U.S. patent application number 11/162517 was filed with the patent office on 2007-08-16 for biosynchronous transdermal drug delivery.
This patent application is currently assigned to CHRONO THERAPEUTICS, INC.. Invention is credited to Guy DiPierro.
Application Number | 20070191815 11/162517 |
Document ID | / |
Family ID | 38024536 |
Filed Date | 2007-08-16 |
United States Patent
Application |
20070191815 |
Kind Code |
A1 |
DiPierro; Guy |
August 16, 2007 |
BIOSYNCHRONOUS TRANSDERMAL DRUG DELIVERY
Abstract
Systems and methods for synchronizing the administration of
compounds with the human body's natural circadian rhythms and
addiction rhythms to counteract symptoms when they are likely to be
at their worst by using an automated and pre programmable
transdermal or other drug administration system.
Inventors: |
DiPierro; Guy; (Nanuet,
NY) |
Correspondence
Address: |
HOGAN & HARTSON LLP
ONE TABOR CENTER, SUITE 1500
1200 SEVENTEENTH ST
DENVER
CO
80202
US
|
Assignee: |
CHRONO THERAPEUTICS, INC.
6 Tulip Court
Nanuet
NY
|
Family ID: |
38024536 |
Appl. No.: |
11/162517 |
Filed: |
September 13, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60609418 |
Sep 13, 2004 |
|
|
|
Current U.S.
Class: |
604/890.1 ;
604/290 |
Current CPC
Class: |
A61K 31/00 20130101;
A61K 31/137 20130101; A61N 1/30 20130101; A61M 2205/0266 20130101;
A61M 37/0015 20130101; A61M 2037/0007 20130101; A61M 39/22
20130101; A61M 37/00 20130101; A61K 9/0009 20130101; A61M 37/0092
20130101; A61M 2205/3337 20130101; A61K 9/703 20130101; A61M
2037/0061 20130101; A61K 31/465 20130101; A61M 2037/0023 20130101;
A61M 2205/50 20130101; A61K 9/0014 20130101; A61K 31/04
20130101 |
Class at
Publication: |
604/890.1 ;
604/290 |
International
Class: |
A61K 9/22 20060101
A61K009/22; A61M 35/00 20060101 A61M035/00 |
Claims
1. A method for delivering a bioactive agent to a human or animal
comprising: providing a transdermal drug delivery device coupled to
the human or animal, the delivery device having a source of the
bioactive agent, a programmable timing mechanism, and a mechanism
for causing the bioactive agent to be delivered transdermally in
response to the timing mechanism; and timing routines implemented
by the timing mechanism, wherein the timing routines are selected
to deliver the bioactive agent at a time, rate, sequence and/or
cycle that is synchronized with a biological rhythm of the human or
animal.
2. The method of claim 1 wherein the bioactive agent comprises a
stimulant and the timing routines are selected to deliver the
stimulant immediately before the human or animal wakes up.
3. The method of claim 1 wherein the bioactive agent comprises
nicotine and the timing routines are selected to deliver the
nicotine at times that are associated with nicotine cravings.
4. The method of claim 3 wherein at least one of the selected times
corresponds to a time at which the human or animal experiences a
morning nicotine craving.
5. The method of claim 1 wherein the bioactive agent comprises an
antihistamine and the timing routines are selected to deliver the
antihistamine while the human or animal sleeps.
6. The method of claim 1 wherein the bioactive agent comprises a
stimulant and the timing routines are selected to deliver the
stimulant immediately before the human or animal wakes up.
7. A method for treating a symptom, condition, and/or disease
comprising: identifying a drug suitable for treating a particular
symptom, condition and/or disease; identifying a biologically
superior time for administering a drug; programming a
time-programmable transdermal drug delivery system with a schedule
selected to synchronize with the identified biologically superior
time; and causing the time-programmable transdermal drug delivery
system to deliver the active ingredient according to the programmed
schedule.
8. A programmable transdermal drug delivery device comprising: an
interface for coupling to the skin of a host; a reservoir storing a
quantity of an active composition; valve mechanism for supplying a
quantity of the active composition from the reservoir to the
interface in response to a control signal; and a timing mechanism
coupled to the valve mechanism and configured to generate the
control signal according to a programmed administration
schedule.
9. The device of claim 7 wherein the valve mechanism controls a
rate at which the active composition is supplied in response to the
control signal.
10. The device of claim 7 further comprising a mechanism for
removing the active composition from the interface in response to
the control signal.
11. The device of claim 7 further comprising a mechanism for
removing carrier materials from the interface.
12. A kit comprising a first container comprising a pharmaceutical
formulation of an active material, said formulation comprising an
amount of active material effective to treat a symptom, condition,
and/or disease, wherein said first container is adapted to coupled
to a programmable transdermal drug delivery system.
13. The kit of claim 11 wherein the first container includes a
specification of an administration schedule that is used to program
the programmable transdermal drug delivery system.
14. A method for delivering a drug to a human or animal comprising:
providing a transdermal drug delivery device coupled to the human
or animal, the delivery device having a source of the drug, a
programmable timing mechanism, and a mechanism for causing the drug
to be delivered transdermally in response to the timing mechanism;
and timing routines implemented by the timing mechanism, wherein
the timing routines are selected to deliver the drug at a time when
the human or animal is expected to be asleep.
15. The method of claim 13 wherein the timing routines initiate
drug delivery at a time when the human or animal is expected to be
asleep.
16. The method of claim 13 wherein the timing routines terminate
drug delivery at a time when the human or animal is expected to be
asleep.
17. The method of claim 13 wherein the timing routines increase the
dosage of drug delivered at a time when the human or animal is
expected to be asleep.
18. The method of claim 13 wherein the timing routines decrease the
dosage of drug delivered at a time when the human or animal is
expected to be asleep.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/609,418 filed on September 13, 2004 which is
incorporated herein by reference. This application also relates to
PCT application No. PCT/IB2004/002947 entitled Transdermal Drug
Delivery Method and System filed on Sep. 13, 2004 which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates, in general, to controlled
drug delivery methods and systems, and, more specifically, to
systems and methods for biosynchronous transdermal drug delivery in
which drugs, pharmaceuticals, and other bioactive substances are
delivered transdermally into a body in a manner that is
synchronized with biological processes and/or biological rhythms so
as to improve performance of the substance in the body.
