WO2017121901A1 - Device for use in the treatment of diseases - Google Patents

Device for use in the treatment of diseases Download PDF

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Publication number
WO2017121901A1
WO2017121901A1 PCT/EP2017/050823 EP2017050823W WO2017121901A1 WO 2017121901 A1 WO2017121901 A1 WO 2017121901A1 EP 2017050823 W EP2017050823 W EP 2017050823W WO 2017121901 A1 WO2017121901 A1 WO 2017121901A1
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WO
WIPO (PCT)
Prior art keywords
user
substance
treatment
skin
diseases according
Prior art date
Application number
PCT/EP2017/050823
Other languages
French (fr)
Inventor
Eduardo Walther JORGENSEN DE VIZCARRONDO
José Carlos MONTESINOS PÉREZ
Patricia CREMADES BELMONTE
Juan César DE MERCADO SANTAMARTA
Original Assignee
Medicsensors Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Medicsensors Ltd. filed Critical Medicsensors Ltd.
Publication of WO2017121901A1 publication Critical patent/WO2017121901A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
    • A61B5/02055—Simultaneously evaluating both cardiovascular condition and temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H40/00—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
    • G16H40/60—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices
    • G16H40/63—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices for local operation
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H40/00—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
    • G16H40/60—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices
    • G16H40/67—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices for remote operation
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/50—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/70—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00—Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/02—Operational features
    • A61B2560/0242—Operational features adapted to measure environmental factors, e.g. temperature, pollution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0015—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system
    • A61B5/0024—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system for multiple sensor units attached to the patient, e.g. using a body or personal area network
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0531—Measuring skin impedance
    • A61B5/0533—Measuring galvanic skin response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/103—Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor, mobility of a limb
    • A61B5/1118—Determining activity level
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6802—Sensor mounted on worn items
    • A61B5/681—Wristwatch-type devices
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • G16H20/17—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients delivered via infusion or injection
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems

Definitions

  • the present invention relates to a device for use in the treatment of diseases comprising a transdermal substance delivery apparatus which allows a non-invasive distribution and absorption of substances by transdermal meanings automatically guided by an algorithm or manually by the final user, through a user interface or acting directly on the transdermal substance delivery apparatus.
  • the present invention also relates to a method of treatment of diseases that comprises a step of applying a non-invasive distribution of at least one substance for the administration of the at least one substance to the user.
  • the invention belongs to the group of biomedical devices and methods and more specifically to that of transdermal substance delivery devices and methods.
  • Diabetes is an illness where the body is unable to supply sufficient amounts of insulin to maintain blood sugar within a healthy range.
  • Managing diabetes typically involves the intermittent or continuous measurement of blood glucose levels followed by the administration of insulin in response to the measured blood glucose levels.
  • Insulin may be administered by syringe or by a pump that reliably administers desired quantities of insulin.
  • the invasive system with needles and catheters is an outdated model that causes patients to prick themselves, have a catheter introduced into the body 24 hours a day (which favors infectious processes), and to be limited economically (sleep impediment, limitation to practice certain sports, difficulty in maintaining discretion regarding the use of equipment).
  • These disadvantages increase the awareness of disease and decrease the quality of life.
  • Insulin pumps are complex systems aimed at more experienced patients, leaving a large segment of the population without the possibility of automating treatment and reducing concerns. It is also a system that involves an enormous expense because of the associated materials (needles, catheters, pump purge elements, etc.).
  • the device for use in the treatment of diseases and the related method of the present invention has a configuration which makes it possible to resolve all the aforementioned drawbacks.
  • the present invention relates to a device for use in the treatment of diseases comprising a non-invasive transdermal substance delivery apparatus which allows a non-invasive distribution of at least one substance for the administration of the at least one substance to the user automatically guided by an algorithm or manually by the final user, through a user I/O interface or acting directly on the non-invasive transdermal substance delivery apparatus.
  • the skin unlike other organs and structures such as intestinal epithelium, is not designed for the absorption of substances useful to the body.
  • the permeability through the skin is very low because it is formed by several layers, some of them very thick, and with a very little blood supply.
