Patent Application
20090281518
This invention is in the field of devices for automatic adjustment of the dose of melatonin and/or delivery of melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland. The exact function of the hormone in adult human beings has not been determined. In healthy young adults, melatonin is secreted as a broad pulse during nighttime sleep in the total amount of approximately 25-30 μg per night, producing peak plasma concentrations of approximately 70 pg/ml, occurring at approximately 02:00 am. Melatonin is secreted into the blood stream and possibly also into cerebrospinal fluid (CSF) simultaneously. The terminal plasma elimination half-life is approximately 45 minutes; volume of distribution is approximately 40 liters; and the metabolic clearance of melatonin is approximately 1 liter per minute
The relationship of the melatonin cycle to the activity/rest (sleep) cycle is not clear, but it is believed that melatonin organizes at least partially the normal sleep pattern.
Melatonin has been given to human beings to treat the phenomenon of “jet lag” following airplane trips associated with a change in time zones (Arendt et al. (1987) Ergonomics 30:1379-1393); U.S. Pat. Nos. 4,600,723 and 4,665,086). It has been given to patients with Parkinson disease (Anton-Tay et al. (1971) Life Sciences 10:841-850), epilepsy (Anton-Tay et al., ibid.), or seasonal affective disorders (Wirz-Justice et al. (1990) J. Psychiat. Res. 24(2) :129-137). It has been tried as a sleep-wake organizer in desynchronized blind persons (Arendt et al. (1988) Lancet pp 772-773; Folkard et al. (1990) Neuroscience Lett. 113:193-198; Sack et al., (1987) in, “Temporal Disorder in Human Oscillatory Systems”, Eds. L. Rensing et al., Springer-Verlag, Heidelberg, pp 219-224; Sack and Lewy (1988) Am. Psychiatric Assoc. 141 Ann. Meeting, Montreal, Quebec). Improved timing of sleep cycles resulted. Oral melatonin has been given to insomniacs (Waldhouser et al. (1990) Psychopharmacology 100:222-226; Arendt et al. (1991) Lancet 337:1121-1124). Melatonin reduced the time awake before sleep onset and diminished sleep latency and number of awakenings. Overall sleep efficiency was increased, and mood, drive, alertness, and reaction time were improved the next day. Most of the published studies are consistent with the assumption that melatonin has mild sedative and hypnotic properties and may be a natural, sleep-inducing and sleep-organizing signal in humans. In addition, melatonin has been reported to lower intraocular pressure in glaucoma, to inhibit breast cancer (U.S. Pat. No. 4,855,305; Barch et al. (1991) Cancer 67:1681-1684), to be useful in the treatment of premenstrual depression (U.S. Pat. No. 4,945,103; Parry et al. (1990) Arch. Gen. Psychiatry 47:1139-1146; Yen et al. (1990) Arch. Gen. Psych. 47:1139-1146), for affecting contraception in humans (PCT Appln. WO 90/14084), and to prevent sudden infant death syndrome (Wurtman et al. (1990) Forensic Science Interntl. 45:171-180).
However, especially since melatonin is also an endogenous compound, it has been found that the optimal dosage is often difficult and the effect of under and/or overdosage often occurs. This is at least in part due to the circadian rhythms that trigger the anabolism and catabolism of melatonin in the human body.
It is therefore an object of the present invention to provide a device for automatic adjustment of the dose of melatonin and/or delivery of melatonin which is for most applications capable to respond to the changes, especially changes in biological functions over time.
This object is solved by a device according to claim 1 of the present invention. Accordingly, a device for automatic adjustment of the dose of melatonin and/or delivery of melatonin is provided, comprising
The term “adapting and/or changing” especially means and/or includes that the dose of melatonin is adapted and/or changed in order to reach a desired sleep pattern and/or interval.
By doing so, at least one of the following advantages is achieved for most of the applications within the present invention:
According to a preferred embodiment of the present invention, the at least one body parameter includes body temperature, core body temperature, skin surface temperature, activity, melatonin level, cortisol level, heart rate, breathing frequency.