RELEVANT BACKGROUND
[0003] In the field of drug delivery, it is recognized that
supplying the drug in a correct temporal pattern is an important
attribute of any drug delivery methodology. Controlled release drug
delivery systems are intended to improve response to a drug and/or
lessen side effects of a drug. The term "controlled release" refers
generally to delivery mechanisms that make an active ingredient
available to the biological system of a host in a manner that
supplies the drug according to a desired temporal pattern.
Controlled release drug delivery may be implemented using
instantaneous release systems, delayed release systems, and
sustained release systems. In most cases, controlled release
systems are designed to maintain a sustained plasma level of an
active ingredient in a drug within a human or animal host over a
period of time.
[0004] Instantaneous release refers to systems that make the active
ingredient available immediately after administration to the
biosystem of the host. Instantaneous release systems include
continuous or pulsed intravenous infusion or injections. Such
systems provide a great deal of control because administration can
be both instantaneously started and stopped and the delivery rate
can be controlled with great precision. However, the administration
is undesirably invasive as they involve administration via a
puncture needle or catheter. `Delayed release` refers to systems in
which the active ingredient made available to the host at some time
after administration. Such systems include oral as well as
injectable drugs in which the active ingredient is coated or
encapsulated with a substance that dissolves at a known rate so as
to release the active ingredient after the delay. Unfortunately, it
is often difficult to control the degradation of the coating or
encapsulant after administration and the actual performance will
vary from patient to patient. Sustained Release generally refers to
release of active ingredient such that the level of active
ingredient available to the host is maintained at some level over a
period of time. Like delayed release systems, sustained release
systems are difficult to control and exhibit variability from
patient to patient. Due to the adsorption through the
gastrointestinal tract, drug concentrations rise quickly in the
body when taking a pill, but the decrease is dependent on excretion
and metabolism, which can not be controlled. In addition, the
adsorption through the gastrointestinal tract in many cases leads
to considerable side effects (such as ulcers), and can severely
damage the liver.
[0005] Transdermal drug delivery has developed primarily for
sustained release of drugs in situations where oral sustained
release systems are inadequate. In some cases, drugs cannot be
effectively administered orally because the active ingredients are
destroyed or altered by the gastrointestinal system. In other cases
the drug may be physically or chemically incompatible with the
coatings and/or chelating agents used to implement sustained
release. In other cases a transdermal delivery system may provide
sustained release over a period of days or weeks whereas orally
administered drugs may offer sustained performance over only a few
hours. A wide variety of active substances can be delivered through
transdermal systems so long as the active substance can be provided
in a form that can cross the skin barrier.
[0006] In most cases transdermal delivery systems are passive,
taking the form of a patch that is adhesively attached to the host.
The patch includes a quantity of the active substance, along with a
suitable carrier if need be, absorbed in a sponge or similar
system. Once applied, the active ingredient diffuses into the host
through the skin at a rate determined by the concentration of the
active substance and the diffusivity of the active substance.
However, a variety of physical and chemical processes at the
skin/patch boundary affect the delivery rate and may eventually
inhibit drug delivery altogether. Active transdermal delivery
systems have been developed to help regulate the delivery rate by
providing mechanisms to improve drug delivery over time by
"pumping" the active ingredient. One such system is described in
U.S. Pat. No. 5,370,635 entitled "DEVICE FOR DELIVERING A
MEDICAMENT" which describes a system for delivering a medicament
and dispensing it to an organism for a relatively long period of
time, for example at least a few days. The device can be adapted
for positioning on the surface of the skin of a human or possibly
an animal body in order to apply a medicament thereto from the
outer side thereof.
[0007] Conventional transdermal systems circumvent the
disadvantages of the adsorption through the gastrointestinal tract,
but they do not optimize or tailor the dosing regiment to offset
peak symptoms. In addition the constant transdermal delivery of a
drug can lead to severe side effects, including debilitating sleep
disorders and ever increasing tolerance.
[0008] Timed delivery is most often used to maintain a sustained
level of a drug in the body. A significant focus of current
research in drug delivery has been to determine the influence of a
patient's circadian or other biological rhythms on drug efficacy
and efficiency. This research demonstrates that certain disease
symptoms follow a daily pattern, with peak symptoms at certain
times of the day. It has been widely acknowledged that hormones,
neurotransmitters and other intra-body compounds are released in
different amounts at different times of the day pursuant to daily
patterns. The Wall Street Journal reported on May 27, 2003 that
`Doctors are increasingly looking at the clock when it comes to
prescribing medicine, instructing patients not only to what drug to
use but also precisely when to take it. The new approach stems from
a growing body of research that demonstrates that certain diseases
tend to get worse at certain times of the day, By synchronizing
medications with a patient's body clock, many physicians believe
that the drugs will work more effectively and with fewer side
effects. In some cases, the improvements have been so pronounced
that doctors have been able to reduce dosages." Similarly, American
Pharmacy reports that `Circadian physiologic processes alter drug
absorption, distribution, metabolism, and excretion. As a result,
drug doses need to be adjusted to meet the differing needs of
target organs or tissues at various times of the day. See, L.
Lamberg, American Pharmacy, 1991; N831(11): 20-23. Doctors have
responded to this growing body of research by prescribing a
carefully timed drug administration regimen to optimize
treatment.
[0009] Recently, an orally administered drug for arthritis
treatment has suggested a chronotherepeutic approach using a delay
release system where the delay is scheduled to release the active
ingredient at the beginning of an interleukin 6 cascade that is
believed to cause early morning stiffness in rheumatoid arthritis
patients. By attempting to synchronize the drug delivery with a
biological cycle it is believed that low doses may be used to
achieve desired results. However, this system does not overcome the
limitations of delayed release systems described above. Although it
is possible to meet the requirements of chronopharmacology with
pills, this requires an enormous amount of discipline by the
patient to comply with the treatment regiment. As illustrated
above, to achieve optimal results, many patients may need to wake
up during the night to take their medication.
[0010] Hence, what is needed is a reliable means of delivering
multiple drugs in precisely timed and measured doses-without the
inconvenience and hazard of injection, yet with improved
performance as compared to orally-delivered drugs.
