WO2015136564A1

WO2015136564A1 - Add-on module for monitoring and control of compliance to therapy for injectable drugs contained in pre-filled syringes

Info

Publication number: WO2015136564A1
Application number: PCT/IT2015/000064
Authority: WO
Inventors: Osvaldo Tufi; Ciro FORMISANO
Original assignee: Osvaldo Tufi; Formisano Ciro
Priority date: 2014-03-10
Filing date: 2015-03-10
Publication date: 2015-09-17

Abstract

A miniaturized device (SDPFS) for monitoring and control of compliance to therapy for injectable drugs contained in pre-filled syringes (PFS) of a known type, wherein said syringes have a body (SBD) with an annular flange (RS) and a plunger (PLG), characterized in that it comprises, in combination: means for removable fixing of the device (SDPFS) on the pre-filled syringe (PFS); means for controlling the amount of injectable liquid and the rate at which the injection is made; means for controlling the inclination at which the injection is made with respect to the skin surface; wireless communication means for exchange of data with a remote control centre, equipped with server (SVR) and database (DTB), and/or with the physician in charge (PHC) via a device for connection to the Internet, such as for example a smartphone (SMPH), a tablet, or a gateway (GTW); means for warning the user of possible anomalies during injection; and means for hardware interface with the user that are present on the device itself, and means for software interface with the user that can be installed on the device for connection to the Internet, for data acquisition, for communication of information from and to the user and for management of the device itself.

Description

ADD-ON MODULE FOR MONITORING AND CONTROL OF COMPLIANCE TO THERAPY FOR INJECTABLE DRUGS CONTAINED IN PRE-FILLED SYRINGES

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SUMMARY OF THE INVENTION

The present invention relates to a method and corresponding device that enables monitoring of patient compliance to therapy for injectable drugs and helps the patient to recall the date and time of the next administration by means of acoustic and visual warnings. The device described may be used with pre-filled syringes and is able to monitor the effective administration of the drug by means of an array of optical sensors that detect the variation of the level of the injectable liquid.

In order to prevent possible reactions in the injection site and problems of absorption of the drug, the device is able to guide the patient during administration of the drug both by identifying possible wrong positions of the syringe and by controlling the duration of injection and is moreover able to manage through a software interface rotation of the injection sites.

The device described is moreover equipped with a wireless system for communication with a remote control centre that enables gathering of the data regarding compliance to therapy and enables direct interaction of the physician with the patient. Said communication is made via a smartphone, a PC tablet, or a gateway of a known type, with which the user is provided.

BACKGROUND OF THE INVENTION

In western countries, compliance to treatment, among patients affected by chronic illnesses is less than 50%, as demonstrated by numerous scientific articles. Poor compliance to treatment is chiefly manifested in omission of administration (rather than in taking an additional dose) and/or in delaying administration with respect to the envisaged time schedule. Poor compliance to treatment is, in practically all illnesses, and in particular in the case of chronic illnesses, among the major causes of unsatisfactory results of therapeutic treatment.

Even the best drug, in fact, may, on account of poor compliance, become ineffective or less effective, such as to expose the patient to risks like side effects due to sudden interruption of therapy, development of resistance, pharmacological dependence, and toxicity due to overdosage. The consequences of poor compliance are clinical and psychosocial, with a negative impact on the quality of life of the patients, but also economic, in so far as it generates a waste of resources of the National Health Service, placing itself as one of the main causes of inappropriate expenditure. The patient does not achieve the benefits expected in terms of health, whilst the National Health Service has frequently already purchased drugs that will not be taken by patients.

There exist different solutions for monitoring compliance to therapy for oral drugs, which are almost all distributed in the form of tablets in blister packages. These are devices that enable housing of the blister in a compartment and remind the patient of the date and time of the next administration, likewise detecting that the tablet has been taken out of the package, so confirming that administration of the daily dose has been made. The most advanced devices are moreover able to count automatically the remaining tablets and their position in the blister, and enable more precise management of monitoring of compliance to therapy, excluding possible errors due to accidental removal of the blister from its housing. This type of approach enables provision of a service of monitoring of compliance to therapy and of support to patients, without involving any change to the system of packaging of the drug, thus reducing times and costs linked to this operation.

Injectable drugs for chronic illnesses are instead distributed prevalently in single-dose formats equipped with everything that is necessary for making the injection, namely pre-filled syringes. The possibility of being able to carry out monitoring of compliance to therapy also for injectable drugs, using a device that is able to interact directly with the original packaging of the drug, i.e., with the pre-filled syringes, would enable a considerable advantage in terms of times and costs for pharmaceutical companies, which, faced with the need to provide a system that will be able to record the date and time of administration of the dose, would be able to do so without having necessarily to adapt the packaging and the system for injection of the drug.

In the phase of registration of a new drug with the bodies responsible for issuing authorisations for launching drugs on the market, pharmaceutical companies also deposit information regarding the type of medium (syringe) and consequently obtain an authorisation for distribution of the drug in that particular format (at times a number of packaging formats are deposited for one and the same drug). In the event of the need to make variations regarding the medium, there would derive the obligation of asking for a new authorisation, which would entail times and costs that are by no means indifferent for the pharmaceutical company.

A first purpose of the present invention is hence to provide a device for monitoring compliance to therapy for injectable drugs employed for the treatment of chronic illnesses, which can be used directly with pre-filled syringes. This approach enables the pharmaceutical company to activate a programme of monitoring of compliance to therapy in a short time and with considerably reduced costs and risks. Advantageously, the solution proposed according to the present invention enables the pharmaceutical company to continue to use the packaging format already existing for the drug and to introduce devices for monitoring compliance to therapy in a gradual way, without having to engineer a new product that will have the function of pre-filled syringe integrated with the additional function of supervisor.