  • the epidermis (the most superficial layer of the skin) is formed by a series of layers, the first being the stratum corneum, which, being impermeable to most substances, is the main barrier for the administration of substances (like drugs) through the skin. It prevents molecules larger than 500 Da from entering through it and is between 10-15 ⁇ thick. Next are the remaining layers of the epidermis and then there is the dermis, 1 -2 mm thick.
  • One possibility is to use both high and low frequency ultrasounds simultaneously so that the former create the bubbles previously named and the latter, in addition to creating the microducts, help to place the bubbles in areas closer to the surface to be treated, increasing the elimination effect of stratum corneum.
  • the device for use in the treatment of diseases of the present invention allows adapting the health care recommendations to the individual needs of the user and the controlled delivery of substances by transdermal procedures, ie without needles and through the skin.
  • the device has a non-invasive medical apparatus which purpose is to facilitate the automated or manual needle-free administration of substances through the skin, for example, in the day-to-day of patients suffering from some type of chronic pathology that needs to be medicated daily, keeping a constant follow-up of the disease (like diabetes).
  • the device also comprises a control unit that predicts the evolution of the disease based on the association of various parameters and optionally analyses the risk of certain situations to make personalized recommendations relevant to the disease and lifestyle.
  • the device also comprises a user I/O interface comprising output data means for showing relevant information for the user and/or input data means for entering data by the user.
  • the device also comprises at least one sensor for measuring various parameters to be supplied to the control unit.
  • the device also comprises a cloud computing system in communication with the control unit and the user I/O interface.
  • the non-invasive transdermal substance delivery apparatus optionally comprises means for applying ultrasonic waves in areas close to the skin of the user, preferably in such a way that part of the upper layers of the skin, in particular part of the stratum corneum, can be removed by means of high frequency ultrasonic waves and in such a way that microducts are opened by means of the application of low frequency ultrasonic waves.
  • the non-invasive transdermal substance delivery apparatus comprises means for applying laser in areas close to the skin of the user.
  • the non-invasive transdermal substance delivery apparatus is capable of adapting to different skin types and desired outcomes the sequential, simultaneous or alternating generation of these waves, in an orderly and controlled way to allow an increase in the absorption capacity of the skin and the diffusion of the substance through it.
  • the device can be operated manually, but thanks to the mass collection of data and their aggregation, the analysis may be able to obtain conclusions about the relationships between variables studied and recommend calculated doses of substance to be administered so the device can work autonomously.
  • the device optionally comprises wireless means for exchanging information with external sources in a bilateral way.
  • the device comprises supply means, preferably a battery, to supply energy to the components of the device.
  • the non-invasive transdermal substance delivery apparatus optionally comprises attachment means for attaching the apparatus to the user, being preferably adhesive means.
  • the non-invasive transdermal substance delivery apparatus optionally comprises at least one reservoir for collecting the substance to administrate.
  • an algorithm executed by the control unit is able to anticipate the user's needs with a predetermined time horizon. Based on these forecasts, an order is sent to the device to increase or reduce the substance supply.
  • the delivery must be controlled and fast, avoiding high dead times during a dose administration. To do this, it is in communication with the user I/O interface authorized for the task, which is responsible for reporting the dose of the substance to be supplied and the time at which it should be provided.
  • the substance in question is acquired and charged in the device by the user, with the periodicity necessary for the administration.
  • the medical device so constituted achieves a non-invasive substance supply, completely free of needles, while being easily concealable and handled from a discrete portable terminal and other user interfaces like the one incorporated in it.
  • the apparatus is placed on the skin, having the device the following characteristics:
  • the invention also relates to a method of treatment of diseases using the device explained above, the method comprising:
  • the method further comprises a step of showing relevant information for the user and/or a step of entering data by the user.
  • the method further comprises a step of communication between a cloud computing system and the control unit prior to the step of showing relevant information for the user and/or after the step of entering data by the user.
  • the method further comprises a step of applying ultrasounds in areas close to the skin of the user.
  • the method further comprises a step of exchanging information with external sources in a bilateral way.
  • the method further comprises a step of supplying energy to the components of the device.
  • the method further comprises a step of attaching the apparatus to the user.
  • the method further comprises a step of collecting the substance to administrate.
  • Figure 1 shows one embodiment of the device for use in the treatment of diseases of the present invention.
  • Figure 2 shows a diagram of the cloud computing system of the device for use in the treatment of diseases of the present invention.