[0011] Currently, patient compliance (taking the proper dosages at
the prescribed times) is a critical problem facing caregivers and
pharmaceutical firms alike. Studies show that only about half of
patients take medications at the times and in the dosages directed
by their physician. It is reported that each year, 125,000 deaths
and up to 20% of all hospital and nursing home admissions result
from patient non compliance. It is estimated that non-compliance
results in additional healthcare costs in excess of $100 billion
per year in United States. These figures are even more pronounced
for the elderly. Hence, a need exists for systems and methods that
increase patient compliance for administration of a variety of
drugs.
[0012] Additional advantages and novel features of this invention
shall be set forth in part in the description that follows, and in
part will become apparent to those skilled in the art upon
examination of the following specification or may be learned by the
practice of the invention. The advantages of the invention may be
realized and attained by means of the instrumentalities,
combinations, compositions, and methods particularly pointed out in
the appended claims.
SUMMARY OF THE INVENTION
[0013] Briefly stated, the present invention involves synchronizing
the administration of compounds with the human body's natural
circadian rhythms and addiction rhythms to counteract symptoms when
they are likely to be at their worst by using an automated and pre
programmable transdermal or other drug administration system.
[0014] Specifically, this invention describes a method to maximize
the efficiency of compound administration, decrease negative side
effects and increase the efficacy of pharmacological therapy by
synchronizing and tailoring the administration of certain compounds
to match these circadian rhythms.
[0015] Thus based on an analysis of the human body's circadian
rhythms, the invention delivers varying dosages at varying times,
pursuant to a pre-programmed dosage profile. This ensures that peak
drug concentrations are present in the bloodstream to offset peak
disease and addiction symptoms arising from variances and
fluctuation in the body's natural circadian rhythms. Further, these
methods ensure that less of a drug is in the bloodstream when
disease and addiction symptoms are at there lowest.
[0016] The present invention describes methods for treating
diseases, addictions and disorders in humans. These methods involve
synchronizing and tailoring the administration of compounds with
the body's natural circadian rhythms to counteract symptoms when
they are likely to be at their worst by using an automated and pre
programmable transdermal drug administration system.
[0017] More specifically, these methods synchronize and tailor drug
administration to the human body's circadian rhythms to deliver
varying dosages at varying times. This ensures that peak drug
concentrations are present in the bloodstream to offset peak
disease and addiction symptoms arising from variances and
fluctuation in the body's natural circadian rhythms. Further, these
methods ensure that less of a drug is in the bloodstream when
disease and addiction symptoms are at there lowest. This minimizes
negative side effects, and increases efficacy of the dosing
regimen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 shows an exemplary device useful for implementing the
present invention;
[0019] FIG. 2A and FIG. 2B illustrate comparative drug release
profiles demonstrating operation of the present invention;
[0020] FIG. 3 is a schematic illustration of a drug delivery device
in accordance with the present invention;
[0021] FIG. 4 is a schematic illustration of an alternative drug
delivery device in accordance with the present invention
[0022] FIG. 5 shows an exemplary administration profile for a
stimulant delivery system;
[0023] FIG. 6 shows an exemplary administration profile for a
nicotine delivery system;
[0024] FIG. 7 shows an exemplary administration profile for a
nitroglycerine delivery system tailored to treat variant angina
attacks; and
[0025] FIG. 8 illustrates an exemplary administration profile for a
nitroglycerine delivery system tailored to treat stress-induced
angina attack.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] The reality of circadian rhythms in animals including humans
is well known. Biological rhythms are periodic fluctuations in
biological characteristics over time, which also include circadian
as well as seasonal variations. Circadian, or approximately
24-hour, rhythms include the production of biological molecules
such as cortisol and adrenaline, the regulation of body temperature
and heart rate, changes in characteristics of blood, such as
stickiness, and behaviors such as wakefulness, sleep and periods of
activity.
[0027] Research demonstrates that certain disease symptoms follow a
daily pattern, with peak symptoms at certain times of the day. It
has been widely acknowledged that hormones, neurotransmitters and
other intra-body compounds are released in different amounts at
different times of the day pursuant to daily patterns. It is
believed that the failure of current transdermal systems to
synchronize drug administration with the body's natural rhythms
often lead to (i) severe side effects, including debilitating sleep
disorders (in the context of nighttime nicotine administration, for
example), (ii) ever increasing tolerance (in the case of
nitroglycerin and other pharmaceuticals for example), (iii) more
expensive therapies, since more of a compound is needed since body
rhythm tailored dosing is not implemented. In addition, many
addictions follow a daily pattern consistent with one's circadian
rhythms. For example, according to studies performed, immediately
upon waking, smoker's have peak nicotine cravings. These peak
cravings return after each meal, due to the interplay of serotonin
release as a trained response to the culmination of a meal. Our
methods precisely time the administration of drugs so that they
reach peak levels when symptoms are likely to be at their worst,
and efficacy is greatly improved.
[0028] The present invention involves precisely timing the
administration of drugs so that they reach peak levels in
synchronization with times when symptoms are likely to be at their
worst, or times at which the drugs are believed to be more
effective in the body and/or better tolerated by the patient. The
present invention is described in terms of a particular example
drug delivery system that provides automated and precise control
over dosing, with single-dose capability, (once while people sleep)
or capability to administer separate and varying-sized doses many
times throughout a multiple day period. The particular
implementation is consistent with a commercial development of a
miniaturized, automated and programmable non-invasive drug delivery
system called the ChronoDose.TM. system being developed by the
assignee of the present invention. The system enables controlling
of the amount of drug exposed to the skin in a controlled time
dependent way according to a programmed administration schedule
that implements a desired dosage profile. In this manner the
present invention enables one to precisely control and vary the
time of drug release and the amount of each dose, pursuant to an
easily set pre-programmed dosage profile.
[0029] Research demonstrates that for certain symptoms, conditions
and diseases, drug effects can be optimized when administered in a
defined (and often varying) dosage at predefined times. This is
known as Chrono-Pharmacology. To illustrate the importance of
Chrono-Pharmacology consider the following facts: [0030] Asthma
attacks are 100 times more likely between 4:00 and 6:00 AM. [0031]
Heart attacks and strokes are most likely to occur around 6:00 AM.