According to a preferred embodiment of the present invention, the adapting means adapts and/or changes the dose of melatonin in order to reach a selected day/night activity ratio. In most cases this ratio has shown to be approximately 100:5 to 100:20 for a wide range of applications within the present invention.
According to a preferred embodiment of the present invention, the device comprises further a normalizing means to generate at least one normalized curve out of the data measured by the measuring means.
The term “normalized curve” means and/or includes especially that from the data derived from the measuring cycles, the normalizing curve is calculated by the equation:
Z=(X−mean(X))/standard deviation*100%
However, in case the first body parameter includes activity, for a wide range of applications within the present invention the normalizing curve is calculated as follows:
Taking the average diurnal activity, taking the actual average (e.g. measured in an interval of 10 to 30 minutes) activity and dividing the actual average activity by the average diurnal activity.
According to a preferred embodiment of the present invention, the daily dose and/or dose for a certain time period of melatonin is set as to be
previous dose+Δmelatonin [Δm],
It should be noted that the term “changed and/or set according to” does not mean that Δm is changed on the basis of the measuring means alone; however, according to the preferred embodiment, the data of the measuring means are taken into account when changing and/or setting Δm.
According to a preferred embodiment of the present invention, Δm is ≦50 μg/day, preferably ≦40 μg/day. This has been shown to be best suitable for a wide range of applications within the invention.
According to a preferred embodiment of the present invention, |Δm| is ≧0% and ≦80% of the maximum dose change Δmmax. By doing so, it has been shown for a wide range of applications within the present invention that “overdosing” due a too high Δm can be avoided.
According to a preferred embodiment of the present invention, Δm is set as
Δm≧[Δmmax*(ratio−a)/(1−a)]*0.8 and ≦[Δmaxmelatonin*(ratio−a)/(1−a)]*1.2
According to another embodiment of the present invention, the amount of melatonin delivered is decreased when the ratio and a have differed ≦0.1 (i.e. that |ratio−a| is ≦0.1), preferably ≦0.05 for at least one measurement cycle, preferably for at least 5 measurement cycles. By doing so, it is possible for a wide range of applications within the present invention to smoothen the adjustment to the preselected ratio and limit melatonin delivery when the endogenous production takes over such as in the treatment of the delayed sleep phase syndrome.
According to a preferred embodiment of the present invention, the decrease in daily melatonin is ≦20% per day and ≧5% per day of the dosage of the previous day until m (melatonin dosage) is ≦2.5 μg/day, preferably ≦1.0 μg/day. This range has been shown within a wide range of applications of the present invention to be most effective while lessening the probability of relapses.
According to a further embodiment of the present invention, while gradually decreasing the daily melatonin dosage, the measuring means is still used and the adapting means becomes active again once the |ratio−a| is no longer ≦0.1.
According to a preferred embodiment of the present invention, when the melatonin dosage drops below 2.5 μg/day, preferably below 1.0 μg/day, the dosage is set to zero.
According to an embodiment of the present invention, the device furthermore comprises a storing means for storing data on the daily melatonin dose, profile and/or activity. This has shown to be advantageous for a wide range of applications within the present invention. According to an embodiment of the present invention, the data stored can be read by the user only, according to a further embodiment of the present invention, the data stored can be read by the user and/or other persons e.g., a physician.
According to an embodiment of the present invention, the stored data can be used to stop the delivery of melatonin when the dosing amount has exceeded a certain preset threshold and/or the effectiveness of the melatonin treatment is below a certain other threshold.
According to an embodiment of the present invention, the stored data can be used to provide information that the delivery of melatonin has stopped after the device slowly decreased the daily amount of melatonin delivery.
According to a preferred embodiment of the present invention, the delivery of melatonin occurs along a drug delivery profile. By doing so it has been shown for a wide range of applications within the present invention that problems and/or inefficacies due to catabolic mechanisms of melatonin in the human body can be avoided or at least be reduced.
