U.S. patent application number 12/835693 was filed with the patent office on 2010-11-04 for biosynchronous transdermal drug delivery.
This patent application is currently assigned to Chrono Therapeutics, Inc.. Invention is credited to Guy DiPierro, Steven A. Giannos.
Application Number | 20100280432 12/835693 |
Document ID | / |
Family ID | 38024536 |
Filed Date | 2010-11-04 |
United States Patent
Application |
20100280432 |
Kind Code |
A1 |
DiPierro; Guy ; et
al. |
November 4, 2010 |
BIOSYNCHRONOUS TRANSDERMAL DRUG DELIVERY
Abstract
Systems and methods for treating diseases, addictions and
disorders in humans and animals involving synchronizing and
tailoring the administration of drug compounds with the body's
natural circadian rhythms, in order to counteract symptoms when
they are likely to be at their worst. Automated and pre
programmable transdermal drug administration system are used. This
system can also utilize a pump or pressurized reservoir, and/or a
system for removing depleted carrier solution, or other modulated
dispensing actuator, in conjunction with micro-fabricated
structures commonly referred to as Micro-needles, or heat, or
iontophoresis, sonophoresis, or a wide range of chemical permeation
enhancers.
Inventors: |
DiPierro; Guy; (Hamilton,
NJ) ; Giannos; Steven A.; (Quincey, MA) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Chrono Therapeutics, Inc.
|
Family ID: |
38024536 |
Appl. No.: |
12/835693 |
Filed: |
July 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11162525 |
Sep 13, 2005 |
7780981 |
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12835693 |
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60609418 |
Sep 13, 2004 |
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Current U.S.
Class: |
604/20 ; 604/22;
604/289; 604/290 |
Current CPC
Class: |
A61K 31/00 20130101;
A61K 9/703 20130101; A61M 2205/3337 20130101; A61K 31/465 20130101;
A61M 37/00 20130101; A61M 2037/0061 20130101; A61K 9/0009 20130101;
A61K 31/04 20130101; A61M 2205/50 20130101; A61N 1/30 20130101;
A61K 31/137 20130101; A61M 37/0092 20130101; A61M 37/0015 20130101;
A61M 39/22 20130101; A61M 2037/0023 20130101; A61K 9/0014 20130101;
A61M 2037/0007 20130101; A61M 2205/0266 20130101 |
Class at
Publication: |
604/20 ; 604/290;
604/22; 604/289 |
International
Class: |
A61M 35/00 20060101
A61M035/00; A61N 1/30 20060101 A61N001/30; A61N 7/00 20060101
A61N007/00 |
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 comprising (a) a source of
the bioactive agent, (b) a programmable timing mechanism which
implements timing routines, 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; and (c) a mechanism for causing the bioactive
agent to be delivered transdermally in response to the timing
mechanism.
2. The method of claim 1, whereby permeation through the skin is
assisted using one or more from the group comprising micro-needles,
heat, iontophoresis, sonophoresis, and a chemical permeation
enhancer.
3. 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.
4. 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.
5. The method of claim 4, wherein at least one of the selected
times corresponds to a time at which the human or animal
experiences a morning nicotine craving.
6. 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.
7. A method for treating a symptom, condition, and/or disease
comprising: (a) identifying a drug suitable for treating a
particular symptom, condition and/or disease; (b) identifying a
biologically superior time for modulating the administration of the
drug; (c) programming a time-programmable transdermal drug delivery
system with a schedule selected to synchronize with the identified
biologically superior time for modulating; and (d) causing the
time-programmable transdermal drug delivery system to deliver the
active ingredient according to the programmed schedule, wherein the
drug delivery system comprises: (i) an interface for coupling to
the skin of a host; (ii) a reservoir storing a quantity of an
active composition; (iii) a delivery mechanism configured to cause
the bioactive agent to be delivered from the reservoir to the skin
of the host, wherein the bioactive agent is delivered transdermally
to the host, and wherein the quantity of the active composition
supplied from the reservoir to the interface is modulated in
response to a control signal; and (iv) a timing mechanism coupled
to the delivery mechanism and configured to generate the control
signal according to a programmed administration schedule.
8. A programmable transdermal drug delivery device comprising: (a)
an interface for coupling to the skin of a host; (b) a reservoir
storing a quantity of an active composition; (c) a delivery
mechanism configured to cause the bioactive agent to be delivered
from the reservoir to the skin of the host, wherein the bioactive
agent is delivered transdermally to the host, and wherein the
quantity of the active composition supplied from the reservoir to
the interface is modulated in response to a control signal; and (d)
a timing mechanism coupled to the delivery mechanism and configured
to generate the control signal according to a programmed
administration schedule.
9. The device of claim 8, wherein a valve mechanism controls a rate
at which the active composition is supplied in response to the
control signal.
10. The device of claim 8, further comprising: (a) a mechanism for
removing the active composition from the interface in response to
the control signal; (b) a mechanism for removing carrier materials
from the interface; or (c) a combination thereof.
11. The device of claim 10, wherein the removal mechanism comprises
a waste reservoir.
12. The device of claim 11, wherein the waste reservoir is an
expandable waste reservoir and comprises at least one desiccant and
at least one hydrophilic substance.
13. The device of claim 11, wherein a portion of the active
composition is removed from the interface via evaporation into the
waste reservoir.
14. The device of claim 10, wherein the removal system is
configured to control discontinuance of transdermal delivery of the
bioactive agent by removing at least a portion of the bioactive
agent and/or a carrier solution from the skin of the host, wherein
the device is maintained coupled to the host during removal of the
portion of the bioactive agent and/or carrier solution.
15. The device of claim 10, further comprising a membrane in
contact with the skin of the host, wherein the bioactive agent is
delivered from the reservoir to the membrane and from the membrane
to the skin of the host, and further wherein the removal system is
configured to remove the portion of the bioactive agent and/or
carrier solution from the membrane.
16. The device of claim 15, wherein the bioactive agent is
delivered from the membrane into the skin of the host by passive
transdermal diffusion.
17. The device of claim 15, wherein the delivery mechanism
comprises a pump configured to cause the bioactive agent to be
delivered from the reservoir to the membrane.
18. The device of claim 17, wherein the reservoir is a collapsible
reservoir.
19. The device of claim 18, wherein the reservoir is a pressurized
reservoir and the delivery mechanism comprises a valve configured
to control release of the bioactive agent from the pressurized
reservoir.
20. The device of claim 8, further comprising an electronic
programmable timing mechanism, wherein the delivery mechanism is
responsive to the timing mechanism to cause the bioactive agent to
be delivered from the reservoir to the skin of the host.
21. The device of claim 20, further comprising timing routines
implemented by the timing mechanism, wherein the timing routines
are configured to deliver the bioactive agent at a time, rate,
sequence and/or cycle that is synchronized with a biological rhythm
of the host.
22. The device of claim 21, wherein the bioactive agent comprises
nicotine and the timing routines are configured to deliver the
nicotine at times that are associated with nicotine cravings.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a Continuation of U.S. patent
application Ser. No. 11/162,525, filed Sep. 13, 2005, which clams
the benefit of U.S. Provisional Patent Application No. 60/609,418,
filed Sep. 13, 2004, both of which are incorporated herein by
reference in their entireties. This application Also relates to the
subject matter of PCT International 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] This invention relates, in general, to controlled drug
delivery methods and systems, and, more specifically, to systems
and methods for biosynchronous transdermal drug delivery. The
invention further relates to the field of chronobiology in that the
invention systems can be designed to modulate active agent delivery
in accordance with biological rhythms. 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. The invention also relates to overcoming active agent
tolerance, which may be experienced from continuous administration,
improve patient compliance, and in some cases reducing the amount
of drug needed per dose due to advantages of
biosynchronization.
