosage level is low, and alerts the patient's caregiver that
additional dosage is recommended. The patient therefore receives
better pain control without receiving excessive amounts of the
opiate.
[0082] An individual with hyperglycemia is prescribed a sweat
sensor device and transdermal delivery patch device according to an
embodiment of the present invention for blood glucose control. The
individual is given a kit with sweat sensor devices for a number of
days, smart transdermal delivery patches, and skin cleaning swabs.
The kit also contains a companion transceiver that communicates
with the Internet. The sweat sensor devices are configured to
detect sweat rate, glucose, and cortisol levels in sweat. The smart
transdermal delivery patch is equipped with a reservoir of insulin
and an iontophoretic delivery mechanism. At night before sleep, the
individual puts on a sweat sensor device and a delivery patch.
During the night, the sweat sensor device detects high glucose
levels, and communicates this to the sweat sensor device and the
delivery patch. The delivery patch activates the iontophoresis
circuits and transdermally administers an appropriate dose of
insulin. The sweat sensor continues to monitor and finds glucose
levels have been restored within selected parameters.
[0083] In another exemplary embodiment of the present invention,
the sweat sensor may be used to determine whether a patient has
received an optimal dose of a drug. Drug efficacy varies depending
on individual genetic phenotypes, pharmacokinetics, and drug
metabolism rates. Such considerations are particularly important
for psychotropic drugs like fluoxetine, sertraline, venlafaxine,
duloxetine, imipramine and others, which have known variances in
efficacy depending on individual phenotypes. In addition, the sweat
sensor will also account for individual differences in sweat sensor
data caused by individual variances in absorption, distribution,
metabolism, and excretion of the drug. The sweat sensor could be
used to monitor drug levels over time after administration,
accounting for these individual variances and discerning overall
dosage, timing and magnitude of peak and minimum sweat
concentrations, and drug half-life to assist in determining a
dosage required to provide the blood concentration profile
associated with optimal drug effectiveness and safety.
Alternatively, the sweat sensor may use such readings to
characterize an individual's pharmacokinetic profile for a
particular drug. This approach will aid administration of drugs
that are prone to abuse, such as opioid pain relievers, as well as
drugs with a narrow range in which they are both effective and
non-toxic, such as oral chemotherapeutics.
[0084] This is a description of the present invention, along with
the preferred method of practicing the present invention and the
invention itself should be defined only by the appended claims.
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