[0032] Variant Angina attacks occur30 times more often in the
middle of the night between 2:00 AM and 4:00 AM. [0033] Smokers
experience the highest cravings immediately upon waking up [0034]
Lethargy and difficulty getting out of bed is highest immediately
upon waking up early in the morning [0035] Cold and flu symptoms
peak during night time and early morning hours, when cold
medications are wearing off
[0036] In accordance with the present invention, substances with
proven or suspected chrono-pharmacological efficiency are
integrated into a miniaturized, automated, programmable watch-like
device, such as device 100 shown in FIG. 1. The delivery system 100
shown in FIG. 1 can be used for a variety of active compositions,
and is small, fully automated and programmable. This system
consists of a re-usable wristwatch-like device 101 to control the
time and dosage of drug delivery; and a small, disposable,
`reservoir` 103, which is about the size of a quarter or 1/2 dollar
coin in a particular example, that the user can simply pop-in to
place on the watch-like platform. This reservoir patch lasts, for
example, up to 72 hours, depending on the application. Shorter and
longer reservoir lifetimes are contemplated. The device is readily
adapted to be worn on the forearm, ankle, or other convenient body
location.
[0037] In a particular application the replaceable reservoir can
include a description of an administration schedule that can be
used to manually or automatically program device 100 with an
administration schedule. For example, written schedule can be
printed on or affixed to the reservoir 101 or electrically
programmed using volatile or non-volatile memory. In this manner a
dosing profile can be prescribed and filled by a pharmacy in much
the same manner as a conventional drug prescription is handled
today.
[0038] An exemplary implementation shown in FIG. 3 comprises a
collapsible drug reservoir, an expandable waste reservoir, a
micro-pump, electronics for automation, a display, and a highly
permeable membrane. An exemplary system is described in a PCT
application No. PCT/IB2004/002947entitled TRANSDERMAL DRUG
DELIVEDRY METHOD AND SYSTEM filed on Sep. 13, 2004 which is
incorporated herein by reference. The drug reservoir will contain
about 3 ml of drug formulation. A tiny, miniaturized pump is
activated at pre-programmed times and releases a pre-defined amount
of drug formulation into the drug chamber, where the formulation
comes into contact with highly permeable membrane. This membrane
rests on the skin, and provides for even diffusion of the drug over
the device's drug absorption surface area. This membrane works
effectively with, and can be coated with, an adhesive. In
operation, when the administration of the drug needs to be
discontinued, the remaining drug formulation is either removed from
the membrane area via a waste chamber, containing a hydrophilic
substance (hydrogel) or the device is taken off.
[0039] In an implementation shown in FIG. 4, a pressurized drug
reservoir is used which minimizes or eliminates need for a
micropump. Electronics control a valve that allows controlled
quantities of the drug to be applied to the drug chamber where the
formulation comes into contact with highly permeable membrane.
[0040] The construction and use of transdermal patches for the
delivery of pharmaceutical agents is known. See, for example, U.S.
Pat. No. 5,370,635 entitled "DEVICE FOR DELIVERING A MEDICAMENT"
the disclosure of which is incorporated herein by reference. Such
patches may be constructed using a saturated media, pressurized
reservoirs, or unpressurized reservoirs with micropumps for
continuous, pulsatile, or on-demand delivery of an active material.
For example, a pharmaceutically acceptable composition of an active
material may be combined with skin penetration enhancers including,
but not limited to, oleic acid, amino acids, oleyl alcohol, long
chain fatty acids, propylene glycol, polyethylene glycol,
isopropanol, ethoxydiglycol, sodium xylene sulfonate, ethanol,
N-methylpyrrolidone, laurocapram, alkanecarboxylic acids,
dimethylsulfoxide, polar lipids, N-methyl-2-pyrrolidone, and the
like, which increase the permeability of the skin to the active
material and permit the active material to penetrate through the
skin and into the bloodstream. Pharmaceutically acceptable
compositions may be combined with one or more agents including, but
not limited to, alcohols, moisturizers, humectants, oils,
emulsifiers, thickeners, thinners, surface active agents,
fragrances, preservatives, antioxidants, vitamins, or minerals.
Pharmaceutically acceptable compositions may also be combined with
a polymeric substance including, but not limited to,
ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate,
polyvinyl pyrrolidone, and the like, to provide the composition in
gel form, which may be dissolved in solvent such as methylene
chloride, evaporated to the desired viscosity, and then applied to
backing material to provide a patch. The backing can be any of the
conventional materials such as polyethylene, ethyl-vinyl acetate
copolymer, polyurethane and the like.
[0041] Example substances include caffeine and a variety of
over-the-counter and prescription stimulants (for treating fatigue,
sleep disorders, attention deficit disorders and a variety of other
conditions), nicotine (for smoking cessation), nitroglycerin (for
treating heart attack and strokes), fentanyl (for treating chronic
pain), albutamol (for treating asthma), and selegiline (for
treating depression, attention deficit disorder or Parkinson's
disease). We have carefully identified these specific drugs and
diseases because they have the following attributes: (i)
Chrono-Pharmacology is critical to optimized dosing but is not
being implemented because no automated transdermal system exists,
and (ii) these drugs can be transdermally absorbed passively (i.e.,
without the need for ultrasound or electrical stimulation or other
permeation enhancers). Exemplary chrono-pharmacological systems
that can make use of the present invention are summarized in Table
1 TABLE-US-00001 DISEASES/ CONDITION CHRONOPHARMACOLOGY Morning
Adrenaline is lowest in the morning, making waking Lethargy
uncomfortable and difficult for many people. This can be treated by
administering OTC Stimulant before waking Smoking Nicotine at night
creates sleeping disorders Cessation (nightmares), but cravings are
the highest after waking up. This can be treated by administering
Nicotine before waking up. Angina Angina (variant) attacks occur 30
(thirty) times more often between 2:00 a.m. and 4:00 a.m. This can
be treated by administering larger nitroglycerin doses in early
morning Asthma Asthma attacks are 100 times more likely between
4:00 a.m. and 6:00 a.m. Adrenaline and Cortisol are virtually
absent at night. This can be treated by administering albutamol in
early morning Colds Heaviest symptoms overnight and in the morning.