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 the response to a drug
and/or lessen side effects of a drug. The recurring interest in
chronopharmacology demonstrates the fact that biological rhythms
are an important aspect of clinical pharmacology and should be
taken into account when evaluating drug delivery systems
(Hrushesky, W., J. Cont. Rel. 19:363 (1992), Lemmer, B., Adv. Drug
Del. Rev. 6:19 (1991), Youn, C. B. J. Cont. Rel. 98 (3) 337 (2004)
and Youn, C. B. J., Ed., "Chronopharmaceutics," John Wiley &
Sons, New York (In preparation)).
[0004] The onset and symptoms of diseases such as asthma attacks,
coronary infarction, angina pectoris, stroke and ventricular
tachycardia are circadian phase dependent. In humans, variations
during the 24 h day in pharmacokinetics (chrono-pharmacokinetics)
have been shown for cardiovascular active drugs (propranolol,
nifedipine, verapamil, enalapril, isosorbide 5-mononitrate and
digoxin), anti-asthmatics (theophylline and terbutaline),
anticancer drugs, psychotropics, analgesics, local anesthetics and
antibiotics, to mention but a few. Even more drugs have been shown
to display significant variations in their effects throughout the
day (chronopharmacodynamics and chronotoxicology) even after
chronic application or constant infusion (Ohdo, S. Drug Safety 26
(14) 999-1010 (2003)). Moreover, there is clear evidence that
dose/concentration-response relationships can be significantly
modified based on the time of day. Thus, circadian time has to be
taken into account as an important variable influencing a drug's
pharmacokinetics and its effects or side-effects (Bruguerolle, B.,
Clin. Pharmacokinet. Aug. 35 (2) 83-94 (1998)).
[0005] Studies indicate that the onset of certain diseases show
strong circadian temporal dependency. This has led to the need for
timed patterning of drug delivery as opposed to constant drug
release (Lemmer B., Ciba Found Symp. 183:235-47; discussion 247-53
(1995).
[0006] 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 systems may be implemented using: a) instantaneous release
systems; b) delayed release systems, and c) 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.
[0007] 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.
[0008] 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 en-capsulated
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.
[0009] 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 cannot 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.
[0010] Transdermal therapeutic systems (TTS) have been 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, see for example, U.S. Pat. No. 6,638,528, which is
incorporated herein by reference.
[0011] In most cases transdermal delivery systems are passive,
taking the form of a patch that is attached to the skin by an
adhesive. The TTS includes a quantity of the active substance,
along with a suitable carrier if need be, in a reservoir, matrix or
in the adhesive itself. Once applied, the active ingredient
diffuses 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.
[0012] The original performance target for controlled drug delivery
is to achieve a zero-order release rate of the drug, so that a
constant efficacious drug concentration is maintained in the blood
plasma. However, more than two decades of research in chronobiology
and chronopharmacology have demonstrated the importance of
biological rhythms to the dosing of medications as well as
determine the influence of a patient's circadian or other
biological rhythms on drug efficacy and efficiency. This research
reveals 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.
[0013] 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. Circadian physiologic processes have been found to
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, N831 (11): 20-23 (1991)).
[0014] The continued interest in chronopharmacology shows the
ever-increasing need to develop technologies to control the
temporal profile in drug delivery. Research findings suggest that
the onset and severity of many diseases are cyclic in nature, or
follow circadian patterns. Drug tolerance adds to the need for
modulation of drug dosing profiles. Additionally, skin irritation
and sensitization caused by medications may require intervals
during which no drug is administered. Therefore, this improved form
of drug delivery will be very important to people who need medicine
easily, painlessly and automatically delivered to their bodies in
timed increments (see Smolensk, M. H. & Lamberg, L. Body Clock
Guide to Better Health How to Use Your Body's Natural Clock to
Fight Illness and Achieve Maximum Health, Henry Holt & Company,
New York (2001) and Grimes, J. et al., J. Pharmacol. Exp. Ther. 285
(2): 457-463 (1998)).
[0015] 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, (U.S. Pat. No. 5,370,635), 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. 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.
[0016] A simple type of transdermal chronotherapy is a biphasic
profile, in which the drug concentration changes from a high to a
low level (or vice versa) over time. Although the system can be
physically applied or removed to alter the drug level, patient
compliance with this procedure may be difficult, particularly
during inconvenient hours. To generate a biphasic profile, the
delivery system may utilize an external regulator, as described in
Fallon et al. (U.S. Pat. No. 5,352,456, 1994) which illustrates a
device for drug administration through intact skin that provides an
initial pulse in the flux of the drug through the skin followed by
a substantially lower flux of drug through the skin. Additionally,
Fallon et al. (U.S. Pat. No. 5,820,875, 1998) later describe a
device for the administration of a drug through an area of intact
skin over a period of time in which the flux of the drug through
the skin varies temporally in a controlled manner. The device is
such that the skin flux of the drug varies in a controlled manner
over the period of administration, typically from a high flux in
the initial stage of administration to a lower flux in the later
stage of administration.
[0017] Transdermal temporally controlled drug delivery systems,
proposed by Giannos et al. (U.S. Pat. No. 6,068,853, 2000) coupled
pH oscillators with membrane diffusion in order to generate a
periodic release of a drug or active ingredient transdermally,
without external power sources and/or electronic controllers. The
intent was to address chronotherapy with a pulsatile transdermal
system. The strategy was based on the observation that a drug may
be rendered charged or uncharged relative to its pK.sub.a value.
Since only the uncharged form of a drug can permeate across
lipophilic membranes, including the skin, a periodic delivery
profile may be obtained by oscillating the pH of the drug solution
(see Giannos, S. A., "Pulsatile Delivery of Drugs and Topical
Actives," in "Novel Topical Actives and Delivery Systems:
Cosmetics, Dermatologicals and Transdermals," Edited by John. J.
Wille, Jr.: Blackwell Publishing, Oxford UK (In press)).
[0018] Recently, an orally administered drug for arthritis
treatment has suggested a chronotherapeutic approach using a delay
release system. 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.
[0019] 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,
see for example, U.S. Pat. No. 6,214,379, which is incorporated
herein by reference. As illustrated earlier, to achieve optimal
results, many patients may need to wake up during the night to take
their medication. Hence, what is needed is a non-invasive, reliable
means of delivering drugs compounds in precisely timed and measured
doses-without the inconvenience and hazard of injection, yet with
improved performance as compared to orally delivered drugs.
[0020] Addressing patient compliance (taking the proper dosages at
the prescribed times) is another 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 noncompliance. 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.
[0021] An individual's failure to comply with a dosing regimen,
e.g. failure to take one or more doses of a drug or taking too many
doses, will have an adverse impact upon the success of the regimen.
Individuals may fail to comply with their drug dosing regimen for a
number of reasons. For example, drug dosing regimens, such as every
4 hours, i.e., 8-12-4-8 involve a rigid dosing schedule that may be
incompatible with an individual's personal schedule. Such a rigid
dosing schedule when combined with normal human traits such as
forgetfulness or denial of a medical condition, as well as a busy
life, represent substantial obstacles to compliance with a drug
dosing regimen. Accordingly, such rigid dosing regimens often
result in the failure by an individual to take one or more doses at
the prescribed time. This has an adverse impact on the levels of
the therapeutic substance at the active site and consequently on
the overall efficacy of the therapeutic substance. Hence, a need
exists for systems and methods that increase patient compliance for
administration of a variety of drugs.
[0022] 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
[0023] The present invention describes methods for treating
diseases, addictions and disorders in humans. These methods involve
synchronizing and tailoring the administration of drug compounds
with the body's natural circadian rhythms, in order to counteract
symptoms when they are likely to be at their worst, and are
accomplished by using an automated and pre programmable transdermal
drug administration system. This system can also utilize a pump or
pressurized reservoir, and/or a system for removing depleted
carrier solution, or other modulated dispensing actuator, in
conjunction with micro-fabricated structures commonly referred to
as Micro-needles, or heat, or iontophoresis, sonophoresis,
(together referred to as the Mechanical Permeation Enhancers) or a
wide range of chemical permeation enhancers.
