BIOSYNCHRONOUS TRANSDERMAL DRUG DELIVERY

Abstract

Systems and methods for synchronizing the administration of compounds with the human body's natural circadian rhythms and addiction rhythms to counteract symptoms when they are likely to be at their worst by using an automated and pre programmable transdermal or other drug administration system.

Description

This application claims the benefit of U.S. Provisional Application No. 60/609,418 filed on September 13, 2004 which is incorporated herein by reference. This application also relates to PCT application No. PCT/IB2004/002947 entitled Transdermal Drug Delivery Method and System filed on Sep. 13, 2004 which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates, in general, to controlled drug delivery methods and systems, and, more specifically, to systems and methods for biosynchronous transdermal drug delivery in which drugs, pharmaceuticals, and other bioactive substances are delivered transdermally into a body in a manner that is synchronized with biological processes and/or biological rhythms so as to improve performance of the substance in the body.

RELEVANT BACKGROUND

In the field of drug delivery, it is recognized that supplying the drug in a correct temporal pattern is an important attribute of any drug delivery methodology. Controlled release drug delivery systems are intended to improve response to a drug and/or lessen side effects of a drug. The term “controlled release” refers generally to delivery mechanisms that make an active ingredient available to the biological system of a host in a manner that supplies the drug according to a desired temporal pattern. Controlled release drug delivery may be implemented using instantaneous release systems, delayed release systems, and sustained release systems. In most cases, controlled release systems are designed to maintain a sustained plasma level of an active ingredient in a drug within a human or animal host over a period of time.

Instantaneous release refers to systems that make the active ingredient available immediately after administration to the biosystem of the host. Instantaneous release systems include continuous or pulsed intravenous infusion or injections. Such systems provide a great deal of control because administration can be both instantaneously started and stopped and the delivery rate can be controlled with great precision. However, the administration is undesirably invasive as they involve administration via a puncture needle or catheter. ‘Delayed release’ refers to systems in which the active ingredient made available to the host at some time after administration. Such systems include oral as well as injectable drugs in which the active ingredient is coated or encapsulated with a substance that dissolves at a known rate so as to release the active ingredient after the delay. Unfortunately, it is often difficult to control the degradation of the coating or encapsulant after administration and the actual performance will vary from patient to patient. Sustained Release generally refers to release of active ingredient such that the level of active ingredient available to the host is maintained at some level over a period of time. Like delayed release systems, sustained release systems are difficult to control and exhibit variability from patient to patient. Due to the adsorption through the gastrointestinal tract, drug concentrations rise quickly in the body when taking a pill, but the decrease is dependent on excretion and metabolism, which can not be controlled. In addition, the adsorption through the gastrointestinal tract in many cases leads to considerable side effects (such as ulcers), and can severely damage the liver.

Transdermal drug delivery has developed primarily for sustained release of drugs in situations where oral sustained release systems are inadequate. In some cases, drugs cannot be effectively administered orally because the active ingredients are destroyed or altered by the gastrointestinal system. In other cases the drug may be physically or chemically incompatible with the coatings and/or chelating agents used to implement sustained release. In other cases a transdermal delivery system may provide sustained release over a period of days or weeks whereas orally administered drugs may offer sustained performance over only a few hours. A wide variety of active substances can be delivered through transdermal systems so long as the active substance can be provided in a form that can cross the skin barrier.

In most cases transdermal delivery systems are passive, taking the form of a patch that is adhesively attached to the host. The patch includes a quantity of the active substance, along with a suitable carrier if need be, absorbed in a sponge or similar system. Once applied, the active ingredient diffuses into the host through the skin at a rate determined by the concentration of the active substance and the diffusivity of the active substance. However, a variety of physical and chemical processes at the skin/patch boundary affect the delivery rate and may eventually inhibit drug delivery altogether. Active transdermal delivery systems have been developed to help regulate the delivery rate by providing mechanisms to improve drug delivery over time by “pumping” the active ingredient. One such system is described in U.S. Pat. No. 5,370,635 entitled “DEVICE FOR DELIVERING A MEDICAMENT” which describes a system for delivering a medicament and dispensing it to an organism for a relatively long period of time, for example at least a few days. The device can be adapted for positioning on the surface of the skin of a human or possibly an animal body in order to apply a medicament thereto from the outer side thereof.

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.

