Background

Perishable products may comprise fluid or granular products that may spoil when exposed to an undesirable condition. Such an undesirable condition may be a temperature outside an acceptable range, such as a temperature that is too high or a temperature that is too low. Other undesirable conditions may be: an exposure to ultraviolet light or infrared light; exposure to pressures outside of an acceptable range; bacterial or fungal contamination; and exposure to radioactivity. Perishable products are utilized across a range of industries and may comprise granular materials, such as powders or particles, or fluids, such as liquids, emulsions or colloidal dispersions. Some example perishable products in the medical field are: vaccines, medicines, intravenous fluids and biological samples, such as blood samples or saliva samples, to name a few non-limiting examples.

Certain perishable products, in particular pharmaceutical products, are thermolabile and should be stored within a specific temperature range recommended by the manufacturer. Thermolabile products that are exposed to temperatures outside of their specific temperature range may lose their chemical stability, degrade and/or lose their potency. It may also cause impurities to form which can pose deadly hazards. These impurities may not be visually detectable.

In some cases, particular transport and storage technology is used to safely transport the perishable product from the production location to the end-user and avoid spoiling. A particular example of said transport and storage technology is a temperature-controlled chain (cold-chain) which is often used for said thermolabile products, such as for vaccines and insulin which are temperature sensitive. In cold chain technology, every environment for which the product is subjected to from the time of production, through packaging, storage and transport until they reach, and/or are administered into, an individual is retained within the product’s specific temperature range. Cold chain logistics ensure the quality and safety of thermolabile products. To ensure correct cold-chain management, every logistics step should be well documented. This should provide transparency should any potential deviation from the specific temperature range occur, for instance as a result of inadequate packaging, shipment/transport delays, and repeated opening and closing the storage area (for example as a result of multiple deliveries).

When a wholesaler delivers thermolabile drugs to a clinical area/pharmacy the drugs are stored according to their temperature sensitivity. The temperature sensitivity is specific to a particular drug variety and dosage and is provided by the drug manufacturer. The clinical areas/pharmacy monitor the temperature of the storage units accordingly. A pharmacy refrigerator is a common piece of equipment found in clinical areas. It is used to ensure specific medicines are safely stored within a narrow temperature range in line with manufacturers' instructions; this is often between 2°C and 8°C. Drugs which may be stored in a pharmacy refrigerator include: vaccines; insulin; chemotherapy drugs; and topical preparations, such as some types of eye drops, to name a few non-limiting examples.

Some injectable drugs, for example insulin, are meant to be used once or more during the day and may be administered via a medical pen. Many injectable drugs should preferably reach room temperature before being administered into a patient since injecting cold medicine may cause discomfort, pain and/or local tissue irritation.

Often when the injectable drug reaches room temperature it should be used during a specific period of time.

For a particular injectable drug, a user may need to know if the drug has reached room temperature and, thus, must not be re-refrigerated, and should be used within the time span defined by the manufacturer. The user may collect a quantity of supply of the drug for a particular time period, for example a three-month supply, from a pharmacy. The user may store the three-month supply within their home. Thus, once the drug (medicine) has left the pharmacy the temperature- controlled chain is broken. The temperature of the drug (medicine) is no longer being carefully monitored and controlled. The temperature of the drug may be exposed to non-storage appropriate environments whilst in the possession of the user. For example, whilst in transit from the pharmacy to the user’s home, or whilst stored in the user’s non-medical refrigerator. Whilst stored in the user’s nonmedical refrigerator there could be a power cut to the electricity supply of the refrigerator, the refrigerator door could be inadvertently left open, or there may be inconsistent refrigeration, all of which could lead to temperature variations within the drug storage environment. Home refrigerators are unlikely to have a monitoring system as sophisticated as those in healthcare establishments.

Another challenge a user may face with thermolabile drugs is how to know that the drug has reached the end of its shelf life at room temperature and is no longer usable. In an example wherein the drug is insulin, at room temperature insulin will start to degrade and lose its potency after approximately 28 days. Insulin is used to maintain blood sugar levels in a normal range. If the user fails to keep a record of how long the drug has been outside the fridge they may use insulin in an ineffective state which may lead to serious health problems.

There are several perishable products, in particular perishable drugs such as insulin, that, in addition to temperature control, also require monitoring of a predefined time interval that the drug can be used after the vials, container or injection pen have been used for the first time.