This and Flu can be treated by administering Cold/Flu medicine
during the night. Heart Heart attacks and strokes are most likely
between Attacks 6:00 a.m. and Noon. This can be treated by adminis-
and tering Anticoagulants before waking up. Strokes Pain
Neurological pain is worst between 3 A.M and 8 A.M. This can be
treated by administering pain medication during sleep. Depression
Selegiline at night can create sleeping disorders (nightmares), but
depression symptoms are high immediately upon waking up. This can
be treated by administering Selegiline before waking up. Rheumatoid
Worst upon awakening. Cortisol and anti-inflammatory Arthritis
hormones are very low at night This can be treated by administering
medication delivered before waking up. Supplements Vitamins and
supplements are best administered in low doses over the course of
the day to be most effective.
[0042] Using this system the present invention can pre-program the
times and amount of each dosage by precisely controlling the amount
of drug exposed to the skin during each dosing. This feature is
advantageous when a drug is best administered during sleep, e.g., 1
to 2 hours before waking up. The present invention precisely
counteracts peak disease symptoms and increase patient
compliance.
[0043] The present invention represents the first true non-invasive
chrono-pharmacological drug delivery device. While current
transdermal applications are restricted to the dosage profile shown
in FIG. 2a, the automated implementation of the present invention
can be programmed for a variety of drug delivery patterns to
achieve customized patient dosing regiments for optimal therapy
(FIG. 2b). There are many advantages for a controlled transdermal
release of an active material such as a drug. As used herein, the
term `controlled` or `sustained` release of an active material
includes continuous or discontinuous, linear or non-linear release
of the active material according to a programmed schedule. Among
the advantages of controlled release are the convenience of a
single application for the patient, avoidance of peaks and valleys
in systemic concentration which can be associated with repeated
injections, the potential to reduce the overall dosage of the
active material, lower body stress, and the potential to enhance
the pharmacological effects of the active material. A lower,
sustained dose can also prevent adverse affects that are
occasionally observed with infusion therapy. In addition to
significantly reducing the cost of care, controlled release drug
therapy can free the patient from repeated treatment or
hospitalization, thus offering the patient greater flexibility and
improving patient compliance. A controlled release formulation of
certain drugs also provides an opportunity to use the drug in a
manner not previously exploited or considered. The present
invention is particularly advantageous when (i) known
chrono-pharmacological information shows that a drug's effects can
optimized when administered in a defined dosage at a predefined
time or times, and/or (ii) patient compliance with the dosing
regimen is greatly increased due to automation, (doses required at
inopportune times, when sleeping, for example).
Applications--ArisePatch.TM.
[0044] A contemplated consumer product is the ArisePatch.TM.. Most
people experience difficulty and discomfort when waking early in
the morning. According to a 2002 National Sleep Foundation poll 49%
of US adults age 18-29 have trouble waking in the morning and 41%
of US adults age 30-64 have trouble waking in the morning. There
are 165,000,000 adults in the US alone age 18-64, meaning
approximately 74,250,000 US adults age 18-64 have trouble waking in
the morning.
[0045] The ArisePatch implementation of the present invention
allows individuals, while asleep, to have an over-the-counter (OTC)
or prescription stimulant automatically administered during a 1-2
hour pre-wake-up period. FIG. 5 illustrates an exemplary stimulant
administration profile showing a blood plasma level of ephedrine in
nanograms per milliliter on the vertical axis, with time on the
horizontal axis. Stimulant concentrations will reach peak levels
immediately prior to having to wake. Immediately upon waking up the
individual will be alert and feel well rested. The ArisePatch.TM.
will eliminate the typical discomfort or difficulty associated with
getting up early. This functionality is attractive to employed
people getting up for work to ensure punctuality, and just about
anyone who wants to offset morning discomfort associated with a
late night, jet lag, or sickness.
Applications--Smoking Cessation
[0046] Nicotine replacement has been the most frequently used
therapy to support smokers in their effort to quit. Smokers report
that the craving for a cigarette is greatest immediately upon
waking in the morning. The time elapsed between wakening and the
first cigarette is the best indicator of addiction. For most
smokers this time only a few minutes.
[0047] Current nicotine patches cause severe sleep disturbances by
releasing nicotine steadily throughout the night to ensure
sufficient morning nicotine levels to offset the strong morning
craving. It is widely accepted that current nicotine patches have a
detrimental and common side effect--sleeping disorders, and
insomnia, including persistent nightmares. Therefore, users are
often forced to remove the patch in the evening before they go to
bed. This eliminates sleep disturbances, but results in nicotine
levels that are insufficient to offset the strong morning craving.
This is a major drawback to current nicotine patches and many users
relapse, resulting in a less efficient smoking cessation therapy.
Current patches present the user with a difficult decision,
choosing between nightmares and relief from the strong morning
cravings.
[0048] An exemplary product contemplated by the present invention
is called Nicotine ChronoDose.TM. system. In accordance with the
present invention, the system can begin to administer nicotine(or
nicotine analogs or any other smoking cessation compound including
but not limited to Zyban) automatically during a one hour period
immediately prior to waking. This will relieve the smoker's peak
craving upon waking without causing nightmares and insomnia. We
believe that this system clearly provides a superior method for
smoking cessation.
[0049] A more advanced nicotine replacement system than that
described above is worn for three days at a time and is programmed
to release nicotine in a daily rhythmic pattern such as shown in
FIG. 6 to offset peaks in a smoker's cravings. FIG. 6 illustrates
an exemplary nicotine administration profile showing a blood plasma
level of nicotine in nanograms per milliliter on the vertical axis,
with time on the horizontal axis. This implementation will reduce
nicotine dependency by administering pre-programmed levels of
nicotine pursuant to typical smoking patterns. For instance many
smokers report that cravings for a cigarette are greatest upon
waking up, after lunch, mid afternoon, after dinner and before
bedtime. This implementation of the present invention will
automatically release larger doses of nicotine to offset peak
cravings and no nicotine when cravings are typically at a minimum.
The present invention may be delivered in a pre-programmed manner
for each treatment regimen. The only involvement by the user will
be the replacement of the `reservoir` every three days, and the
replacement of the platform housing as needed.
