CORONARY EVENTS

Field of the invention: The invention relates to a portable pharmaceutical kit or medical device comprising at least a platelet aggregation inhibitor, preferably a thienopyridine compound, provided in an oral administration form, and at least an anticoagulant, preferably a factor-Xa inhibitor or a low-molecular weight heparin, provided in a subcutaneous administration form. The device / kit may additionally contain further drugs assisting the treatment of the heart dysfunction or heart disease of the patient, including drugs increasing the tolerability of the primary drugs.

The invention relates further to a medical device in a portable size and shape comprising said kit in form of different containers, one of them is provided in size and form of a syringe for subcutaneous administration. The medical device may further contain technical equipments that allow the patient to inform the doctor or other persons or institutions by an emergency call or signal.

The kit and the medical device are useful for the immediate self-application shortly after the sudden occurrence of severe chest pain in context with acute coronary syndrome (ACS) or pulmonary embolism in persons previously identified by their doctors as ACS patients or individuals having a high risk to suffer from ACS.

Background of the invention:

Myocardial infarction, commonly known as heart attack, is a widely spread heart disease in the Western hemisphere from which a high percentage of the population suffers and die. Acute myocardial infarction can be successfully treated by

medicaments, provided that the person hit by a sudden heart attack can be rapidly treated with suitable drugs within a few minutes. Thus, the time factor is critical for survival.

Acute coronary syndrome (ACS) is a set of signs and symptoms (syndrome) related to the heart. ACS is compatible with a diagnosis of acute myocardial ischemia, but it is not characteristic of the diagnosis. The sub-types of acute coronary syndrome include unstable angina and two forms of myocardial infarction in which heart muscle is damaged. These types are named according to the appearance of the

electrocardiogram (ECG/EKG) as non-ST segment elevation myocardial infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI). There can be some variation as to which forms of Ml are classified under acute coronary syndrome.

Therefore, the current American College of Cardiology and American Heart

Association (ACC/AHA) guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) endorse the concept that faster times to reperfusion and better systems of care are associated with important reductions in morbidity and mortality rates (Antman et al., J Am Coll Cardiol 2008; 51 :210-247; Kushner et al., J Am Coll Cardiol 2009; 54:2205-2241).

In selected therapy fields, such as arterial fibrillation and diabetes, the "pill/drug in the pocket" concept was already successfully established thus securing that the respective patient can be immediately provided with the suitable medicament independent on the location he/her she is just present.

Therefore, there is a need to apply this fast-supply approach to patients suffering from acute coronary syndrome (ACS) and / or pulmonary embolism, wherein the

dysfunction starts with suddenly occurring severe chest pain. Summary of the invention:

The invention provides a portable medical device comprising drugs of different pharmaceutical activity and effectiveness in the therapy and prevention of acute coronary syndrome (ACS) and / or pulmonary embolism which may occur in connection with acute heart attack / myocardial infarction / ischemic heart disease and all related events and syndromes directed thereto. The portable pharmaceutical kit or medical device is based on well known compounds effective in ACS and conditions developed from myocardial infarction, and comprise at least two drugs of different pharmaceutical activity, namely

(i) anti-platelet activity and (ii) anti-coagulant activity. The portable medical kit / device according to the invention is suitable for use in patients previously selected and risk-stratified by a cardiologist or another skilled physician, in case of suddenly occurring severe chest pain. Self-application of some drugs immediately after calling the emergency doctor might improve the outcome in ACS and pulmonary embolism. In particular, the medical device of the invention is specifically suitable in less developed areas where it might take a long time for an emergency doctor to arrive, early self-application may be significant.

Suitable patients to which the portable medical device or kit can be applied include patients with previous history of ST-elevation myocardial infarction (STEMI) or non- ST-elevation myocardial infarction (NSTEMI) or elective percutaneous coronary intervention (PCI), who are currently treated with mono-antithrombotic therapy with acetylsalicylic acid (ASA) in a dose of 81-325 mg/day.

Furthermore, suitable individuals according to this invention are patients without history of coronary artery disease (CAD) and with a less well established indication (class Mb) for coronary angiography according to the ACC/AHA guidelines (patients with Canadian Cardiovascular Society class I or II angina without high-risk findings on non-invasive testing, patients with nonspecific chest pain, recurrent contact with physician and without high-risk findings on non-invasive testing, etc.).