According to a preferred embodiment of the present invention, the drug delivery profile includes an increasing delivery phase whereby the amount of delivered melatonin increases with ≧1% and ≦12% per hr, preferably 5% and ≦10% per hr of the total daily melatonin dosage.
According to a preferred embodiment of the present invention, the drug delivery profile includes that the maximum delivery of melatonin in 1 hr is ≧10% and ≦30% of the total daily melatonin dosage. According to a preferred embodiment of the present invention, the drug delivery profile includes a decreasing delivery phase whereby the amount of delivered melatonin decreases with ≧1% and ≦12% per hr, preferably 5% and ≦10% per hr of the total daily melatonin dosage.
According to a preferred embodiment of the present invention, the adapting means is able to take into account information supplied by the person to be treated and/or a user of the device. Such information may include—but not be limited to—the judgement of the user of its own sleep pattern, a desired sleep interval and/or information of a physician concerning the status of the person to be treated.
According to a preferred embodiment of the present invention, the device comprises an input means for inputting the data from the person to be treated and/or a user of the device. These input means may include—but not be limited to—buttons or keys, interfaces for communication with e.g. computers in hospitals or doctor's surgery and/or means for wireless communication.
According to a preferred embodiment of the present invention, the delivery device comprises a patch or has a patch-like build-up. This has proved to be beneficial for a wide range of applications especially for users and/or patients who suffer from DSPS or other syndromes, which are more of a temporary nature.
According to a different preferred embodiment of the present invention, the delivery device comprises an implant or has an implant-like build-up. This has proved to be beneficial for a wide range of applications especially for users and/or patients who suffer from chronic sleep disturbances, e.g. in connection with Alzheimer.
The present invention furthermore relates to a method for the controlled release of drugs, comprising the steps of
A device and/or a method according to the present invention may be of use in a wide variety of systems and/or applications, amongst them one or more of the following:
The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations.
Additional details, features, characteristics and advantages of the object of the invention are disclosed in the dependent claims, the figures and the following description of the respective figures, tables and examples, which—in an exemplary fashion—show one example of a melatonin treatment (i.e. dosage change) according to the invention.
The desired period of sleep was set from 23:00 to 7:00, however, prior to treatment the activity curve was clearly shifted with activity until about 3:00 and rising at about 11:00 (This data was used from a person suffering from delayed sleep phase syndrom (DSPS)).
The data of
The initial melatonin dosage (i.e. the dosage of day 1) was 20 μg. Using the formula:
Δm≧[Δm
max*(ratio−a)/(1−a)]
Δmmax is set at 40 μg/day
Δm for day 2 was calculated to be 19 μg, Δm for day 3 was calculated to be 13 μg. The overall daily dosage for day 2 was therefore 39 μg, for day 3 it was 52 μg.
The data of
Please note that the delivery started on Day 3 an hour earlier than in Day 1 and Day 2
The device (beside the watch case 10, which also comprises the sensors and computing units for the device) 1 comprises a drug reservoir 40, from which the melatonin may be delivered to the skin 100 of the user and/or the person to be treated by several controllable valves 50. The device 1 is furthermore equipped with an antigliding material 60 located in proximity to the drug reservoir 40 in order to ensure the contact between the drug reservoir 40 and the skin 100.
It should be noted that instead of the valves 50, also further means might be possible to deliver the melatonin. According to one embodiment of the present invention (not shown in the Figs), the device uses electrophoresis to provide active delivery of melatonin.
As can be seen from
Subsequently, the nocturnal and diurnal activity is compared by a comparing means. This comparing means also takes into account possible settings of the desired ratio between the nocturnal and diurnal activity and/or the required sleep interval.
In case the melatonin dose does not need to be adjusted (path “no” in the flow chart), the melatonin dosage and timing is continued without a change.
In case the melatonin dose needs to be adjusted, the change in melatonin dose and/or timing is calculated, taking into account possible settings in the maximum dosage of the melatonin dose as well as the initial melatonin dose.
From this change (Δm), the new melatonin dose & timing is calculated.
The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06120569.6 | Sep 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB07/53553 | 9/4/2007 | WO | 00 | 3/10/2009 |
