FIELD OF THE INVENTION

The present invention relates to the field of medical devices. More specifically, the invention relates to a stimulation device arranged for stimulating sensory nerves causing vasomotor activity which thus subsequently increase or decrease subcutaneous blood flow.

BACKGROUND OF THE INVENTION

Diabetes is a serious illness affecting millions of people today. Many diabetic patients require injection of insulin to maintain proper levels of glucose in their blood in order to survive. The pancreas in patients with diabetes type 1 is without the ability to produce insulin, and for this reason they need to inject themselves with insulin. The process on insulin injection is rather complicated, because the glucose level is highly dependent on what, when and how much is eaten and how the activity level is for the patients. Intake of food would make the glucose level rise, where insulin would be produced in the pancreas and counteract the rising glucose level, but only for healthy people. Diabetes patients need to inject themselves with insulin before or after the meal, in order to counteract hyperglycaemia. The problem is that the absorption of insulin injected in respect to insulin produced in the pancreas is much slower. This slow absorption results in an undesired high peak in blood glucose levels, while at the same time the slow absorption gives a risk of later hypoglycaemia, because the insulin absorption is still significant even 2-3 hours after injection with the present "quick absorption" types of insulin. Thus, an improved insulin treatment resulting in a lower long term blood glucose level in terms of HbAIc, will benefit from ways of increasing the absorption of insulin, even with the possibility that potentially dangerous incidences of hypoglycaemia can be significantly reduced.

The same problem is known with slow and/or undesired temporal behaviour of other types of drug absorption, e.g. drugs used in pain therapy. This is the case when drugs are provided through subcutaneous absorption, i.e. both in case of transdermal, subcutaneous, and transcutaneous drug delivery. It is well known that by providing heat to the skin, an increased transport of drugs through the skin can be obtained from a transdermal patch of drugs. Further, it is also known that heating can stimulate regional subcutaneous vasomotor activity and thus increase vascular absorption of drugs.

The patent application US 2008/0281297 Al discloses an insulin pump providing heat to a skin area during infusion of insulin to increase the insulin absorption. Fig. 25 in US2008/0281297 Al shows a maximum effect after 50 minutes of heating. However, 50 minutes of constant heating is power consuming even in a limited skin region, and to provide a small battery driven stimulation device, such stimulation is too demanding. WO 2006/086513 A2 discloses system and methods for portably delivering a therapeutic dose of heat to the skin to relieve pain, reduce accommodation of thermal nerve receptors, promote healing, and deliver transcutaneous medications.

SUMMARY OF THE INVENTION According to the above, it may be seen as an object of the present invention to provide a method and a device capable of stimulating blood flow to allow fast absorption of drugs over a longer period of time with limited power consumption, thus allowing operating by a limited battery size.

The above described object and several other objects are intended to be obtained in a first aspect of the invention by providing a device arranged for stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow, the device comprising

- a stimulation element (1) arranged for receiving a control signal and for generating a physical stimulation accordingly, wherein the physical stimulation is capable of affecting the sensory nerves under the skin surface and thus influences subcutaneous blood flow, and

- a processor (2) arranged to generate the control signal to the stimulation element (1) in order to control parameters including a magnitude and a duration of the physical stimulation, wherein the processor (2) is arranged to generate the control signal to provide a limited duration of the physical stimulation being within the range of 5 to 300 seconds. In another aspect the invention relates to a device arranged for stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow, the device comprising

- a stimulation element (1) arranged for receiving a control signal and for generating a physical stimulation accordingly, wherein the physical stimulation is capable of affecting the sensory nerves under the skin surface and thus influences subcutaneous blood flow, and

- a processor (2) arranged to generate the control signal to the stimulation element (1) in order to control parameters including a magnitude and a duration of the physical stimulation,

wherein the stimulation element is a heating element, and

wherein the processor (2) is arranged to generate the control signal to provide a stimulation pattern comprising

- a limited duration of the physical stimulation being within the range of 5 to 300 seconds,

- an intermediate interval substantially without stimulation within the range of 1 to 20 minutes,

- repeating the stimulation pattern at least 2-100 times,

The above described device has the advantage of being able to stimulate a desired skin area for a defined period of time. E.g. by heating for less than 1 minute, preferably at a rather high but still non-painful temperature, a significant increase in blood flow is obtained which lasts for a period of time which is significantly longer than the time of heating. Even shorter periods of stimulation may be advantageous since it can save battery power in a portable device.

Furthermore, a short period of stimulation makes the device more user-friendly. When repeating even very short stimulations in the range of seconds at intervals of several minutes, a surprisingly stable and high blood flow can be maintained over a long period, e.g. more than 30 minutes. Thus, with a limited total stimulation period, a high drug absorption can be obtained for a long period, thereby providing an efficient drug absorption with a low power requirement. Furthermore, a faster absorbance of a drug results in a faster systemic clearance of a drug, which in the case of insulin reduces the risk for later hypoglycaemia.

By the term "sensory nerves causing vasomotor activity" it is to be understood : A nerve or its related sensory receptor which is activated directly or indirectly by an adequate external stimulus.

By the term "duration of stimulation" is to be understood a period in which the stimulation is within a target range of stimulation magnitude, i.e. an effective stimulation. E.g. in case of heating, it will in practice take some time from activating a heating element until a target skin temperature of e.g. 42-43 °C is reached, and thus by "duration of stimulation" is understood the period where the target temperature is applied, and not the duration of activating the heating element. For e.g. electrical stimulation it is the duration of the single or repeated electrical pulses.