Perishable products may unintentionally be exposed to undesirable conditions. For instance, cooling installations may malfunction, insufficient sterilization may occur, or human errors may arise during handling of the perishable product. As mentioned it is often not apparent from visual observation of the perishable product that spoiling has occurred. Failing to detect spoiling, especially for perishable products in the medical field, such as vaccines or medicines, may have severe or even life-threatening consequences. Therefore, it is essential to monitor and signal whether the perishable product has been exposed to an undesirable condition during transport, storage or the drug has exceeded a predefined time interval for use. The above-described problems are common problems with temperature sensitive medications. The invention described herein aim to mitigate some of these above- mentioned problems with temperature sensitive drugs.

Summary of the Invention

According to a first aspect of the invention there is provided a device for indicating one or more conditions of a product comprising: a first indicator configured to be in a first state when the product is maintained in one or more first predetermined conditions, and change state to indicate one or more further conditions of the product; and a timer having a predetermined duration configured to be activated contemporaneously with the change of state of the first indicator; wherein the device is further configured to indicate when the predetermined duration of the timer has elapsed.

The first indicator may be configured to change to a further state upon elapse of the predetermined duration of the timer to provide the indication that the predetermined duration has elapsed.

The first indicator may be configured such that the change of state from the first state to one or more of the further states is irreversible.

The timer may be configured such that activation is irreversible.

The first indicator may be a visual indicator.

The one or more first predetermined conditions may comprise at least one of: a predetermined temperature range; and a first use of the product not having started. The one or more further conditions may comprise at least one of: a first use having commenced; and the product, or a container that the product is contained in, being subjected to a temperature outside of the predetermined temperature range.

The first indicator may comprise a manual actuator for changing the state of the indicator manually by a user and/or is configured to change state in response to a thermo-chemical reaction.

The first indicator and/or the timer may be a chemical-based indicator/timer and/or an electronic indicator/timer.

The product may be a medicine.

The medicine may be insulin.

The first indicator may be further configured to be a first colour when the indicator is in the first state and one or more further colours when the indicator is in the one or more further states, respectively.

The first indicator may comprise incremental subindicators which are configured to sequentially change from a first state to a further state upon incremental elapse of the predetermined duration.

According to a second aspect of the invention there is provided a medical pen comprising the device according to the first aspect of the invention, wherein the device may be integrated into the pen and/or attached to the medical pen.

According to a third aspect of the invention there is provided a method for indicating one or more conditions of a product comprising: indicating that the product has been maintained in first predetermined conditions; indicating when the predetermined conditions have changed; activating a timer contemporaneously upon changing of the predetermined conditions; and indicating when a predetermined duration of the timer has elapsed.

Indicating that the product has been maintained in first predetermined conditions, indicating when the predetermined conditions have changed, and indicating when a predetermined duration of the timer has elapsed may comprise visual indication.

The method may further comprise indicating that the product has been maintained in first predetermined conditions when a first use of the product has not started and/or the product has been maintained within a predetermined temperature range.

The method may further comprise indicating the predetermined conditions have changed when a first use has commenced and/or the product, or a container that the product is contained in, is subjected to temperatures outside of the predetermined temperature range.

The method may further comprise providing an indicator in a first colour to indicate that the product has been maintained in first predetermined conditions.

The method may further comprise changing the indicator from the first colour to a second colour to indicate that the predetermined conditions have changed.

The method may further comprise changing the indicator from the second colour to a third colour, or providing a second indicator, to indicate that a predetermined duration of the timer has elapsed.

The method may further comprise indicating elapse of incremental periods of the predetermined duration. Brief Description of the Drawings

Fig. 1 is a flow diagram of a method for indicating one or more conditions of a product;

Fig. 2 is a flowchart of a method of operation of the device according to the invention concerning exposure of a product to certain temperatures;

Fig. 3 is a flowchart of a method of operation of a particular example device concerning a first use of the product;

Fig. 4 is a flowchart of a method of operation of a particular example hybrid device;

Fig. 5a shows a first example of how a device according to the invention can be implemented on, or integrated with, a medical pen;

Fig. 5b shows a second example of how a device according to the invention can be implemented on, or integrated with, a medical pen;

Fig. 5c shows a third example of how a device according to the invention can be implemented on, or integrated with, a medical pen;

Fig. 5d shows a fourth example of how a device according to the invention can be implemented on, or integrated with, a medical pen;

Fig. 5e shows a fifth example of how a device according to the invention can be implemented on, or integrated with, a medical pen;

Fig. 6a shows a first example progressive indicator;

Fig. 6b shows a second example progressive indicator;

Fig. 6c shows a third example progressive indicator; and

Fig. 6d shows a fourth example progressive indicator.