The above approach does not jn effect introduce any change in the method of administration of the drug and leaves the patient the possibility of following his or her usual habits. The device that is described is in fact proposed to patients as an accessory with functions aimed at improving compliance to therapy rather than as a medical device dedicated to administration of the drug. The patient is left free to acquire confidence with the device without this involving, in effect, any obligation to use it. A patient who is under treatment for a chronic illness is already forced to use the same drug for a long period of his life: any further "imposition" could be a source of stress and refusal. Adhesion to the programme of monitoring of compliance to therapy will hence be obtained by the choice of the patient at the moment when he or she has perceived the actual utility of the device. The function of reminder, supervision of the rate of administration of the drug, and management of rotation of the injection sites, as well as the possibility of interacting directly with the physician, represent services that the pharmaceutical company offers to the patient with the aim of improving the latter's experience with the drug and with the therapy, as well as of reducing the stress correlated to repeated administration of the medicine, thus obtaining as natural spin-off an improvement in compliance to therapy to which there corresponds an increase in the quality of the treatment.

Another task of the present invention is to provide a new device for remote and real-time monitoring of the state of compliance to therapy by patients who have received the device and have decided to adhere to the programme. This enables gathering of statistical information regarding compliance to therapy, such as for example the percentage of compliance with respect to the age range, the sex, the geographical area, or rather a variation of compliance according to possible seasonal and climatic factors. This information, appropriately processed and analysed by the pharmaceutical companies may be useful in the choice of possible strategies aimed at removing the obstacles that prevent maximization of compliance to pharmacological treatment.

Given that the device that is described is designed to gather information regarding compliance to therapy for each individual patient in real time, it is also envisaged to transmit this information automatically to the physician and to warn him in the case where the percentage regarding compliance to therapy were to drop below a certain threshold, likewise enabling at any moment display of the historic data, with weekly, monthly, and yearly aggregation. According to the invention, the patient's physician manages to evaluate the correlation of possible lack of success of a given therapy with the poor compliance to administration of the drug and possibly correct the dosage and/or mode of administration.

The present monitoring and remote-control device moreover enables interaction at a distance, enabling, for example, re-programming of the frequency and schedule of administration. This enables the patient's physician to make a variation in the therapy and to transmit the updatings at a distance.

PRIOR ART

References to the prior art in the field of monitoring of compliance to therapy for injectable drugs regard electronic injection devices that envisage insertion of a cartridge containing the drug and automatically inject the contents after the patient has positioned the device in the injection site and has pressed the pushbutton for start of delivery. Once injection has been made, the patient removes the cartridge preparing the device for a new operation. In addition to carrying out automatic injection, some devices are able to store the date and time of administration and to guarantee filing of the data for a long period, thus enabling monitoring of the therapy. This type of solution envisages packaging of the drug in particular pre-dosed cartridges that are compatible exclusively with the dispensing device for which they are designed. In this case, the patient is forced to use the electronic injection device to be able to self-administer the dose of drug, without which the pre-dosed cartridges would be unusable.

Currently known electronic auto-injectors are usually supplied with rechargeable batteries, which hinders the patient from being able to administer the drug in the case where the batteries are run down. Since moreover these devices are equipped with complex mechanical drives, they are usually cumbersome and inconvenient to carry around. In the case where the patient were to need to carry out therapy away from home, he would be forced to take the device along with him given that it is not at all possible to make the injection without using the device.

The device RebiSmart™, designed and distributed by Merck Serono for patients affected by multiple sclerosis represents an embodiment of electronic auto-injector equipped with functions for support to compliance to therapy, such as storage of the date and time of the last injection and an alarm to remind the patient when the next administration is due. This device envisages use of cartridges containing the drug and of disposable needles that are inserted by the patient in the device before he proceeds to administration and are removed once the procedure is completed. The device is provided in a small case that contains the consumables and protects the device during transport. At the same time, it does not have particularly contained dimensions and weight. Furthermore, in the case where the pharmaceutical company wishes to use this device also in combination with other drugs, it would be forced to distribute them in the same cartridges or in possible variants that are compatible with the auto-injector.

The patent No. EP2361647A1 , filed in the name of Seiji KIKUCHI er a/. (Panasonic Corporation Kadoma-shi), describes a motor-driven electronic auto-injector, equipped with LCD, which uses cartridges pre- filled with a drug, which in addition to having the function of automation of injection, records the date of the first administration and hence of expiration of the drug .

The patent No. WO 2014/005955, filed in the name of Charley HENDERSON et al. (Sanofi Aventis Deutschland Gmbh), describes an electronic auto-injector equipped with batteries, motors, an LCD, and a user interface that is able to provide the user with a visual or acoustic feedback in order to enable configuration of the profiles of the patient, amongst which possibly also the frequency of treatment, and to communicate, if need be, with other devices through wireless protocols (cellphone, RFID, Bluetooth, etc.). This device envisages the use of replaceable cartridges containing the drug and a housing for the disposable needles and, thanks to the presence of three motors, also automatically sets the needles and the ampule containing the drug in the injection position.