Less suitable patients according to this invention are individuals with dual antiplatelet therapy or with anticoagulation with a vitamin K antagonists controlled by international normalized ratio (INR) or aortic aneurysms (as the most important criteria among others) and patients with contraindication for one or more of the drugs of the medical device according to the invention (e.g. ASA, thienopyridine derivates, factor-Xa inhibitors, low molecular weight heparin) The principal idea of the present invention is that the medical device or "Chest Pain Kit" can be taken by the patient him or herself immediately after calling the emergency doctor, ideally with a technical system that allows localization of the patient. As in the real world, it remains the patient ^' s decision when to call the emergency doctor and consequently to initialize self-treatment with the drugs. Furthermore the portable medical device / kit according to the invention can provide in one embodiment additional information for the emergency doctor, noted or stored by different technical systems on or inside the "Chest Pain Kit", for example: "Patient takes ASA 81-325 mg daily" or "Patient does not take ASA 81-325 mg daily".

Typically, the portable medical device can contain, for example, (i) a thienopyridine derivate (e.g. per os), and / or (ii) a factor-Xa inhibitor or low molecular weight heparin (e.g. by subcutaneous injection). Depending on house-medication, additionally, the device/kit may contain, for example: acetyl salicylic acid (ASA) (e.g. per os), a proton pump inhibitor (e.g. per os), and a statin (CSE - inhibitor) (e.g. per os). The invention includes also a combination tablet with these drugs that could improve the compliance of the patient and simplify the administration. Moreover, the "Chest Pain Kit" can be designed in shape and form to be easy to use. In particular, in less developed areas where it might take a long time for the emergency doctor to arrive, this "pill in the pocket" concept may be significant.

In patients previously selected, for example, by a cardiologist, early self-application of dual antiplatelet therapy (e.g., ASA plus thienopyridine) and a direct thrombin (II) inhibitor or a anticoagulant, such as a factor Xa inhibitor (e.g. fondaparinux) immediately after calling the emergency doctor might be of significance in case of ACS or pulmonary embolism. The combination of drugs inside the "Chest Pain Kit" can be individually adapted by a cardiologist or the house doctor to allow

exclusion/inclusion of other suitable drugs, such as ASA, statins, PPIs etc. To sum up, the invention relates to the following subject matters:

• A portable medical device or pharmaceutical kit comprising

(i) a first package or container comprising at least a first platelet inhibitor and

(ii) a second package or container comprising an anticoagulant, and

(iii) equipments that allow (a) to determine the location of the portable medical device and thereby of a patient in possession of the device, and / or (b) to send an emergency call or signal to a pre-determined person or institution,

for use in the treatment of acute coronary syndrome (ACS) and / or pulmonary embolism accompanied by suddenly occurring chest pain, wherein the device is designed and provided for self-administration in case of emergency by said patient pre-diagnosed by a physician. Alternatively, a portable medical device or pharmaceutical kit comprising (i) at least a package comprising a first platelet inhibitor or a package comprising an anticoagulant, and (ii) equipments that allow (a) to determine the location of the portable medical device and thereby of a patient in possession of the device, and / or (b) to send an emergency call or signal to a pre-determined person or institution,

for use in the treatment of acute coronary syndrome (ACS) and / or pulmonary embolism accompanied by suddenly occurring chest pain, wherein the device is designed and provided for self-administration in case of emergency by said patient pre-diag nosed by a physician.

A respective portable medical device or pharmaceutical kit, wherein the first platelet inhibitor is a thienopyridine compound, preferably selected from the group of drugs consisting of Clopidogrel, Prasugrel, Ticlopidine, and Ticagrelor.

A respective portable medical device or pharmaceutical kit, wherein the first package or container or further packages or containers comprises a second platelet inhibitor that secures a dual inhibition of thrombocyte aggregation in connection with the first platelet inhibitor, wherein the second platelet inhibitor is preferably acetyl salicylic acid (ASA).

A respective portable medical device, wherein said first and said second platelet inhibitor are combined to form a single formulation, preferably provided for oral administration in form of a tablet or capsule.

A respective portable medical device, wherein the anticoagulant is factor-Xa inhibitor or a low-molecular weight heparin, preferably the factor-Xa inhibitor Fondaparinux, which is preferably provided for subcutaneous administration.