Timed delivery is most often used to maintain a sustained level of a drug in the body. A significant focus of current research in drug delivery has been to determine the influence of a patient's circadian or other biological rhythms on drug efficacy and efficiency. This research demonstrates that certain disease symptoms follow a daily pattern, with peak symptoms at certain times of the day. It has been widely acknowledged that hormones, neurotransmitters and other intra-body compounds are released in different amounts at different times of the day pursuant to daily patterns. The Wall Street Journal reported on May 27, 2003 that ‘Doctors are increasingly looking at the clock when it comes to prescribing medicine, instructing patients not only to what drug to use but also precisely when to take it. The new approach stems from a growing body of research that demonstrates that certain diseases tend to get worse at certain times of the day, By synchronizing medications with a patient's body clock, many physicians believe that the drugs will work more effectively and with fewer side effects. In some cases, the improvements have been so pronounced that doctors have been able to reduce dosages.” Similarly, American Pharmacy reports that ‘Circadian physiologic processes alter drug absorption, distribution, metabolism, and excretion. As a result, drug doses need to be adjusted to meet the differing needs of target organs or tissues at various times of the day. See, L. Lamberg, American Pharmacy, 1991; N831(11): 20-23. Doctors have responded to this growing body of research by prescribing a carefully timed drug administration regimen to optimize treatment.

Recently, an orally administered drug for arthritis treatment has suggested a chronotherepeutic approach using a delay release system where the delay is scheduled to release the active ingredient at the beginning of an interleukin 6 cascade that is believed to cause early morning stiffness in rheumatoid arthritis patients. By attempting to synchronize the drug delivery with a biological cycle it is believed that low doses may be used to achieve desired results. However, this system does not overcome the limitations of delayed release systems described above. Although it is possible to meet the requirements of chronopharmacology with pills, this requires an enormous amount of discipline by the patient to comply with the treatment regiment. As illustrated above, to achieve optimal results, many patients may need to wake up during the night to take their medication.

Hence, what is needed is a reliable means of delivering multiple drugs in precisely timed and measured doses-without the inconvenience and hazard of injection, yet with improved performance as compared to orally-delivered drugs.

Currently, patient compliance (taking the proper dosages at the prescribed times) is a critical problem facing caregivers and pharmaceutical firms alike. Studies show that only about half of patients take medications at the times and in the dosages directed by their physician. It is reported that each year, 125,000 deaths and up to 20% of all hospital and nursing home admissions result from patient non compliance. It is estimated that non-compliance results in additional healthcare costs in excess of $100 billion per year in United States. These figures are even more pronounced for the elderly. Hence, a need exists for systems and methods that increase patient compliance for administration of a variety of drugs.

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

Briefly stated, the present invention involves synchronizing the administration of compounds with the human body's natural circadian rhythms and addiction rhythms to counteract symptoms when they are likely to be at their worst by using an automated and pre programmable transdermal or other drug administration system.

Specifically, this invention describes a method to maximize the efficiency of compound administration, decrease negative side effects and increase the efficacy of pharmacological therapy by synchronizing and tailoring the administration of certain compounds to match these circadian rhythms.

Thus based on an analysis of the human body's circadian rhythms, the invention delivers varying dosages at varying times, pursuant to a pre-programmed dosage profile. This ensures that peak drug concentrations are present in the bloodstream to offset peak disease and addiction symptoms arising from variances and fluctuation in the body's natural circadian rhythms. Further, these methods ensure that less of a drug is in the bloodstream when disease and addiction symptoms are at there lowest.

The present invention describes methods for treating diseases, addictions and disorders in humans. These methods involve synchronizing and tailoring the administration of compounds with the body's natural circadian rhythms to counteract symptoms when they are likely to be at their worst by using an automated and pre programmable transdermal drug administration system.

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

FIG. 1 shows an exemplary device useful for implementing the present invention;

FIG. 2A and FIG. 2B illustrate comparative drug release profiles demonstrating operation of the present invention;

FIG. 3 is a schematic illustration of a drug delivery device in accordance with the present invention;

FIG. 4 is a schematic illustration of an alternative drug delivery device in accordance with the present invention

FIG. 5 shows an exemplary administration profile for a stimulant delivery system;

FIG. 6 shows an exemplary administration profile for a nicotine delivery system;

FIG. 7 shows an exemplary administration profile for a nitroglycerine delivery system tailored to treat variant angina attacks; and

FIG. 8 illustrates an exemplary administration profile for a nitroglycerine delivery system tailored to treat stress-induced angina attack.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The reality of circadian rhythms in animals including humans is well known. Biological rhythms are periodic fluctuations in biological characteristics over time, which also include circadian as well as seasonal variations. Circadian, or approximately 24-hour, rhythms include the production of biological molecules such as cortisol and adrenaline, the regulation of body temperature and heart rate, changes in characteristics of blood, such as stickiness, and behaviors such as wakefulness, sleep and periods of activity.