In an embodiment the processor is programmed to generate a control signal so as to provide the physical stimulation with a limited duration of 5-240 seconds, such as 5-180 seconds, such as 30-180 seconds, such as 5-120 seconds, such as 10- 90 seconds, such as 10-60 seconds, such as 10-59 seconds, such as 20-59 seconds, such as 20-50 seconds, such as 5-40 seconds, such as 5-30 seconds, such as 5-20 seconds, such as 20 seconds, such as 30 seconds and such as 40 seconds.

It is likely that by shortening the periods of stimulation the time of increased blood flow will not last as long as by longer periods of stimulation. However, as mentioned, it may be seen as advantageous to repeat the stimulation after a period of time. Thus, in another embodiment the processor is arranged to generate a control signal so as to provide a repeated stimulation with an intermediate interval.

The period of the intermediate interval between stimulations is likely to influence how well the blood flow is maintained. Therefore precise control of intermediate intervals is advantageous. Thus in yet an embodiment the intermediate interval is within the range 1-20 minutes, such as 1-15 minutes, such as 1-10 minutes, such as 1-5 minutes, such as 30-120 seconds, such as 3-15 minutes, such as 3-10 minutes, such as 2-5 minutes, or such as 3-5 minutes.

One way of performing the intermediate intervals would be to remove the device from the skin, alternatively the stimulation element may be switched off the device during these intermediate intervals, so as to save power. Thus, in an embodiment the processor is arranged to switch off the stimulation element in the intermediate interval. By switching of the stimulation element the skin temperature will return to the basal skin temperature at a given time. Though the basal skin temperature may increase during a stimulation pattern (due to an increased temperature), during the intermediate interval the skin temperature will return to basal temperature at the given point in time.

The inventors have discovered the surprising effect that repeating heat stimulation can stimulate sensory nerves causing vasomotor activity which results in an increased blood flow in the skin. In addition, no basal level of heat needs to be applied in the intermediate interval for maintaining the effect for a longer period of time. Thus, by switching off the power in the intermediate period the lifetime of the battery can be substantially prolonged. This is important for handheld devices (e.g. an insulin pen) which have to sustain power by the use of a battery. This is in contrast to WO 2006/086513 A2 which discloses that a basal heating level should be sustained for providing pain relief.

It is to be understood that the wording "switching off" in the present context also relates to situations where the stimulation element is reduced in power by 50- 100% such as 75-100%, such as 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-95%, such as 95-100%, or such as 100%. The % may be calculated by the reduction of input power or the change of the parameter.

To be able to maintain an increased blood flow under the skin for as long a period as possible, it is advantageous to repeat the stimulation, with the above described intervals, a number of times. Thus, in an embodiment the processor is arranged to generate a control signal providing a number of repeated stimulations within the range 2-100 times, such as 3-50 times, such as 4-25 times, or such as 5-10 times.

It is a known phenomenon that constant heating of a skin area is stressful to the skin and that the blood flow may decrease again at the later stages of heating since the nerves adapt to the heating, i.e. the well-known biological adaptation. Surprisingly, by using intervals of heating a constant increased blood flow over a longer period of time can be maintained, as mentioned. Furthermore, it is saving battery power of a portable device, when it does not have to provide a constant power output.

It may also be advantageous to have a device capable of adjusting one or more of the parameters of the physical stimulation in order to optimize the stimulation in accordance with a biological response. Thus, in another embodiment the processor 2 is arranged to generate the control signal based on a feedback signal, in order to adjust at least one of the parameters of the physical stimulation selected from the group consisting of: duration, magnitude and intermediate interval between repeated stimulations, in response to the feedback signal, such as both of the duration and a temperature, such as both of the duration and intermediate interval between repeated stimulations, such as both of the a temperature and the intermediate interval between repeated stimulations.

It should be understood that the one or more parameters may vary during a stimulation sequence and may be changed during the stimulation sequence based on a feed-back mechanism from the one or more sensors.

By the term "magnitude" it is to be understood that it refers to the intensity of the stimulation. In regard of heating and cooling it refers to temperature, and in regard of electric stimulation an applied voltage and/or current may be used to define stimulation magnitude.

For the device to be able to have a feedback system, one or more sensors have to be present in the device. Thus in a further embodiment, the device may include at least one sensor arranged to sense a physical quantity and to generate the feedback signal accordingly. Many different types of sensors may be incorporated in the device to provide feedback signals such as the sensor being at least one of: a temperature sensor, a blood-flow sensor, a skin impedance sensor, an infrared sensor, a skin colour sensor, a reflectivity sensor, a unit for receiving a blood sample and for measuring one or more blood values accordingly, and sensors which can directly measure blood-values by light. A sensor capable of directly measuring blood-values by light is e.g. provided by RSP systems A/S.

Following a period of stimulation, it may be advantageous to measure one or more values from the above mentioned sensors to determine the parameters in the rest of a stimulation pattern. Especially when a skin temperature measurement is required, a shift in time in relation to the stimulation is desirable, since the stimulator may give away heat and therefore imprecise values of the skin temperature may be obtained. Thus, in an embodiment the feedback signal is shifted in time in relation to the stimulation, such as the processor (2) being arranged to receive the feedback signal prior to generating the control signal, such as the processor 2 being arranged to receive the feedback signal after generating the control signal. E.g. in case of repeated stimulations, a feedback measured after a first stimulation has been finalized can be used to determine magnitude and/or duration and/or length of intermediate interval of the next stimulation.