  • Figure 3 shows a diagram of a predictive and managing algorithm executed in the cloud computing system that receives data from the user I/O interface and transmits it in return.
  • Figure 4 shows a scheme of the non-invasive transdermal substance delivery apparatus of the device for use in the treatment of diseases of the present invention according to a first preferred embodiment.
  • Figure 5 shows an algorithm flow chart of the predictive and managing algorithm shown in Figure 3.
  • Figure 6 shows a view of a central assembly of the non-invasive transdermal substance delivery apparatus of the device for use in the treatment of diseases of the present invention with all parts attached according to a second preferred embodiment.
  • Figure 7 shows an exploded view of all parts of the central assembly, including the substance container according to a second preferred embodiment.
  • Figure 8 shows a view of all parts of the central assembly, including the substance container and attachable pieces which can be connected to the central assembly by means of adapters.
  • Figure 9 shows an exploded view of Figure 8.
  • Figure 10 shows a bottom view of the central assembly allowing to observe the fit of the pieces being prepared for its use.
  • Figure 1 1 shows a top view of the central assembly with a piece removed from one attachable piece.
  • Figure 12 shows a filler cut with all parts assembled and channels closed.
  • Figure 13 shows a schematic view of the activation of the device for use in the treatment of diseases acting as insulin supplier, generating high frequency ultrasound and low frequency ultrasound.
  • the device for use in the treatment of diseases of the present invention the disease being preferably diabetes, is described in detail.
  • the main components of the device are interconnected with WIFI, mobile networks and/or Bluetooth technology and include: 1 - A user I/O interface, preferably a mobile app, comprising output data means for showing relevant information for the user and/or input data means for entering data by the user (e.g., meals, time performing activities, sickness/fever, and special events) and otherwise supplied by sensors explained below, issuing commands controlling the administration of a substance, preferably insulin, and offloading data to other computing resources for processing.
  • the mobile app may execute on a smartphone, tablet, phablet, laptop, desktop computer, NUC, etc.
  • the mobile app provides a variety of functions, including but not limited to:
  • Data display showing relevant information for the user (current and average glucose, trends, carbs intake, sports time, insulin units needed, predicted glucose and behavior advice, % of measured values within target range).
  • Events diary logbook of daily events (meals, sports, insulin injection). Day selection through calendar.
  • Chatbot feature chat-like interface to present and request information in an automated fashion.
  • 2- Sensors for measuring various parameters to be supplied to a control unit that commands the mobile app and/or the non-invasive transdermal substance delivery apparatus Exemplary sensors that may be used include but are not limited to:
  • Glucometer or continuous glucose monitor (invasive or non-invasive) for measuring blood/interstitial glucose level.
  • 3- Cloud computing system illustrated further in Fig.2, is in communication with the control unit and mobile app, offering a variety of functions:
  • Predictive and managing algorithm (illustrated in Fig. 3) executed in the cloud computing system or in other technological support related to the device, receiving data from the mobile app and transmitting results in return.
  • Non-invasive transdermal substance delivery apparatus this entails the opening of a micro-pore (micro-duct) on the upper layers of the skin, as illustrated in figure 4.
  • Dots represent sticky material to increase skin adherence (must be hypoallergenic material to avoid dermatitis). (Facing the skin).
  • Electronic module receiver + transmitter. Unique device identifier.
  • Pore-opening and delivery module Laser and/or ultrasound technology to open a micro-pore on the upper layers of the skin that allows non-invasive substance infusion.
  • substance reservoir (separated chambers for different substances). It needs to be replaced when it runs out of substance. Different to current pumps reservoirs, connected to the hole for substance infusion.
  • the delivery system can be extracted from the support platform whenever it loses stickiness and be placed on another one.
  • This modular design allows the different parts of the device to be positioned so that they fit better into the user's body contours, avoiding discomfort and being easily concealed. It also facilitates the localization of future device problems and the improvement of the different parts without greatly modifying the rest of the non-invasive transdermal substance delivery apparatus.
  • a series of elements are needed to be changed each given time period so the device can keep operating, amongst them are supply means to supply energy to the components of the device, preferably being a battery that can be separated from the rest of the apparatus easily.
  • supply means to supply energy to the components of the device, preferably being a battery that can be separated from the rest of the apparatus easily.