[0024] 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
[0025] FIG. 1 shows an exemplary device useful for implementing the
present invention.
[0026] FIGS. 2A-2B illustrate comparative drug release profiles
demonstrating operation of the present invention.
[0027] FIG. 3 is a schematic illustration of a drug delivery device
in accordance with the present invention. Alternatively, permeation
through the skin may be assisted by using micro-fabricated
structures commonly referred to as Micro-needles, heating devices,
iontophoretic devices, or sonophoretic devices that are attached to
this device.
[0028] FIG. 4 is a schematic illustration of an alternative drug
delivery device in accordance with the present invention.
Alternatively, permeation through the skin may be assisted by using
micro-fabricated structures commonly referred to as Micro-needles,
heating devices, iontophoretic devices, or sonophoretic devices
that are attached to this device.
[0029] FIG. 5 shows an exemplary administration profile for a
stimulant delivery system.
[0030] FIG. 6 shows an exemplary administration profile for a
nicotine delivery system.
[0031] FIG. 7 shows an exemplary administration profile for a
nitroglycerin delivery system tailored to treat variant angina
attacks.
[0032] FIG. 8 illustrates an exemplary administration profile for a
nitroglycerin delivery system tailored to treat stress-induced
angina attack.
[0033] FIG. 9. illustrates an exemplary administration profile for
an indomethacin delivery system tailored to arthritis.
[0034] FIG. 10 illustrates an exemplary administration profile for
a valdecoxib delivery system tailored to treat arthritis.
[0035] FIG. 11 illustrates an exemplary administration profile for
a tulobuterol delivery system tailored to treat asthma.
[0036] FIG. 12 illustrates an exemplary administration profile for
a clonidine delivery system tailored to treat hypertension.
[0037] FIG. 13 illustrates an exemplary administration profile for
a selegiline delivery system tailored to treat CNS degenerative
disorders (Parkinson's Disease).
[0038] FIG. 14 illustrates an exemplary administration profile for
a selegiline delivery system tailored to treat Alzheimer's Disease
and attention deficit disorder.
[0039] FIG. 15 illustrates an exemplary administration profile for
a methylphenidate delivery system tailored to treat ADD.
[0040] FIG. 16 illustrates an exemplary administration profile for
a selegiline delivery system tailored to treat depression.
[0041] FIG. 17 illustrates an exemplary administration profile for
an oxybutynin delivery system tailored to urinary incontinence.
[0042] FIG. 18 illustrates an exemplary administration profile for
a zolmitriptan delivery system tailored to treat migraine.
[0043] FIG. 19 illustrates an exemplary administration profile for
a miglitol delivery system tailored to treat diabetes.
[0044] FIG. 20 illustrates an exemplary administration profile for
a fentanyl delivery system tailored to treat pain.
[0045] FIGS. 21A-C illustrates an exemplary administration profile
for 5-fluorouracil, doxorubicin and cisplatin delivery system
tailored to treat cancer.
[0046] FIG. 22 illustrates an exemplary administration profile for
a zidovudine delivery system tailored to treat AIDS.
[0047] FIG. 23 illustrates an exemplary administration profile for
a gabapentin delivery system tailored to epilepsy.
[0048] FIG. 24 illustrates an exemplary administration profile for
a triprolidine delivery system tailored to treat colds and flu.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0049] Biological rhythms are periodic fluctuations in biological
characteristics over time, which also include circadian as well as
seasonal variations. The reality of circadian rhythms in animals
including humans is well known (Halberg et al. J. Exp. Ther. Oncol.
3 (5) 223-260 (2003), Redfern et al. Chronobiology International 11
(4) 253-265 (1994)).
[0050] Circadian (approximately 24-hour) rhythms include the
production of biological molecules such as endorphins, gonadotropin
releasing hormone (GnRH), cortisol and adrenaline. These regulate
the body's temperature and heart rate, changes in characteristics
of blood, such as stickiness, and behaviors such as wakefulness,
sleep and periods of activity.
[0051] Some of the rhythms that affect our bodies include:
[0052] ultradian, which are cycles shorter than a day (for example,
the milliseconds it takes for a neuron to fire, or a 90-minute
sleep cycle)
[0053] circadian, which last about 24 hours (such as sleeping and
waking patterns)
[0054] infradian, referring to cycles longer than 24 hours (for
example monthly menstruation)
[0055] seasonal, such as seasonal affective disorder (SAD), which
causes depression in susceptible people during the short days of
winter.
[0056] 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 night-time nicotine administration,
for example), (ii) ever increasing tolerance (in the case of
nitroglycerin and other pharmaceuticals for example), (iii) more
expensive therapies, due to the fact that more of a compound is
needed because the daily body rhythm is ignored and time based
dosing is not implemented.
[0057] In addition, many addictions follow a daily pattern
consistent with one's circadian rhythms. For example, according to
studies performed, immediately upon waking, smokers 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.
[0058] 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 of
a 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 present invention also
relates to the administration of different, distinct, drugs and
dosages at different times of the day. 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. 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 Chronopharmacology
(Reinberg, A. E., Concepts of Circadian Chronopharmacology, In
"Temporal Control of Drug Delivery" edited by Hrushesky, W. J. M.,
Langer, R. S. and Theeuwes, F. Annal NY Academy of Science, New
York. Volume 618 102-115 (1991), Lemmer, B. Pharmacol Res. 33(2)
107-15 (1996)).
[0059] To illustrate the importance of Chronopharmacology consider
the following facts:
[0060] Asthma attacks are 100 times more likely between 4:00 and
6:00 AM.
[0061] Heart attacks and strokes are most likely to occur around
6:00 AM.
[0062] Variant Angina attacks occur 30 times more often in the
middle of the night between 2:00 AM and 4:00 AM.
[0063] Smokers experience the highest cravings immediately upon
waking up.
[0064] Lethargy and difficulty getting out of bed is highest
immediately upon waking up early in the morning.
[0065] Cold and flu symptoms peak during nighttime and early
morning hours, when cold medications are wearing off.
[0066] 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 reusable 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, or is cylindrical in
shape, that the user can simply pop-in to place on the watch-like
platform. This reservoir 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.
[0067] 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, a 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.
[0068] An exemplary implementation (shown in FIG. 3) comprises a
collapsible drug reservoir (301), an expandable waste reservoir
(305), a micro-pump (307), electronics for automation, a display
(309), and a highly permeable membrane (303). Further, a heating
element or a gas or air blowing apparatus may be used to assist
evaporation of liquids into the waste reservoir or the environment.
An exemplary system is described in a United Kingdom patent
entitled Transdermal Drug Delivery and Method filed on Sep. 13,
2004, Application Number PCT/IB2004/002947, which is incorporated
herein by reference. The drug reservoir (301) will contain between
about 0.4 ml and 4 ml of drug formulation. A tiny, miniaturized
pump (307) is activated at pre-programmed times and releases a
predefined amount of drug formulation into the drug chamber, where
the formulation comes into contact with diffusion matrix. This
diffusional matrix is in intimate contact with a 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, hydrogel or polymer substance, which allows for rapid
transport kinetics. In operation, when the administration of the
drug needs to be discontinued, the remaining drug formulation is
either removed or evaporated from the membrane area via the waste
receptacle (305) containing a desiccant, containing a hydrophilic
substance (hydrogel) or the device is taken off. Further, to
achieve chronopharmacological drug delivery for drugs that may not
passively pass through the skin adequately, the above described
device may use permeation enhancers whereby permeation through the
skin is assisted, such as mechanical permeation enhancers that
include micro-fabricated structures commonly referred to as
Micro-needles, or heat, or iontophoresis, sonophoresis, (together
referred to as the Mechanical Permeation Enhancers) or a wide range
of chemical permeation enhancers.