The patent No. WO 2013/154954, filed in the name of Edmund

PRIBITKIN, describes a portable device, having the shape of a case of a personal electronic device, such as for example an jPhone as represented in the various drawings, which is able to house a particular cartridge made up of a container for the drug and a pre-loaded spring, release of which - obtained via a pushbutton - brings about injection of the medicine. The patent describes a method for protecting the needle from any contamination and envisages interfacing with the various electronic devices contained in the case such as cellphones, digital music players, and personal digital assistants. This enables, according to what is represented in the text of the patent, checking of the progress of the therapy and sending of possible alarm signals to known numbers in the event of use of the device in combination with drugs to be used only in the case of acute events, such as for example anaphylactic shock.

The patent No. WO 2012/072559, filed in the name of Garen KOUYOUMJIAN et al. (Sanofi Aventis Deutschland Gmbh), describes an electronic auto-injector, which is also provided with an LCD and is able to manage therapies involving a number of injectable drugs and to remind the patient of the time of administration of the drugs carrying out, before injection, mixing thereof in so far as they are contained in multiple cartridges housed within the device.

None of the devices or patents referred to above proposes a solution for monitoring compliance to therapy for injectable drugs that will enable use of standard pre-filled syringes, which are by now widespread owing to their simplicity of use and low production cost.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the present invention will be obtained from the ensuing detailed description and with reference to the attached ^drawings, which illustrate, purely by way of non-limiting- example, some preferred embodiments thereof.

In the drawings:

Figure 1 shows a pre-filled syringe PFS of a known type;

Figure 2 shows a pre-filled syringe PFS with a grip for favouring injection of a known type;

Figure 3 illustrates a first embodiment of the device SDPFS forming the subject of the present invention installed on a pre-filled syringe PFS;

Figure 4 is a top plan view of the device SDPFS illustrated in Figure

3;

Figure 5 illustrates the mode of insertion of the pre-filled syringe FPS in the compartment of the device SDPFS;

Figure 6 is an exploded view of the device in the version for pre- filled syringes SDPFS;

Figure 7 is a view of the device for pre-filled syringes, shown in which is the compartment for housing the electronic circuit and the flexible circuit on which the optical sensors are mounted;

Figures 8A and 8B are, respectively, a side view of the invention installed on a syringe of a known type and a longitudinal sectional view, according to the plane of trace B-B of Figure 8A;

Figure 9 is a view of the upper side of the electronic card of the device for pre-filled syringes SDPFS;

Figure 10 is a view of the underside of the electronic card of the device for pre-filled syringes SDPFS;

Figure 11 is a block diagram regarding the electronic subsystem of the device forming the subject of the present invention;

Figure 12 is a representation illustrating the principle of operation of the optical sensors for detection of the level of the injectable liquid;

Figure 13 is the screenful of the software application for smartphones by which rotation of the injection sites is managed;

Figure 14 illustrates the mode of communication between the device and a smartphone and moreover shows the screenful of the application on which the result of compliance to therapy is displayed;

Figure 15A is the screenful of the software application for smartphones on which the information regarding the next administration is displayed;

Figure 15B is the screenful of the software application for smartphones on which the level of the injectable liquid and the information on the state of the device is visually displayed; and

Figure 16 is a schematic illustration of the infrastructure for remote management of the device and for gathering the data.

DETAILED DESCRIPTION OF THE INVENTION

The advantage of being able to monitor and check compliance to therapy for injectable drugs, and in particular for therapies correlated to chronic illnesses that require rather long periods of treatment, may primarily give rise to a better effectiveness of the treatment for the patient, who frequently, on account of a poor compliance to therapy, obtains only limited benefits or even ho benefit at all from the pharmacological treatment. Furthermore, an intervention aimed at improvement of compliance of administration may produce, in the medium-to-long term, a reduction of waste of resources for the National Health Service, which is required to purchase drugs that, on account of poor patient compliance to treatment, do not produce results, and is possibly thus likewise forced to sustain the costs of untoward events linked to a therapy conducted in an incorrect way. Also pharmaceutical companies would benefit from the introduction of a system for monitoring compliance to treatment in so far as the loss of income deriving from the lack of sales of the medicine, associated to the patients with low index of compliance, would be reduced.

A considerable number of extremely rigorous studies conducted in the last few years has highlighted that in industrialized countries compliance to treatment for patients affected by chronic illnesses is in the region of 50% (Haymes et al. 2001 ; Sackett ef al. 1978). This means that on average only half of the drugs prescribed are taken by patients, with obvious consequences on the quality of treatment.

One of the major difficulties that pharmaceutical companies or physicians encounter in any attempt to improve compliance of patients to administration of drugs is linked to the lack of adequate instruments for measuring directly or indirectly the factor of compliance to therapy. Frequently, it is the pharmaceutical companies themselves who make available to patients electronic devices or other instruments that are able to monitor compliance to therapy and to act as aid to patients in managing treatment. On account of the cost of these devices or appliances, frequently pharmaceutical companies that sustain entirely the cost thereof limit this approach only to the most costly drugs.

In particular, as regards injectable drugs, in the case where a pharmaceutical company were to decide to adopt these devices in support of therapies that use drugs already existing on the market and already distributed in the form of pre-filled syringes, it would be forced to change format of the medium and of the packaging, with consequent increase in costs and with times that may be very long on account of the certifications and authorisations necessary on the part of the bodies responsible for controlling launching of drugs on the market.

A first purpose of the present invention is to overcome the aforementioned drawbacks by providing a low-cost device that will enable monitoring of compliance to therapy for injectable drugs.

A second purpose of the invention is to provide a device that will be readily integratable with the most widely used appliances for injection of drugs, i.e., pre-filled syringes.