[0050] This implementation represents a tremendous move forward in
nicotine replacement therapy, and is far superior to the
old-technology systems that simply release the same amount of
nicotine all day and night. With the present invention, one can
systematically decrease a smoker's tolerance without increasing
dependence (the result of a constant flow) and better wean a smoker
off nicotine. This will allow the smoker to better `tailor-down`
and decrease the amount of nicotine he needs to quit. Modern
smoking cessation is much more than nicotine replacement therapy.
Programs also include weight control, diet and psychological
support. The present invention fits well into these programs, since
it addresses the key component of being able to quit smoking by
efficiently countering the withdrawal symptoms while doing away
with the negative side effects of current nicotine replacement
therapy systems, namely sleep disturbance.
Applications--Cold and Flu treatment
[0051] Cold and flu symptoms are worst from midnight until the
early morning because the concentration of cortisol is lowest at
that time. Current night time cold and flu medication end up losing
efficacy by early morning when cold and flu symptoms are highest.
Therefore people suffering from a cold or flu are often
unpleasantly awoken by an increase in symptoms, cutting sleep
short. Set and put on before bedtime, the present invention will
automatically deliver a larger dose of medication and
immuno-boosters in the early morning hours to more effectively
combat the peak cold and flu symptoms that occur in the morning.
Users will experience less severe cold and flu symptoms during the
morning hours, will not have their sleep cycle cut short, and will
wake up feeling symptom-free. This implementation uses prescription
or OTC cold medicine alone or optionally in combination with
certain transdermally efficacious vitamins and immune system
boosters to provide a total solution to cold and flu ailments. This
is the first cold therapy that combines OTC medicine with
supplemental immuno-boosters in a comprehensive and automated
manner. Our system will treat the cold symptoms directly and boost
the body's immune system to help it heal naturally.
[0052] In a particular application, the Cold and Flu automated
transdermal drug delivery system utilizes OTC cold medicine,
Vitamin C, Echinacea, and Zinc to provide a total solution to cold
and flu ailments, and all while you sleep. Cold and flu symptoms
are worst in the middle of the night and early morning because the
hormone cortisol, a key inflammation fighter, is missing at that
time. Cold and flu symptoms are worst from midnight until the early
morning because the concentration of cortisol is lowest at that
time. Current night time cold and flu medication end up losing
efficacy by early morning when cold and flu symptoms are highest.
Therefore people suffering from a cold or flu are often
unpleasantly awoken by an increase in symptoms, cutting sleep
short
[0053] Set and put on before bedtime, the Cold and Flu automated
transdermal drug delivery system utilizes our proprietary
technology to automatically deliver a larger dose of medication and
immuno-boosters in the early morning hours to more effectively
combat the peak cold and flu symptoms that occur in the morning.
Users will experience less severe cold and flu symptoms during the
morning hours, will not have their sleep cycle cut short, and will
wake up feeling symptom-free.
[0054] Our system not only combats statistically proven peak
nighttime and early morning cold symptoms by releasing OTC cold
medicine, but actually helps your body to heal by boosting its
immune system through Vitamin C, Echinacea and Zinc supplementation
in small but distinct doses all night long.
[0055] Our Cold/Flu system releases these combination of compounds
every 2 hours throughout the night, with a higher dosage of
compounds being released in the morning to combat these proven
middle of the night and early morning symptoms, which are the worst
of the day.
[0056] Cold and flu symptoms are worst in the middle of the night
and early morning because the hormone cortisol, a key inflammation
fighter, is missing at that time. Our system utilizes its core
competitive advantage by pre-programming our System to release more
medicaments precisely at that time to offset these peak symptoms.
Current cold and flu medications end up losing efficacy by early
morning when cold symptoms peak, so the user either has sleep cut
short due to the onset of these symptoms, or wakes up out of
slumber feeling sick with peak symptoms. Our system will ensure
that a while a person is actually sleeping, a sufficient dose of
cold and flu medicine is freshly delivered to offset these peak
morning symptoms.
Applications--Weight Control, Vitamin and Herbal
Supplementation
[0057] In yet another application, a series of weight loss vitamins
and supplements is administered in small distinct doses many times
over a multiple day period. Vitamins and supplements are absorbed
by the body in small dosages. Contrary to popular belief,
once-a-day products are not maximally effective because excess
dosages are excreted unused. This implementation of the present
invention precisely controls the timing and dosage of small but
distinct amounts of vitamins and supplements during a 24 hour
period to ensure that vitamins and supplements are constantly
bio-available for optimal absorption and cellular function. Greater
doses are automatically released prior to mealtimes to counter
appetite cravings, resulting in a much more effective diet
program.
Applications--Angina
[0058] Research shows that variant angina occurs 30 times more
often between 2:00 a.m. and 4:00 a.m. (`critical angina phase`)
than at any other time of the day. Nitroglycerin effectively
combats angina attacks, if administered in optimal doses. Current
nitroglycerin patches exist, but they can only release a constant
amount of nitroglycerine steadily over time. Current patches cannot
tailor the release of nitroglycerine to optimize treatment by
releasing more nitroglycerine precisely during the critical angina
phase to offset these peak symptoms.
[0059] In addition, nitroglycerine loses its effectiveness and
requires higher and higher dosages when administered constantly.
Our bodies become tolerant to it. Current systems cannot stop or
decrease the release of nitroglycerine when disease symptoms are
lowest. Thus, these current `dumb` patches cannot offset the
critical angina phase by releasing more of the drug, nor can they
shut down or stop nitroglycerine administration when the body
doesn't need it. It is a `one dose fits all` type of scenario once
each "dumb" patch is applied to the patient.
[0060] The method in accordance with the present invention utilizes
an automated transdermal system in order to transdermally
administer more nitroglycerine during the critical angina phase to
ensure adequate offset of these symptoms and less nitroglycerine
when it is not needed so that no tolerance builds up. Our method
utilizes a `smart` patch medicine system at this time to offset
these peak critical phases in the disease cycle arising due to the
human body's circadian rhythm.