  • those considered as disposable which are composed of adhesives, to allow anchorage of the device to the user's skin, and at least one reservoir for collecting the substance to administrate.
  • the latter is in charge of containing a series of holes that house the substance to be distributed. To fill them, the user has a two-way coupling system but not attached to the device (The filler). Rotating certain parts of it to certain positions, the desired substance can be collected and, after another series of rotations, injected into the holes and get the reservoir/s sealed.
  • a series of ultrasounds are applied in areas close to the skin. These are divided into two groups according to their capacities, being high and low frequency. Those of low frequency (40-300kHz) are placed so that the advance of the wavefront created is perpendicular to the skin and allows the creation of micro-paths (micro-ducts) in the skin, through which the molecule can circulate. Those of high frequency (1 -3 MHz) are placed so that their advance is parallel to the skin and are in charge of eliminating certain parts of the more superficial layers of the skin, in part thanks to the cavitation effect.
  • the powers and waveforms of both groups avoid any discomfort or damage to the user's skin that would be annoying or undesirable such as excessive redness or excessive removal of the upper layers of the skin.
  • the device is intended to deliver substances to the user by transdermal methods.
  • the device is composed of a series of assemblies, each in charge of a particular function and interconnected to each other.
  • a user I/O interface through which communication between the device and the user is established;
  • a non-invasive transdermal substance delivery apparatus with the reservoirs and the delivery substance system; and
  • the electronics assembly in which the power supply, unit control and ultrasound system are grouped together.
  • the non-invasive transdermal substance delivery apparatus is modular, being divided into a series of rigid parts where the main elements are as we can see in Fig.6 and Fig.7. These parts operate by their own, but can be connected to attachable modules by means of semi-rigid units (8.5) enabling them to be partially rotated and moved away from or close to one another and extend functionalities. In this way, a better positioning of the assembly is provided, being adapted to the shape of the surface to which it is attached (reaching the shape seen in Fig.8).
  • the device can be placed in different areas of the body of the user suitable for the skin characteristics, including upper arm, abdomen and thigh but not limited to them.
  • the device In relation to biosecurity, the device must be changed from time to time to avoid possible conditions that may occur on the skin because of the continuous flow or deposit of substance through or on it.
  • the device is designed to be detached from the skin and recharged each time the stipulated days are reached. It is necessary to reset the device once the process is complete.
  • the only items that need to be renewed are the adhesive and the reservoir/s.
  • the user has several batteries allowing their exchange and recharge every time the position is changed and there is an extra reserve included in the central assembly for manual activation in case of failure or discharge.
  • the device has several elements to allow communication with the user in both outgoing and incoming direction:
  • the device can provide information about the number of reservoirs remaining, the battery charge level, or the condition of the non-invasive transdermal substance delivery apparatus. For this, a series of LEDs and other interfaces are activated with the appropriate message that is wanted to be transmitted to the user. It is only activated for a short time after request, avoiding sending information when it is not needed.
  • the device interfaces include but are not limited to the the apparatus interfaces, these being a series of buttons (6.3) located in the main housing which must be activated by a small sized key (7.4) that is inside the housing and can be removed and inserted at will. These buttons allow the device to be started and reset as well as the supply of a certain number of reservoirs. For the user to be able to make confirmations to the device, a push button (6.2) is placed in an accessible site of the device.
  • the system stores and communicates to the user and algorithm both the amount of substance administered and the amount remaining in the device. In this way, a constant bilateral communication between the different parts of the device is established and the information is stored to ensure its correct operation
  • Any communication with external electronic elements is done by wireless methods which must be accessed through a series of security keys to begin communication. These keys are provided to the user upon obtaining the product.
  • a main support platform comprises a polymeric disk, which has a certain balance between rigidity and flexibility, providing greater ergonomics to the user.
  • pluralities of holes or reservoirs Within the disk are pluralities of holes or reservoirs (10.1 ) into which a certain amount of substance may be introduced.
  • This disk is between two layers that prevent the exit of the substance, allowing some internal pressure.
  • the upper layer made of a material biocompatible with the substance, makes the sealant of the non-invasive transdermal substance delivery apparatus reservoir after filling, having dimensions that allow its coupling to the main disk.