In an embodiment the processor 2 is arranged to determine an amount of drug, such as an amount of insulin, to be delivered in accordance with the feedback signal, such as a feedback signal indicative of a surface skin temperature.

The type of stimulation to increase the blood flow can be provided by different stimulation sources. Thus, in a specific embodiment the stimulating element includes at least one of: a heating element, an electric stimulator, a cooling element, and a combination of a heating and cooling element.

An effective and simple way of increasing the blood flow under the skin is by providing heat to the skin. Thus, in an embodiment the stimulation element is a heating element arranged to apply heat to a skin surface in accordance with the control signal. Many different heating elements are known, but to provide an optimal heating stimulation it is desirable if the heater is precise, compact and is able to obtain a target skin temperature relatively fast. Thus, in an embodiment the heating element is one of: a heating foil arranged for heating upon application of an electric signal, a Peltier element, chemicals, and heating electrodes.

It is well known that mixing of two or more chemicals may result in heating (exothermic reaction) or cooling (endothermic reaction). Using these principles heating or cooling of a skin area can be obtained.

To be able to save energy it is desirable only to heat a skin area sufficiently large to increase the blood flow in the desired area, i.e. the area where the drug is placed. Since heating activates the sensory nerves which connect to other nerves close by, an area larger than the heated area will have an increase in the blood flow. Thus a cumulative effect is obtained. Furthermore, by only having to heat a small area a very compact device can be constructed which can work alone or be incorporated into another device, without taking up to much space. Thus, in an embodiment a stimulation surface of the heating element has an area with the range 1-40 cm ² , such as 1-30 cm ² , such as 1-20 cm ² , such as 1-10 cm ² , or such as 1-5 cm ² .

The temperature of the heating element is important to accurately control, since a too high temperature will be damaging to the skin and may also be painful, e.g. skin temperatures above some 43-45 ⁰ C. Thus, in an embodiment the processor is programmed to provide a control signal to the heating element so as to provide a surface skin temperature in the range of 37-45°C, such as 38-44°C, such as 39- 43°C, such as 41-45 ⁰ C, such as 41-43 ⁰ C, such as 42-44 ⁰ C, such as 40-41 ⁰ C, such as 41-42 ⁰ C, such as 42-43 ⁰ C, such as 43-44 ⁰ C, and such as 40-42 ⁰ C.

In yet an embodiment the processor is programmed to provide a control signal to the heating element so as to provide a surface skin temperature in the range 41- 43 ⁰ C, wherein the limited duration of application of heat to the skin surface is in the range 20-59 seconds. In a further embodiment the processor is programmed to repeat said control signal to the heating element with an intermediate interval in the range 1-20 minutes, such as in the range 2-15 minutes, such as in the range 3-10 minutes.

Specific examples of preferred physical stimulation sequences are:

1) 40-43 ⁰ C for 50 seconds with 3-5 minutes interval without stimulation repeated 10 times.

2) 40-43 ⁰ C for 30 seconds with 2-4 minutes interval without stimulation repeated 15 times. 3) 43°C for 40 seconds with 4 minutes interval without stimulation repeated 5 times.

4) 43-46°C for less than 40 seconds with 4 minutes interval without stimulation repeated 5 times. To be able to provide an optimal stimulation sequence for the individual person it may be advantageous to use individual parameters to optimize the treatment. Such parameters could be gender, age, blood pressure, medical history etc. Furthermore, it may be possible to use information following a physical stimulation to improve the next stimulation, by measuring e.g. blood flow, skin temperature or blood glucose levels following a physical stimulation.

In an embodiment the stimulation element 1 includes an electric stimulator, such as an electric stimulator arranged to apply an electric stimulation to a surface of the skin, such as an electric stimulator arranged to apply an intracutaneous electric stimulation.

When the electric stimulation is to be provided intracutaneously, it may be advantageous to connect an electric stimulator circuit to a syringe which can also be used for injecting a substance (e.g. insulin). Another advantage of this setup is that the current is provided exactly at the same site as the substance is positioned under the skin, and thus only the sensory nerves close to the substance deposit site are affected. Specific examples of electric stimulations are e.g. 20 mA constant current stimulation delivered at 10 Hz for 10 seconds. The duration of electric stimulation could be 5-120 seconds, such as 5-60 seconds, such as 10-45 seconds, such as 20-30 seconds, and such as 30-60 seconds. If electric stimulation is repeated, intermediate intervals between each of the electric stimulations could be 15-180 seconds, such as such as 30-180 seconds, such as 60-180 seconds, such as 60-120 seconds, or such as 60-90 seconds. The electric stimulations can be provided a number of times within the range 2- 100 times, such as 3-50 times, such as 4-25 times, or such as 5-10 times. Thus, in an embodiment the stimulation element includes a syringe arranged for drug injection, wherein the syringe has at least an electrically conducting portion connected with an electric stimulator circuit arranged to apply an electric stimulation signal to the conducting portion in accordance with the control signal.

