WO2011006857A1

WO2011006857A1 - Blister packaging for pharmaceutical preparations

Info

Publication number: WO2011006857A1
Application number: PCT/EP2010/059962
Authority: WO
Inventors: Josephus Antonius Geboers
Original assignee: Dsm Ip Assets B.V.
Priority date: 2009-07-13
Filing date: 2010-07-12
Publication date: 2011-01-20

Abstract

Blister packaging for pharmaceutical or nutritional preparations with a compliance monitoring system wherein the blister packaging containing at least one pharmaceutical or nutritional preparation is equipped with an electronic circuitry containing- label at the side where the at least one pharmaceutical or nutritional preparation is dispensed from the blister packaging and whereby the electronic circuitry on the label is connected with a separate reading/ writing device in a housing through contact points and wherein the housing is securely connected to the medication blister by one or more means present in the housing, this one or more means comprise a) a pad made out of a high-friction material which pad is present in at least part of the housing or b) a cooperative combination of one or more recesses for receiving one or more protrusions.

Description

BLISTER PACKAGING FOR PHARMACEUTICAL PREPARATIONS

The invention relates to a blister packaging for pharmaceutical or nutritional preparations with a monitoring system, especially a therapy monitoring system.

Solid pharmaceutical preparations are generally prescribed by a physician to the patient; however some pharmaceutical preparations can be obtained without prescription (so-called "over- the- counter- medication"). Whether the medication is prescribed by a physician or obtained free over-the-counter, best results are generally obtained when the medication is taken at regular intervals so that the effective ingredient in the medication is replenished at regular and precise intervals and/or at fixed moments in time, for example before going to sleep.

Daily or otherwise regular usage is not only important in the normal use of medication so as to have an as regular dosage pattern as possible, but it is even more important in clinical trials. Before any drug is allowed to be prescribed by a physician, the drugs must be registered at local agencies, such as the FDA (Food and Drug Administration) in the USA and the EMA (European Medicines Agency) in Europe. Only after registration the drugs may be prescribed and put on the market and sold. To pass the registration procedure lots of data regarding the drug need to be collected and supplied to the authorities. Part of these data is the result of clinical trials. In several phases of the clinical trials, patients are administered a certain dose of the drug. The effects of the drug on the patient are carefully followed, so as to be able not only to determine the effect of the drug but also possible side effects. For the correct determination of the side effects it is important that the patient strictly follows the prescribed medication regime, or in other words that he complies with the regime. When he deviates from the regime he is considered not to be compliant. Here and hereinafter "to be compliant with" and "to adhere to" a prescribed medication regime are used interchangeably. With "compliance" or "adherence" is here and hereinafter meant the behaviour of a patient to follow a prescribed medication regime in a therapy. With therapy is meant the treatment to cure a disease or to prevent or lessen the malfunction of the body, including prophylactic treatments. Therapy can encompass the prescription of pharmaceutical preparations and/ or nutritional preparations.

The risks of non-compliance in clinical trials are for example the underestimation of the effectiveness of the drug, the underestimation of the side effect of the drug or the overestimation of the side effect of the drug. Side effects can in some instances lead to serious complications. For clinical trials the ICHGCP (International Conference on Harmonization Good Clinical Practice) requires that the investigator regularly checks whether the patient follows the prescriptions.

The consequence of non-compliant behaviour will strongly depend on the kind of drug the patient was taking. Maybe it will not have such a serious effect with one type of drug however it can lead to severe symptoms and side effects for another drug. When a patient who is participating in a clinical trial shows side effects, the conclusion could be drawn, possibly erroneously, that the side effects are adverse effects of the drug itself.

For all the reasons given above it would be an advantage to the patient, researcher and physician participating in the clinical trials to be able to follow the patient's compliance behaviour.

Another factor influencing patient's compliance either in clinical trials or during normal use, is posed by new developments in therapeutics such as for example the use of combinations of pharmaceuticals, so-called "cocktails" and the use of chrono-therapeutics. Since the recent discovery that combinations of

pharmaceuticals are more effective than mono-therapies in for example treating AIDS (Acquired Immune Deficiency Syndrome), some cancers and infectious diseases, some of these patients need to take considerable numbers of pills each day without missing doses, else resistance to treatment could develop. Chrono-therapeutics are used for example for illnesses that fluctuate with the biological rhythm of a patient such as for example asthma. Asthma is often more severe at night than during the day. Therefore it is not necessary to maintain a steady dose. It would be better to adjust the medication to the moment when it is needed most. A preferred treatment should match the level of the effective ingredient of a drug to the level of the symptoms by matching the prescription regime of the medicament comprising the effective ingredient to the level of the symptoms. This is exactly what can be done with chrono- therapeutics. However it is essential that the patient is very precise in complying with the prescribed (time) scheme. Chrono- therapy thus aims at the optimization of the regime for administering medication.