The device according to the invention is advantageously able to function with pre-filled syringes already present on the market and used by pharmaceutical companies for distributing various drugs for which self- administration is required. Pre-filled syringes are instruments that enable the patient to administer a drug in absolute autonomy and in the most complete privacy and in the last few years have been gaining a wide diffusion in the field of chronic therapies.

Unlike other known methods for monitoring compliance to therapy, the present invention envisages insertion of the pre-filled syringe into a housing present within the new device proposed, where particular sensors are arranged that are able to determine that administration of the drug has been carried out, all this without it being necessary to make any constructional and/or functional modification to the pre-filled syringe.

The device according to the invention is moreover able to remind the patient of the date and time of the next administration, signalling by means of an acoustic and visual warning when the drug is to be taken. Through a Bluetooth interface the device is able to interact with mobile devices, such as smartphones and tablets, installed on which IS a purposely provided management software that enables re-programming of the interval and schedule of administration of the drug, display of the data regarding compliance to therapy, and gathering of possible feedback on the progress of the therapy that will be correlated directly to the data regarding compliance to therapy in order to make available to the patient's physician a wide range of information that may possibly be used for improving the quality and effectiveness of the treatment.

According to a peculiar characteristic of the invention, the device is able to monitor also the rate and hence the duration of injection through the sensors that check in real time the level of the liquid present in the syringe and hence the real of emptying of the container. In the case where the injection were to occur at an excessively high rate, the device would alert the patient by means of an acoustic or visual warning, inviting him to reduce the pressure on the plunger of the syringe. It has in fact been proven that an excessively fast administration of the drug can cause pain, problems of absorption, and localized reactions in the injection site.

Another function of the device that can be implemented through the software interface is linked to managing rotation of the injection site. One of the problems linked to therapies that use injectable drugs derives from the repeated use of the same injection site, which can cause formation of lipodystrophy and pseudo-hypertrophy, cicatricial tissue, and anomalous absorption of the drug.

The patient is guided via the software application in the choice of the most appropriate site for the injection, a choice that is made taking into account the previous use of each site.

At first use (device with cleared memory), the patient chooses the injection site and notifies it by touching the corresponding point on the display of the smartphone or of the tablet. The next time this site is highlighted as having already been used previously, and hence the software that is running on the smartphone or tablet suggests use of one of the alternative sites not used previously, highlighting them in a colour, for example, green, different from the colours of the sites already used, which will be highlighted, for example, in red; the procedure is iterated up to exhaustion of the sites that have not yet been used. In the course of the therapy, the sites used at a longer distance in time are recommended to the patient by being highlighted with the colour, for example, green. It is also possible to use an intermediate, colour, such as for example orange, to indicate priority of use. The software moreover stores all the administrations and the corresponding injection sites, being able to communicate to the patient, through a number or a percentage value, the frequency of use of a given injection site. In relation to each injection site, the device moreover checks, by means of inclination sensors present on the device, the correct inclination of the syringe and hence the angle between the needle and the skin surface, preventing any potential improper use that, in addition to causing problems of absorption, might also cause even serious reactions in the injection site.

The device described herein is likewise able to communicate with a remote server that acts from a control and data-collection centre. This is obtained using connection, to the Internet, of the smartphone or tablet to which it is combined and with which it communicates via Bluetooth interface (in the example described) or alternatively via a dedicated gateway that is appropriately connected to the modem/router present in the patient's home. Through the remote-management infrastructure provided by the aforesaid control centre, the patient's physician can monitor in real time progress of the therapy and interact with the patient. Furthermore, the data gathered and duly processed can supply extremely useful information regarding problems linked to compliance to therapy and enable conduct of observational studies aimed at improving the therapeutic scheme and more in general acceptance of the drug by the patients.

An additional function of the device forming the subject of the present invention regards management of drugs that require refrigeration for their preservation. A sensor present on the device enables monitoring of the temperature of the pre-filled syringes that will be appropriately conserved in a container, in which it is possible to house also the device.

With reference to the attached figures, a typical example of pre- filled syringe PFS used for injecting drugs for the treatment of chronic illnesses may be represented as in Figure 1. The syringe PFS is made up of a transparent glass body SBD, incorporated in which is a fine needle protected by a cap that ensures sterility thereof and by a plunger PLG that provides for compression of the drug to enable exit thereof. In a syringe not yet used, the injectable liquid occupies almost the entire the volume, and consequently the plunger remains in a retracted position with respect to the glass body. Frequently, these syringes are provided with a finger grip FG that enables convenient positioning of the index finger and middle finger thus facilitating pushing of the plunger, as illustrated in Figure 2.

A first embodiment of the invention is represented in Figure 3 and Figure 4, which show the device SDPFS, which is positioned on the pre- filled syringe PFS and remains blocked there thanks to the annular flange RS present at the proximal end of the body of the syringe itself. The shape of the device SDPFS is studied for being ergonomic and is aimed at facilitating gripping of the syringe, pressing of the plunger, as well as fixing of the device on the syringe itself.

The device SDPFS thus represents an element designed to replace the finger grip FG represented in Figure 2 mechanically since it is able to perform the same supporting function. With reference to Figure 5, the pre- filled syringe PFS is housed in the device SDPFS from above, by getting the annular flange RS to coincide with the housing DFC and by exerting a slight force in the transverse direction such as to enable the two parts to remain anchored together. Once the syringe PFS is positioned inside the device SDPFS, a microswitch SW1 detects insertion and activates the electronic circuit present within the body of the device SDPFS. In the same way, extraction of the syringe PFS sends the electronic circuit into stand- by, so reducing energy consumption. With reference to Figure 4, present on the body of the device SDPFS is a pushbutton SW2, which performs different functions according to the logic state of the electronic circuit, and a semitransparent window WND1 , positioned under which are the warning LEDs that notify the user of the state of the device and of possible alarms.