Detailed Description

The invention describes a device that is suitable for pen-administrated drugs that are temperature sensitive, restricted for use over a predetermined time interval or a combination thereof. The device is preferably visual-based and provides multistep monitoring. The invention will now be described with reference to the drawings. All the feature described in any of the drawings, and throughout the description generally are combinable except where clearly incompatible.

Figure 1 is a flow diagram of a method 100 for indicating one or more conditions of a product.

The method starts at 10, wherein it is indicated that a product has been maintained in first predetermined conditions. These first predetermined conditions may be a predetermined temperature range. For example, many products need to be kept below room temperature i.e. , during storage and/or transport. To achieve this the products may be stored in a refrigerator. Many products need to be maintained within the specific temperature range from manufacture through to use and, thus, require handling with cold-chain technology wherein an uninterrupted series of refrigerated production, storage and distribution activities, along with associated equipment and logistics, maintain quality via a desired low-temperature range. Many medical products need to be stored in the temperature range of two to eight degrees Celsius. Insulin is an example of one of these medical products which needs to be within this temperature range before use. The table below shows a number of example medical products and their associated storage temperature ranges.

Another example first predetermined condition may be that a first use of the product has not taken place.

At 20, it is indicated when the first predetermined conditions have changed. For example, when the product is exposed to a temperature outside of the predetermined (safe storage) temperature range or when a first use of the product has occurred.

At 30, a timer is activated contemporaneously with the change of the first predetermined conditions. The timer has a predetermined duration which is dependent on the time of expiry of the product as a result of the change in the first predetermined conditions. The predetermined duration is product specific and often specified by the product manufacturer. For example, once a product has been exposed to a temperature outside a predetermined associated storage temperature, it may have a predetermined number of days until the product spoils and becomes unusable. In the particular case of insulin, once exposed to temperatures outside of the storage temperature range of 2 to 8°C, it becomes unusable after around 4 to 6 weeks. The timer may also be activated in response to a first use having occurred.

The table below shows a number of example medical products and their associated durations until expiry after a change in the predetermined conditions.

At 40, it is indicated when the predetermined duration has elapsed and the product becomes unusable. The method may also indicate that the product is unusable 40 at any stage in the case of an adverse event 13 wherein the product is exposed to non-tolerable conditions which render the product immediately unusable.

Device for product durability with respect to storage temperatures A first application for the device according to the invention is for indicating a durability of an associated product with respect to predetermined storage temperatures. The device has a first temperature dependent indicator. The first temperature dependent indicator may be a chemical indicator. Alternatively, the first temperature dependent indicator may be an electronic indicator comprising at least one LED. The electronic indicator may have a single LED or an array of LEDs of different colours. In a further alternative arrangement the indicator is a combined chemical/electronic indicator. The device also comprises a timer configured with a predetermined duration substantially equal to the shelf life of the product outside storage temperature conditions. The first indicator may also provide the timer.

The device for durability with respect to storage temperatures is configured to perform the method of operation 200 of figure 2.

With reference to figure 2, wherein the product has been maintained in stable storage conditions 205, the device shows a first indication 210. This first indication is provided by the first temperature dependent indicator in a first state. The first state of the first indicator may be a particular colour, such as the colour green. Wherein the first indicator is a chemical indicator, the colour changes upon a thermochemical reaction when exposed to different temperatures. In a particular example wherein the product is to be kept within the temperature range of between 2 and 8°C, the thermochemical indicator may be configured to be the colour green when inside this temperature range. Wherein the first indicator is an electronic indicator comprising an LED, the LED is in a first state in the safe storage temperature range. For example, the LED is off (not illuminated). Wherein the first indicator is an electronic indicator comprising an array of coloured LEDs, a first LED (for example a green LED) in the array may be on when the product is within the safe storage temperature range.

At 215, the product is exposed to temperatures outside of the safe storage temperature range. In response, the device shows a change from the first indication to a second indication 220. Preferably this change is irreversible. This second indication may be provided by the first temperature dependent indicator in a second state. The second state of the first indicator may be a further particular colour, such as the colour yellow. Wherein the first indicator is a chemical indicator, the first indicator changes colour (by a thermochemical reaction). In the particular example wherein the product’s storage temperature is between 2 and 8°C, the thermochemical indicator may be configured to change colour, such as to the colour yellow, when exposed to a temperature above 8°C. Wherein the first indicator is an electronic indicator comprising a single LED, the LED may be configured to change state upon exposure to a temperature exceeding the safe storage temperature, such as changing the colour, intensity, opacity, or frequencies of off/on illuminations. Wherein the first indicator is an electronic indicator comprising an array of coloured LEDs, the first (e.g., green) LED may be configured to turn off, and a second LED (e.g. yellow) may be configured to be turned on, upon exposure to a temperature exceeding the safe storage temperature.