Patients sometimes tend to forget to take their medication.

Consequently they are non-compliant with the prescribed medication regime.

Forgetfulness is, next to the patient's attitude, also dependent on external factors, such as for example holidays, travelling through different time- zones and stress. Patients that experience more often these situations are at a higher risk for non-compliance. Another group of patients with an increased risk for non-compliance are patients with a chronic disease. As it is easier to obey prescription regimes for only 10 days than for 10 years, especially patients with a chronic disease may have difficulties in complying with the medication regime as prescribed by their physician as part of their therapy. Again another example of patients with an increased risk of non-compliance is elderly people who suffer from forgetfulness.

All the factors mentioned above, either alone or in combination in addition to the recent developments in medication can make it difficult for a patient to take his medication right in time so as to comply with the medication regime prescribed by the physician as part of the therapy. This is reflected by the fact that less than 70% of the prescribed medication is really consumed! For chronic diseases, such as for example hypertension and diabetes this is even lower: approximately 50%. When diseases or conditions are treated sub-optimally, symptoms and complications may worsen, leading to increased use of hospital and emergency services, doctor's office visits and other medical resources.

Increased adherence will generate medical savings already by the fact that less medication needs to be prescribed as for example a treatment will be shorter. Savings will additionally come from the fact that not- consumed medication must be disposed of in a sensible way, giving rise to additional costs. The not- consumed medication can pose a health risk when it is not brought back to the pharmacy or is not disposed of in another sensible way. Additionally the presence of the medication in some system can generate immunity against the active ingredient in the medication.

Increased adherence can thus increase the patient's well-being and health, decrease the negative side effects, decrease the risk of immunity, increase the effectiveness of the therapy, decrease secondary medical costs such as emergency services, decrease the amount of medication that needs to be treated as waste because it is not consumed, it overall decreases the costs of the health care system in a country.

For the reasons described above, either separately or combined, it is desirable to have means available to aid for example a patient, researcher, physician and/or pharmacist and other to increase the rate of compliance for taking medication. Possibly it not only increases the rate, but also increases the convenience, that is "the ease" with which compliance can be reached. In addition to the mentioned persons, it could also be advantageous for family and/ or friends and/ or other care- takers around - A -

the patient who are involved in some way in the medical treatment of a patient.

Therefore it is an object of the invention to provide means which could increase the rate of patient's compliance (adherence).

A blister packaging with therapy monitoring system is known from WO2004/1 10336. The blister packaging in WO2004/110336 consists of a set of insertable cards that are combined with a blister card that is laid out such that it can receive and hold medication tablets. One of those insertable cards is a trace card containing circuitry. This trace card also contains an area where an electronic monitoring device should be located.

A disadvantage of the blister packaging as described in

WO2004/110336 is that the total blister packaging comprises a set of insertable cards which makes it difficult to incorporate this type of packaging in a standard

manufacturing process. Additionally the monitoring system is vulnerable to intentional or unintentional tampering. That is, the monitoring device is not tightly secured to its position on the trace card and therefore the monitoring device can easily be removed from the card. When the monitoring device is intentionally or unintentionally removed, the monitoring of the removal of the medication from the blister is disturbed and thus not reliable anymore which makes the effort of monitoring therapy compliance worthless.

Therefore there is a need for an improved blister packaging for pharmaceutical or nutritional preparations with a therapy compliance monitoring system.

It is an object of the present invention to overcome the above mentioned disadvantages and to provide an improved blister packaging which is easily produced in a standard manufacturing process and wherein the compliance monitoring device is tightly connected to the blister packaging so as to generate compliance data with increased reliability compared to the prior art.

This object is reached by a blister packaging for pharmaceutical or nutritional preparations with a compliance monitoring system wherein the blister packaging containing at least one pharmaceutical or nutritional preparation is equipped with an electronic circuitry containing- label at the side where the at least one pharmaceutical or nutritional preparation is dispensed from the blister packaging and whereby the electronic circuitry on the label is connected with a separate reading/ writing device in a housing through contact points and wherein the housing is securely connected to the medication blister by one or more means present in the housing, this one or more means comprise a) a pad made out of a high-friction material which pad is present in at least part of the housing or b) a cooperative combination of one or more recesses for receiving one or more protrusions. In the improved blister packaging according to the invention the electronic circuitry on the label is connected with the separate reading/writing device in such a way that the signal that is generated by the removal of a pharmaceutical or nutritional preparation from its location in the blister, is effectively transferred to the reading/writing device. The pharmaceutical or nutritional preparation is removed from its location in the blister by applying a force (for example pushing) on the blister at the opposite side of the electronic circuitry by which force the label with the electronic circuitry at the pill position is broken. The rupture of the electronic circuitry and the time of the rupture is registered and stored in the system.