Figure 6 is an exploded view of the first embodiment of the device

DPFS described so far, comprising:

- a substantially hollow main body P1 made of plastic material;

- a printed circuit board PCB1 that contains the microprocessor and the other electronic components;

- a flexible circuit PFC1, on which optical sensors are positioned, such as for example transmitting LEDs and receiving photodiodes (or else phototransistors);

- a cover P2 that protects the flexible circuit PFC1 ;

- a rechargeable battery BATT1 ; and

- a plastic lid P3 that closes the compartment for housing the printed circuit board PCB1 present in the body P1.

The electronic card (pr printed circuit board) PCB1 and the battery BATT1 are housed in the aforesaid compartment present within the main body P1 on the side opposite to the housing for the syringe PFS, as illustrated in Figure 7, whereas the flexible circuit PFC1 is positioned on the long part of the body P1 , with the sensors positioned in the proximity of the transparent windows WND2 in such a way as to enable the transmitting LEDs PHTR and the receiving phototransistors (or photodiodes) PHRC to assume a specular position, i.e., in front of one another.

Figure 8B is a longitudinal sectional view of the device SDPFS, where positioning of the transmitting LEDs PHTR and of the phototransistors (or photodiodes) PHRC, as well as the presence of the plunger PLG, are evident. According to the invention, each transmitting diode PHTR is optically coupled to a receiving phototransistor (or photodiode) PHRC: this enables, through the transmission of light pulses modulated by means of a pulse signal, determination of the exact position of the plunger with respect to the body of the syringe, and consequently the level of the injectable liquid.

Figures 9 and 10 show in detail a preferred embodiment of the electronic card PCB1 on which there are present at least:

- a microprocessor MCU that manages the system logic, the user interface, the wireless communication, and processing of the data coming from the optical sensors;

- a Bluetooth Low-Energy module BLE and the corresponding antenna ANT for connection to a smartphone, tablet, or other personal device, or alternatively to a gateway to enable the device to interface with a remote server;

- a USB connector, which, in addition to enabling connection of the device to a PC, also enables battery charging;

- an EEPROM MEM1 for storage of the historic file of the data and of the operating parameters;

- a buzzer BZ1 for acoustic warning;

- an accelerometer ACC for managing positioning of the injector;

- a first connector CON1 for connection of the flexible circuit on which the optical sensors are positioned;

- a second connector for connection of the rechargeable battery ΒΑΊΓΤ1 ; and

- an integrated circuit for managing charging CHRG.

Figure 11 is a block diagram of the system according to the invention, based upon a microprocessor architecture. From what has been said, the liquid-level sensor is constituted by an array of preferably infrared transmitting LEDs PHTR driven by a PWM module present within the microprocessor MCU and by an array of preferably infrared receiving phototransistors (or photodiodes) PHRC that interface with the input- capture module of the microprocessor MCU itself, which detects the modulating pattern transmitted by the transmitting diodes PHTR. From what has been said in this connection, it should be noted how, as an alternative to infrared another wavelength could be used. Infrared has been chosen simply because it renders the light pulse invisible. Among the other things, it should also be noted that, in actual fact, any other optical sensor could be used that is made up of a first unit that is able to transmit a light pulse and a second unit that is able to receive it and to convert it into an electrical signal.

The microprocessor MCU manages the user interface, which is substantially provided by means of at least:

- an ON/OFF pushbutton SW2, which is used also for management of the device (e.g., start of injection); - a buzzer BZ1, which provides for acoustic feedback and for the alarms; and

- three LEDs of different colour that indicate the state of Bluetooth connection, the possible alarms, and the state of the system by means of appropriate light warnings visible through the window

WND1.

The microprocessor MCU is equipped with a real-time clock module that is used for management of the alarms, as well as for management of the temporal events, such as for example storage of the time of the last administration.

An EEPROM MEM1 connected to the microprocessor MCU enables storage of the events, such as for example the date and time of administration of the drug, the therapeutic scheme, and information on the use of the injection sites. The microprocessor MCU also manages the Bluetooth Low-Energy wireless module, which is made up of a transceiver radio and a 2.4-GHz antenna.

The USB connector enables, instead, connection of the device to a personal computer, on which a purposely provided software is installed that manages updating of the firmware, programming of the system parameters and personal settings of the user, display and download of the historic data filed, as well as testing for proper operation of the sensors. The device is supplied by a rechargeable battery BATT1 , management of which is entrusted to a purposely provided circuit CHRG, which provides for supply of the charging cycles and monitoring of the state of the battery.

Also connected to the microprocessor MCU is an accelerometer

ACC, which supplies information on the position of the device in order to identify the correct position/inclination of the syringe during administration of the drug, and moreover enables management of some motion-activated functions, such as for example deactivation of the acoustic alarm. In the example described, the patient indicates the injection site on the smartphone, and it is hence hypothetically possible to deduce the position of the skin surface with respect to the ground and, consequently, by measuring with the accelerometer and the inclinometer the inclination (and more in general the position) with respect to the ground, positioning of the syringe with respect to the skin surface in the area where the injection is made can be determined by subtraction.