[0069] In an implementation shown in FIG. 4, a pressurized drug
reservoir (401) 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. The
implementation shown in FIG. 4, further includes display (409),
housing (402), chamber (407) and expandable waste reservoir (405).
Further, to achieve chronopharmacological drug delivery for drugs
that may not passively pass through the skin adequately, the above
described device may use permeation enhancers whereby permeation
through the skin is assisted, such as mechanical permeation
enhancers that include micro-fabricated structures commonly
referred to as Micro-needles, or heat, or iontophoresis,
sonophoresis, (together referred to as the Mechanical Permeation
Enhancers) or a wide range of chemical permeation enhancers.
[0070] 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, 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.
[0071] For example, when administering a an active compound
pursuant to a chronopharmacological dosage profile as set forth
herein, using a programmed, transdermal, pulsatile drug delivery
device, a pharmaceutically acceptable composition of an active
material may be combined with either mechanical skin penetration
enhancers including, but not limited to, micro-fabricated
structures commonly referred to as Micro-needles, heat,
iontophoresis, or sonophoresis, or a wide range of chemical
permeation enhancers such as oleic acid, ethanol, 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.
[0072] 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.
[0073] Device-skin interface coupling media and/or control
membranes include, but are not limited to, ethylcellulose,
hydroxypropyl cellulose, poly (ethylene co-vinyl acetate),
polyvinyl pyrrolidone, poly (ethylene oxide), poly (ethylene vinyl
alcohol) and the like, to provide the composition in gel or
hydrogel form. which may be dissolved in solvents such as water,
methylene chloride or ethanol evaporated to the desired viscosity,
and then applied to backing material to provide a patch. The
control membranes can be any of the conventional materials such as
microporous polyethylene, polyethylene co-vinyl acetate (EVA
copolymer), polyurethane and the like.
[0074] Chronopharmacokinetics is defined as the predictable changes
observed in the plasma levels of drugs and in the parameters used
to characterize the pharmacokinetics of a drug. Studies on animals
and humans indicate that the C.sub.max, T.sub.max, AUC and
half-life often vary as a function of the hour of administration of
the drug. Table 1 presents a list of medications for which temporal
changes in pharmacokinetics have been documented.
TABLE-US-00001 TABLE 1 Drugs with documented time-dependent changes
in pharmacokinetics* CLASSES OF DRUGS SPECIFIC MEDICATIONS
Analgesic and NSAID aspirin, sodium salicylate, acetaminophen,
ketoprofene, phenyl butazone, indomethacin CNS Drugs hexabarbitol,
carbamazepine, clorazepate, diazepam, lorazepam, midazolam,
triazolam, amitryptiline, sodium valproate Cardiovascular Drugs
atenolol, metoprolol, lidocaine, dipyridamole, digoxine
Anti-asthmatic Drugs aminophylline, theophyline, terbutaline
Antibiotic ampicillin, erythromicin, griseofulvin, cefoxizime
Anti-cancer Agents cisplatin *Labrecque, G. et al.
Chronopharmacokinetics. Pharmaceutical News, 4 (2) 17-21
(1997).
[0075] We have carefully identified specific drugs and diseases
because they have the following attributes: (i) Chronopharmacology
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 external modulation or pre-treatment such as sonophoresis,
iontophoresis, electroporesis, microneedles, etc. or other
permeation enhancement. Example substances include caffeine and
ephedrine, and a variety of over-the-counter (OTC) and prescription
stimulants (for treating fatigue, sleep disorders, attention
deficit disorders and a variety of other conditions) in addition to
herbal supplements, 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). Exemplary chronopharmacological systems that can make use
of the present invention are summarized in Table 2.
TABLE-US-00002 TABLE 2 Examples of disease states for ChronoDose
.TM. application THERAPEUTIC CHRONO-PHARMACOLOGY AREA
DISEASES/CONDITION RATIONALE Cancer Various forms Chemotherapy may
be more effective and less toxic if drugs are administered at
carefully selected times that take advantage of tumor cell cycle
times while less toxic to normal tissue. Cardiovascular Angina
Angina (variant) attacks occur 30 times more often between 2:00
a.m. and 4:00 a.m. .fwdarw. Larger doses of Nitroglycerin early in
the morning Heart Attacks and Heart attacks and strokes are Strokes
most likely between 6:00 a.m. and Noon. .fwdarw. Cardiovascular
active drugs before waking. Hypercholesterolemia A circadian rhythm
occurs during hepatic cholesterol synthesis. Cholesterol synthesis
is generally higher during the night than during daylight. Studies
with HMG CoA reductase inhibitors have suggested that evening
dosing is more effective than morning dosing. .fwdarw. Simvastatin
in evening and during the night. Hypertension Automatically and
precisely release clonidine or other hypertension drugs in peak
amounts to offset the peak symptoms associated with the dangerous
morning symptoms. .fwdarw. Clinidine, Captopril or other medication
in the morning. CNS Degenerative Parkinson's Disease Automated
dosing for patient Disorders compliance .fwdarw. Selegiline,
Benztropine, Apomorphine Alzheimer's Disease Automated dosing for
patient compliance .fwdarw. Rivastigmine, Memantine Diabetes
Diabetes (Type II) Automated dosing for elderly patient compliance.
Oral medication is poorly absorbed. .fwdarw. Miglitol before meals.
Glibenclamide Epilepsy Epileptic seizure Epileptic seizures are
most likely between 6:00 a.m. and 7:00 a.m. .fwdarw. Gabapentan or
other Epileptic drugs before waking up Pulmonary 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. .fwdarw.
Albuterol or Tulobuterol in early morning. Pain Acute Pain
Neurological pain is worst between 3:00 a.m. and 8:00 a.m .fwdarw.
Fentanyl in the middle of night. Migraine Headaches Migraine
headaches usually and/or Cluster begin and occur between 8:00 a.m.
headaches and 10:00 a.m. Cluster headaches start earlier, around
4:00 a.m. .fwdarw. Zolmitriptan or dihydroergotamine in the middle
of night. Mental Health Depression Selegiline at night can create
sleeping disorders (nightmares), but depression symptoms are high
immediately upon waking up .fwdarw. Selegiline before waking up
Inflammation Rheumatoid Arthritis, Worst upon awakening.
Osteoarthritis Cortisol and anti-inflammatory hormones are very low
at night .fwdarw. Indomethacin or Valdecoxib before waking up.
Women's Health Tocolytic Therapy Programmed-in-time administration
of tocolytic medication relative to the circadian rhythm in uterine
contractility to avert preterm labor and birth. .fwdarw.
Nifedipine, Terbutaline or Ritodrine synchronized with uterine
contractions. OTC Smoking Cessation Nicotine at night creates
sleeping disorders (nightmares), but cravings are the highest
immediately upon waking .fwdarw. Nicotine before waking up.
Circadian rhythm Adrenaline is lowest in the sleep disorders
morning, making early (CRSD) and Morning morning waking
uncomfortable Lethargy and difficult for many people. .fwdarw. OTC
Stimulant before waking Insomnia Some sleep medications induce
drowsiness but do not provide for continuous sleep in sensitive
patients. .fwdarw. Pulsatile and low dose delivery of sleep
medication will provide continuous sleep. Peptic Ulcer Disease
Gastric acid secretion increases in late afternoon and early night.
Also, partial nocturnal resistance to H.sub.2-blockade has been
noted. .fwdarw. H.sub.2-blockers (ranitidine, cimetidine,
famotidine, roxatidine, nizatidine) during the night. Drugs other
than H.sub.2-blockers or antibiotics during the night. Jet lag
Melatonin can be used to reset Shift work circadian rhythms. Colds
and Flu Heaviest symptoms overnight and in the morning. .fwdarw.