An additional advantage of the blister packaging according to the invention is that the electronic circuitry is located on a label that is provided with means to be securely connected to the blister. The label is after it is applied to the blister packaging always in direct and tight contact with the blister packaging. Therefore there is no risk that the removal of the pharmaceutical or nutritional preparations from the blister is unnoticed as could be the case in the set-up as described in WO2004/110336 for example. As the blister packaging in WO2004/110336 consists of a set of separate, loose cards there is always a risk that the cards get misplaced towards each other and that the removal of a pharmaceutical or nutritional preparation is not adequately registered. In the lay-out according to the present invention such a situation can't arise.

With blister packaging is here and hereinafter referred to the type of packaging that is widely known and used in the pharmaceutical industry and whereby a solid preparation is stored in its own separate location. By this arrangement it is possible to dispense such a solid preparation individually. This arrangement is therefore different from a standard bottle or container, where all solid preparations would be contained together in one compartment.

A blister packaging according to the present invention can be used in combination with all kinds of pharmaceutical or nutritional preparations. The type of preparation is not particularly relevant as long as the preparation is solid at room temperature as else reliable dispensing can not always be obtained.

The wording "solid preparation" is meant to encompass each and any form of solid dosage of a certain p re-determined amount and shape. With solid dosage is meant a dosage that during normal use by the user, such as for example a patient, retains its shape. It encompasses a dosage of a liquid or liquid-like substance that is captured within a solid skin. Examples of solid preparations are tablets, dragees, capsules and pills. Examples of solid preparations with a liquid or liquid-like substance captured in a solid skin are dragees with a gel-like substance contained in it. With solid pharmaceutical preparation is meant a solid preparation containing at least one pharmaceutically active compound. With solid nutritional preparation is meant a solid preparation containing at least one nutritionally active compound.

In a preferred embodiment the blister packaging according to the invention comprises both of the above described means for securely connecting the housing to the medication blister. Thus a preferred blister packaging is a blister packaging for pharmaceutical or nutritional preparations with a compliance monitoring system wherein the blister packaging containing at least one pharmaceutical or nutritional preparation is equipped with an electronic circuitry containing- label at the side where the at least one pharmaceutical or nutritional preparation is dispensed from the blister packaging and whereby the electronic circuitry on the label is connected with a separate reading/ writing device in a housing through contact points and wherein the housing is securely connected to the medication blister by means present in the housing, these means comprising a) at least a pad made out of a high-friction material which pad is present in at least part of the housing combined with b) a cooperative combination of one or more recesses for receiving one or more protrusions.

In another preferred embodiment the blister packaging according to the invention has as the sole means for securely connecting the housing to the medication blister at least one pad made out of a high-friction material which pad is present in at least part of the housing combined with b) a cooperative combination of one or more recesses for receiving one or more protrusions. Thus a preferred blister packaging is a blister packaging for pharmaceutical or nutritional preparations with a compliance monitoring system wherein the blister packaging containing at least one pharmaceutical or nutritional preparation is equipped with an electronic circuitry containing- label at the side where the at least one pharmaceutical or nutritional preparation is dispensed from the blister packaging and whereby the electronic circuitry on the label is connected with a separate reading/ writing device in a housing through contact points and wherein the housing is securely connected to the medication blister by means present in the housing, these means consisting of a) at least one pad made out of a high-friction material which pad is present in at least part of the housing combined with b) a cooperative combination of one or more recesses for receiving one or more protrusions. The blister packaging according to the invention is for example suitable for use in combination with medication to treat disorders of the Cardiovascular System (CVS), such as for example heart attack and stroke thrombosis, heart failure and angina pectoris, hypertension or dyslipidemia. Other suitable medication for use in combination with the blister packaging according to the invention is medication to treat disorders of the Central Nerve system (CNS) such as for example schizophrenia, depression, Alzheimer, Parkinson or epilepsy or medication to treat disorders such as for example type 2 diabetes, hepatitis or HIV (Human Immunodeficiency Virus) and medication used after transplantation to prevent rejections and medication used in oncology. Further examples of suitable medication are oral anti-biotic and anti-fungal drugs and oral drugs for treating obesity, thrombosis, asthma and chronic pain.

The blister packaging according to the invention is especially suitable for use in combination with medication whose dosage needs to be determined by the patient's blood values. Mal-compliance or non-compliance is very critical with this type of medication.