  • the substance is expelled from the support platform through the bottom of each hole or reservoir by an individual channel.
  • an impermeable sheet formed by very thin layers of various metals is placed covering the hole floor.
  • an electric current is generated between two of the ends of the metal sheet, acting as a fuse, breaking and letting the dose of substance pass to the skin.
  • a series of conductive tracks are coupled to a thin layer of silicon deposited on the underside of the disk.
  • a thin layer of a polymer biocompatible with the specific substance being capable of maintaining the chemical stability of the whole.
  • the biocompatible nature of this surface also prevents a phenomenon of adsorption of the substance in the walls of the reservoir.
  • the substance may remain in the reservoir the established days without risk of changes in structure and effectiveness.
  • the morphology of the hole prevents the remaining of substance inside after being activated, facilitating the arrival of the same to the skin without losses.
  • an anchorage (7.6) is made that allows its easy extraction and introduction in the central assembly holes of the device (7.5).
  • This central structure or piece (6.1 ) is composed of two pieces which can be joined by joining means that can include threads but are not limited to them, so that there is an upper (7.1 ) and a lower (7.2) piece, taking into account the skin as ground height.
  • it contains several holes (7.5) in which the support platform of the substance is fitted, being immobilized by screwing or fitting the lower part (7.2). To avoid rotation of the support platform, a series of notches are made into which the teeth (7.6) of the reservoir container are inserted. These teeth also make an additional stop so that together with the lower part prevent axial movements of the support platform.
  • the lower part of the central module is unscrewed or unfitted and the container disk with the reservoirs is removed.
  • a filler (Fig.12) operates as a two-way system.
  • the substance can be absorbed from its usual container, and with another turn injected into the reservoirs, which are sealed with pressure when the lid is placed.
  • the disk is inserted again in the central module and the lower part is screwed or fitted.
  • the reservoirs must be filled by the user when he changes the position of the device.
  • the filler operates as follows:
  • An upper part (12.1 ) and a lower part (12.4) are rotated to a series of marks indicating that the top hole is open and the bottom hole closed. To better indicate that the position has been reached, some mechanical resistance is applied to leave this position.
  • the assembly is then used as if it were a syringe absorbing the substance through the upper hole (12.5, 12.6), remaining between connectors (12.2, 12.3).
  • the reservoir container is closed by turning it so that the top cap engages.
  • the container is removed from the filler and ready for use.
  • the container disk and the filler are for single use and are manufactured with a series of biocompatible polymers for each of the substances to be used.
  • the container can also be filled with the current administration systems such as syringes or pens / medicine pens.
  • the number of reservoirs in the device determines the dose ranges that can be administered. Depending on the quantity and type of substance required, a given number of reservoirs are activated automatically (algorithm-guided) or manually (user- guided).
  • top cap being formed of a polymer sheet, coated with the same biocompatible material as the inner faces of the reservoir.
  • a bandage (10.3) in the form of a circular crown is used to adhere comfortably, but without covering the holes in the reservoirs, which are arranged in an orderly manner over the entire surface of the support platform. Its function is to keep the device as still as possible with respect to the specific area of the skin of the user that has been selected as the absorption zone. Its shape allows a correct grip of the whole to the user and contemplates evolutions of it and the complete apparatus towards more ergonomic designs that allow adaptation to the body morphology and are flexible.
  • the adhesive is hypo-allergenic, thus avoiding allergic reactions on the skin that can lead to dermal problems. Since each skin is different, there may be users with skins that generate some type of reaction, in which case they should consult their dermatologist. In addition, it is characterized by its water resistance, elasticity and permeability, facilitating removal of the exudate.
  • the adhesive is changed every time the device is detached so as to prevent it from losing its effectiveness and being peeled off the skin.
  • the electronics of the device can be separated into three different modules differentiated by their use and operation.
  • the first module is the power supply
  • a second module is the control part of the circuit whose operation coordinates all the apparatus
  • the ultrasonic module which facilitates the absorption of the substance.
  • These modules are integrated into a single electronic module that encompasses all the circuitry of the device and is housed in the central assembly (6.1 ).
  • the circuitry is designed so that it does not reach temperatures or powers that could endanger the health of the user or the stability of the components of the device, including in this section the substance.