A physical stimulation including cooling a skin area may also increase or decrease the blood flow under the skin. Thus, in an embodiment the stimulation element includes or is a cooling element. Specific examples of stimulation temperatures are 0-15 ⁰ C, such as 0-10 ⁰ C, such as 5-10 ⁰ C, such as 0-5 ⁰ C, and such as 1-5°C. The period of cooling could be such as 5-120 seconds, such as 5-60 seconds, such as 10-45 seconds, such as 20-30 seconds, and such as 30-60 seconds. If a cooling stimulation is repeated, intermediate intervals between cooling stimulations may be such as 15-180 seconds, such as such as 30-180 seconds, such as 60-180 seconds, such as 60-120 seconds, or such as 60-90 seconds. Cooling stimulation can be provided a number of times within the range 2-100 times, such as 3-50 times, such as 4-25 times, or such as 5-10 times. When the device includes a stimulation element which is also able to cool a skin area, which may lead to decreased blood flow, thus a tight control of blood flow and therefore also a tight control of uptake of e.g. a subcutaneously positioned drug may be obtained. Cold pulses of different duration can cause vaso-constriction or vaso- dilation depending on the stimulus configuration and intensity. This tight control may preferably be obtained when the device according to the invention includes at least one sensor (3) arranged to sense a physical quantity and to generate the feedback signal accordingly. In this specific example it may be a blood flow or temperature sensor which would be the most suited.

For providing a substance using the syringe it may be advantageous also to include a drug storage container in the device.

Examples of drugs which can be used with the device of the invention are analgesics (or compounds also shown to provide pain relief e.g. nicotin), insulin, incretin mimetics such as GLP-I (Glucagon-like peptide-1), GLP-I Agonists such as exenatide and liraglutide, incretin. Many other drugs may be used in the systems of this invention. They include: anesthetics, anti-arthritis drugs, antiinflammatory drugs, anti-migraine drugs, cardiovascularly active drugs, smoke cessation drugs, hormones. Other potential drugs include, but are not limited to: androgen, estrogen, non-steroidal anti-inflammatory agents, anti-hypertensive agents, analgesic agents, anti-depressants, antibiotics, anti-cancer agents, local anesthetics, antiemetics, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, agents for smoking cessation, and anti-obesity agents. Specific drugs can include without limitation nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine, lidocaine, fentanyl, sufentanil, alfentanil and other potent mu-receptor agonists, progestrone, Vitamin A, Vitamin C, Vitamin E, prilocaine, bupivacaine, sumatriptan, scopolamine and dihydroergotamine.

Thus, in an embodiment the device comprises a drug storage container. It is to be understood that the drug storage container is intended to be connected to an injection unit such as a syringe or a catheter.

Thus, in an embodiment the device further comprises an injection unit connected to the drug storage container.

The device may be especially suited in connection with patients diagnosed with diabetes, since administration of insulin under the skin is wide-spread. Thus, in another embodiment the invention relates to a device, wherein the device is an insulin injection pen including an insulin storage container and with a first end arranged for attachment of a syringe. When heating is the source of stimulation, it may be advantageous to integrate the heating element in an insulin pen. In this way a person using the device can first heat the skin by using e.g. a pre-installed stimulation pattern and subsequently inject the insulin. It may also be advantageous to heat the area of the skin positioned over the drug deposit site after injection if a faster flow of the drug into the circulation system is desired. Especially, the stimulation element may be a heating element, wherein the heating element is arranged in an end of the insulin injection pen, opposite the first end. Similarly, many ongoing projects relate to letting a drug be transdermally absorbed. One well-known substance which can be absorbed through the skin is nicotine, which is often deposited in a patch, but other drugs can be absorbed through the skin in a similar manner. As another example, the company

Phosphagenics Limited claims to have developed a version of insulin which can be absorbed through the skin.

The patches deliver a fixed amount of drugs per time unit and the reservoir in the skin is passively absorbed. Actively controlled absorption by single or repeated thermal cutaneous pulses is a novel way of "bolus" administration. Increased on demand absorption and hence increase in plasma concentration of the active drug is required if patients expect to do certain activities (e.g. getting out of bed) which is expected to cause pain (break through pain). This feature of on demand delivery combined by the convenience of patch application would potentially further increase the use of patches and open up new areas of applications (e.g. post-operative pain). Thus, in an embodiment the device comprises a patch integrated with the stimulation element.

Another way to provide a drug to a patient is by an integrated catheter, such as a drug pump. In this instance it may also be advantageous to heat the skin area near the drug deposit site. Thus, in an embodiment the device comprises a catheter for drug delivery.

It is to be understood that catheters also includes syringes and micro-needles

To increase user-friendliness of the device it may be equipped with one or more indicators which bring important information to the user. This could be the skin temperature which the user can use to choose an appropriate stimulation pattern, the temperature of a heating element, an indication of which interval between stimulations is appropriate. This may be important if e.g. a heating device is used which does not cool down between stimulations, requiring the user to remove the device from the skin between the stimulation periods. Furthermore, when the device comprises an injection unit it would be appropriate to have an indication of the amount of drug which is going to be injected. Thus, in an embodiment the device comprises an indicator for indicating to a user a value of at least one parameter being one of: skin temperature, temperature of heating element, time of interval between stimulations, amount of drug to be injected. Besides having indicators of specific values, the device may also have one or more setting possibilities. In this way a desired stimulation pattern can be chosen. Similar an amount of drug to inject can be chosen, if the device is equipped with an injection unit. It is to be understood that the device may also be equipped with pre-installed programs combining one or more of the features in a pattern of physical stimulation pattern, i.e. magnitude, stimulation duration, intermediate intervals between repeated stimulations, number of stimulations in a sequence, etc. Thus, in an embodiment the device further comprises at least one of the setting possibilities selected from the group consisting of: drug amount, skin temperature, temperature of heating element, time of stimulation, time of interval between stimulations and the periods of stimulations in a stimulation pattern.