Cold/Flu medicine during the night. Triprolidine, Doxylamine
Supplements/weight Vitamins and Supplements are loss best
administered in low doses over the course of the day to be most
effective.
[0076] Using this system the present invention can preprogram 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.
[0077] The present invention represents the first true non-invasive
chronopharmacological 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).
[0078] 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.
[0079] 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 chronopharmacological information
indicates that a drug's effects can be 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, i.e. doses are required at inopportune times, i.e.
at night while sleeping.
[0080] The present invention may be used to treat, cure, prevent,
control or alleviate a wide range of conditions and symptoms. For
example, the drug delivery regimen of the present invention is
administered to treat a condition selected from the group
consisting of vitamin and/or mineral deficiency, Cancer, Addiction,
Arthritis, Parkinson's Disease, Attention Deficit Disorder,
Cardiovascular Disorder, Cold/Flu Symptoms, Pain, Childhood
Bronchial Asthma, Peptic Ulcer, Post-operative Recuperation, and so
forth as shown below.
Applications--ArisePatch.TM.
[0081] 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.
Chronotherapeutic Rationale:
[0082] 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
Example
Nicotine
[0083] 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. Additionally, research has
shown that nicotine transdermal delivery is influenced by
chronopharmacokinetics. Nicotine patch design should compensate by
decreasing the dose at night as well as increasing the dose in the
morning and after meals (Gries et al., 1998).
Chronotherapeutic Rationale:
[0084] 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.
Example
[0085] 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 bupropion) 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.
[0086] 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 preprogrammed 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.
[0087] 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--Angina
Example
Nitroglycerin
[0088] 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 nitroglycerin steadily over time. Current patches cannot
tailor the release of nitroglycerin to optimize treatment by
releasing more nitroglycerine precisely during the critical angina
phase to offset these peak symptoms.
[0089] 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 nitroglycerin 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.
Chronotherapeutic Rationale:
[0090] The method in accordance with the present invention utilizes
an automated transdermal system in order to transdermally
administer more nitroglycerin during the critical angina phase to
ensure adequate offset of these symptoms and less nitroglycerin
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.
[0091] The pre-programmable automated transdermal system is worn
around the wrist-like a watch (or the forearm arm or ankle) and
releases nitroglycerin 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.
Example
[0092] The nitroglycerin system in accordance with the present
invention has three primary advantages over current nitroglycerin
patches. First, the system automatically and precisely releases
nitroglycerin in peak amounts to offset the peak symptoms of
morning attacks occurring during the critical angina phase. Current
nitroglycerin 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.
[0093] The 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.
[0094] This system can be either an `wear each night and remove in
the morning` system, whereby it only releases nitroglycerin
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 nitroglycerin in tailored
amounts and at tailored times as synchronized with the body's
circadian rhythm (and conveniently taken off while showering or
swimming).
[0095] The system is an innovative new drug therapy for angina.
With the advantage of optimized and automated time and dose
administration synchronized with a person's 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, the present invention is superior to current steady
release nitroglycerin patches. Our system's increased advantages
are extremely relevant for those patients with moderate to severe
angina.
[0096] FIG. 7 shows an exemplary administration profile for a
nitroglycerin 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 nitroglycerin. 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.
[0097] FIG. 8 illustrates an exemplary administration profile for a
nitroglycerin 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: Arthritis
Examples
Indomethacin, Valdecoxib
[0098] An automated, and programmed, pulsatile drug delivery
regimen is desired to in order to increase drug concentrations
automatically in the morning, just before a person awakes and the
symptoms of arthritis are the worst. Later, towards mid-day, the
drug concentration is also increased. Then in the evening, the drug
dose is increased prior to bedtime.
Chronotherapeutic Rationale:
[0099] The most common forms, osteoarthritis and rheumatoid
arthritis, both show distinctive circadian patterns of pain. While
many people feel stiff for an hour or so after first getting up in
the morning, people with osteoarthritis typically hurt most and
have the most difficulty moving in the afternoon and evening. Those
with rheumatoid arthritis almost always feel much worst in the
morning. By dosing at night, early morning and mid-day, the
benefits of non-steroidal anti-inflammatory drugs (NSAIDs) and
cyclocoygenase-2 inhibitors (COX-2) can be maximized and side
effects reduced.
[0100] Examples of medications for arthritis include:
[0101] Indomethacin (Indocin.RTM.)
[0102] Diclofinac (Voltarin.RTM. and Cataflam.RTM.)
[0103] Flurbiprofen (ANSAID.RTM.)
[0104] Celecoxib (Celebrex.RTM.)
[0105] Valdecoxib (Bextra.RTM.)
[0106] Acetomenophen (Tylenol.RTM.)
[0107] Oxaceprol
Example 1
Indomethacin (NSAID)
[0108] The primary adverse side effect of Indomethacin is
gastrointestinal upset and bleeding. Therefore a transdermal
arthritis patch would be a beneficial dosage form as opposed to
oral tablets and capsules. Additionally, studies using indomethacin
showed better efficacy and patient compliance when dosed at night
than when dosed at 8:00 am.
[0109] Theoretical unenhanced transdermal flux for indomethacin
(Berner-Cooper predictive model) is 0.93 ug/cm.sup.2/hr.
[0110] Thus, dosing could be optimized using the ChronoDose system.
For example, pulsatile delivery should have blood plasma
concentrations (BPC) as set forth below within the following ranges
at the following times:
[0111] Peak 1 (Highest)
[0112] 5:00 am-9:00 am: BPC should be in the highest therapeutic
range of between 0.5-2.0 mcg/ml.
[0113] Peak 2 (Medium)
[0114] 12:00 pm to 8:00 pm: BPC should be in the medium therapeutic
range of between 0.25-1.5 mcg/ml.
[0115] Peak 3 (Highest)
[0116] 8:00 pm-11:00 pm: BPC should be in the highest therapeutic
range of between 0.5 to 2.0 mcg/ml.
[0117] The time/dose chart should appear as shown in FIG. 9.
Example 2
Valdecoxib (COX-2 Inhibitor)
[0118] Like indomethacin, the primary adverse side effect of COX-2
inhibitors is gastrointestinal upset and bleeding. Therefore a
transdermal arthritis patch would be a beneficial dosage form as
opposed to oral tablets and capsules. Lower blood plasma
concentrations of COX-2 inhibors delivered transdermally has been
suggested as therapeutically equivalent to higher BPC obtained by
oral dosing.
[0119] Thus, dosing could be optimized using the ChronoDose system.
For example, pulsatile delivery should have blood plasma
concentrations (BPC) as set forth below within the following ranges
at the following times:
[0120] Peak 1 (Highest)
[0121] 5:00 am-9:00 am: BPC should be in the highest therapeutic
range of between 50-175 ng/ml.
[0122] Peak 2 (Medium)
[0123] 12:00 pm to 8:00 pm: BPC should be in the medium therapeutic
range of between 21-125 ng/ml.
[0124] Peak 3 (Highest)
[0125] 8:00 pm-11:00 pm: BPC should be in the highest therapeutic
range of between 50 to 175 ng/ml.
[0126] The time/dose chart should appear as shown in FIG. 10.
Applications--Asthma
Example
Tulobuterol
[0127] The automated transdermal asthma system automatically
administers a morning dose of albuterol, tulobuterol, 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."
Chronotherapeutic Rationale:
[0128] 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.
[0129] 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.
[0130] 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
tulobuterol 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.
[0131] 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.
[0132] 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 tulobuterol 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.
[0133] The time/dose chart should appear as shown in FIG. 11.
Applications--Hypertension
Example
Clonidine
[0134] Current clonidine 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.