The blister packaging according to the invention used in combination with medication to treat heart attack and stroke thrombosis has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the prevention or reduction of severe pains, prevention or reduction of bleeding, paralysis and death that are connected to the non-compliant use of those types of CVS- medication. Examples of medication to treat heart attack and stroke thrombosis are Plavix (Trademark of Sanofi- Aventis), Persantin Retard (trademark of Boehringer-lngelheim), Asasantin Retard (trademark of Boehringer-lngelheim), acenoncoumarol and Prasugrel (marketed under the tradename Effient or Efient by Daiichi Sankyo Co and EIi Lilly). Especially

advantageous is the use of the blister packaging according to the present invention in combination with acenoncoumarol, Plavix and Prasugrel as by increasing the compliance of these medications additionally the risk of internal bleedings is reduced.

The blister packaging used in combination with medication to treat heart failure and angina pectoris has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the prevention or reduction of severe complications and death that are connected to the non-compliant use of those types of medication.

Examples of medication to treat heart failure and angina pectoris are Lanoxin (trademark of GlaxoSmithKline), isosorbidemononitrate retard, isosorbidedinitrate retard, Promocard durette (trademark of Astra- Zeneca),

Monocedocard retard (trademark of Altana). Especially advantageous is the use of the blister packaging according to the present invention in combination with Lanoxin (trademark of GlaxoSmithKline).

The blister packaging according to the invention used in combination with medication to treat hypertension has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the prevention or reduction of early death due to heart failure or irregularities and other complications.

Examples of medication to treat hypertension are calcium

antagonists, angiotensine II- antagonists, ACE inhibitors, β-blockers (blood pressure reducers), renin inhibitors or diuretica. Examples of calcium antagonists are

amlodipine, nifedipine retard and amlodipinemaleaat. Examples of angiotensine II- antagonists are Cozaar/ Hyzaar (trademark of MSD), Diovan/ Co-Diovan (trademark of Novartis) and Aprovel (trademark of Sanofi- Aventis). Examples of ACE inhibitors are perindopril, enalaprilmaleaat, fosinopril, lisinopril, perindopril and captopril. Examples of β-blockers are metoprolol succinate, metoprolol tartrate, metoprolol succinate, metoprolol, sotalol, bisoprolol fumarate, atenolol, carvediol and propanolol. Example of renin inhibitor is Rasilez/Tekturna (trademark of Novartis). Examples of diuretica are furosemide, spironolacton, bumetamide, hydrochlorothiazide and triamtereen.

The blister packaging according to the invention used in combination with medication to treat dyslipidemia, for example a high cholesterol level, has over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the prevention or reduction of myocardial infarction and diabetes and hypertension that often occur as side effects.

Examples of medication to treat dyslipidemia are statines (HMG - CoA reductase inhibitor) such as for example rosuvastatin, atorvastatin, pitavastatin, rivastatin, fluvastatin, pravastatin, simvastatin, lovastatin. Other types of medication used in the treatment of cholesterol are compounds in the class of fibrates, such as for example gemfibrozil and fenofibrate. These medications can be used in combination with other cholesterol medication. Examples of these type of medication are Lipitor (trademark of Pfizer), Crestor (trademark of AstraZeneca), Pravachol (trademark of Bristol-Myers Squibb), Mevacor (trademark of Merck), Zocor (trademark of Merck) and Lescol (trademark of Novartis).

The blister packaging used in combination with medication to treat disorders of the central nerve system (CNS) like schizophrenia, depression, Alzheimer, Parkinson or epilepsy has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are for example the reduction of societal costs for example due to production loss, reduction of costs related to dedicated treatment centres, reduction or prevention of loss of muscle control and reduction or prevention of severe complications on the eyes.

Examples of medication to treat disorders of the central nerve system such as depression are arecitalopram, paroxetine, amitryptiline, haloperidol, mirtazepine, sertraline, Efexor (trademark of Wyeth) and Nortrilen (trademark of Lundbeck). Examples of medication to treat disorders of the central nerve system such as schizophrenia are haloperidol, dipiperon, clozapine, pipamperon, risperidon, Zyprexa (trademark of Eli-Lilly) and Seroquel (trademark of Astra-Zeneca). Examples of medication to treat disorders of the central nerve system such as Alzheimer are Exelon (trademark of Novartis), Ebixa (trademark of Lundbeck) and Reminyl

(trademark of Janssen-Cilag). Examples of medication to treat disorders of the central nerve system such as Parkinson are levodopa/ carbidopa, akineton, Madopar

(trademark of Roche), Sifrol (trademark of Boehringer-lngelheim), Sinemet (trademark of MSD) and Comtan (trademark of Novartis). Examples of medication to treat disorders of the central nerve system such as epilepsy are Depakine chrono

(trademark of Sanofi- Aventis), carbamazepine, Keppra (trademark of UCB), diphantoine-Z, gabapentine, carbamazepine Retard, natrium valproaat and lamotrigine.