Research demonstrates that certain disease symptoms follow a daily pattern, with peak symptoms at certain times of the day. It has been widely acknowledged that hormones, neurotransmitters and other intra-body compounds are released in different amounts at different times of the day pursuant to daily patterns. It is believed that the failure of current transdermal systems to synchronize drug administration with the body's natural rhythms often lead to (i) severe side effects, including debilitating sleep disorders (in the context of nighttime nicotine administration, for example), (ii) ever increasing tolerance (in the case of nitroglycerin and other pharmaceuticals for example), (iii) more expensive therapies, since more of a compound is needed since body rhythm tailored dosing is not implemented. In addition, many addictions follow a daily pattern consistent with one's circadian rhythms. For example, according to studies performed, immediately upon waking, smoker's have peak nicotine cravings. These peak cravings return after each meal, due to the interplay of serotonin release as a trained response to the culmination of a meal. Our methods precisely time the administration of drugs so that they reach peak levels when symptoms are likely to be at their worst, and efficacy is greatly improved.

The present invention involves precisely timing the administration of drugs so that they reach peak levels in synchronization with times when symptoms are likely to be at their worst, or times at which the drugs are believed to be more effective in the body and/or better tolerated by the patient. The present invention is described in terms of a particular example drug delivery system that provides automated and precise control over dosing, with single-dose capability, (once while people sleep) or capability to administer separate and varying-sized doses many times throughout a multiple day period. The particular implementation is consistent with a commercial development of a miniaturized, automated and programmable non-invasive drug delivery system called the ChronoDose™ 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 Chrono-Pharmacology. To illustrate the importance of Chrono-Pharmacology consider the following facts:

• • Asthma attacks are 100 times more likely between 4:00 and 6:00 AM.
  • Heart attacks and strokes are most likely to occur around 6:00 AM.
  • Variant Angina attacks occur30 times more often in the middle of the night between 2:00 AM and 4:00 AM.
  • Smokers experience the highest cravings immediately upon waking up
  • Lethargy and difficulty getting out of bed is highest immediately upon waking up early in the morning
  • Cold and flu symptoms peak during night time and early morning hours, when cold medications are wearing off

In accordance with the present invention, substances with proven or suspected chrono-pharmacological efficiency are integrated into a miniaturized, automated, programmable watch-like device, such as device 100 shown in FIG. 1. The delivery system 100 shown in FIG. 1 can be used for a variety of active compositions, and is small, fully automated and programmable. This system consists of a re-usable wristwatch-like device 101 to control the time and dosage of drug delivery; and a small, disposable, ‘reservoir’ 103, which is about the size of a quarter or ½ dollar coin in a particular example, that the user can simply pop-in to place on the watch-like platform. This reservoir patch lasts, for example, up to 72 hours, depending on the application. Shorter and longer reservoir lifetimes are contemplated. The device is readily adapted to be worn on the forearm, ankle, or other convenient body location.

In a particular application the replaceable reservoir can include a description of an administration schedule that can be used to manually or automatically program device 100 with an administration schedule. For example, written schedule can be printed on or affixed to the reservoir 101 or electrically programmed using volatile or non-volatile memory. In this manner a dosing profile can be prescribed and filled by a pharmacy in much the same manner as a conventional drug prescription is handled today.

An exemplary implementation shown in FIG. 3 comprises a collapsible drug reservoir, an expandable waste reservoir, a micro-pump, electronics for automation, a display, and a highly permeable membrane. An exemplary system is described in a PCT application No. PCT/IB2004/002947entitled TRANSDERMAL DRUG DELIVEDRY METHOD AND SYSTEM filed on Sep. 13, 2004 which is incorporated herein by reference. The drug reservoir will contain about 3 ml of drug formulation. A tiny, miniaturized pump is activated at pre-programmed times and releases a pre-defined amount of drug formulation into the drug chamber, where the formulation comes into contact with highly permeable membrane. This membrane rests on the skin, and provides for even diffusion of the drug over the device's drug absorption surface area. This membrane works effectively with, and can be coated with, an adhesive. In operation, when the administration of the drug needs to be discontinued, the remaining drug formulation is either removed from the membrane area via a waste chamber, containing a hydrophilic substance (hydrogel) or the device is taken off.

In an implementation shown in FIG. 4, a pressurized drug reservoir is used which minimizes or eliminates need for a micropump. Electronics control a valve that allows controlled quantities of the drug to be applied to the drug chamber where the formulation comes into contact with highly permeable membrane.

The construction and use of transdermal patches for the delivery of pharmaceutical agents is known. See, for example, U.S. Pat. No. 5,370,635 entitled “DEVICE FOR DELIVERING A MEDICAMENT” the disclosure of which is incorporated herein by reference. Such patches may be constructed using a saturated media, pressurized reservoirs, or unpressurized reservoirs with micropumps for continuous, pulsatile, or on-demand delivery of an active material. For example, a pharmaceutically acceptable composition of an active material may be combined with skin penetration enhancers including, but not limited to, oleic acid, amino acids, oleyl alcohol, long chain fatty acids, propylene glycol, polyethylene glycol, isopropanol, ethoxydiglycol, sodium xylene sulfonate, ethanol, N-methylpyrrolidone, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, N-methyl-2-pyrrolidone, and the like, which increase the permeability of the skin to the active material and permit the active material to penetrate through the skin and into the bloodstream. Pharmaceutically acceptable compositions may be combined with one or more agents including, but not limited to, alcohols, moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. Pharmaceutically acceptable compositions may also be combined with a polymeric substance including, but not limited to, ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to provide the composition in gel form, which may be dissolved in solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to backing material to provide a patch. The backing can be any of the conventional materials such as polyethylene, ethyl-vinyl acetate copolymer, polyurethane and the like.