[0061] The preprogrammable automated transdermal system is worn
around the wrist like a watch (or the forearm arm or ankle) and
releases nitroglycerine in optimal dosages at times that are
optimally synchronized. This is pursuant to a pre-programmed and
tailored dosage profile. Current nitroglycerin patches only have
the capability to release a constant dose of nitroglycerin over a
period of time. Current nitroglycerin patches simply cannot alter
or vary dosages to increase dosages at different times of the day,
and decrease dosages at other times of the day.
[0062] The nitroglycerin system in accordance with the present
invention has three primary advantages over current nitroglycerin
patches. First, the system utilizes its core competitive advantage
to automatically and precisely release nitroglycerin in peak
amounts to offset the peak symptoms of morning attacks occurring
during the critical angina phase. Current nitroglycerine patches
have release rates that stay constant and do not increase to offset
critical phases, and do not decrease as symptoms decrease. Second,
our system solves the tolerance issue by releasing less (or no)
nitroglycerin in off-peak hours, and then releasing nitroglycerin
at just the right time so that it is present during critical
periods, without increasing tolerance. Third, our system
accomplishes 1 and 2 above automatically, without the need for a
patient to wake up to take a drug at this critical phase, which
does away with the need for any increased patient compliance.
[0063] As a result we believe that our nitroglycerin system
represents an ideal delivery system for patients who use
nitroglycerin regularly for the treatment and/or the prevention of
heart attacks and strokes. Patient compliance regarding the timing
and dose of heart attack medication is crucial. Patient
non-compliance with physician's instructions for this is often a
cause of re-hospitalization, according to the US Department of
Health and Human Services. The system solves this problem, and will
decrease the need for re-hospitalization by dramatically increasing
patient compliance.
[0064] This system can be either an `wear each night and remove in
the morning` system, whereby it only releases nitroglycerine
automatically to offset the critical angina phase in the morning,
or a `total solution` system, that is worn for a period of 24 hours
to several days, and that administers nitroglycerine in tailored
amounts and at tailored times as synchronized with the body's
circadian rhythm (and conveniently taken off while showering or
swimming).
[0065] The system is an innovative new drug therapy for angina.
With its superior advantage of optimized and automated time and
dose administration synchronized with our circadian rhythms, the
system in accordance with the present invention ensures that
nitroglycerin will circulate in the bloodstream exactly when the
patient needs it, and without any build up tolerance. For these
reasons, our system is superior to current steady release nicotine
patches. Our system's increased advantages are extremely relevant
for those patients with moderate to severe angina.
[0066] FIG. 7 shows an exemplary administration profile for a
nitroglycerine delivery system tailored to treat variant angina
attacks or angina pectoris. This type of angina attack has a peak
frequency in many patients between the hours of 2:00 and 4:00 AM.
This is a particularly difficult time to wake up to take a drug
such as nitroglycerine. In accordance with the present invention an
administration profile substantially like that shown in FIG. 7 is
automatically administered. In FIG. 7 the vertical axis indicates
blood plasma level in nanograms per milliliter, and the horizontal
axis indicates time from 10:00 PM through the night to 8:00 AM.
[0067] FIG. 8 illustrates an exemplary administration profile for a
nitroglycerine delivery system tailored to treat stress-induced
angina attack. In FIG. 8 the vertical axis indicates blood plasma
level in nanograms per milliliter, and the horizontal axis
indicates time from 12:00 AM through the day until about 4:00 PM.
The administration profile shown in FIG. 8 provides a high blood
plasma concentration throughout the waking hours of a day when
stress is likely occur.
Applications--Asthma
[0068] The automated transdermal asthma system automatically
administers a morning dose of albuterol, tolobuterol, salmeterol,
beta 2 agonist or any other antiarrhythmic drug (an `Asthma drug`)
to combat the peak symptom of morning asthma attacks known as the
`morning dip`.
[0069] Asthma attacks occur 100 (one hundred) times more often
between the hours 4 A.M. and 6 A.M., when most people are asleep.
This is due to the early morning deterioration of respiratory
function known as `morning dip`, which is the time of day that
respiratory function is at its lowest. These early morning asthma
attacks cause great distress to sufferers and care providers. The
morning dip represents the dip in respiratory function at this time
when asthma attacks are 100 times more likely to occur. Our system
effectively combats the morning dip by releasing more Asthma drug
at this time to offset this peak morning symptom . In other words,
our `smart` patch varies the level of drug in the bloodstream so
that drug concentrations are highest when respiratory function is
at its lowest.
[0070] Current `dumb` asthma patches exist, but they can only
release a constant amount of drug steadily over time. Current
patches cannot tailor the release of drug to optimize treatment by
releasing more drug precisely during the morning dip to offset
these peak critical symptoms.
[0071] The Asthma system has two primary advantages over current
patches. First, the system of the present invention utilizes its
core competitive advantage to automatically and precisely release
albuterol or other asthma drugs in peak amounts to offset the peak
symptoms associated with the morning dip. Current patches have
release rates that stay constant and do not increase to offset this
peak critical phases, and do not decrease as symptoms decrease.
Second, our system accomplishes 1 and 2 above automatically,
without the need for a patient to wake up to take a drug at this
critical phase, which does away with the need for any increased
patient compliance.
[0072] The automated transdermal system for Asthma is worn around
the wrist like a watch (or the forearm arm or ankle) and releases
albuterol or other Asthma drugs in optimal dosages at times that
are optimally synchronized, especially to offset the morning dip,
pursuant to a pre-programmed and tailored dosage profile. Current
Asthma patches only have the capability to release a constant dose
over a period of time. Current Asthma patches simply cannot alter
or vary dosages to increase dosages at different times of the day,
and decrease dosages at other times of the day.
[0073] The system is an innovative new drug therapy for asthma.
With its superior advantage of optimized and automated time and
dose administration synchronized with our circadian rhythms, our
system ensures that albuterol or another asthma drug will circulate
in increased amounts in the bloodstream exactly when the patient
needs it. For these reasons, our system is superior to current
steady release patches. Our system's increased advantages are
extremely relevant for those patients with moderate to severe
asthma.
Applications--Hypertension
[0074] The clondine automated transdermal system utilizes clondine,
(or another hypertension drug) an effective drug that combats high
blood pressure. The clondine automated transdermal drug delivery
system has an automated morning release of Clondine to combat the
peak symptom of morning heart attacks.