The blister packaging used in combination with medication to treat HIV has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the prevention or reduction of the deterioration of the immune system, reduction of the speed with which the virus develops, the reduction of build-up of the concentration of the virus and prevention of the development of AIDS.

HIV medicine is often prescribed as a combination therapy in which two or more types of medication need to be taken. Sometimes the order of the medication is very important and/or sometimes the timeframe within which the different medicines need to be taken is very important. Thus, for example, in some combination therapies medicine A needs to be taken first and medicine B needs to be taken within a time frame that is not shorter than for example 1 hour and not longer than 2 hours. This kind of therapies is for a patient very difficult to strictly adhere to, especially as this kind of therapies need to be taken for very long times, sometimes even life-long. Therefore th e use of a blister packaging according to the present invention in combination with HIV therapies and especially with HIV- combination therapies is very advantageous as it reduces the risks of non-compliance and the risks of side effects. The combination of the blister packaging according to the invention and the HIV medication makes life for the patient easier and reduces the risks and reduces costs of medical care for society in general.

Examples of medication to treat HIV are Norvir (trademark of Abbott), Reyataz (trademark of Bristol-Myers Squibb), Viramune (trademark of Boehringer- Ingelheim), Viread (trademark of Gilead), Stocrin (trademark of MSD). Examples of medication used in combination therapy are Kaletra (trademark of Abbott), Truvada (trademark of Gilead), Kivexa (trademark of Gilead) and Atripla (trademark of Gilead).

The blister packaging according to the invention used in combination with medication to treat type 2- diabetes has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages comprise both short term and long term effects. Additional advantages for the short term are the prevention or reduction of too low (hypoglycemia) or too high (hyperglycemia) blood sugar values, often already within a day. Additional advantages for the long term are the prevention or reduction of micro- and macro- vascular complications, eye or ear implications and the prevention or reduction of the risk of amputations.

Examples of medication to treat type-2 diabetes are Actos (trademark of EIi Lilly), Avandia (trademark of GlaxoSmithKline), Januvia (trademark of MSD), Janumet (trademark of MSD), Byetta (trademark of Amylin), Onglyza (trademark of Bristol-Myers Squibb), Eucreas (trademark of Novartis), Galvus (trademark of

Novartis), glimepiride, glibenclamide, metformine, glicazide retard and tolbutamide.

The blister packaging according to the invention used in combination with medication used after transplantation to prevent rejections has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the better results in the prevention of rejection of donor organs and/or the reduction of the chance of the necessity to return to pre-transplant treatments such as for example return to dialysis. Additionally it is known that toxicity is a serious side effect when the therapy is not adhered to (non- compliance). Examples of medication used after transplantation are Cellcept

(trademark of Roche), Prograft (trademark of Astellas), Neoral (trademark of Novartis) and Advagraf (trademark of Astellas). The blister packaging according to the invention used in combination with medication used in oncology has, over the already mentioned advantages that are connected to better compliance in general, additional advantages. Those additional advantages are the prevention or reduction of the growth of a tumour and prevention of unnecessary death. Examples of medication used in oncology are tamoxifen, Arimidex (trademark of AstraZeneca), Glivec (trademark of Novartis) Tasigna (trademark of Novartis), Femara (trademark of Novartis) for breast cancer, Casodex (trademark of AstraZeneca) for prostate cancer, Revlimid (trademark of Celgene Corp.), Sprycel (trademark of Bristol-Myers Squibb), Sutent (trademark of Pfizer), Tyverb (trademark of GlaxoSmithKline) and Xeloda (trademark of Roche).

The blister packaging according to the present invention comprises at least the following elements: a medication blister containing at least one

pharmaceutical or nutritional preparation, an electronic circuitry containing- label and a separate reading/writing device in a housing.

The medication blister containing at least one pharmaceutical or nutritional preparation is well-known in the art of packaging. One or more solid pharmaceutical or nutritional preparations are each separately packed in a medication blister. The medication blister is traditionally made out of a material that can be shaped for example by thermoforming so that the desired number of recesses, or

compartments, can be formed to receive the separate dosages of solid preparations, such as pills for example. A thermoformable material often used here is PVDC. Each solid preparation is stored in a separate, individual, recess in the medication blister. Such an arrangement makes it possible to dispense only one solid preparation at a time. The material of the medication blister is generally a laminate with more than one layer; however it can also have only one layer when the properties of the material are sufficient to meet the requirements. By using more than one layer the properties can be adapted to the requirements that are posed by the solid preparations that are stored in the compartments of the blister. In the case of pharmaceutical preparations, protection against, amongst others, humidity and oxygen is very important. Therefore the laminate generally comprises at least one barrier layer. Although the medication blister as described above is generally used in this field, other forms of medication blisters are also suitable to be used in the present invention.