  • the battery module is responsible for powering the entire device. Thanks to its load, it is possible to use the whole device for a long time without the need to recharge.
  • an attachable piece (8.3) is made, which can be connected to the attachable module by means of adapters, such as that seen at (8.2), with the suitable connectors (1 1.3).
  • Certain movements for extraction may be made thanks to various mechanical systems (9.1 , 1 1.2), preferably connectors, in addition to systems to prevent their exit (8.4, 9.2, 1 1.1 ). It can be found as an accessory piece or forming part of the central assembly. If connected as an accessory piece to the central module (attachable module), it is done through the previously mentioned semi-rigid structures (8.5).
  • the control unit of the apparatus is responsible for controlling and coordinating all circuits in the apparatus. To do this, it processes the information received from external sources such as the algorithm and sensors, makes the necessary control orders and finally, applies them on the apparatus.
  • the calculation power is not high because of the low device requirements.
  • the wireless communication module receives and processes the different signals so that they can be interpreted by the control unit. As a security measure, it carries a predefined address and key, thus avoiding possible manipulation by others than the user.
  • the main barrier to overcome for the substance in order to reach the bloodstream is the stratum corneum. It is the most superficial layer of the skin and consists of dead cells that greatly limit its permeability. In order to facilitate absorption, an ultrasound field is applied to the surface on which the substance is deposited.
  • An electric current with a certain frequency which is amplified to the required voltages, is generated by a series of resonator circuits for the production of ultrasounds. These currents reach a series of piezoelectric elements, responsible for producing a vibration and, consequently, a series of mechanical waves in the spectrum of the ultrasounds.
  • These ultrasounds are divided into two categories, the low frequency ultrasounds (10.2) being those whose oscillation frequency is less than 1 MHz and high frequency ultrasounds (7.7) those with values greater than 1 MHZ.
  • the low frequency ultrasounds (10.2) are located in the upper part of the central module, the furthest from the skin, at the lower end of columns that pass through the support platform of reservoirs.
  • the main direction of advance of the waves generated in this case is perpendicular to the plane of the skin. This type of wave is used to generate microducts in the surface allowing large molecules, such as those that can be part of a substance or drug, to reach the inner layers of the skin.
  • the high frequency ultrasounds (7.7) are placed in the shape of small piezoelectrics at a very small distance from the skin in the walls of the cavity left by the central assembly ' s casing to deposit the substance, being part of the lower part of the central module (7.2), so that the main direction of movement of the waves is parallel to the plane of the skin.
  • the use of high frequency ultrasound for the generation of cavitation is a great ally in the effect of transdermal absorption. This effect consists on the generation of small bubbles that explode upon colliding with the skin, resulting in a considerable increase of local pressure, thus eliminating part of the stratum corneum.
  • the state of various areas of the skin can be managed at all times. They are placed in areas close to the place of deposition of the substance. With this system, the substance penetrates the skin in a non-invasive way reaching the cutaneous capillaries from where it is incorporated into the circulatory system.
  • the performance of both types of ultrasound is possible as its operation is independent of one another.
  • the performance of high frequency ultrasounds is less in terms of time than the low frequency ones since their effect is more pronounced and the regeneration of the removed stratum corneum may be slower than the time between two activations of the low ones. In addition, this avoids problems or discomforts that could create slight injuries to the skin.
  • the activation of the low frequency is more common, since the disappearance of microducts is faster.
  • the activation of the high frequency ultrasounds must occur while the low are activated to maximize the effect of cavitation. And above all, the activation of either type should be performed after the deposition of the substance.
  • An example of use is that observed in Fig.8, but it can vary depending on skin types, locations and desired outcomes.
  • the app receives measurements of blood/interstitial glucose levels and one or more other parameters (including but not limited to heart rate, blood pressure, temperature, galvanic skin response, activity) from external devices such as continuous glucose monitoring sensors, smartwatches or fitbands and inputs entered by users using the app (meals and sports quantity and quality, sickness, fever, special events like the period or extreme focus).
  • one or more other parameters including but not limited to heart rate, blood pressure, temperature, galvanic skin response, activity
  • the learning algorithm gathers the data for the analysis, makes predictions of future parameter (like glucose) levels and risky events and, according to that, it gives personalized management advice and tells the user the amount of insulin (and/or any other substance) they need and at what time. If low time within optimal parameter (like glucose) range is detected over a week, therapy changes will be implemented (like insulin increase/decrease/ redistribution of daily doses).