After exposure to temperatures outside the first predetermined range 215, the product starts to degrade 225. In response, the device is further configured to start the timer for a predetermined time limit 230. Preferably, starting of the timer is irreversible. The predetermined time limit is equal to a lifetime of the product after exposure to non-storage temperatures. This predetermined time limit may be in the order of months, weeks, days, hours, minutes or seconds depending on the particular situation/product/condition. This may be demonstrated to the user by the device in two different ways 240a, 240b.

At 240a, the device indicates that the timer has commenced by continuing to show the second indication. For example, the first indicator stays the colour yellow (chemical indicator/electronic indicator with LED colour array) or the LED continues to show the same second state intensity, opacity, or frequencies of off/on illumination (electronic indicator). Alternatively, a second indicator may be used to indicate the timer has commenced. At 240b, the device indicates that the timer has commenced and additionally shows the amount of remaining time/amount of time already expired. This may be achieved by a time-dependent increasing/decreasing opacity, intensity, or activated portions of the first indicator or the separate second indicator.

At 245, the predetermined duration expires. In response, the device shows a third indication indicating that the product is unusable 250. Preferably, showing of the third indication is irreversible. The third indication may be provided by a further change of state of the first indicator. For example, the first indicator may change from the colour yellow to the colour red (chemical indicator/electronic indicator with LED colour array). Alternatively, the second indicator may change state, for example colour, intensity, or opacity (electronic indicator). Yet further a third indicator may change state, for example by being activated, illuminated.

The device may be further configured show the third indication 250 indicating that the product is unusable immediately after exposure to intolerable conditions 213, thus bypassing all other steps in the method of operation. The triggering of the third indication 250 in response to intolerable conditions 13 may occur at any stage in the method of operation.

When the device shows the third indication 250, the user should discard the product.

Device for durability after first use

A second application for the device according to the invention is for indicating a durability of an associated product after a first use. The device has a first manually activated indicator. Thus, the device also has a manual actuator for manually activating the first indicator. The manual actuator may be a push button, pull button, or a pull-out insulation follie. The first manually activated indicator may be a chemical indicator. Alternatively, the first manually activated indicator may be an electronic indicator comprising at least one LED. The electronic indicator may have a single LED or an array of LEDs of different colours. In a further alternative arrangement the indicator is a combined chemical/electronic indicator. The device also comprises a timer configured with a predetermined duration substantially equal to the shelf life of the product after first use. The first indicator may also provide the timer.

This device is particularly useful for products that have a specific time duration after first use after which the product expires and becomes unsafe to use. In an example wherein the product is the medical product insulin, after a first use of an insulin pen, it has a lifetime (predetermined usable duration) of around 4 to 6 weeks.

The device for durability after first use is configured to perform the method of operation 300 of figure 3.

With reference to figure 3, at 305, a first use has not yet taken place. As a result, the device shows a first indication 310. This first indication may be provided via the first indicator having a first colour, for example green. Alternatively, and in particular when the first indicator is an electronic indicator, the first indication may be provided by an LED in a first state, such as off.

Upon manual activation by a user after a first use of the product 315, the device shows a second indication 320 to indicate that said first use has occurred and that the product is in the process of degrading 325. Preferably, once the first indication has changed to the second indication, the second indication cannot be reversed back into the first indication. The second indication may be provided by a change of state of the first indicator. For example, the first indicator may change from green to yellow (chemical indicator/electronic indicator with LED colour array). In the particular example wherein the first indicator is a single LED electronic indicator, the LED may change state, for example be turned on or start flashing.

After manual activation by the user to indicate first use 315, the device is also configured to start the timer 330 for a predetermined time limit equal to the lifetime of the product after first use. Preferably, once the timer has started, the timer continues to run until expiry of the time limit and cannot be reversed. This predetermined time limit may be in the order of months, weeks, days, hours, minutes or seconds depending on the particular situation/product. Similarly to the method of operation described in figure 2, this may be demonstrated to the user by the device in two different ways 340a, 340b.