The one or more recesses in the medication blister are sealed by a foil after the solid pharmaceutical or nutritional preparation is provided. This foil generally also has to be a barrier against amongst others, humidity and oxygen. Therefore this sealing foil comprises often a metallic layer such as for example aluminium. The foil can comprise next to the metallic layer, other layers too. Those other layers can provide the foil with various properties and can therefore for example be a layer for heat sealing and a layer for printing. The medication blister used in the blister packaging according to the invention is a well-known, off-the-shelf, standard medication blister. The fact that the blister packaging according to the present invention makes use of such a well-known and broadly available medication blister is a big advantage as for using the blister packaging according to the invention no

modifications need to be applied to the packaging process of the pharmaceutical or nutritional solid preparation.

The blister packaging according to the invention is compounded after the pharmaceutical or nutritional preparation is already safely packaged under the conditions to assure the quality and meet all necessary requirements.

The blister packaging according to the invention further comprises an electronic circuitry containing- label. This is schematically shown in Figure 1. An electronic circuitry containing- label is a label that comprises in at least one of its one or more layers, an electronic circuitry.

In the present invention the side of the medication blister where the sealing foil is (generally a metallic foil such as for example an aluminium foil), is covered with an electronic circuitry-containing label. The label is adjoined with the medication blister by suitable means. An example of such a suitable means is an adhesive. However the man skilled in the art is well aware of other suitable means to adjoin two or more layers, for example heat-welding. It is preferred to use a suitable adhesive for bonding as it can be conveniently used in an industrial- scale process and it is easy to change to another type of adhesive when the materials in the blister and label necessitate this. A suitable adhesive is an adhesive that displays the desired level of bonding strength, so as to prevent that the label, when attached to the medication blister, would get separated from the medication blister during storage or use. The characteristics of the suitable adhesive are dictated by the choice of materials in the label and the sealing foil of the medication blister. The man skilled in the art can easily determine a suitable adhesive based on the required level of bonding strength.

The material used for the label is chosen such that the push-through characteristics of the medication blister are not significantly impaired. When a person, for example the patient, wants to dispense the pharmaceutical or nutritional preparation (shortly "the pill") from the medication blister, he applies some force on the pliable side of the medication blister; that is normally on the side where the thermo- formable material is located. By applying this force the patient is able to push the pill through the sealing foil. Now that the label containing the electronic circuitry is attached to the sealing foil of the medication blister it will take slightly more force to push the pill through the sealing foil and the label. The amount of additional force required can be steered by the choice of the material of which the label is made, preferably this additional force is low, more preferably minimal. Alternatively, to allow for push- through, the material may be mechanically weakened by introducing local stress- enhancing defects e.g. by cutting techniques or laser ablation techniques. These techniques itself are well-known to the man skilled in the art.

Examples of materials suitable for use as a label in the blister packaging according to the invention are paper, cardboard, laminates, polymers such as for example polyester (for example PET, polyethylene terephtalate), polyacrylate, polyimide, polyolefins such as for example polypropylene.

The label comprises at least one layer; however the label may comprise more than one layer. The label comprises at least an electronic circuitry in at least one of its one or more layers. The electronic circuitry is composed of amongst others one or more conductive lines that are printed on a layer of the label. The conductive lines are aligned in such a way that each recess in the medication blister (containing a pill) has at least one conductive line running over it. Preferably each recess has one unique conductive line running over it. The one or more conductive lines in the electronic circuitry can be printed in any suitable pattern. The printing is of course adapted to the dimensions of the medication blister and its recesses. When a pill is pushed out through the sealing foil and thereafter through the label material, the conductive line will lose continuity, it breaks. This event is detected by monitoring the conductive lines through the electronic circuitry. The date and time of this event are stored into the memory comprised in the electronic circuit and can be further processed from the memory. By the fact that each recess has its own conductive line, it is possible to observe whether a dose present in a recess is dispensed. In this way it can be observed whether the patient has taken his medication and whether he has done so according to the prescribed regime and thus whether he is compliant.

The electronic circuitry containing- label can take any suitable shape as long as the conductive lines are aligned in such a way that each recess in the medication blister (containing a pill) has at least one conductive line running over it. Generally the label will be at least of the same size as the medication blister. Preferably th e label will be larger than the medication blister. For practical purposes it is advantageous to extend the label on at least one side so that the label on that one side is longer than the medication blister.

In a preferred embodiment the electronic circuitry containing label has in its length or in its width approximately the same dimension as the medication blister it is going to be attached to: the other side has a larger dimension than the medicine blister. Therefore in this embodiment, when the width of the label is of approximately the same dimension as the width of the medication blister then the length of the label is longer than the length of the medication blister. Alternatively in this embodiment: when the length of the label is of approximately the same dimension as the length of the medication blister then the width of the label is longer than the width of the medication blister

In another preferred embodiment, the electronic circuitry containing label is longer than the medication blister it is going to be attached to and the width of the part of the label that extends over the blister is smaller than the width of the blister. In this way a kind of "tongue" is formed that makes a better connection to the housing possible (see figure 5 A and B).