Example substances include caffeine and a variety of over-the-counter and prescription stimulants (for treating fatigue, sleep disorders, attention deficit disorders and a variety of other conditions), nicotine (for smoking cessation), nitroglycerin (for treating heart attack and strokes), fentanyl (for treating chronic pain), albutamol (for treating asthma), and selegiline (for treating depression, attention deficit disorder or Parkinson's disease). We have carefully identified these specific drugs and diseases because they have the following attributes: (i) Chrono-Pharmacology is critical to optimized dosing but is not being implemented because no automated transdermal system exists, and (ii) these drugs can be transdermally absorbed passively (i.e., without the need for ultrasound or electrical stimulation or other permeation enhancers). Exemplary chrono-pharmacological systems that can make use of the present invention are summarized in Table 1

DISEASES/
CONDITION   CHRONOPHARMACOLOGY
Morning     Adrenaline is lowest in the morning, making waking
Lethargy    uncomfortable and difficult for many people. This can
            be treated by administering OTC Stimulant before
            waking
Smoking     Nicotine at night creates sleeping disorders
Cessation   (nightmares), but cravings are the highest after
            waking up. This can be treated by administering
            Nicotine before waking up.
Angina      Angina (variant) attacks occur 30 (thirty) times more
            often between 2:00 a.m. and 4:00 a.m. This can be
            treated by administering larger nitroglycerin doses
            in early morning
Asthma      Asthma attacks are 100 times more likely between 4:00
            a.m. and 6:00 a.m. Adrenaline and Cortisol are
            virtually absent at night. This can be treated by
            administering albutamol in early morning
Colds       Heaviest symptoms overnight and in the morning. This
and Flu     can be treated by administering Cold/Flu medicine
            during the night.
Heart       Heart attacks and strokes are most likely between
Attacks     6:00 a.m. and Noon. This can be treated by adminis-
and         tering Anticoagulants before waking up.
Strokes
Pain        Neurological pain is worst between 3 A.M and 8 A.M.
            This can be treated by administering pain medication
            during sleep.
Depression  Selegiline at night can create sleeping disorders
            (nightmares), but depression symptoms are high
            immediately upon waking up. This can be treated by
            administering Selegiline before waking up.
Rheumatoid  Worst upon awakening. Cortisol and anti-inflammatory
Arthritis   hormones are very low at night This can be treated by
            administering medication delivered before waking up.
Supplements Vitamins and supplements are best administered in low
            doses over the course of the day to be most effective.

Using this system the present invention can pre-program the times and amount of each dosage by precisely controlling the amount of drug exposed to the skin during each dosing. This feature is advantageous when a drug is best administered during sleep, e.g., 1 to 2 hours before waking up. The present invention precisely counteracts peak disease symptoms and increase patient compliance.

The present invention represents the first true non-invasive chrono-pharmacological drug delivery device. While current transdermal applications are restricted to the dosage profile shown in FIG. 2a, the automated implementation of the present invention can be programmed for a variety of drug delivery patterns to achieve customized patient dosing regiments for optimal therapy (FIG. 2b). There are many advantages for a controlled transdermal release of an active material such as a drug. As used herein, the term ‘controlled’ or ‘sustained’ release of an active material includes continuous or discontinuous, linear or non-linear release of the active material according to a programmed schedule. Among the advantages of controlled release are the convenience of a single application for the patient, avoidance of peaks and valleys in systemic concentration which can be associated with repeated injections, the potential to reduce the overall dosage of the active material, lower body stress, and the potential to enhance the pharmacological effects of the active material. A lower, sustained dose can also prevent adverse affects that are occasionally observed with infusion therapy. In addition to significantly reducing the cost of care, controlled release drug therapy can free the patient from repeated treatment or hospitalization, thus offering the patient greater flexibility and improving patient compliance. A controlled release formulation of certain drugs also provides an opportunity to use the drug in a manner not previously exploited or considered. The present invention is particularly advantageous when (i) known chrono-pharmacological information shows that a drug's effects can optimized when administered in a defined dosage at a predefined time or times, and/or (ii) patient compliance with the dosing regimen is greatly increased due to automation, (doses required at inopportune times, when sleeping, for example).

Applications—ArisePatch™

A contemplated consumer product is the ArisePatch™. 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.

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™ 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

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.

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.