At 340a, the device continues to show the second indication that first use has occurred until expiry of the time limit 345. At 340b, the device shows incremental elapse of the time limit up to expiry of the time limit 345. In both cases, the device demonstrates to the user that the product has entered a new phase wherein the product will soon expire after a predetermined time or after elapse of its designed shelf-life.

At 350, the device shows a third indication that the product is unusable. This third indication may be shown via the first indicator in a third state. Preferably, once the second indication has changed to the third indication, the third indication cannot be reversed back into the second indication. The third state may be a further colour, such as red (chemical indicator/electronic indicator with LED colour array) or a further state of the single LED, such as continually on (a single LED electronic indicator). The third indication is shown by the device upon expiry of the predetermined time limit or product shelf life.

The device may be further configured to show the third indication 350, indicating that the product is unusable, immediately after exposure to intolerable conditions 313, thus bypassing all other steps in the method of operation. The triggering of the third indication 350 in response to intolerable conditions 313 may occur at any stage in the method of operation.

When the device shows the third indication 350, the user should discard the product. Hybrid Device for durability with respect to storage temperature and after first use

A third application for the device according to the invention is a combined device for both indicating a durability of an associated product with respect to storage temperatures and after a first use.

The device has a first hybrid indicator which is both temperature-activated and manually-activated. Thus, the device also has a manual actuator for manually activating the first indicator. The manual actuator may be a push button, pull button, or a pull-out insulation follie. The first hybrid indicator may be a chemical indicator. Alternatively, the first hybrid indicator may be an electronic indicator comprising at least one LED. The electronic indicator may have a single LED or an array of LEDs of different colours. In a further alternative arrangement the hybrid indicator is a combined chemical/electronic indicator. The device also comprises a hybrid timer configured with a first predetermined duration substantially equal to the expiry time of the product after exposure to non-storage temperatures, and a second predetermined duration substantially equal to the shelf life of the product after first use. The first hybrid indicator may also provide the timer.

Figure 4 is a flowchart of a method of operation 400 of a hybrid device wherein the indicator(s) and timer are triggered by either exposure of the product to unstable storage conditions or by manual activation by a user upon first use of the product.

With reference to figure 4, at 405, the product has not been exposed to nonstorage conditions, neither has a first use taken place. As a result, the device shows a first indication 410. This first indication is provided via the first hybrid indicator. The first hybrid indicator may show a first colour, for example green. Alternatively, and in particular when the first indicator is an electronic indicator the first indication may be provided by an LED in a first state, such as off.

If the product is exposed to non-storage temperatures before a first use has occurred 415a, the device is configured to proceed with steps 210 to 240 of the method of operation 200 described above. The timer than has a predetermined duration equal to the time of degradation of the product after exposure to nonstorage temperatures. Once this duration has expired 425, the device is configured to indicate to the user that the product is unusable 450 and should be discarded irrespective of the fact that a first use may or may not have occurred.

If the product undergoes first use before exposure to non-storage temperatures 415b, the device is configured to proceed with steps 310 to 340 of the method of operation 300 described above. The timer than has a predetermined duration equal to the time of degradation of the product after first use. Once this duration has expired 425, the device is configured to indicate to the user that the product is unusable 450 and should be discarded, irrespective of whether or not the device has been exposed to non-storage temperatures.

At any stage, if the product is exposed to non-tolerable conditions 413, the device is configured to immediately show the third indication 450 that the product is unusable. This can happen at any stage in the method of operation 400 of the hybrid device.

Once the device indicates the third indication, the user should discard the product. Preferably, showing of the third indication is irreversible.

The device according to the invention is configured to be incorporated into a medical apparatus, such as a medical pen. The device and its incorporation into a medical apparatus are configured such that when using the medical apparatus, the indicator state changes may be observed without the need for any additional external device such as a personal computer, smart phone, or any other electronic device. The state changes are easily visible to the user by eye. The indicator can be place anywhere along a body of the medical apparatus but visible to the user before or during the application of the medical apparatus. Alternatively, the indicator could be placed at the top or around the top push bottom (injection button) of the medical apparatus but visible to the user before or during the application of the medical apparatus. The device according to the invention may be designed and manufactured in a complementary form, shape, and size as the existing medical apparatus. It may be produced separately before it is assembled into the existing assembling process for producing the medical apparatus. In order to avoid interference with the existing assembling process and equipment for the production of the medical apparatus, the device containing the indicator could be manufactured in a separate process or at a separate stage.

Figures 5a to 5e show examples of how the device according to the invention can be implemented on, or integrated with, a medical pen. Each of the medical pens in figures 5a to 5e have a pen body 10, a product reservoir 6 for containing a medical product 8, a dosage dial 13, and an injection button 14. The medical pens also have a needle attachment means (not shown) for attachment of a disposable needle 12.