  • the algorithm detects specific situations and triggers alarms when appropriate (for example: combination of accelerometer, temperature and heart rate data can indicate sport activity; combination of blood pressure, heart rate and galvanic skin response can indicate stress). These situations vary the parameter-substance (like glucose-insulin) kinetics and therefore, user ' s needs. Identifying them allows the measured parameter (like glucose) values, the advice given, and/or the substances to be administered to be adjusted to address the situations affecting the user and better manage the studied parameter (like glucose).
  • the multi-parameter approach allows personalization of the analysis for each user at any given moment of daily activity. It establishes different categories depending on the user ' s parameters (weight, height, sex, age, years from diagnosis, standard glucose levels recommended for each user) and measured parameters (glucose, etc.). Based on these categories and the current measurements, it gives personalized advice on how to act.
  • the algorithm sends the trigger to the non-invasive transdermal delivery apparatus through the app, for example specifying how much insulin and/or glucagon it should deliver and the speed of infusion; when the algorithm detects a glucose decreasing trend, it sends a signal to the non-invasive transdermal delivery apparatus to stop infusion of insulin and might initiate glucagon delivery, i.e., similar to when the user has hypoglycemia.
  • the data and the results of the algorithm may be accessed not only by means of the device of the invention, but also remotely by the user ' s personal choice (himself or others).
  • the information is sent back to the app to inform the user.
  • the doctor can use the cloud computing platform to inform the user about specific needs for him.
  • the proposed algorithm is an innovative, computing system that allows for a personalized real-time treatment of diabetes users and for a lifestyle intervention.
  • the algorithm features include
  • Detecting special events e.g., stress situation
  • behavioral habits e.g., sport activity
  • physical e.g., temperature
  • biological e.g., heart rate
  • behavioral parameters e.g., habits
  • the algorithm in one embodiment, includes various levels for processing measured values.
  • Aim Send an Forecasting Making decisions Modeling insulin alarm glucose level about hyper- or metabolism (+/- immediately hypoglycemia glucagon) due to a episode
  • One or more of the levels will typically operate at the same time, potentially providing their outputs to other levels:
  • This level monitors if the parameter (like glucose) levels go critically high or low in a short period of time that could't have been predicted. It takes as inputs the measured values and throws as output one or more alarms for the following situations:
  • Very high parameter (like glucose) levels alarm that alerts about the immediate need of substance (like insulin) to be administered to decrease parameter (like glucose) levels.
  • Very low parameter (like glucose) levels alarm that alerts about the immediate need to take or administer a substance (like glucagon) to increase parameter (like glucose) in blood levels.
  • ⁇ First level parameter (like glucose) level forecasting algorithm:
  • This algorithm monitors and predicts future parameter (like glucose) levels for several predicting horizons up to 90 minutes. It provides an accurate forecast of the parameter (like glucose) levels as output, based on several inputs such as past glucose, blood pressure, heart rate, galvanic skin response, body and external temperature, activity tracking, meals, sickness/fever and special events.
  • This algorithm represents the core component of the device, it returns its output to the next level component, and it would be always working in order to monitor the parameter (like glucose) in real-time.
  • a forecasting algorithm for special situations (like hyper- and hypoglycemia) risk. It represents the second level of the device and it receives the first level output (i.e., predicted glucose level) as input and past values of sensor measurements. This component predicts whether a special situation (like hyper- or hypoglycemia) will occur. It would work when the received signal exceeds a pre-specified parameter (like glucose) level threshold, and then computes the risk of the situation occurrence.
  • a pre-specified parameter like glucose
  • Behavior advice provider and effector trigger (substance delivery/ stop delivery + recommend substance oral or transdermal administration): A mathematical model of substance (like insulin and/or glucagon) metabolism. It receives the first level output, the second level output (like hyper or hypoglycemia episode occurrence), and/or past sensor values as input. This component determines the substance (like insulin and/or glucagon) level that should be administered. It starts when the received input exceeds a pre-specified risk threshold. For example: If the episode is hyperglycemia (high level of parameter situation), it provides advice to reduce levels of glycaemia (medium level of episode risk) or it computes the insulin (substance) quantity that needs to be administered and the period of injection (high level of episode risk).