An exemplary product contemplated by the present invention is called Nicotine ChronoDose™ system. In accordance with the present invention, the system can begin to administer nicotine(or nicotine analogs or any other smoking cessation compound including but not limited to Zyban) automatically during a one hour period immediately prior to waking. This will relieve the smoker's peak craving upon waking without causing nightmares and insomnia. We believe that this system clearly provides a superior method for smoking cessation.

A more advanced nicotine replacement system than that described above is worn for three days at a time and is programmed to release nicotine in a daily rhythmic pattern such as shown in FIG. 6 to offset peaks in a smoker's cravings. FIG. 6 illustrates an exemplary nicotine administration profile showing a blood plasma level of nicotine in nanograms per milliliter on the vertical axis, with time on the horizontal axis. This implementation will reduce nicotine dependency by administering pre-programmed levels of nicotine pursuant to typical smoking patterns. For instance many smokers report that cravings for a cigarette are greatest upon waking up, after lunch, mid afternoon, after dinner and before bedtime. This implementation of the present invention will automatically release larger doses of nicotine to offset peak cravings and no nicotine when cravings are typically at a minimum. The present invention may be delivered in a pre-programmed manner for each treatment regimen. The only involvement by the user will be the replacement of the ‘reservoir’ every three days, and the replacement of the platform housing as needed.

This implementation represents a tremendous move forward in nicotine replacement therapy, and is far superior to the old-technology systems that simply release the same amount of nicotine all day and night. With the present invention, one can systematically decrease a smoker's tolerance without increasing dependence (the result of a constant flow) and better wean a smoker off nicotine. This will allow the smoker to better ‘tailor-down’ and decrease the amount of nicotine he needs to quit. Modern smoking cessation is much more than nicotine replacement therapy. Programs also include weight control, diet and psychological support. The present invention fits well into these programs, since it addresses the key component of being able to quit smoking by efficiently countering the withdrawal symptoms while doing away with the negative side effects of current nicotine replacement therapy systems, namely sleep disturbance.

Applications—Cold and Flu treatment

Cold and flu symptoms are worst from midnight until the early morning because the concentration of cortisol is lowest at that time. Current night time cold and flu medication end up losing efficacy by early morning when cold and flu symptoms are highest. Therefore people suffering from a cold or flu are often unpleasantly awoken by an increase in symptoms, cutting sleep short. Set and put on before bedtime, the present invention will automatically deliver a larger dose of medication and immuno-boosters in the early morning hours to more effectively combat the peak cold and flu symptoms that occur in the morning. Users will experience less severe cold and flu symptoms during the morning hours, will not have their sleep cycle cut short, and will wake up feeling symptom-free. This implementation uses prescription or OTC cold medicine alone or optionally in combination with certain transdermally efficacious vitamins and immune system boosters to provide a total solution to cold and flu ailments. This is the first cold therapy that combines OTC medicine with supplemental immuno-boosters in a comprehensive and automated manner. Our system will treat the cold symptoms directly and boost the body's immune system to help it heal naturally.

In a particular application, the Cold and Flu automated transdermal drug delivery system utilizes OTC cold medicine, Vitamin C, Echinacea, and Zinc to provide a total solution to cold and flu ailments, and all while you sleep. Cold and flu symptoms are worst in the middle of the night and early morning because the hormone cortisol, a key inflammation fighter, is missing at that time. Cold and flu symptoms are worst from midnight until the early morning because the concentration of cortisol is lowest at that time. Current night time cold and flu medication end up losing efficacy by early morning when cold and flu symptoms are highest. Therefore people suffering from a cold or flu are often unpleasantly awoken by an increase in symptoms, cutting sleep short

Set and put on before bedtime, the Cold and Flu automated transdermal drug delivery system utilizes our proprietary technology to automatically deliver a larger dose of medication and immuno-boosters in the early morning hours to more effectively combat the peak cold and flu symptoms that occur in the morning. Users will experience less severe cold and flu symptoms during the morning hours, will not have their sleep cycle cut short, and will wake up feeling symptom-free.

Our system not only combats statistically proven peak nighttime and early morning cold symptoms by releasing OTC cold medicine, but actually helps your body to heal by boosting its immune system through Vitamin C, Echinacea and Zinc supplementation in small but distinct doses all night long.

Our Cold/Flu system releases these combination of compounds every 2 hours throughout the night, with a higher dosage of compounds being released in the morning to combat these proven middle of the night and early morning symptoms, which are the worst of the day.

Cold and flu symptoms are worst in the middle of the night and early morning because the hormone cortisol, a key inflammation fighter, is missing at that time. Our system utilizes its core competitive advantage by pre-programming our System to release more medicaments precisely at that time to offset these peak symptoms. Current cold and flu medications end up losing efficacy by early morning when cold symptoms peak, so the user either has sleep cut short due to the onset of these symptoms, or wakes up out of slumber feeling sick with peak symptoms. Our system will ensure that a while a person is actually sleeping, a sufficient dose of cold and flu medicine is freshly delivered to offset these peak morning symptoms.