The medical pens for use in combination with the device according to the invention may be disposable pens, wherein the product reservoir (cartridge) is integrated into the medical pen body. The medical pens for use in combination with the device according to the invention may also be reusable pens, wherein replaceable cartridges can be attached to the pen body 10.

In the example of figure 5a, the device is attached longitudinally to the body 10 of the medical pen. The device could be fixed to an outer surface of the body 10 or be an integrated part of the pen body 10.

In the example of figure 5b, the device is attached at least partially circumferentially to the body 10 of the medical pen. The device could be fixed to an outer surface of the body 10 or be an integrated part of the pen body 10.

In the example of figure 5c, the device is attached to the product retainer (cartridge) 6 of the medical pen. The device could be fixed to an outer surface of the cartridge 6 or be an integrated part of the cartridge 6.

In the example of figures 5d and 5e, the device is attached to or integrated with the injection button 14 of the medical pen. In the example of figure 5d the device is arranged at least partially circumferentially around the injection button 14. In figure 5e, the device is arranged on an end face of the of the injection button 14.

Figure 5e further shows an end on view of two example devices arranged on the end face of the injection button. A first example 1 A has a circular shape concentrically within the end face of the injection button 14. A second example 1 B is oblong and extends around the edges of the injection button 14. A benefit of the arrangement wherein the device is attached onto or integrated with the injection button is that the device can be easily attached and replaced onto a medical pen by easy attachment of the injection button wherein the injection button is not an integrated part of the medical pen. In this way, the device can be easily retrofit to standard medical pens.

In the arrangement of figure 5d or 5e, the indicator can be incorporated as an integrated part into the injection button of the injection pen. The injection button containing the indicator may be designed and manufactured in a complementary form, shape, and size as the existing medical apparatus. It may be produced separately before it is assembled into the existing assembling process for producing the medical apparatus. In order to avoid interference with the existing assembling process and equipment for the production of the medical apparatus the push bottom (injection button) containing the indicator could be manufactured in a separate process or at a separate stage.

Figures 6a to 6d show example progressive indicators such as those suitable for implementing the method of operation steps 240b, and 340b of method of operations 200 and 300, respectively.

Figure 6a shows progressive indicator 610 in the form of an elongated bar having 6 progressively activated substates 610a-610f. The first substate 610a of the progressive indicator 610 demonstrates that the product has experienced non predetermined conditions, and a timer has started. In the second substate 610b the progressive indicator 610 demonstrates that one quarter of the total expiry time has elapsed. This is indicated by changing state of one quarter of the first indicator. Wherein the first indicator is a chemical indicator, one quarter may be configured to change colour (e.g. to red) after a quarter of the total expiry time has elapsed. Wherein the first indicator is an electronic indicator one quarter of the first indicator is configured to be unilluminated. The third substates 610c indicates half the total expiry time has elapsed (thus half the first indicator changes colour/is unilluminated), the fourth substate 61 Od three quarters (three quarters of the first indicator changes colour/is unilluminated) and the fifth substate 61 Oe all of the total expiry time has elapsed (all of the first indicator changes colour/is unilluminated). The substate 61 Of is an end state indicating that the product is no longer safe to use.

Figure 6b shows progressive indicator 620 in the form of a bar having 6 progressively activated substates 620a-620f. Intermediate substates 620b, 620c, 620d and 620e are essentially the reverse of corresponding substates 610b, 610c, 61 Od, and 610e of example progressive indicator 610, i.e., in progressive indicator 620, after each quarterly expiry of the total time, a quarter of the first indicator is activated/illuminated.

Figure 6c shows progressive indicator 630 in the form of a circle having 6 progressively activated substates 630a-630f. The first substate 630a of the progressive indicator 630 demonstrates that the product has experienced non predetermined conditions, and a timer has started. Each intermediate substate 630b, 630c, 630d, and 630e represent a passing of a quarter of the total expiry time and is visualised by a changing state of a quarter of the circle area. Similarly to the progressive indicator 610, wherein the first indicator is a chemical indicator, the increments of the total circle area may be configured to sequentially change colour (e.g. to red). Alternatively, wherein the first indicator is an electronic indicator, the increments of the total circle area may be configured to sequentially be unilluminated. The substate 630f is an end state indicating that the product is no longer safe to use.