A respective portable medical device or pharmaceutical kit comprising in said first or further packages or containers a proton pump inhibitor and / or a statin and / or a beta-blocker and /or a nitro-derivate and / or a sedative, wherein one or more of said drugs are provided separate or in combination for oral administration in form of a tablet or capsule. A specific respective portable medical device or kit, wherein the first package or container comprises a thienopyridine compound and optionally ASA separate or in combination for oral administration in form of a tablet or capsule, and the second package comprises a factor-Xa inhibitor, preferably Fondaparinux, or a low-molecular heparin, preferably provided for subcutaneous administration.

A respective portable medical device or pharmaceutical kit, wherein the acute coronary syndrome (ACS) is based on previous ST-elevated myocardial infarction (STEMI) or non-ST-elevated myocardial infarction (NSTEMI).

A respective portable medical or pharmaceutical kit, which is equipped with a needle and a movable bolt to form a syringe for subcutaneous administration of the factor-Xa inhibitor or low-molecular heparin and / or another drug selected from the group consisting of a platelet inhibitor, an anticoagulant, a proton pump inhibitor and / or a statin and / or a beta-blocker and /or a nitro-derivate and / or a sedative solved in a liquid formulation, wherein the liquid formulation is filled in said syringe or in a container or package of the device, from that the drug(s) is (are) mounted by said syringe.

A respective portable medical or pharmaceutical kit, further comprising an equipment that includes a GPS- and / or a mobile radio-, and / or a mobile phone system, and or a USB connection, and / or a digitally / electronically stored information system including pictures or movies regarding the medical history of the said patient.

A respective portable medical device or pharmaceutical kit that has the size and shape of a bolt, a pen, a ball pen, a mobile phone, an USB stick or similar devices.

Detailed description of the invention:

As stated above, the medical device of the invention comprises at least one drug, preferably at least two drugs of different pharmaceutical activity, wherein said drug or drugs elicit (i) anti-platelet activity and / or (ii) anti-coagulant activity. Moreover, additional drugs assisting the desired therapeutic effect can be present in the device or kit. The drugs are placed in one or more chambers or containers of the portable medical kit / device. The chambers / containers should constructed in way that they can be easily unblocked (in case of emergency) and closed by the patient for release und storage of the drugs. This includes drugs in solid as well as in liquid form for oral or subcutaneous application.

In case of oral formulations the respective drug is formulated as tablet, capsule, granulate or powder, that is filled in said container or chamber.

In case of liquid formulations for subcutaneous applications the respective drug solved in a suitable pharmaceutical formulation is filled, in one embodiment of the invention, in a separate sealed leak-proof box or flask from which the drug can be extricated (for example, via a typical cartridge seal) by means of a separate syringe, which preferably is a component of the portable medical device according to the invention. In another modified embodiment, the liquid formulation of the respective drug was directly filled into the volume of a prefabricated syringe, which is a

component of the medical device of the invention. In the latter case the prefabricated syringe may be an integral part of the portable device or kit: By pressing, for example, a button on top of the device a needle, as part of the prefabricated syringe, is released and by further pressing the button the bolt of the syringe is activated to press the liquid drug through the needle into skin tissue for subcutaneous application.

The syringe for the subcutaneous application of the liquid anticoagulant may be physically separate from the medical device but is preferably an integral part thereof and may be hidden within the medical device. The needle of the syringe may be easily expanded or unplugged from the interior of the device, for example, by pressing a button or a pin or by using a comparable release system. With respect to the necessary simple handling of the syringe, the liquid pharmaceutical formulation containing the solved anticoagulant is already prefilled in the syringe volume in a preferred embodiment of the invention. It is also possible that the liquid anticoagulant formulation is stored in a separate box, bottle or container as part of the medical device, and then must be mounted by the needle of the syringe into the container volume of the syringe. The containers, boxes, and chambers of the medical device according to the invention may be distinctly marked, e.g. by shape, color, or printed labeling, in order to unambiguously indicate to the patient in case of emergency which drug is stored in which container or chamber, thus preventing mistakes with respect to the drug(s) to be administered and optionally scheduling and / or sequence of administration.