Applications—Weight Control, Vitamin and Herbal Supplementation

In yet another application, a series of weight loss vitamins and supplements is administered in small distinct doses many times over a multiple day period. Vitamins and supplements are absorbed by the body in small dosages. Contrary to popular belief, once-a-day products are not maximally effective because excess dosages are excreted unused. This implementation of the present invention precisely controls the timing and dosage of small but distinct amounts of vitamins and supplements during a 24 hour period to ensure that vitamins and supplements are constantly bio-available for optimal absorption and cellular function. Greater doses are automatically released prior to mealtimes to counter appetite cravings, resulting in a much more effective diet program.

Applications—Angina

Research shows that variant angina occurs 30 times more often between 2:00 a.m. and 4:00 a.m. (‘critical angina phase’) than at any other time of the day. Nitroglycerin effectively combats angina attacks, if administered in optimal doses. Current nitroglycerin patches exist, but they can only release a constant amount of nitroglycerine steadily over time. Current patches cannot tailor the release of nitroglycerine to optimize treatment by releasing more nitroglycerine precisely during the critical angina phase to offset these peak symptoms.

In addition, nitroglycerine loses its effectiveness and requires higher and higher dosages when administered constantly. Our bodies become tolerant to it. Current systems cannot stop or decrease the release of nitroglycerine when disease symptoms are lowest. Thus, these current ‘dumb’ patches cannot offset the critical angina phase by releasing more of the drug, nor can they shut down or stop nitroglycerine administration when the body doesn't need it. It is a ‘one dose fits all’ type of scenario once each “dumb” patch is applied to the patient.

The method in accordance with the present invention utilizes an automated transdermal system in order to transdermally administer more nitroglycerine during the critical angina phase to ensure adequate offset of these symptoms and less nitroglycerine when it is not needed so that no tolerance builds up. Our method utilizes a ‘smart’ patch medicine system at this time to offset these peak critical phases in the disease cycle arising due to the human body's circadian rhythm.

The preprogrammable automated transdermal system is worn around the wrist like a watch (or the forearm arm or ankle) and releases nitroglycerine in optimal dosages at times that are optimally synchronized. This is pursuant to a pre-programmed and tailored dosage profile. Current nitroglycerin patches only have the capability to release a constant dose of nitroglycerin over a period of time. Current nitroglycerin patches simply cannot alter or vary dosages to increase dosages at different times of the day, and decrease dosages at other times of the day.

The nitroglycerin system in accordance with the present invention has three primary advantages over current nitroglycerin patches. First, the system utilizes its core competitive advantage to automatically and precisely release nitroglycerin in peak amounts to offset the peak symptoms of morning attacks occurring during the critical angina phase. Current nitroglycerine patches have release rates that stay constant and do not increase to offset critical phases, and do not decrease as symptoms decrease. Second, our system solves the tolerance issue by releasing less (or no) nitroglycerin in off-peak hours, and then releasing nitroglycerin at just the right time so that it is present during critical periods, without increasing tolerance. Third, our system accomplishes 1 and 2 above automatically, without the need for a patient to wake up to take a drug at this critical phase, which does away with the need for any increased patient compliance.

As a result we believe that our nitroglycerin system represents an ideal delivery system for patients who use nitroglycerin regularly for the treatment and/or the prevention of heart attacks and strokes. Patient compliance regarding the timing and dose of heart attack medication is crucial. Patient non-compliance with physician's instructions for this is often a cause of re-hospitalization, according to the US Department of Health and Human Services. The system solves this problem, and will decrease the need for re-hospitalization by dramatically increasing patient compliance.

This system can be either an ‘wear each night and remove in the morning’ system, whereby it only releases nitroglycerine automatically to offset the critical angina phase in the morning, or a ‘total solution’ system, that is worn for a period of 24 hours to several days, and that administers nitroglycerine in tailored amounts and at tailored times as synchronized with the body's circadian rhythm (and conveniently taken off while showering or swimming).

The system is an innovative new drug therapy for angina. With its superior advantage of optimized and automated time and dose administration synchronized with our circadian rhythms, the system in accordance with the present invention ensures that nitroglycerin will circulate in the bloodstream exactly when the patient needs it, and without any build up tolerance. For these reasons, our system is superior to current steady release nicotine patches. Our system's increased advantages are extremely relevant for those patients with moderate to severe angina.

FIG. 7 shows an exemplary administration profile for a nitroglycerine delivery system tailored to treat variant angina attacks or angina pectoris. This type of angina attack has a peak frequency in many patients between the hours of 2:00 and 4:00 AM. This is a particularly difficult time to wake up to take a drug such as nitroglycerine. In accordance with the present invention an administration profile substantially like that shown in FIG. 7 is automatically administered. In FIG. 7 the vertical axis indicates blood plasma level in nanograms per milliliter, and the horizontal axis indicates time from 10:00 PM through the night to 8:00 AM.