The present invention also relates to a method for modulating vascular absorbtion of a substance.

Thus, in another aspect the invention relates to method for modulating vascular absorption of a substance, the method comprising the steps of

a) positioning a substance on/in a person, and

b) stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow by providing a physical stimulation of a skin area near the drug position depot for a limited duration of 5 to 300 seconds.

In a similar aspect the invention relates to a method for modulating vascular absorption of a substance, the method comprising the steps of

a) providing a person having a substance in or on the skin

b) stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow by providing a physical stimulation of a skin area near the drug position depot for a limited duration of 5 to 300 seconds.

In another aspect the invention relates to a method for modulating vascular absorption of a substance, the method comprising the steps of

a) positioning a substance on/in a person, and

b) stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow by providing a physical stimulation of a skin area near the drug position depot for a limited duration of 5 to 300 seconds.

In an embodiment according to the invention a person or subject is provided who already has the substance/medicament positioned in or on the skin. Thus, in this specific embodiment the positioning of the substance in or on the subject does not form part of the invention.

Especially, the limited duration of stimulation may be 5-240 seconds, such as 5- 180 seconds, such as 30-180 seconds, such as 5-120 seconds, such as 5-90 seconds, such as 10-60 seconds, such as 10-59 seconds, such as 20-59 seconds, such as 20-50 seconds, such as 5-40 seconds, such as 5-30 seconds, such as 5- 20 seconds, such as 20 seconds, such as 30 seconds and such as 40 seconds. It may also be reasonable to increase the time of stimulation to e.g. 120-800 seconds, such as 120-600 seconds, such as 120-400 seconds, or such as 120-240 seconds.

In some embodiments, the stimulation is repeated with an intermediate interval. E.g. the intermediate interval may be within the range 1-20 minutes, such as 1- 15 minutes, such as 1-10 minutes, such as 1-5 minutes, such as 30-120 seconds, such as 3-15 minutes, such as 3-10 minutes, such as 2-5 minutes, such as 3-5 minutes. The stimulations may be repeated within the range 2-100 times, such as 3-50 times, such as 4-25 times, such as 5-10 times with intermediate intervals. A stimulation surface may have an area within the range 1-40 cm ² , such as 1-30 cm ² , such as 1-20 cm ² , such as 1-10 cm ² , or such as 1-5 cm ² .

In preferred embodiments, the stimulation is heating, cooling or electric stimulation.

In case the stimulation is heating, the surface skin temperature may be heated to a temperature in the range of 37-45 ⁰ C, such as 38-44 ⁰ C, such as 39-43 ⁰ C, such as 41-45 ⁰ C, such as 41-43 ⁰ C, such as 42-44 ⁰ C, and such as 40-42 ⁰ C. In one embodiment, the surface skin temperature is heated to a temperature in the range 41-43 ⁰ C, and wherein the limited duration of application of heat to the skin surface is in the range 20-59 seconds. More specifically, an intermediate interval in the range 1-20 minutes, such as in the range 2-15 minutes, such as in the range 3-10 minutes without heating may be included before the limited duration of application of heat is repeated. The limited duration of application of heat may be repeated 2-100 times, such as 3-50 times, such as 4-25 times, such as 5-10 times with intermediate intervals.

It is appreciated that the same advantages and equivalent embodiments as described for the first aspect apply as well for the second aspect.

BRIEF DESCRIPTION OF THE FIGURES

The aspects and embodiments according to the invention will now be described in more detail with regard to the accompanying figures. The figures show one way of implementing the present invention and is not to be construed as being limiting to other possible embodiments falling within the scope of the attached claim set.

Fig. 1 shows three graphs indicating blood flow (% baseline) in the forehead skin of healthy men and women (n=28) following physical stimulation in the form of heating.

A: Heat delivery of 38 ⁰ C, 41 ⁰ C and 43 ⁰ C for 15 seconds. B: Heat delivery of 38 ⁰ C, 41 ⁰ C and 43 ⁰ C for 30 seconds. C: Heat delivery of 38 ⁰ C, 41 ⁰ C and 43 ⁰ C for 60 seconds. Fig. 2 shows three graphs indicating temperature in the forehead skin of healthy men and women (n = 28) following physical stimulation in the form of heating. A: Heat delivery of 38 ⁰ C, 41 ⁰ C and 43 ⁰ C for 15 seconds. B: Heat delivery of 38 ⁰ C, 41 ⁰ C and 43 ⁰ C for 30 seconds. C: Heat delivery of 38 ⁰ C, 41 ⁰ C and 43 ⁰ C for 60 seconds.

Fig. 3 shows two graphs indicating blood flow (% baseline) in the forearm skin of healthy women (n=10) in response to physical stimulation in the form of heating. Arrows indicate the time of repeated stimulations. A: Heat delivery of 43 ⁰ C for 30 seconds. B: Heat delivery of 43 ⁰ C for 60 seconds.

Fig. 4 shows two graphs indicating the temperature in the forearm skin of healthy women (n = 10). Arrows indicate the physical stimulation in the form of repeated stimulations.

A: Heat delivery of 43 ⁰ C for 30 seconds. B: Heat delivery of 43 ⁰ C for 60 seconds.