Figure 6d shows a further example progressive indicator 640 also in the form of a circle and also having 6 progressively activated substates 640a-640f. Intermediate substates 640b, 640c, 640d and 640e are essentially the reverse of corresponding substates 630b, 630c, 630d, and 630e of example progressive indicator 630, i.e., in progressive indicator 640, after each quarterly expiry of the total time, a quarter of the circle area is activated/illuminated.

In the example progressive indicators of 610 to 640, the time increments are quarterly. However, this is exemplary only and the time increments may be other divisions of the total expiry time, for example, as little as half the total expiry time up to one thirty of the total expiry time.

The invention is not restricted to only use of chemical-based indicators, only electronic-based indicators or solutions, but a combination thereof may also be used to monitor both temperature restrictions and restrictions of time intervals where the product can safely be used.

Chemical/polymer-based solutions

The indicator may be designed and manufactured to be fully chemical/polymer based with a chemical/polymer solution where colour changes results from one or more of: chemical reactions to undesired temperature, reaction time (timer) and manual activation.

To monitor or visualize that an item (pen) has been exposed to an undesired temperature, the irreversible chemical-based indicator may be produced according to, but not limited to, examples 1 to 3 below. In these embodiments, the chemicals react with each other when the solvent melts at a predefined temperature, to govern the chemical reaction.

In the particular example of an injection pen containing insulin, the pen should not be exposed to a temperature below freezing. Pre-frozen solutions of insulin should never be injected and must be discarded. To monitor such a situation, an indicator connected at any visual place to an injector pen, can be manufactured according to, but not limited to, examples 1 and 3 below. In the particular example wherein the product is a drug with other restrictions regarding temperatures, for example, the drug should not be exposed to temperature below approximately -14 °C, a chemical-based indicator as described in example 2 is suitable.

Example preparations of chemical-based indicators

The following examples 1 to 3 are non-limiting examples of a method of manufacture of chemical-based indicators that irreversibly change color when exposed to given temperatures.

Example 1 : Preparation of indicator means for color change at 0°C using acid/base systems.

Reagent 1 : NaOH (0.1 M) and Reagent 2: Citric acid (0.033 M) + Phenolphthalein, was chilled to 0 °C. 1 ml of Reagent 1 was introduced into the vial. The vial was chilled to -80 °C, and the solution allowed to harden, for 30 minutes. One to two layers of 1 ml of water was frozen on top of Reagent 1 in the same way. Finally, Reagent 2 was introduced and frozen. The resulting indicators were then stored at either -20 or -80 ° C until needed. On heating, the indicator turned red in a temperature interval -0,5°C - 0°C. Re-freezing of indicator showed no color change.

Example 2: Preparation of indicator means for color change at -15°C using acid/base systems.

Reagent 1 : NaOH (0.1 M) and Reagent 2: Citric acid (0.033 M) + Phenolphthalein, were chilled to 0 °C, and 1 ml of reagent 1 was introduced into the vial. The vial was chilled to -80 °C, and the solution allowed to harden for 30 minutes. One to two layers of a solution DI water: ethanol = 40:60 (each layer 1 ml) were frozen on top of reagent 1 in the same way. Finally, reagent 2 was introduced and frozen. The indicators were then stored at either -20 or -80 °C until needed. On heating, the indicator turned red in a temperature interval -15°C to -14°C. Re-freezing of indicator showed no color change.

Example 3: Preparation of indicator means for color change at interval 2 to 4°C using Schiff reagent systems.

Reagent 1 : Schiff reagent and Reagent 2: Glutaraldehyde aqueous solution (50 % vol.), were chilled to 0 °C, and 1 ml of reagent 1 was introduced into the vial. The vial was chilled to -80 °C, and the solution allowed to harden for 30 minutes. 1 to 2 layers of DI water (each 1 ml) were frozen on top of reagent 1 in the same way. Finally, reagent 2 was introduced and frozen. The indicators were then stored at either -20 or -80 ° C until needed. On heating, the indicator turned purple at a temperature interval 2°C to 4°C. Re-freezing of the indicator showed no color change.

Chemical-based timer indicators

Regarding chemical-based indicators that provide the timer of the device, an injector pen may be activated for the first time when the actuator (piston) is pressed. In some examples, the piston breaks a barrier material that keeps the chemicals apart. Thus, the chemicals are mixed, and a chemical reaction starts.

Example chemical-based methods for manufacturing an indicator that acts as a clock/timer in cases where a restricted time of use applies are described below.