FIG. 8 illustrates an exemplary administration profile for a nitroglycerine delivery system tailored to treat stress-induced angina attack. In FIG. 8 the vertical axis indicates blood plasma level in nanograms per milliliter, and the horizontal axis indicates time from 12:00 AM through the day until about 4:00 PM. The administration profile shown in FIG. 8 provides a high blood plasma concentration throughout the waking hours of a day when stress is likely occur.

Applications—Asthma

The automated transdermal asthma system automatically administers a morning dose of albuterol, tolobuterol, salmeterol, beta 2 agonist or any other antiarrhythmic drug (an ‘Asthma drug’) to combat the peak symptom of morning asthma attacks known as the ‘morning dip’.

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.

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.

The Asthma system has two primary advantages over current patches. First, the system of the present invention utilizes its core competitive advantage to automatically and precisely release albuterol or other asthma drugs in peak amounts to offset the peak symptoms associated with the morning dip. Current patches have release rates that stay constant and do not increase to offset this peak critical phases, and do not decrease as symptoms decrease. Second, our system accomplishes 1 and 2 above automatically, without the need for a patient to wake up to take a drug at this critical phase, which does away with the need for any increased patient compliance.

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.

The system is an innovative new drug therapy for asthma. With its superior advantage of optimized and automated time and dose administration synchronized with our circadian rhythms, our system ensures that albuterol or another asthma drug will circulate in increased amounts in the bloodstream exactly when the patient needs it. For these reasons, our system is superior to current steady release patches. Our system's increased advantages are extremely relevant for those patients with moderate to severe asthma.

Applications—Hypertension

The clondine automated transdermal system utilizes clondine, (or another hypertension drug) an effective drug that combats high blood pressure. The clondine automated transdermal drug delivery system has an automated morning release of Clondine to combat the peak symptom of morning heart attacks.

Blood pressure differs at different times of the day. Blood pressure surges upon waking, and is lower by 20 to 30 per cent while sleeping. Our preprogrammed automatic transdermal system utilizes its core competitive advantage by releasing clondine in a tailored fashion to counter high blood pressure when symptoms are highest, while releasing less clondine when symptoms are less severe.

Current clondine patches release the drug consistently over time. It cannot release more of the drug when symptoms are worst. People die most when the symptoms peak. Having the advantage of administering more of the drug when a patient needs it the most can mean the difference between life and death, especially in patients with moderate to severe high blood pressure.

The automated transdermal system for hypertension has two primary advantages over current patches. First, our system utilizes its core competitive advantage to automatically and precisely release clondine or other hypertension drugs in peak amounts to offset the peak symptoms associated with the dangerous morning symptoms. Current hypertension patches have release rates that stay constant and do not increase to offset this peak critical phases, and do not decrease as symptoms decrease. Second, our system accomplishes 1 and 2 above automatically, without the need for a patient to wake up to take a drug at this critical phase, which does away with the need for any increased patient compliance.

Applications—Depression, Alzheimer's, Attention Deficit

The selegiline automated transdermal system utilizes selegiline, an effective MAO inhibitor for the treatment of depression, Alzheimer's and Attention Deficit Disorder.

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 an hour or 2 before morning, so symptom of morning depression would be corrected by our system without subjecting the patient to sleep disturbances.

Primary negative side effects of the selegiline patches are abnormal dreams, insomnia, and difficulty sleeping. We believe that by specifically refraining from administering selegiline at night, and utilizing our system's core competitive advantage to turn it on an hour or so before waking, we can do away with this negative side effect and still offset the critical phase of morning symptoms of depression. It has been reported that patients have increased symptoms of depression upon waking if the critical amount of Selegiline is not circulating through their system. Our system utilizes its core competitive advantage to provide a compelling solution to this problem. Our system is applied before bed, it would not release the drug until an hour or two before morning, so symptom of morning depression would be corrected by our system without subjecting the patient to sleep disturbances

Current Oral Selegiline produces horrible side effects. There is a new Selegiline patch coming out on the market, but it to produces sleep disturbances. It is believed that the system in accordance with the present invention would be superior to conventional Selegiline product delivery systems.

Applications—In General

The present invention is particularly useful in applications in which it is necessary and/or desirable to start the administration of a drug, stop the administration of a drug, and/or increase/decrease the dosage of a drug at a time when it is inconvenient or impossible for a patient to initiate the necessary actions. This is particularly useful for a wide variety of drug administration applications that benefit when administration is started, stopped, or changed while a person is sleeping. As chronotherapy knowledge increases, it is contemplated that a wide variety of applications will be discovered in which benefit is realized by starting, stopping and/or changing the drug administration while a patient sleeps.