[0075] Blood pressure differs at different times of the day. Blood
pressure surges upon waking, and is lower by 20 to 30 per cent
while sleeping. Our preprogrammed automatic transdermal system
utilizes its core competitive advantage by releasing clondine in a
tailored fashion to counter high blood pressure when symptoms are
highest, while releasing less clondine when symptoms are less
severe.
[0076] Current clondine patches release the drug consistently over
time. It cannot release more of the drug when symptoms are worst.
People die most when the symptoms peak. Having the advantage of
administering more of the drug when a patient needs it the most can
mean the difference between life and death, especially in patients
with moderate to severe high blood pressure.
[0077] The automated transdermal system for hypertension has two
primary advantages over current patches. First, our system utilizes
its core competitive advantage to automatically and precisely
release clondine or other hypertension drugs in peak amounts to
offset the peak symptoms associated with the dangerous morning
symptoms. Current hypertension patches have release rates that stay
constant and do not increase to offset this peak critical phases,
and do not decrease as symptoms decrease. Second, our system
accomplishes 1 and 2 above automatically, without the need for a
patient to wake up to take a drug at this critical phase, which
does away with the need for any increased patient compliance.
Applications--Depression, Alzheimer's, Attention Deficit
[0078] The selegiline automated transdermal system utilizes
selegiline, an effective MAO inhibitor for the treatment of
depression, Alzheimer's and Attention Deficit Disorder.
[0079] The selegiline automated transdermal drug delivery system
gives an automated morning release of selegiline to combat the peak
symptom of morning depression without the side effect of sleep
disturbances.
[0080] The system in accordance with the present invention is
applied before bed. It does not release the drug until an hour or 2
before morning, so symptom of morning depression would be corrected
by our system without subjecting the patient to sleep
disturbances.
[0081] Primary negative side effects of the selegiline patches are
abnormal dreams, insomnia, and difficulty sleeping. We believe that
by specifically refraining from administering selegiline at night,
and utilizing our system's core competitive advantage to turn it on
an hour or so before waking, we can do away with this negative side
effect and still offset the critical phase of morning symptoms of
depression. It has been reported that patients have increased
symptoms of depression upon waking if the critical amount of
Selegiline is not circulating through their system. Our system
utilizes its core competitive advantage to provide a compelling
solution to this problem. Our system is applied before bed, it
would not release the drug until an hour or two before morning, so
symptom of morning depression would be corrected by our system
without subjecting the patient to sleep disturbances
[0082] Current Oral Selegiline produces horrible side effects.
There is a new Selegiline patch coming out on the market, but it to
produces sleep disturbances. It is believed that the system in
accordance with the present invention would be superior to
conventional Selegiline product delivery systems.
Applications--In General
[0083] The present invention is particularly useful in applications
in which it is necessary and/or desirable to start the
administration of a drug, stop the administration of a drug, and/or
increase/decrease the dosage of a drug at a time when it is
inconvenient or impossible for a patient to initiate the necessary
actions. This is particularly useful for a wide variety of drug
administration applications that benefit when administration is
started, stopped, or changed while a person is sleeping. As
chronotherapy knowledge increases, it is contemplated that a wide
variety of applications will be discovered in which benefit is
realized by starting, stopping and/or changing the drug
administration while a patient sleeps.
[0084] In each of the examples, treatment is continued as needed to
provide superior symptomatic relief, prevent exacerbation of
symptoms, and/or prevent and/or delay progression of the disease
state or condition in the patient, or until it is no longer well
tolerated by the patient, or until a physician terminates
treatment. For example, a physician may monitor one or more
symptoms and/or serum levels of active material and/or metabolic
by-product(s) in a patient being treated according to this
invention and, upon observing attenuation of one or more symptoms
for a period of time, conclude that the patient can sustain the
positive effects of the above-described treatment without further
administration for a period of time. When necessary, the patient
may then return at a later point in time for additional treatment
as needed.
[0085] As used herein, `day` means a 24-hour period. Thus, for
example, `for at least three consecutive days` means for at least a
72-hour period. During or after the treatment, a physician may
monitor one or more symptoms and/or serum levels in the patient
and, upon observing an improvement in one or more of the parameters
for a period of time, conclude that the patient can sustain the
positive effects of the treatment without further administration of
the active material for a period of time.
[0086] In order to use an active material for therapeutic treatment
(including prophylactic treatment) of mammals including humans
according to the methods of this invention, the active material is
normally formulated in accordance with standard pharmaceutical
practice as a pharmaceutical composition. According to this aspect
of the invention there is provided a pharmaceutical composition
comprising an active material in association with a
pharmaceutically acceptable diluting substance or carrier, wherein
the active material is present in an amount for effective treating
or preventing a particular condition. While individual needs may
vary, determination of optimal ranges for effective amounts of an
active ingredient (alone or in combination with other drugs) within
the ranges disclosed herein is within the expertise of those
skilled in the art. Accordingly, `effective amounts` of each
component for purposes herein are determined by such considerations
and are amounts that improve one or more active ingredient
functions and/or ameliorate on or more deleterious conditions in
patients and/or improve the quality of life in patients.
[0087] The present invention also provides pharmaceutical kits for
treating a particular symptom, condition and/or disease and/or
improving a particular biological function, comprising one or more
containers comprising one or more active compositions in accordance
with this invention. Such kits can also include additional drugs or
therapeutics for co-use with the active composition for treatment
or prevention of a particular symptom, condition and/or disease
and/or improving a particular biological function . In this
embodiment, the active composition and the drug can be formulated
in admixture in one container, or can be contained in separate
containers for simultaneous or separate administration. The kit can
further comprise a device(s) for administering the compounds and/or
compositions, such as device 100 shown in FIG. 1, and written
instructions in a form prescribed by a governmental agency
regulating the manufacture, use or sale of pharmaceuticals or
biological products, which instructions can also reflect approval
by the agency of manufacture, use or sale for human
administration.
[0088] Although the invention has been described and illustrated
with a certain degree of particularity, it is understood that the
present disclosure has been made only by way of example, and that
numerous changes in the dosages, administration profiles, timing,
as well as the combination and arrangement of parts can be resorted
to by those skilled in the art without departing from the spirit
and scope of the invention, as hereinafter claimed.
* * * * *