In a first example, the reaction time to induce an irreversible colour change, may be manipulated by temperature and the concentration of reagents, the degree of solubility of reagents (free in solution, reagents in a suspension), solid reagents and the chemical properties of reagents with respect to chemical functional reactive groups within the molecules. Examples of chemical functional groups constituting reagents may be amines, aldehydes, ketones, carboxylic acids, isocyanates, thiols, to name a few non-limiting examples. In a second example, degradable polymers are used, wherein the degradation of a polymer starts when the piston is pressed the first time. A fluid will then be mixed with the polymer and the fluid will slowly degrade the polymer over a given predefined time. The concentration of degradation products will irreversibly react with each other and generate an irreversible change in opacity or colour after a predefined time. Non-limiting examples of such polymers that may be used include: polyanhydrides, polyesters, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), Dextron, polylactic acid, polyamides, polyurethanes and polyurea poly(amide- enamine)s. Degradation time needed to induce a final opacity or colour after a given time interval, may therefore be tailored by type of polymer, type of degradation products and temperature.

In a third example, initiators for radical polymerization of monomers/co-monomers are suitable. The type of initiator and monomer system will influence the speed and time for completion of the reaction leading to an irreversible change in opacity or colour. By varying the concentration and type of respective initiator and monomer composition, a gradual change in opacity or colour may be induced and after a predefine time interval, the reaction is completed to induce a permanent opacity or colour.

Electronic-based solutions

The indicator may be designed and manufactured to be fully electronic-based for example with the application of light diodes, crystals, liquid crystals or similar. In this case opacity or colour changes are controlled by electronic solutions to detect and highlight situations as items/pens are exposed to undesired temperature, on/off of light signals, timers/clocks, and manual activation.

There exists a number of commercial electronic circuits that act as a thermometer and/or a timer/clock unit. These units may be coupled to light emitting diodes to irreversibly emit a desired opacity or colour. A first circuit may control signals for emitting a specific light if said first circuit is exposed to a given temperature or a temperature range. The first circuit, or a second circuit, may also be activated, for example by pressing the piston of an injection pen to start a clock/timer function. The timer function starts when the piston is pressed for the first time and, after reaching a predefined time (time interval), the electronic circuit irreversibly activates a power signal to the diode and a specific light will be emitted. Based on the colour being emitted, the end-user can clearly see if the injection pen is safe to use. based and electronic based solutions:

The indicator may be designed and manufactured to be a combination of chemical/polymer-based solutions combined with electronic based solutions for example with the application of: electronic devices, switches, light diodes, crystals, liquid crystals or similar.

In a particular example, colour changes in response to exceeding a given temperature or a temperature range may be controlled and indicated by use of a chemical reaction, whereas a specific time interval (clock/timer) may be controlled and verified by use of an electronic circuit. Alternatively, colour changes in response to exceeding a given temperature or a temperature range may be controlled and indicated by use of an electronic circuit, whereas a specific time interval (clock/timer) may be controlled and verified by a chemical reaction.

In another example, a temperature range may be controlled by an electronic circuit to emit or induce a given irreversible change in opacity or colour after activation. The timer (time interval) may be activated by pressing a piston a first time. The clock is started and when reaching a predefined time, an electronic circuit provides power to a unit containing liquid crystals. The type of liquid crystals can be tailored to give a defined opacity or colour.

Chemical-based and electronic-based solutions will be case specific and dependent on the specific product, application area, medical apparatus device or other desired properties of an application. The best combination of solutions may be chosen accordingly. The invention seeks to give the user of products, in particular medicinal drugs, an easy way to monitor the status of the drug with respect to both temperature stability and how long it is safe to administer the drug after first time use. The device and method are based on visual detection of indicators that clearly show the different statuses of the product. As described above, the visual status is achieved by a change in opacity, color or a combination thereof. As long as the temperature indicator stays in a first state, for example the colour green, the user knows that the product has not been exposed to temperatures outside a given temperature range, and is safe to use. However, if the indicator has changed to a second state, for example the colour red, the product should not be used, and discarded according to guidelines. Likewise, if the time interval indicator changes state, for example turns yellow after first time use of an associated administrator pen, the product is safe to use. The injection pen is hence safe to use for new injections as long as the time dependent stability interval has not been exceeded. When the time interval indicator changes state, for example to the colour red, the user easily will be aware of this. The injection pen is unsafe to use and should be discarded.

Having described preferred examples of the invention it will be apparent to those skilled in the art that other embodiments incorporating the invention may be used. These and other examples of the invention illustrated above are intended by way of example only and the actual scope of the invention is to be determined from the appended claims.