In again another preferred embodiment, the electronic circuitry containing label is wider than the medication blister it is going to be attached to and the length of the part of the label that extends over the blister is smaller than the length of the blister. Also in this way a kind of "tongue" is formed that makes a better connection to the housing possible (see figure 5 A and C).

Usually the conductive lines will be printed on one of the layers of the label, making use of conductive inks. The man skilled in the art is familiar with this technique of printing, for example screen printing can be used.

To monitor the event of a pill push-through, the conductive lines are connected to a PCB (printed circuit board) containing suitable electronics. Standard ACF (anisotropic conductive film) bonding techniques suffice for both conductivity and mechanical strength.

The blister packaging according to the invention further comprises a separate reading/ writing device in a housing. The housing is used to contain and protect the part of the electronic circuitry that is not located on the label. The dimensions of the housing are not particularly relevant, however it is preferred to use a housing with dimensions as small as possible as that improves the ease with which the blister packaging can be taken along by the patient. When taking along the blister packaging is easy, the patient is less likely to forget taking his medication when away from home, therefore compliance to his medication regime and therapy is enhanced. The dimensions of the housing are preferably at most equal to the dimensions of a credit card but more preferably the dimensions of the housing are smaller than the dimensions of a credit card. Dimensions of a credit card are approximately 85 mm by 55 mm.

The housing needs to be made out of suitable material so as to be capable of protecting the electronic circuitry at least during the life-time of the medication blister. Suitable materials for the housing are therefore polymeric materials such as for example polyolefins. A suitable example of a polyolefin is polypropylene.

The housing comprising the separate reading/writing device and electronic circuitry is securely connected to the medication blister that is equipped with the label containing an electronic circuitry, by one or more means present in the housing. This is schematically shown in Figure 2. These means can comprise a) a pad made out of a high-friction material which pad is present in at least part of the housing or b) a cooperative combination of one or more recesses for receiving one or more protrusions. The recess and the cooperating protrusion are located on opposite sides of the housing. The housing can take many forms, for example the form of a small booklet that can be opened and which then contains a left and a right-hand side. These left- and right- hand sides become after closing the front and back side of the housing with the blister packaging in between. This is exemplified in Figure 3, which is included for illustrative purposes and is not meant to be limiting the scope of the invention.

The recess as a possible part of the means for securely connecting the medication blister with the housing is located on one side of the housing, for example on the left-hand side as depicted in Figure 3. The protrusion as the other part of the securing means is located opposite of the recess, thus on the opposite side of the housing. In Figure 3 that would be the right-hand side (the recess and the protrusion are not shown in Figure 3). The relative position of the recess and the protrusion is such that they can cooperate with each other so as to make a tight, fitting connection.

The form and size of the recess and protrusion are not particularly relevant as long as they can cooperate together. An example of a cooperating recess and protrusion are a hole and a pin.

The nature of the high- friction material as a possible part of the means for securely connecting the medication blister with the housing is not particularly relevant, as long as the friction it provides to the opposite side of the housing is relatively high. Whatever the combination chosen, the friction between the housing and the high-friction material must be such so as to prevent the medication blister from slipping-out of the housing. The necessary friction to be provided by the high-friction material depends on the material of the opposite side of the housing. When the material of the housing is very smooth, the friction provided by the high-friction material must be higher than when the housing itself already provides for a substantial amount of friction. A suitable example of a high-friction material is rubber or a rubber- like material. An additional advantage of rubber or rubber- like material is that it can be compressed. This is advantageous as it provides to the electronic elements present in the housing, protection against shocks.

The separate reading/writing device in the housing has, amongst others, the function to make transfer of the registered data and communication with for example the data base, possible. The man skilled in the art knows what type of reading/ writing device he can use to fit this purpose. An example is shown in figure 4: NFC r.f.front end using the PN512 or any similar device.

The electronic circuitry on the label is connected to the electronic circuitry and the separate reading/ writing device in the housing, through one or more contact points. Those one or more contact points are preferably located on the high- friction material.

The housing comprising the separate reading/writing device and electronic circuitry can be securely connected to the medication blister by the means as described above. In a preferred embodiment of the invention another, additional securing means is applied on the opposite side of the housing compared to the location where the high- friction material is located. The preferred additional securing means comprises another layer of high- friction material, preferably ethylene vinyl acetate (EVA).

When the housing is open, the label can be inserted such that the electronic circuitry of the printed label and the electronic circuitry in the housing are automatically in the proper position and closing the housing will press the housing's high- friction pad against the label contacts such that it will be impossible to remove the label from the housing.