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.

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.

In order to use an active material for therapeutic treatment (including prophylactic treatment) of mammals including humans according to the methods of this invention, the active material is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition comprising an active material in association with a pharmaceutically acceptable diluting substance or carrier, wherein the active material is present in an amount for effective treating or preventing a particular condition. While individual needs may vary, determination of optimal ranges for effective amounts of an active ingredient (alone or in combination with other drugs) within the ranges disclosed herein is within the expertise of those skilled in the art. Accordingly, ‘effective amounts’ of each component for purposes herein are determined by such considerations and are amounts that improve one or more active ingredient functions and/or ameliorate on or more deleterious conditions in patients and/or improve the quality of life in patients.

The present invention also provides pharmaceutical kits for treating a particular symptom, condition and/or disease and/or improving a particular biological function, comprising one or more containers comprising one or more active compositions in accordance with this invention. Such kits can also include additional drugs or therapeutics for co-use with the active composition for treatment or prevention of a particular symptom, condition and/or disease and/or improving a particular biological function . In this embodiment, the active composition and the drug can be formulated in admixture in one container, or can be contained in separate containers for simultaneous or separate administration. The kit can further comprise a device(s) for administering the compounds and/or compositions, such as device 100 shown in FIG. 1, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflect approval by the agency of manufacture, use or sale for human administration.

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.

Claims

1. A method for delivering a bioactive agent to a human or animal comprising:

providing a transdermal drug delivery device coupled to the human or animal, the delivery device having a source of the bioactive agent, a programmable timing mechanism, and a mechanism for causing the bioactive agent to be delivered transdermally in response to the timing mechanism; and

timing routines implemented by the timing mechanism, wherein the timing routines are selected to deliver the bioactive agent at a time, rate, sequence and/or cycle that is synchronized with a biological rhythm of the human or animal.

2. The method of claim 1 wherein the bioactive agent comprises a stimulant and the timing routines are selected to deliver the stimulant immediately before the human or animal wakes up.

3. The method of claim 1 wherein the bioactive agent comprises nicotine and the timing routines are selected to deliver the nicotine at times that are associated with nicotine cravings.

4. The method of claim 3 wherein at least one of the selected times corresponds to a time at which the human or animal experiences a morning nicotine craving.

5. The method of claim 1 wherein the bioactive agent comprises an antihistamine and the timing routines are selected to deliver the antihistamine while the human or animal sleeps.

6. The method of claim 1 wherein the bioactive agent comprises a stimulant and the timing routines are selected to deliver the stimulant immediately before the human or animal wakes up.

7. A method for treating a symptom, condition, and/or disease comprising:

identifying a drug suitable for treating a particular symptom, condition and/or disease;

identifying a biologically superior time for administering a drug;

programming a time-programmable transdermal drug delivery system with a schedule selected to synchronize with the identified biologically superior time; and

causing the time-programmable transdermal drug delivery system to deliver the active ingredient according to the programmed schedule.

8. A programmable transdermal drug delivery device comprising:

an interface for coupling to the skin of a host;

a reservoir storing a quantity of an active composition;

valve mechanism for supplying a quantity of the active composition from the reservoir to the interface in response to a control signal; and

a timing mechanism coupled to the valve mechanism and configured to generate the control signal according to a programmed administration schedule.

9. The device of claim 7 wherein the valve mechanism controls a rate at which the active composition is supplied in response to the control signal.

10. The device of claim 7 further comprising a mechanism for removing the active composition from the interface in response to the control signal.

11. The device of claim 7 further comprising a mechanism for removing carrier materials from the interface.

12. A kit comprising a first container comprising a pharmaceutical formulation of an active material, said formulation comprising an amount of active material effective to treat a symptom, condition, and/or disease, wherein said first container is adapted to coupled to a programmable transdermal drug delivery system.

13. The kit of claim 11 wherein the first container includes a specification of an administration schedule that is used to program the programmable transdermal drug delivery system.

14. A method for delivering a drug to a human or animal comprising:

providing a transdermal drug delivery device coupled to the human or animal, the delivery device having a source of the drug, a programmable timing mechanism, and a mechanism

for causing the drug to be delivered transdermally in response to the timing mechanism; and

timing routines implemented by the timing mechanism, wherein the timing routines are selected to deliver the drug at a time when the human or animal is expected to be asleep.

15. The method of claim 13 wherein the timing routines initiate drug delivery at a time when the human or animal is expected to be asleep.

16. The method of claim 13 wherein the timing routines terminate drug delivery at a time when the human or animal is expected to be asleep.

17. The method of claim 13 wherein the timing routines increase the dosage of drug delivered at a time when the human or animal is expected to be asleep.

18. The method of claim 13 wherein the timing routines decrease the dosage of drug delivered at a time when the human or animal is expected to be asleep.