Chronotherapeutic Rationale:
[0135] 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 clonidine 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. The
clonidine automated transdermal system utilizes clonidine, (or
another hypertension drug) an effective drug that combats high
blood pressure.
Example
[0136] The clonidine automated transdermal drug delivery system has
an automated morning release of Clonidine to combat the peak
symptom of morning heart attacks. Blood pressure differs at
different times of the day. Blood pressure surges upon waking, and
is lower by 20 to 30 percent while sleeping. Our preprogrammed
automatic transdermal system utilizes its core competitive
advantage by releasing clonidine in a tailored fashion to counter
high blood pressure when symptoms are highest, while releasing less
clonidine when symptoms are less severe.
[0137] The time/dose chart should appear as shown in FIG. 12.
Applications--CNS Degenerative Disorders
Example
Selegiline
Parkinson's Disease
[0138] Sleep disturbances in Parkinson's disease patients reveal
alterations of circadian rhythms. Autonomic dysfunction, described
in Parkinson's disease, reveals numerous alterations in circadian
regulations including loss of circadian rhythm of blood pressure,
increased diurnal blood pressure variability, and postprandial
hypotension. Many biologic indices such as cortisol,
catecholamines, and melatonin are also altered. Circadian rhythms
in dopaminergic systems as well as possible daily fluctuations in
kinetics of drug treatments are likely involved in such
variations.
Chronotherapeutic Rationale:
[0139] 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 riot circulating through their system.
[0140] 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. The system in accordance with the present invention
is applied before bed. It does not release the drug until one or
two hours before morning, so symptom of morning depression would be
corrected by our system without subjecting the patient to sleep
disturbances.
[0141] The time/dose chart should appear as shown in FIG. 13.
Alzheimer's Disease
[0142] Selegiline is an effective MAO inhibitor for the treatment
of depression, Alzheimer's and Attention Deficit Disorder.
Currently oral selegiline produces many undesirable side effects. A
transdermal form of selegiline, EMSAM.TM., is currently being
developed. However, it also produces sleep disturbances as well. It
is believed that the system in accordance with the present
invention would be superior to conventional selegiline product
delivery systems.
Chronotherapeutic Rationale:
[0143] 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.
[0144] 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. The system in accordance with the present invention
is applied before bed. It does not release the drug until one or
two hours before morning, so symptom of morning depression would be
corrected by our system without subjecting the patient to sleep
disturbances.
[0145] The time/dose chart should appear as shown in FIG. 14.
Applications--Attention Deficit Disorder
Example
Methylphenidate
[0146] Ritalin is indicated as an integral part of a total
treatment program which typically includes other remedial measures
(psychological, educational, social) for a stabilizing effect in
children with a behavioral syndrome characterized by the following
group of developmentally inappropriate symptoms: moderate-to-severe
distractibility, short attention span, hyperactivity, emotional
liability, and impulsivity.
[0147] Methylphenidate is usually administered in divided doses 2
or 3 times daily, preferably 30 to 45 minutes before meals.
Patients who are unable to sleep if medication is taken late in the
day should take the last dose before 6 p.m. Since the suggested
first dose is early in the morning, it would be beneficial to
automatically control the dosage.
[0148] Thus, dosing could be optimized using the ChronoDose system.
For example, pulsatile delivery should have blood plasma
concentrations (BPC) as set forth below within the following ranges
at the following times:
[0149] Peak 1 (Highest)
[0150] 6:00 am-8:00 am: BPC should be in the highest therapeutic
range of between 8-25 ng/ml.
[0151] Peak 2 (Highest)
[0152] 10:00 am to 12:00 pm: BPC should be in the highest
therapeutic range of between 8-25 ng/ml.
[0153] Peak 3 (Highest)
[0154] 3:00 pm-5:00 pm: BPC should be in the highest therapeutic
range of between 8 to 25 ng/ml.
[0155] The time/dose chart should appear as shown in FIG. 15.
Applications--Depression
Example
Selegiline
[0156] Selegiline is an effective MAO inhibitor for the treatment
of depression, Alzheimer's and Attention Deficit Disorder.
Currently oral selegiline produces many undesirable side effects. A
transdermal form of selegiline, EMSAM.TM., is currently being
developed. However, it also produces sleep disturbances as well. It
is believed that the system in accordance with the present
invention would be superior to conventional selegiline product
delivery systems.
Chronotherapeutic Rationale:
[0157] 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.
[0158] 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. The system in accordance with the present invention
is applied before bed. It does not release the drug until one or
two hours before morning, so symptom of morning depression would be
corrected by our system without subjecting the patient to sleep
disturbances.
[0159] The time/dose chart should appear as shown in FIG. 16.
Applications: Urinary Incontinence
Example
Oxtybutynin
[0160] An automated, and programmed, pulsatile drug delivery
regimen is desired to in order to increase drug concentrations
automatically at night while asleep, and to decrease concentrations
during the daytime work hours, and again to slightly increase drug
concentrations after work and prior to bed.
Chronotherapeutic Rationale:
[0161] The primary adverse side effect of Oxybutynin is daytime
sleepiness, daytime attention and cognitive deficits, drowsiness,
dizzyness, blurred vision, (must use caution when driving,
operating machinery, or performing other hazardous activities).
Therefore, it seems that a dose in the lower end of the therapeutic
range should be administered during the daytime, with a slightly
larger dose administered after working hours, and with an even
higher dose administered during the sleeping hours.
[0162] This would reduce the potentially serious adverse side
effect of daytime drowsiness and daytime cognitive impairment. This
dosing regimen would also give the user a higher dose at night,
when one sleeps. At this time, increased drowsiness would be
advantageous as well as providing a period of undisturbed sleep due
to the inhibition of urge incontinence.
[0163] Medications for incontinence include:
Oxybutynin (Ditropan.RTM. and Oxytrol.RTM.)
Tolterodine (Detrol.RTM.)
Duloxetine (Yentreve.RTM.)
Example 1
Oxybutynin
[0164] The mean maximum blood plasma concentration following oral
dosing with 5 mg oxybutynin or transdermally with 39 mg is 3 ng/mL.
Blood plasma concentration between 1 and 3 ng/ml
[0165] Theoretical unenhanced transdermal flux for oxybutynin
(Berner-Cooper predictive model) is 10.98 ug/cm.sup.2/hr.
NOTE: Dose of current Oxytrol patches are 3.9 mg per day.
[0166] Thus, dosing could be optimized using the ChronoDose system.
For example, pulsatile delivery should have blood plasma
concentrations (BPC) as set forth below within the following ranges
at the following times:
[0167] Peak 1 (Highest)
[0168] 11:00 pm-7:00 am: BPC should be in the highest therapeutic
range of between 2.5-4.5 ng/ml.
[0169] Peak 2 (Low)
[0170] 7:00 am to 5:00 pm: BPC should be in the lowest therapeutic
range of between 0.75-1.5 ng/ml.
[0171] Peak 3 (Medium)
[0172] 5:00 pm-11:00 pm: BPC should be in the medium therapeutic
range of between 1.5 to 2.5 ng/ml.
[0173] The time/dose chart should appear as shown in FIG. 17.
Applications: Headache and Migraine
Example
Zolmitriptan
[0174] An automated, and programmed, pulsatile drug delivery
regimen is desired to in order to increase drug concentrations
automatically in the evening to provide needed medication, in the
very early morning (0200-0400) while asleep, and again later on
(0800-1000) upon waking. Then, during the daytime work hours,
decrease concentrations to allow for normal activities.
Chronotherapeutic Rationale:
[0175] Migraine, cluster and tension-type headaches may produce a
headache that awakens an individual in the early morning hours
(usually between 2 and 4 AM), or is present upon awakening. Those
individuals with chronic tension-type headache are most likely to
be awakened in the early morning hours due to headache. This
headache also tends to be at its worst severity at that time of
day. A variety of causes may account for this early-morning pattern
to the headaches.