Anti-platelet drugs of the invention: In a preferred embodiment of the invention, the anti-platelet activity is initiated by a dual-drug approach using two antiplatelet medicaments with different specificities. Only in case that the patient is / was already under permanent therapy with one of these anti-platelet drugs, the kit / medical device should contain only one drug with platelet formation inhibitory activity, which is / was not yet applied to the patient.

In a preferred embodiment, the first container or package comprises a thienopyridine compound as first anti-platelet inhibitor. Thienopyridines are a class of ADP receptor / P2Y12 inhibitor, which are well known as being effective in inhibiting platelet formation and aggregation. Marketed thieonopyridines are, for example, Clopidogrel, Prasugrel, Ticlopidine and Ticagrelor. The thieonpyridines according to the invention are preferably used in an oral formulation, such as tablets or capsules or powders. One or more of these tablets, capsules or powders are given and stored in one or more container or package of the portable medical device according to the invention.

In a specifically embodiment of the invention the dual platelet aggregation inhibition is carried out providing a second platelet inhibitor, preferably acetyl salicylic acid (ASA). In a preferred embodiment of the invention the first (mandatory) anti-platelet compound is a thienopyridine compound, such as Prasugrel, and the second

(optional) platelet inhibitor is ASA, each in an oral administration form, in one single or two different tablets or capsules, placed in one or two containers.

Anticoagulants of the invention: The anticoagulants according to the invention are selected from the group consisting of factor-Xa inhibitors, preferably from the glyosaminoglycan group, and low-molecular weight heparin. In a preferred

embodiment according to the invention the factor-Xa inhibitor is Fondaparinux or Idraparinux, or alternatively, low-molecular weight heparin, such as Bemiparin, Certoparin, Dalteparin, Enoxaparin, Parnaparin or Reviparin. According to the invention, the anticoagulants can be administered orally or subcutaneously dependent on the market availability of the suitable respective drug. Preferably, and in case of the use of glycosaminoglycans, such as Fondaparinux, the drug is administered subcutaneously via a syringe system as described above. Drugs assisting the therapy: In some cases, dependent on the individual medical profile of the patient, it is recommendable that the medical device of the invention further comprises medicaments which assist the ACS therapy or prevent or reduce side-effect caused by the drugs of the medical device as described above. These drugs should be placed in other containers than that which comprise the anticoagulant and the anti-platelet medicament. They may be placed, however, in one or different containers or chambers, in one or different medical units. Preferably, if available, they should be suitable for oral administration and provide as tablets, capsules, granulates or powders.

The assisting drugs according to the invention are selected from the group consisting of a proton pump inhibitor and / or a statin and / or a beta-blocker and /or a nitro- derivate and / or a sedative, or drugs with identical or similar biological activity.

Proton pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They belong to the most potent inhibitors of acid secretion known so far. Examples for suitable proton pump inhibitors according to the invention are Omeprazole, Lansoprazole or Pantoprazole.

Statins are a class of drug used to lower plasma cholesterol level. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase. Examples of suitable statins according to the invention are: Atorvastatin, Lovastatin, Rosuvastatin and others available in the market. Beta blockers form a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias, cardio-protection after myocardial infarction (heart attack), and hypertension. Examples of suitable beta blockers according to the invention are: Bisoprolol, Atenolol, Alprenolol, Timolol, Betaxolol and others available in the market. Practical use of the invention: The portable medical device / kit is for use in the treatment of acute cardiovascular events in an individual who was pre-determined or pre-diagnosed by a physician and identified as heart patient or risk-stratified for a heart disease or a heart dysfunction. Thus, the composition of drugs and their dose contained in the medical device of the invention are determined by the physician in advance, individualized to the patient. Therefore, the medical device can be provided with the specific drugs according to the individual disease / health condition of the patient. The medical device / kit should be used as permanent attendant of the risk- stratified patient and allows him or her to move more free and independent outside the clinic or doctor's practice, because the device is designed and provided for self- administration by said individual in case of emergency in context with suddenly occurring chest pain indicating ACS or pulmonary embolism, or similar cardiovascular symptoms or events. Thus, the patient can treat himself/herself at any time when and wherever heart deriving chest pain occurs. The medical device of the invention is preferably easily portable for the patient, and thus, has to be of a convenient size and shape, such as a ball pen, a stick, a box, a case. It may be have also the size and shape of a mobile phone or of other convenient shapes or sizes suitable for individual handling, guidance and transportation.