The blister packaging according to the invention contains a clock- calendar function so that the blister packaging can register the time and date stamp when a pill has been removed from the medication blister. The information on the date and times that the medication is taken from the blister packaging are stored into the memory. Optionally, additional information, for example about the medication, can be stored into the same memory.

Using communication devices working with near- field communication (NFC) such as the for example an NFC enabled telephone, the information contained in the memory in the blister packaging according to the invention can be read out and optionally displayed, and can be transmitted for example via a GPRS radio link, to a database where patients' medication therapy behavior (compliance behavior) can be recorded.

The database contains all kinds of patient related information and these records can be accessed via the Internet, preferably via appropriate security settings. This information is correlated and analyzed in the database and, in case of mal- or non- compliance, the patient can be warned via an SMS service or the like such as for example call centre, pharmacist or care organization.

By logging on to this database, the patient can follow his pill- intake history. This information has been gathered from the blister packaging during the period of time that the blister packaging has been used by the patient and can when desirable be stored and retrieved for a long time.

The blister packaging according to the invention can be supplied with options such as for example a number of questionnaire buttons, one or more colored LEDs, a buzzer and/or vibration signal to warn for example the patient when a pill needs to be taken.

An example of a possible lay-out of the electronic circuitry of the blister packaging according to the invention is shown in Figure 4. As the man skilled in the art will understand, this is only one of the possibilities and is therefore not meant to limit the scope of the invention. The blister packaging according to the invention is a self-contained, battery-operated unit. The man skilled in the art is familiar with the type of electric circuitry as used in the present invention. He will easily understand that modification is possible while not deviating from the scope of the present invention. Reference for this purpose can be made to WO2009/080309 and WO2010/066904.

The figures are intended for clarification only; they do not limit the scope of the invention.

Claims

1. Blister packaging for pharmaceutical or nutritional preparations with a

compliance monitoring system wherein the blister packaging containing at least one pharmaceutical or nutritional preparation is equipped with an electronic circuitry containing- label at the side where the at least one pharmaceutical or nutritional preparation is dispensed from the blister packaging and whereby the electronic circuitry on the label is connected with a separate reading/ writing device in a housing through contact points and wherein the housing is securely connected to the medication blister by one or more means present in the housing, this one or more means comprise a) a pad made out of a high-friction material which pad is present in at least part of the housing or b) a cooperative combination of one or more recesses for receiving one or more protrusions.

2. Blister packaging for pharmaceutical or nutritional preparations with a therapy monitoring system characterized in that the blister packaging containing at least one pharmaceutical or nutritional preparation is equipped with an electronic circuitry containing- label at the side where the at least one pharmaceutical or nutritional preparation is dispensed from the blister packaging and whereby the electronic circuitry on the label is connected with a separate reading/ writing device in a housing through contact points and wherein the housing is securely connected to the medication blister by means present in the housing, these means comprising a) at least a pad made out of a high-friction material which pad is present in at least part of the housing combined with b) a cooperative combination of one or more recesses for receiving one or more protrusions.

3. Blister packaging according to claim 1 or 2 wherein the label is connected to the blister packaging by the use of an adhesive

4. Blister packaging according to any of the preceding claims characterized in that the high-friction material is a rubber or rubber-like material.

5. Blister packaging according to any of the preceding claims characterized in that the one or more contact points are located on the high-friction material.

6. Blister packaging according to any of the preceding claims characterized in that the pharmaceutical preparation is medication to treat disorders of the Cardiovascular System or disorders of the Central Nerve System, medication to treat type 2 diabetes, HIV, hepatitis, medication used after transplantation, medication used in oncology, anti- biotic or anti- fungal drugs, medication to treat obesity, thrombosis, asthma or chronic pain.

7. Blister packaging according to claim 6 characterized in that the medication to treat disorders of the Central Nerve System is medication to treat

schizophrenia, depression, Alzheimer, Parkinson or epilepsy.

8. Blister packaging according to claim 6 characterized in that the medication to treat disorders of the Cardiovascular System is medication to treat heart attack and stroke thrombosis, heart failure and angina pectoris, hypertension or dyslipidemia.

9. Blister packaging according to claim 8 characterized in that the medication to treat dyslipidemia is a statin.

10. Blister packaging according to claim 9 characterized in that the statin is

rosuvastatin or a pharmaceutically acceptable salt or solvate thereof.

11. Blister packaging according to claim 9 characterized in that the statin is

atorvastatin or a pharmaceutically acceptable salt or solvate thereof.

12. Blister packaging according to claim 8 characterized in that the medication to treat hypertension is an angiotensine II- antagonist

13. Blister packaging according to claim 6 characterized in that the medication used in oncology is used to treat breast cancer