Fig. 5 shows blood flow (% baseline) in the dorsum of the hand, dorsum of the foot and abdomen skin of healthy men (n = 20) following stimulation in the form of heat delivery of 43 ⁰ C for 60 seconds.

Fig. 6 shows blood flow according to cold stimulation of 0 ⁰ C applied 3 times for 3 different durations (10, 20 and 30 seconds) at the volar forearm. Evaluation of blood flow for a sequence of 5 minutes is shown.

Fig. 7 shows a diagram showing a device embodiment with an integrated feedback mechanism.

Fig. 8 shows a device embodiment in the form of an insulin pen with an integrated heating element.

Fig. 9 shows a device embodiment in the form of a drug patch with an integrated heating element. Fig. 10 shows a heat stimulation pattern of 120 seconds of 4O ⁰ C stimulation with intervals without heating for 5 minutes applied to the right and left abdomen. X- axis: time; Y-axis: Blood flow?

Fig. 11 shows 300 seconds of heating with different temperatures. X-axis shows temperature; Y-axis shows blood flow. Blood flow mean value as well as upper and lower 95% confidence intervals are indicated for each temperature point.

Fig. 12 shows the blood flow during a stimulation pattern of 300 seconds of stimulation at 43 ⁰ C followed by an intermediate interval of 300 seconds with no stimulation. This pattern was repeated numerous times. The stimuli rekindled the flow and kept it around a 10 fold increase. Thus, this figure shows the mean blood flow over 30 minutes when the skin is repeatedly reheated to 43 ⁰ C.

DETAILED DESCRIPTION In the following experiments with different types of physical stimulation magnitudes and durations will be explained by reference to results illustrated in

Figs. 1-6.

Methods

Subjects and design Twenty eight healthy volunteers (20-30 years) were recruited for this study through on-campus advertisements at Aalborg University, Denmark. Initial screening involved recording of demographic information and a review of medical history. The use of alcohol and caffeine, cold and hot drinks as well as smoking were prohibited. No subject had a past or present history of current systemic or skin diseases and none were taking any medication. Application of topical creams, lotions or cosmetics on the test sites was not allowed. Written informed consent was obtained from all the participants prior to taking part in the study. The study protocol was approved by the local ethics committee (Counties of Nordjylland and Viborg, Denmark; case no. VN2005/62). The study was conducted in accordance with the Declaration of Helsinki and was performed at the research laboratories of Aalborg University, Denmark. The study was designed in a way that the subjects were blinded to the selected temperature and duration of heat application. The site of the application was chosen in random. The measurement techniques were objective. An interval of 24 hours was considered between the two visits. The subject relaxed on a comfortable bed at a supine position and exposed the test sites. Before starting the experiment, subject was familiarized with the environment. All experiments were done in a quiet room with a constant temperature (23-24°C). Subjects were asked to keep their eyes closed at the time of scanning because of the laser beam. For the forehead part special goggles were given.

Induction of heat

Mild heat temperatures (38, 41, 43°C) were delivered by a custom made heat inducing device (Aalborg University) for short durations of 15, 30 and 60 seconds. The thermal head dimension was 1.5x 1.5 cm. The device was placed on the skin of the desired region to deliver the short heat pulse.

Measurements of the skin reaction Laser Doppler Imaging

Blood flow changes in the microvasculature of the skin were measured using a laser Doppler system and associated software (Moor Instruments, Devon, UK), which produces an output signal that is proportional to the blood cell perfusion (or flux). Measurements of blood flow were taken for 5 min prior to heat test and 5- 10-15 min post test. An area of 7.5 x 7.5 cm covering the test site was scanned at a distance of 30 cm with a resolution of 118 x 70 pixels and a speed of 4 ms/pix. The mean blood flow was calculated using relative flux (arbitrary units).

Infra-red thermography Measurements of skin temperature were taken by means of thermography camera (Thermovision, Scanner 900 SW-TE, AGEMA Infrared System, Sweden). The pictures were taken for 5 min prior to heat test and 5-10-15 min post test. The temperature resolution of the device was 0.1 ⁰ C. Thermographic images were stored on computer's hard disk for off-line analysis of the profile and local changes of skin temperature. Any report for pain, irritation or discomfort was recorded in a safety profile sheet.

Statistical analysis

All values are presented as mean and standard errors of the mean. Data were analyzed with repeated measures ANOVA (RM ANOVA) for factors of temperature, time, site and sex. Holm-Sidak Test was used as post hoc test. The statistical evaluation was made by means of the Sigmastat version 3.0 (SPSS Inc., Chicago, US). P<0.05 was considered as significant.

Example 1: Heating the skin at the forehead

Fig. 1 shows an increased blood flow when a skin area is heated for a defined period of time at a specific temperature. In this region, three different temperatures (38°C, 41°C and 43°C) for three different times (15, 30 and 60 seconds) were used in any possible combinations (n=28).

In Fig. IA heating for 15 seconds at 38°C, 41°C and 43°C are performed showing an increased blood flow for approximately 5 minutes before the blood flow returns to the baseline. Heating at 43°C is slightly better than 38°C and 41°C. Though only a limited increase in blood flow is measured, the increase can be clearly seen in the graph.

In Fig. IB the time of heating is increased to 30 seconds. A clear increase in blood flow is still present after 10 minutes, when the temperature is 41°C and 43°C. In figure 1C the time of heating is increased to 60 seconds. A clear increase in blood flow is still present after 15 minutes, when the temperature is 41°C and 43°C. Thus, heating the skin for even very short periods of time, leads to an increased blood flow for a substantial longer period of time than the actual heating period.