[0176] Additionally, primary headaches associated with late
sleeping or weekends are caused by caffeine withdrawal. Sleeping in
late delays morning caffeine intake, which often leads to
withdrawal and migraine. Many people reduce their caffeine intake
on weekends, which readily explains the weekend increase in
migraine attacks. Fewer migraines occur on Mondays and Tuesdays
than on other days of the week.
[0177] Medications for headache and migraine include:
[0178] Abortive Medications
[0179] Analgesics with caffeine such as Excedrin.RTM. Migraine
(acetaminophen, aspirin and caffeine).
[0180] Analgesics with caffeine and barbiturates such as
Fiorinal.RTM. (butalbital, aspirin and caffeine) and Fioricet.RTM.
(butalbital, acetaminophen and caffeine).
[0181] Non steroidal antiinflammatory drugs (NSAIDs) such as
Advil.RTM. (ibuprofen), and Aleve.RTM. (naproxen sodium).
[0182] Ergotamines such as Cafergot.RTM. (caffeine and ergotamine
tartrate) and Migranal.RTM. (dihydroergotamine).
[0183] Triptans such as Zomig.RTM. (zolmitriptan), Maxalt.RTM.
(rizatriptan), Imitrex.RTM. (sumatriptan), Frova.RTM.
(frovatriptan), Axert.RTM. (almotriptan) and Amerge.RTM.
(naratriptan).
[0184] Excedrin Migraine is a registered trademark of Bristol-Myers
Squibb Company
[0185] Fiorinal and Fioricet are registered trademarks of Novartis
Pharmaceuticals Corporation
[0186] Advil is a registered trademark of Whitehall-Robbins
Healthcare
[0187] Aleve is a registered trademark of Bayer Corporation
[0188] Cafergot and Migranal are registered trademarks of Novartis
Pharmaceuticals Corporation
[0189] Zomig is a registered trademark of AstraZeneca
[0190] Maxalt is a registered trademark of Merck & Co.,
Inc.
[0191] Imitrex is a registered trademark of GlaxoSmithKline
[0192] Frova is a registered trademark of Elan Pharmaceuticals/UCB
Pharma, Inc.
[0193] Axert is a registered trademark of Pharmacia
[0194] Amerge is a registered trademark of GlaxoSmithKline
Preventive Medications
[0195] Beta blockers such as Inderal.RTM. (propranolol)*,
Blocadren.RTM. (timolol maleate)*, and metoprolol.
[0196] Calcium-channel blockers such as Cardizem.RTM. (diltiazem)
and Procardia.RTM. (nifedipine).
[0197] Antidepressants such as Prozac.RTM. (fluoxetine), Paxil.RTM.
(paroxetine) and Zoloft.RTM. (sertraline).
[0198] Anticonvulsants such as Depakote.RTM. (valproic acid or
divalproex sodium).*
[0199] NSAIDs such as Orudis.RTM. (ketoprofen) and Aleve.RTM.
(naproxen sodium).
[0200] Inderal is a registered trademark of AstraZeneca
[0201] Blocadren is a registered trademark of Merck & Co,
Inc.
[0202] Cardizem is a registered trademark of Aventis
Pharmaceuticals
[0203] Procardia is a registered trademark of Pfizer Inc.
[0204] Prozac is a registered trademark of Eli Lilly and
Company
[0205] Paxil is a registered trademark of GlaxoSmithKline
[0206] Zoloft is a registered trademark of Pfizer Inc.
[0207] Depakote is a registered trademark of Abbott
Laboratories
[0208] Orudis is a registered trademark of Aventis
Pharmaceuticals
[0209] Aleve is a registered trademark of Bayer Corporation
Example
Zolmitriptan
[0210] Blood plasma concentration between 1.0 and 5.0 ng/ml.
Theoretical unenhanced transdermal flux for zolmitriptan
(Berner-Cooper predictive model) is 6.02 ug/cm.sup.2/hr. Thus,
dosing could be optimized using the ChronoDose system. For example,
pulsatile delivery should have blood plasma concentrations (BPC) as
set forth below within the following ranges at the following
times:
[0211] Peak 1 (Highest)
[0212] 2:00 am-4:00 am: BPC should be in the highest therapeutic
range of between 3.5-4.0 ng/ml.
[0213] Peak 2 (Highest)
[0214] 8:00 am-10:00 am: BPC should be in the highest therapeutic
range of between 3.5-4.0 ng/ml.
[0215] Trough (Lowest)
[0216] 12:00 pm to 12:00 am: BPC should be in the lowest
therapeutic range of between 1.0-3.0 ng/ml.
[0217] The time/dose chart should appear as shown in FIG. 18.
Applications: Diabetes
Example
Miglitol
[0218] An automated, and programmed, pulsatile drug delivery
regimen is desired to in order to increase drug concentrations
automatically in the morning (0800), midday (1200) and evening
(1800) which coincide with mealtimes.
[0219] Miglitol is indicated as an adjunct to diet to improve
glycemic control in patients with non-insulin-dependent diabetes
mellitus (NIDDM) whose hyperglycemia cannot be managed with diet
alone.
[0220] Theoretical unenhanced transdermal flux for miglitol
(Berner-Cooper predictive model) is 49.24 ug/cm.sup.2/hr.
[0221] Thus, dosing could be optimized using the ChronoDose system.
For example, pulsatile delivery should have blood plasma
concentrations (BPC) as set forth below within the following ranges
at the following times:
[0222] Peak 1 (Highest)
[0223] 8:00 am-10:00 am: BPC should be in the highest therapeutic
range.
[0224] Peak 2 (Highest)
[0225] 12:00 am-2:00 pm: BPC should be in the highest therapeutic
range.
[0226] Trough (Highest)
[0227] 6:00 pm to 8:00 am: BPC should be in the lowest therapeutic
range.
[0228] The time/dose chart should appear as shown in FIG. 19.
Applications--Pain Management
Example
Fentanyl
[0229] Many diseases and pain-causing situations (post-surgery,
post trauma) have predictable pain patterns. For example, cortisol
is virtually absent in the body overnight, and this is what fights
inflammation. Thus, any pain resulting from inflammation
(rheumatoid arthritis, post-surgical pain, post-traumatic pain,
back pain, neurological pain) is most common in the early morning
hours between 3:00 a.m. and 8:00 a.m. Migraine pain is worst around
6:00 a.m. Ankylosing spondylitis pain surges between 6:00 a.m. and
9:00 a.m. Osteoarthritis pain surges in mid-afternoon.
[0230] Pain varies tremendously from one patient to the next, and
there are also some studies suggesting that the intensity of pain
varies according to time of day. In human studies, pain induced
experimentally was reported to be maximal in the morning, or in the
afternoon or at night. A circadian pattern of pain has been seen in
patients suffering from pain produced by different diseases. For
instance, highest toothache intensity occurred in the morning,
while biliary colic, migraine, and intractable pain were highest at
night. Patients with rheumatoid arthritis reported peak pain early
in the morning, while those with osteoarthritis of the knee
indicated that the maximal pain occurred at the end of the day. The
effectiveness of opioids appears also to vary according to time of
day, but large differences in the time of peak and low effects were
found. Peak pain intensity and narcotic demands occur early in the
morning, or it can be at the end of the day. Pain is a complex
phenomenon and specific to each clinical situation.
[0231] An automated, and programmed, pulsatile transdermal drug
delivery regimen is needed to substantially increase blood plasma
concentrations of Fentanyl or other pain medications, automatically
between 3:00 am and 8:00 am, while people sleep, where pain results
from inflammation, because cortisone, a key inflammation fighter,
is lowest in the body at that time. Additionally, an automated, and
programmed, pulsatile transdermal drug delivery regimen is needed
to substantially increase blood plasma concentrations of Fentanyl
or other pain medications automatically between 6:00 am and 9:00 am
for Ankylosing spondylitis pain, and in mid-afternoon for
Osteoarthritis pain.