A microswitch SW1 provides for detection of the presence of the syringe PFS and sends the information to the microprocessor MCU, which, in the case where the syringe is not inserted, configures the device in energy-saving mode.

Figure 12 shows in detail the principle of operation of the optical sensors. The microcontroller generates a pulse signal TS1 for the transmitting diode PHTR1 , which transmits this signal as light pulses preferably in the range of the infrared. On account of the presence of the plunger PLG that hinders the optical path, the signal received by the photodiode or phototransistor PHRC1 is constant, as represented by the signal RS1. The train of pulses transmitted by each transmitting LED PHTR1 .... PHRT9 lasts a limited time, for example in the region of 20 ms, and at the same time the microcontroller reads the signal received on the corresponding photodiode or phototransistor PHRC1 .... PHRC9 and analyses it, looking for a pattern compatible with the signal transmitted. This is repeated in sequence for each pair of transmitting LED PHTR and photodiode or phototransistor PHRC, until scanning is through, which in the case represented in Figure 12 will have a duration of approximately 180 ms. In the case of the signal TS6 transmitted by the transmitting diode PHTR6, since the optical path is free, a signal with a pattern similar to the transmitted one will be obtained at the photodiode or phototransistor PHRC6, as represented by the signal RS6. The result of scanning will return as information the level of the liquid still present in the syringe, whiqh in the case of the example represented in Figure 12 corresponds to approximately 45%, in so far as only the pairs PHTR6-PHRC6, PHTR7- PHRC7, PHTR8-PHRC8, PHTR9-PHRC9 - since they have the optical path free - manage to complete transmission of the signal.

It should be noted that the number of photodiodes and phototransistors may be more or less than nine, according to the need.

Figure 13 illustrates an example of embodiment of an application for smartphone SMPH that enables management of rotation of the injection sites and supervision on the correct position of the injector. The patient manages to display in a software screenful a map of the injection sites. The pull-down menu MFS enables the patient to select the most appropriate silhouette (male/female). On the map, each injection site is identified by a numbered spot that assumes a different colour according to the frequency of use. The software suggests the most appropriate injection site for the next injection by getting the corresponding spot to flash on the display. The patient selects the site that he or she prefers, and confirms the selection with the OK key, thus activating communication between the smartphone and the device, which acquires the information regarding the recommended inclination of the syringe with respect to the skin surface according to the particular injection site and the recommended time for preventing problems of absorption. The patient is guided by the device through light warnings (red/green LEDs) on the correct positioning of the syringe, and once injection has started he or she is warned by the device by means of an acoustic feedback in the case where the rate of injection were to be too fast with respect to the recommended one. Once injection is through, the device sends an appropriate acoustic and visual warning and stores, not only the date and time of administration, but also the site and the duration of injection. This information will subsequently be used for managing rotation of the injection sites.

It should be noted that the aforesaid acoustic and visual warning is important since it prevents the patient from having to observe continuously the syringe, thus rendering administration of the drug more convenient.

Figure 14 illustrates an example of an embodiment of an application for smartphone SMPH that enables monitoring of compliance to therapy. The device SDPFS communicates with the smartphone SMPH by means of the Bluetooth Low-Energy protocol and transmits the information regarding the parameters of compliance to therapy. The device SDPFS is in fact equipped with an internal memory and is able to store the date and time of all the administrations even for relatively long periods.

In any case, at each connection to the smartphone this information is transferred to the local memory, both in the EEPROM of the device and in the memory of the associated smartphone or tablet, and is possibly transmitted to the remote-management server in the presence of connection to the Internet.

Thanks to the dedicated software, the information regarding "compliance is presented to the patient in the form of a numeric percentage ADH, which represents the number of injections made with respect to the ones envisaged as a whole by the therapy for each reference period. Highlighted on the calendar CAL are also the dates when the patient has missed administrations. The number of the corresponding day is in fact marked with a circle SGN. The patient can run through the calendar and display the data regarding compliance for each month, or else can select a reference period chosen from the ones proposed by the software, or else again select a period at will. It is also possible to display on a graph the pattern of compliance to therapy in order to be able to evaluate evolution thereof in time.

Figure 15A shows, instead, an example of the screenful containing the information on the next administration. At the centre of the screen the date and time of the next administration DTNI are indicated, and in the same screenful it is possible to activate or deactivate the alarm reminder using the purposely provided flag ALM. The pushbutton CLB enables, instead, passage to another mode of display, where a calendar is present, highlighted in which are the days when administration of the drug is envisaged.

Figure 15B regards a possible embodiment of the user interface for smartphone dedicated to monitoring of the injections. The indicator LEV indicates visually the amount of drug still present in the pre-filled syringe, whereas the indicator PERC shows the same information in the form of a percentage.

The indicator DIR, in the form of an arrow pointing downwards, indicates that the plunger of the syringe is moving downwards and that the level of the medicine is dropping gradually. In the case where the patient were to cease to exert pressure on the plunger of the syringe, the arrow would disappear and a horizontal line would appear to indicate a wait state.

Another indicator present on the software screenful is the one regarding the time TM that remains for completion of injection. This value is calculated by the software, taking into account the amount of liquid remaining and the rate at which this level drops.