Main findings showed that the best combination was 43°C for 60 seconds that could enhance blood flow and temperature without any pain or discomfort. The effect lasted for about 15 minutes after the stimulation. Furthermore, an increase in blood flow could be measured 5 minutes after heating for only 15 seconds at 38°C. Besides measuring the blood flow the temperature following a period of heating was also measured, Figs. 2A-2C.

Thus, very short periods of heating maintain an increased blood flow and an increased skin temperature for long periods of time after the heating has been terminated. Therefore by heating the skin temperature repeatedly with intervals without heating can be used to maintain an increased blood flow. In this way a heating device programmed to provide cycles of heating for defined periods with a defined temperature followed by periods without heating would advantageous. It will save battery power of a portable device and at the same time maintain a high blood flow under the skin.

Example 2: Forearm

The heat application paradigm for this site was 43 ⁰ C for 30 and 60 seconds of female volunteers (n = 10). Blood flow changed reached to its peak at 5 min after the application of the heat (180±13% for 43°C/30 seconds and 2OO±15% for 43°C/60 seconds compared with baseline). The maximum skin temperature peak captured by the thermocamera was at 5 min after the application for both paradigms (1.8±0.6°C for 43°C/30 seconds and 2.6±0.8°C for 43°C/60 seconds compared with baseline.

Example 3: Repeated measurements on forearm skin

To investigate the effect of the repeated application of the heat on the vasomotor responses, mild heating; 43°C for 30 seconds (Figs. 3A and 4A) and 43°C for 60 seconds (Figs. 3B and 4B) was performed and repeated after 3 minutes and every 5 minutes for 15 minutes followed by a gap of 15 minutes without any stimulation and the last heating was applied after the gap. The experiment was performed on forearm skin of female volunteers (n=10).

Figs. 3A-B illustrate that an increased blood flow can be maintained over a longer period of time by only applying short pulses of heat with defined intervals without heat. Furthermore, even after a longer period without heating the increased blood flow can be reinstated by a single pulse of heating. Similarly Figs. 4A-B illustrate that an increased skin temperature can be maintained using repeated pulses of heating. The results show that repeated application of heat maintains the vasomotor response. Example 4:

To verify if an increased blood flow could be obtained at several positions on the body, heating was provided to the dorsum of hand, the dorsum of foot and the abdomen.

Dorsum of hand Fig. 5 illustrates data from laser scanning showed that the raise in the blood flow was higher in the first 5 min of the measurement (125±15% compared with baseline) and after 10 minutes, the change was back to the baseline (102±10%). The heat application paradigm was 43 ⁰ C for 60 seconds.

Dorsum of foot

Fig. 5 illustrates blood flow changed reached to its peak at 5 min after the application of the heat (145±21% compared with baseline). At 10 min it was 110% and it came back to the normal, (100% ±10 of the baseline) after 15 min. The heat application paradigm was 43 ⁰ C for 60 seconds.

Abdomen

Fig. 5 illustrates Recordings from the abdomen showed a significant change in the blood flow 5 min after the application of the heat (148%±15 compared with baseline). The changes came back to the baseline after 10 min. The heat application paradigm was 43 ⁰ C for 60 seconds.

Thus, heating of the skin seems to result in a general raise in blood flow independent of the position on the body. This is of special interest for patients diagnosed with diabetes, since they often inject insulin just beneath the skin on the abdomen. Thus, by providing heat at the site of injection (before injection, during injection or after injection) insulin (or another drug) can be absorbed in the circulation system faster than without heating. Furthermore, a faster clearance of e.g. insulin in the circulation is a result of the faster uptake, which is an advantage because late hypoglycaemic incidences are less probable to occur. Potentially, a smaller dose of insulin can be used to prevent a high blood glucose peak after a meal, the smaller dose further reducing the risk of hypoglycaemic incidences. This can be achieved by relatively short heating stimulations below the normally accepted threshold of pain, 43 ⁰ C. Example 5: Cooling the skin may also lead to increased blood flow Cold stimulation on forearm

Fig. 6 illustrates results of experiments, where cooling stimulation in the form of stimulation of 0 ⁰ C was applied for 3 different durations (10 seconds, 20 seconds and 30 seconds) at the volar forearm. Blood flow was scanned before the cold stimulation and 5 subsequent times right after the stimulation so that an evaluation of blood flow for a sequence of 5 minutes can be seen. Control scanning was done without cold stimulation. A clear increase in blood flow was measured for all periods of cooling for at least 3 minutes.

Thus, cooling of the skin can also be applied for increasing the blood flow beneath the skin and for increasing the uptake of a drug positioned beneath the skin. Cooling may be an alternative to heating when a drug which is going to enter circulation is sensitive to temperatures above e.g. 37 ⁰ C. Some insulin types are known to be heat sensitive.

Fig. 7 shows how a device according to the invention may be arranged. A stimulation element 1 which can be a heating element, a cooling element or an electric stimulator receives signals from a processor 2 which provides information like temperature, interval between stimulations and number of repeated stimulations. It may be advantageous to have pre-installed stimulation patterns installed in the processor, but also individual settings may be applied. The processor may also receive signals from one or more sensors 3, which may form part of the device. Based on these inputs, the processor may adjust the signals which are sent to the stimulation element and in this way modify part of a stimulation pattern. Arrows indicate in which directions signals are communicated between the different elements of the device.