Further equipment of the medical device: In a further embodiment of the invention the portable medical device is equipped with technical arrangements that support information exchange, preferably information which can be provided from the patient to the doctor, a medical hospital, a third person or institution, in case of emergency when the patient gets sudden severe chest pain in consequence of ACS or a heart attack, or pulmonary embolism, or other heart derived dysfunction displaying chest pain. Therefore, the portable medical device is provided with an emergency button, which can be pressed by the patient when sudden chest pain occurs. The button is linked to a technical electronic equipment inside the medical device that sends signals with data informing about the current location of the patient determined, for example, by GPS, or other comparable location destination systems. The information is automatically sent to a pre-determined physician, a hospital or another person. This emergency signal enables aid facilities, e.g., an ambulance, to locate the position of the patient and to pick him / her up for transportation to the hospital or to the physician for further therapeutic treatment, if necessary. Together with the emergency signal it is principally possible to send from and / or to the patient patient-specific data stored by a digital and / electronic storage system in the portable medical device of the invention. Thus, the responsible physician can prepare the necessary therapeutic measures in advance. In an alternative variant according to the invention, the GPS signal and / or information signal can be supplemented or replaced by a standard mobile phone system or another wireless / radio system, e.g. a voice radio. In this case, the patient has the possibility to inform the physician, hospital, third person or institution by a call, where he or her is just sojourning and from which problems or conditions he or her is just suffering. In a further variant of the invention the portable medical device / kit of the invention is alternatively or additionally equipped with a USB interface and storage unit, that enables to exchange easily patient specific information and data including patient history, pictures, dosage regimen, etc., automatically via wireless signals initiated by the patient and / or the doctor (or any other medical institution). The following Examples are provided to describe the invention in more detail and by specific embodiments without limiting it.

Example 1 : The portable device in size and shape of a thick stick is equipped with an emergency button, a GPS sender and a USB interface / storage unit. The device contains at least two chambers. The first one comprises a thienopyridine compound as anti-platelet compound as tablets or capsules in a typical dose, predetermined by the patient's doctor. The second container contains an anticoagulant, such as Fondaparinux in a liquid formulation, wherein the container is a syringe system with bolt and needle. The needle can be pulled out from the medical device by a separate button. Example 2: The same device as described in Example 1 , however containing a separate syringe and a separate sealed box containing the anticoagulant in liquid formulation. The patient has to take the syringe and to mount the pre-determined volume from the sealed box (for example through a rubber seal) into the container of the syringe. Example 3: In the same or similar portable device as described in Example 1 , at least three containers are placed. The first and second container comprise the drugs as indicated above. The third container comprises a second platelet inhibitor, for example, ASA in an oral administration form, for example, as tablets. The container can hold one, two or more tablets / capsules. The portable device is additionally equipped with a mobile phone system. Example 4: In the same or similar portable medical device as described in

Example 1 , 2 or 3, a fourth container is placed comprising one or more tablets / capsules comprising a proton pump inhibitor, such as Omeprazol in a typical standard or pre-determined dose.

Example 5: In the same or similar portable medical device as described in any of the Example above, wherein one container comprises one, two or more tablets comprising a combination of two different drugs selected from a statin and a proton pump inhibitor.

Example 6: The portable device in size and shape of a mobile phones equipped with an emergency button, a GPS sender, a USB interface / storage unit and a mobile phone unit. The device contains at least three containers. The first one comprises ASA tablets, the second one a thienopyridine compound, and the third container comprises a liquid formulation of low molecular weight heparin in a box with a rubber seal. The device further comprises a separate prefabricated syringe.

Example 7: The portable device in size and shape of a thick stick or a mobile phone is equipped with an emergency button, a GPS sender and a USB interface / storage unit. The device contains at least one chamber / container. The container comprises a thienopyridine compound as anti-platelet compound in form of tablets or capsules in a typical dose, pre-determined by the patient's doctor.

Example 8: Alternatively, the container of the device of Example 7 contains an anticoagulant, such as Fondaparinux in a liquid formulation, wherein the container is a syringe system with bolt and needle. The needle can be pulled out from the medical device by a separate button.