A final indicator represented in the figure is the state indicator STA, which supplies a feedback to the patient on correct execution of the injection. In the case where the rate of execution of injection were too high, the state would change in real time from OK to "Injection too fast", enabling the patient to modify the pressure exerted on the plunger of the syringe. The same indicator changes state also in the presence of a variation of the position of the syringe during injection (variation of the injection angle, i.e., of the position of the syringe with respect to the skin surface) or in the event of sharp movements that could give rise to reactions in the injection site. This inclination may be obtained thanks to the presence of an accelerometer and a triaxial gyroscope present on the device that verify instant by instant the position of the syringe with respect to the perpendicular to the ground and the variation of rotation with respect to the three axes of rotation. As has already been mentioned, the direction of the skin surface is calculated following upon selection of the injection site via the software that is running on the smartphone, assuming for example that the patient makes the injection in the sitting position. In this case, the injection sites on the thighs are substantially parallel to ground, whereas the injection sites on the trunk are substantially orthogonal thereto.

According to a peculiar characteristic of the invention, in order to determine correct inclination of the syringe with respect to the skin surface corresponding to the area chosen for injection, the following operating procedure is envisaged:

- the injection site is selected by means of the software described previously (e.g., Figure 13);

- the free end of the plunger PLG of the syringe is rested on the skin at the injection site by setting the syringe substantially perpendicular to the skin surface;

- a pushbutton of the device is pressed to confirm said positioning so that the software will assume said position as reference position for calculating and checking correct inclination according to the injection site selected;

- the syringe is set with the needle facing the skin, following the indications of the software and/or of a warning light of the device SDPFS and/or of a buzzer of the device SDPFS itself that notify that the correct inclination has been reached; and

- injection is carried out.

The foregoing procedure is possible thanks to the software and to the accelerometer and gyroscope already mensiont, both of which are triaxial.

As illustrated in Figure 16, the devices SDPFS are able to transfer the information regarding compliance to therapy stored in the EEPROM to a remote server to enable remote monitoring and gathering of data that may be appropriately processed in order to obtain statistical information on compliance to therapy.

Figure 16 shows two modes in which the data are transferred from the device to the server. The first envisages the presence of a smartphone SMPH or some other personal device connected to the Internet with which the device SDPFS interacts through the Bluetooth Low-Energy protocol. The smartphone SMPH in this case manages the functions of the device, as illustrated in Figures 13, 14, 15A, and 15B, and acts as gateway to the Internet, enabling the device to communicate with the remote server SRV.

Specifically, there are two options.

Option 1 : the device communicates with the smartphone, which via the app sends the data to the server;

Option 2: the device communicates with the gateway, which sends the data to the server.

In either case, communication with the remote server is bidirectional.

The data regarding compliance to therapy, once transferred to the server SRV are stored in a database DBT and become available for consultation through a dedicated webpage published by the server. The patient's physician PHC can for example access the information on compliance to therapy of his patients by means of a PC through the dedicated webpage, after prior authentication, and can modify the therapy by re-programming, via the aforesaid remote server SRV, the device and the calendar of the administrations stored therein.

The second mode in which the device manages to interface with the remote server envisages the presence of a gateway GTW in the home, to which the device connects up in Bluetooth wireless mode. The gateway GTW provides for routing of communication between the device SDPFS and the remote server SRV using the connection to the Internet, in this way enabling transfer of data.

Finally, it should be noted that obviously, as an alternative to the Bluetooth protocol described herein, other wireless protocols could be used, amongst which ZigBee, WiFi, NFC, RFID, RF communication in general, etc. It should also be noted that, even though the present invention has been described with reference to its application to pre-filled disposable syringes of a known type, the same inventive idea can be applied without any substantial modifications also to the known auto-injectors, with the same purposes and obtaining the same advantages described previously.

Claims

1) A miniaturized device (SDPFS) for monitoring and control of compliance to therapy for injectable drugs contained in pre-filled syringes (PFS) of a known type, wherein said syringes have a body (SBD) with an annular flange (RS) and a plunger (PLG), said device being characterized in that it comprises, in combination:

- means for removable fixing of the device (SDPFS) on the pre-filled syringe (PFS);

- means for controlling the amount of injectable liquid and the rate at which the injection is made;

- means for controlling the inclination at which the injection is made with respect to the skin surface in the area where the injection is made;

- wireless communication means for exchange of data with a remote control centre, equipped with a server (SVR) and a database (DTB), and/or with the physician in charge (PHC) via a device for connection to the Internet, such as for example a smartphone (SMPH), a tablet, or a gateway (GTW);

- means for warning the user of possible anomalies during injection; and

- means for hardware interface with the user that are present on the device itself and means for software interface with the user that can be installed on the device for connection to the Internet, for data acquisition, for communication of information from and to the user, and for management of the device itself.

2) The device (SDPFS) according to Claim 1 , characterized in that it envisages a longitudinal housing, in which to insert the syringe^body (SBD) having a part specifically designed to house the annular flange (RS) of the syringe itself.

3) The device according to Claim 2, characterized in that it comprises:

a substantially hollow main body (P1 ) made of plastic material;

- a printed circuit board or electronic card (PCB1) that contains the microprocessor and the other electronic components;

a flexible circuit (PFC1), on which optical sensors are positioned;

- a cover (P2) that protects the flexible circuit (PFC1);

- a rechargeable battery (BATT1); and

- a plastic lid (P3), which closes the compartment for housing the printed circuit board (PCB1) present in the body (P1).

4) The device according to Claim 3, characterized in that the flexible circuit (PFC1) is positioned on the long part of the body (P1) with the sensors positioned in the proximity of purposely provided transparent windows (WND2) in such a way as to enable the emitting optical sensors and the receiving optical sensors to assume a specular position, i.e., in front of one another.