Fig. 8 shows an insulin injection device 4 comprising a stimulation element 1 one or more sensors 3, a processor 2 and a syringe 5. This could be particular advantageous when a person is self-administrating insulin. By having an integrated stimulation element, e.g. a heating element, a person can pre-heat the skin area where an injection is going to be performed. Since the device of the invention can operate with very short stimulation periods it is not particular inconvenient to the user of he/she has to preheat for a single period below e.g. 1 minute before injecting the insulin. Subsequent to the injection the user may reapply heat for a short period to injection site, e.g. 5 minutes after injection, to maintain a high blood flow. This may be of particular importance if a fast uptake of insulin is required. After injection the user may apply a stimulation pattern to the injection site to maintain a high blood flow. It is important to note that by having a stimulation device with installed stimulation sequences with periods without using power to the stimulation element, battery power is saved, while an increased blood flow is maintained.

Examples of sensors which may be incorporated in the device of the invention are a temperature sensor, a blood-flow sensor, a skin impedance sensor, an infrared sensors, a skin colour sensor, a reflectivity sensor, a unit for receiving a blood sample and for measuring one or more blood values accordingly, and sensors which can directly measure blood-values by light. A device which can directly measure blood-values by light is e.g. provided by RSP systems A/S.

Fig. 9 shows an embodiment of the invention wherein the stimulation element 5 is integrated in a patch 6. The processor 2 may be linked to the patch by wires 7. By having the patch and the processor physically separated, the processor and battery 8 can be stored e.g. in a pocket while the patch is in direct contact with the skin.

In another embodiment the processor is integrated in the patch while the battery is connected to the patch and the processor by wires. Thus, only the battery is physically separated from the patch. In a further embodiment the patch, the processor and the battery are integrated in a compact device. It is to be understood that the patches according to the invention may also comprise one or more sensors, as previously described. Since such patch devices are likely to be powered by batteries the use of stimulation sequences compared to a constant stimulation will save battery power. It is to be understood that the patches of the invention may be drug patches and thus contain one or more drugs which can be transdermally absorbed through the skin. A person skilled in the art knows how drug patches are constructed.

The invention can be implemented by means of hardware, software, firmware or any combination of these. The invention or some of the features thereof can also be implemented as software running on one or more data processors and/or digital signal processors. The individual elements of an embodiment of the invention may be physically, functionally and logically implemented in any suitable way such as in a single unit, in a plurality of units or as part of separate functional units. The invention may be implemented in a single unit, or be both physically and functionally distributed between different units and processors.

Fig. 10 shows that a stimulation pattern of 120 seconds of 40 ⁰ C repeated every 5 minute can sustain an increased blood flow over a longer period of time. Stimulation was applied to the right and left abdomen.

Fig. 11 shows that the increase in blood flow depends on the provided temperature. Thus, by controlling the temperature to be provided to the skin the blood flow may be tightly controlled.

Fig. 12 shows that by using the stimulation patterns according to the invention an increased blood flow can be maintained for a longer period of time.

Taken together the data in figures 10-12 indicate that by using e.g. a feedback system as disclosed in the present invention, the uptake into the circulation system of a subject, of e.g. a subcutaneous positioned medicament, may be tightly controlled over a longer period of time. Thus, depending of the medicament and the need of the subject an optimal dosing may be provided using the methods and or the device according to the invention.

To sum up, the invention provides a stimulating device for stimulating sensory nerves causing vasomotor activity which thus subsequently increases or decreases subcutaneous blood flow. The device includes a stimulation element (1), e.g. a heating element, for generating a physical stimulation, e.g. heating applies to a skin surface, according to a control signal. The physical stimulation is capable of affecting the sensory nerves under the skin surface and thus influences subcutaneous blood flow. A processor (2) generates the control signal to the stimulation element (1) in order to control parameters including magnitude and duration of the physical stimulation. The processor (2) generates the control signal to provide a limited duration of the physical stimulation within the range 5 to 120 seconds, preferably 15-60 seconds. The rather short term stimulations may be repeated, e.g. with intermediate intervals of 1-10 minutes, such as 2-5 minutes, and thereby a long term stable increase in blood flow can be obtained with use of very short physical stimulations in the form of heat, cold, or electric stimulations. Heating of skin surface to a temperature of 41-43 °C is effective, and still it is not painful. Such device can significantly increase absorption of subcutaneous drugs, e.g. injected insulin or transdermally applied pain drugs. Such rapid drug absorption is desired in many types of therapy e.g. diabetes therapy, where a better control of both hypo- and hyperglycemia can be obtained. In one embodiment, the device is an insulin pen (4) with a heating element (1) mounted in one end.

Although the present invention has been described in connection with the specified embodiments, it should not be construed as being in any way limited to the presented examples. The scope of the present invention is to be interpreted in the light of the accompanying claim set. In the context of the claims, the terms "including", "includes", "comprising" or "comprises" do not exclude other possible elements or steps. Also, the mentioning of references such as "a" or "an" etc. should not be construed as excluding a plurality. The use of reference signs in the claims with respect to elements indicated in the figures shall also not be construed as limiting the scope of the invention. Furthermore, individual features mentioned in different claims, may possibly be advantageously combined, and the mentioning of these features in different claims does not exclude that a combination of features is not possible and advantageous.