[0232] Other pain medication includes: codeine, dihydrocodeine,
hydrocodone or hydromorphone, Sufentanil, Nalbuphine,
Buprenorphine, Hydromorphone and any type of opiate derivative.
[0233] These are exemplary choices for transdermal pain management
since they are effective, there is considerable hepatic first pass
effect and a short half life, and they are skin permeable.
[0234] For example, for pain that increases with inflammation, as
in the situations noted above, our regimen would suggest automated
and programmed, transdermal pulsatile delivery of fentanyl to reach
blood plasma concentrations (BPC) as set forth below within the
following ranges at the following times:
[0235] Peak 1 (Highest)
[0236] 3:00 am-8:00 am: BPC of fentanyl should be in the highest
therapeutic range of between 2-8 ng/ml.
[0237] Peak 2 (Lowest)
[0238] 8:00 am-5:00 pm: BPC should be in a moderate therapeutic
range of between 1-3 ng/m.
[0239] Peak 3 (Middle)
[0240] 5:00 pm to 3:00 am: BPC should be in the lowest therapeutic
range of between 2-5 g/ml.
[0241] The time/dose chart should appear as shown in FIG. 20.
Applications--Cancer
Example
[0242] Cancer chronotherapy is attracting attention as a novel and
logical therapy in which anti-cancer drugs are administered with
optimal timing according to circadian rhythms of anti-cancer action
and those of adverse effects on normal cells. Advances in
chronobiology have identified the suprachiasmatic nucleus (SCN) as
the center of biological rhythms and the area in which clock genes
such as PERT, PER2, PER3, CLOCK, BMAL1, TIM, CRY1, CRY2, tau act to
generate and coordinate biological rhythms. These findings have led
to the development of chronotherapy. Clinically, patients with
advanced gastrointestinal cancer have been treated by
chrono-modulated chemotherapy with good response. For colorectal
cancer patients with un resectable liver metastases, chronotherapy
with g-OHP+5-FU+FA (folinic acid) has been reported to allow
complete surgical resection of liver metastases, resulting in
39-50% 5-year survival.
[0243] The circadian timing of surgery, anticancer drugs, radiation
therapy, and biologic agents can result in improved toxicity
profiles, tumor control, and host survival. Optimally timed cancer
chemotherapy with doxorubicin or pirarubicin (06:00 h) and
cisplatin (18:00 h) enhanced the control of advanced ovarian cancer
while minimizing side effects, and increased the response rate in
metastatic endometrial cancer. Therapy of metastatic bladder cancer
with doxorubicin-cisplatin was made more tolerable by this same
circadian approach resulting in a 57% objective response rate. This
optimally timed therapy is also effective in the adjuvant setting,
decreasing the expected frequency of metastasis from locally
advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR)
continuous infusion (70% of the daily dose given between 15:00 h
and 21:00 h) has been shown effective for metastatic renal cell
carcinoma resulting in 29% objective response and stable disease of
more than 1 yr duration in the majority of patients. Toxicity is
reduced markedly when FUDR infusion is modulated to circadian
rhythms.
[0244] Chronotherapy has also been used to lower the amount of side
effects from chemotherapy drugs. Over the years, doctors have
realized that by giving two of these drugs, Adriamycin and
cisplatin, in the morning and evening, respectively, side effects
could be cut in half.
[0245] Thus, dosing could be optimized using the ChronoDose system.
For example, pulsatile delivery should have blood plasma
concentrations (BPC) as set forth for each specific medication.
[0246] The time/dose charts should appear as shown in FIG. 21 (a, b
& c).
Applications--Acquired Immune Deficiency Syndrome (AIDS/HIV)
Examples
Zidovudine, Didanosine
[0247] Currently available antiretroviral drug regimens are able to
suppress HIV replication and allow CD4 recovery in the vast
majority of patients with HIV infection. The challenge is to match
each patient to the regimen that is most likely to durably suppress
HIV replication enough to prevent resistance selection without
causing treatment-limiting toxicities. It is also critical, but
difficult, to know when to begin treatment relative to CD4 cell
count and plasma viral load.
[0248] Adherence to antiretroviral therapy for the treatment of HIV
infection and AIDS has become one of the most important clinical
challenges among HIV health care providers and patients. Adherence
to the prescribed regimen may predict which patients achieve
undetectable viral loads. Unfortunately, non-adherence is common in
antiretroviral therapy and has been associated with increases in
viral load and the development of drug resistance. Efforts to
maximize patient adherence are critical for suppressing HIV
replication and preventing the transmission of drug-resistant
virus.
[0249] Automated and programmed, transdermal pulsatile delivery of
zidovudine to reach blood plasma concentrations (BPC) as set forth
below within the following ranges at the following times:
[0250] Peak 1 (Highest)
[0251] 5:00 am-9:00 am: BPC of zidovudine should be in the highest
therapeutic range.
[0252] Peak 2 (Highest)
[0253] 7:00 pm to 11:00 pm: BPC should be in the highest
therapeutic range.
[0254] Theoretical unenhanced transdermal flux for zidovudine
(Berner-Cooper predictive model) is 17.94 ug/cm.sup.2/hr.
[0255] The time/dose chart should appear as shown in FIG. 22.
Applications--Epilepsy
Example
Gabapentan
[0256] In the majority of persons with the brain disorder epilepsy,
seizures recur at predictable times of day. About half of those
with epilepsy experience seizures mainly in waking hours. About
one-quarter have them mainly in sleep. In the others, timing is
less consistent; their seizures strike both day and night.
[0257] More than twenty anti-seizure medications (also called
anticonvulsant or anti-epilepsy drugs) currently are available in
the United States. Some are specifically designed not to interfere
with the activity of other drugs, including birth control pills.
They include gabapentin (Neurontin), lamotrigine (Lamictal),
topiramate (Topamax), tiagabine (Gabatril), levetiracetam (Keppra),
and oxcarbazepine (Trileptal).
[0258] None of the newer medications and only two of the older
ones, valproate and phenyloin, have been studied with regard to how
they work when taken at different times of the day or in different
phases of the menstrual cycle. Whether the findings in valproate
and phenyloin can be generalized to other anti-epilepsy drugs is
not known; the results do raise issues, however, that urgently need
further study. Studies of valproate show that people absorb it more
slowly and less efficiently when they take it in the evening than
in the morning. This finding is of concern because protection
against seizures usually is needed most in NREM sleep, the state
that dominates the first half of a night's sleep.
[0259] Automated and programmed, transdermal pulsatile delivery of
gabapentan to reach blood plasma concentrations (BPC) as set forth
below within the following ranges at the following times:
[0260] Peak 1 (Highest)
[0261] 5:00 am-9:00 am: BPC of gabapentan should be in the highest
therapeutic range.
[0262] Peak 2 (Highest)
[0263] 7:00 pm to 11:00 pm: BPC should be in the highestest
therapeutic range.
[0264] The time/dose chart should appear as shown in FIG. 23.
Applications--Cold and Flu treatment
Example
Triprolidine
[0265] Cold and flu symptoms are worst from midnight until the
early morning because the concentration of cortisol is lowest at
that time. Current nighttime 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.
[0266] 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.
[0267] 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 a person sleeps. The 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. 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.
[0268] The time/dose chart should appear as shown in FIG. 24.
Applications--Weight Control, Vitamin and Herbal
Supplementation
[0269] In yet another application, a series of weight loss vitamins
and supplements is administered in small distinct doses many times
over several days. 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--In general
[0270] 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 an administration is
started, stopped, or changed while a person is sleeping. As
research and knowledge of chronotherapy 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.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
Pharmaceutical Kits
[0275] 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 ad-ministering 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.
[0276] 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.
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