5) The device according to Claim 4, characterized in that the optical sensors are constituted by transmitting LEDs (PHTR) and by receiving photodiodes or phototransistors (PHRC).

6) The device according to Claim 5, characterized in that each transmitting LED (PHTR) is optically coupled to a receiving photodiode or phototransistor (PHRC), thus obtaining that, through the transmission of light pulses modulated by means of a pulsed signal, the exact position of the plunger with respect to the body of the syringe is determined, and consequently the level of the injectable liquid.

7) The device according to Claim 3, characterized in that said electronic card (PCB1) comprises at least:

- a microprocessor (MCU) for managing the logic of the system, the user interface, and the wireless communication, and for processing the data coming from the optical sensors;

- a Bluetooth-Low-Energy module (BLE) and the corresponding antenna (ANT), or else normal Bluetooth or other form of radio- frequency communication, for connection to a smartphone, a tablet, or other personal devices, or alternatively to a gateway for connection to a remote server; - a USB connector, which, in addition to providing for connection of the device with a PC, also enables charging of the battery;

- an EEPROM (MEM1) for storage of the historic file of the data and of the operating parameters;

- a buzzer (BZ1) for acoustic warning;

- an accelerometer (ACC) for managing positioning of the injector;

- a first connector (CON1 ) for connection of the flexible circuit on which the optical sensors are positioned;

- a second connector for connection of the rechargeable battery (BATT1); and

- an integrated circuit for managing charging (CHRG).

8) The device according to Claim 7, characterized in that said transmitting LEDs (PHTR) are preferably infrared LEDs and are driven by a PWM module present within the microprocessor (MCU), whereas said receiving photodiodes or phototransistors (PHRC), which are also preferably infrared ones, are interfaced with an Input-Capture module of the microprocessor (MCU) itself, which detects the modulating pattern transmitted by the transmitting LEDs (PHTR).

9) The device according to Claim 7, characterized in that said means for hardware interface with the user are managed by the microprocessor (MCU) and comprise at least:

- an ON/OFF pushbutton (SW2) used also for management of the device (e.g., start of injection);

- a buzzer (BZ1) that provides for acoustic feedback and for the alarms; and

- three LEDs of different colour that indicate the state of the Bluetooth connection, the possible alarms, and the state of the system by means of appropriate light warnings visible through a window (WND1).

10) The device according to Claim 7, characterized in that it envisages an EEPROM (MEM1) connected to the microprocessor (MCU) for storage of the events, such as for example the date and time of administration of the drug, the therapeutic scheme, and information on use of the injection sites.

11) The device according to Claim 3, characterized in that said rechargeable battery (BATT1) is managed by a purposely provided circuit

(CHRG), which provides for supply of the charging cycles and monitoring of the state of the battery.

12) The device according to Claim 7, characterized in that said microprocessor (MCU) is also connected to an accelerometer (ACC), which supplies information on the position of the device in order to identify the correct position/inclination of the syringe during administration of the drug, and moreover enables management of some motion-activated functions, such as for example deactivation of the acoustic alarm.

13) The device according to Claim 7, characterized in that a microswitch (SW1) is provided for detecting the presence of the syringe

(PFS) and sending the information to the microprocessor (MCU), which, in the case where the syringe is not inserted, configures the device in energy-saving mode.

14) The device according to Claim 7, characterized in that said means for software interface with the user/patient enable management of rotation of the injection sites and supervision on the correct position of the injector; for this purpose, it is envisaged that the patient can display on a software screenful a map of the injection sites, in which the software suggests the most appropriate injection site for the next injection by getting a corresponding spot to flash.

15) The device according to Claim 14, characterized in that, via said software interface, when the patient selects the site that he or she prefers and confirms the selection with the OK key, there is in this way activated communication between the smartphone and the device, which acquires the information regarding the recommended inclination of the syringe with respect to the skin surface according to the particular injection site and the recommended time to prevent problems of absorption.

16) The device according to Claim 15, characterized in that via said software interface the patient is guided by the device through light warnings (red/green LEDs) on the correct positioning of the syringe, and once injection has started he or she is warned by the device by means of an acoustic and/or visual feedback in the case where the rate of injection were to be too high with respect to the one recommended, and once injection is through the device stores, not only the date and time of administration, but also the site and the duration of injection.

17) The device according to any one of the preceding claims, characterized in that, as an alternative to Bluetooth, other wireless protocols may be Used, amongst which ZigBee, WiFi, NFC, RFID, RF communication in general, etc.

18) A method for monitoring and control of correct inclination of a syringe with respect to the skin surface corresponding to the area chosen for injection for a therapy with injectable drugs contained in pre- filled syringes (PFS) of a known type by means of the miniaturized device (SDPFS) according to any one of the preceding claims, said method being characterized in that it comprises the following steps:

- the injection site is selected by means of a purposely provided control software;

- the free end of a plunger (PLG) of the syringe (PFS) is rested on the skin at the injection site by setting the syringe substantially perpendicular to the skin surface;

- a pushbutton of the device (SDPFS) is pressed to confirm said positioning so that the software will assume said position as reference point for calculating and checking correct inclination according to the injection site selected;

- the syringe (PFS) is set with the needle facing the skin, following the indications of the software and/or of a warning light of the device

(SDPFS) and/or of a buzzer of the device (SDPFS) itself that notify that the correct inclination has been reached; and

- injection is carried out;

said software using the data coming from at least one accelerometer and/or at least one gyroscope, which are both triaxial and which are purposely provided in the device (SDPFS).