  • hyperglycemia high level of parameter situation
  • it provides advice to reduce levels of glycaemia (medium level of episode risk) or it computes the insulin (substance) quantity that needs to be administered and the period of injection (high level of episode risk).
  • the episode is hypoglycemia, it returns an alarm to the user about the need to take sugar or meals to increase blood glucose levels or might compute the glucagon quantity that needs to be administered and the period of injection.
  • the mathematical model may be calibrated individually for each user in a training period.
  • An extra level for the algorithm will consist on deep learning network acting as a pattern detector module that will be capable of relating user ' s parameters values, situations, moments, and different inputs in order to identify individually repeated patterns and aggregate them in order to reach conclusions about the disease, market and treatment.
  • the algorithm is developed in a given programming language such as C/C++. Some simple computations (as data manipulation or matrix algebra operations) might be carried out by invoking open-source libraries.
  • Cloud computing system receives measured values at time t.
  • step 2 If received glucose level is within a pre-specified security interval: go to step 2.
  • glucose level is below the lower interval, an alarm alerts about immediate need to take sugar (and/or glucagon need).
  • Level 1 algorithm is trained based on measured values data stored in the database until time t. Extra parameters are used to correct glucose levels to their real values according to the specific situations that the user is living and his individual biology. 2.1 . Level 1 algorithm is updated for the user (up-to-date training based on past patterns and values) and predictions up to 90-minutes-ahead glucose levels are obtained.
  • step 5 If all the 90-minutes-ahead predictions are within a pre-specified security interval: go to step 5.
  • Level 2 algorithm is trained based on measured values data stored in the database until time t and the 90-minutes-ahead predicted glucose levels.
  • Level 2 algorithm is updated for the user and risk of hyper o hypoglycemia episode for the 90-minutes-ahead moments are obtained.
  • step 5 If all the 90-minutes-ahead associated risk are below a pre-specified value: go to step 5.
  • step 3. 1 If the associated risk computed in step 3. 1 . is below or above the pre-specified value: qualify the episode as actual hypo or hyperglycemia, respectively.
  • Level 3 algorithm is a mathematical model of insulin metabolism (and also Glucagon metabolism mathematical model might be used). It bases drug delivery (trigger) on the output of 3.3.1 ., the anthropometric and therapy parameters of the user (weight, height, sex, years with diabetes, daily insulin shots and quantity, type of insulin), APP MEASURES data stored in the database until time t and the 90- minutes-ahead predicted glucose levels.
  • episode is qualified as hyperglycemia: The mathematical model computes the insulin quantity and the moment for it to be injected or gives advices to prevent the future problem (for example do sports).
  • Trigger activate effector (substance delivery) and give behavior advice.
  • the device receives an order, wirelessly or manually, to supply a determined number of doses of substance.
  • A.1 If the order is wireless, it will occur by an order from the algorithm, which communicates the necessary dosages of substance and starts the supply device automatically.
  • the user must select the doses required and activate the device by using the security key (7.4), which will be inserted in one of the side buttons (6.3) of the device to activate a certain number of reservoirs, or by interaction with the activation button (6.2), with which the desired doses can be selected and delivered from the reservoirs.
  • the device Upon receiving the command, the device activates an electric current that causes the membranes under the reservoirs (10.1 ) to be activated, acting as gates when they break.
  • the substance Upon opening the gate, the substance falls to the skin, without loss, on the selected region for administration.
  • the ultrasound system is activated, which will facilitate the absorption of the substance.
  • An electric current is generated with a certain frequency, which will be amplified to the required voltages.
  • These currents reach a series of piezoelectric elements responsible for producing a vibration and, consequently, a series of mechanical waves in the spectrum of the ultrasounds.
  • These ultrasounds are divided into two categories whose addition will increase the absorption capacity of the substance by the skin.
  • D.2 Low-frequency ultrasound (10.2) will be activated taking a direction perpendicular to the plane of the skin, generating microducts on the surface that will facilitate the substance passing to deeper layers of the skin.
  • the device stores and communicates to the user and algorithm both the amount of substance administered and the amount remaining in the device. In this way, a constant bilateral communication between the different parts of the device is established and the information is stored to ensure its correct operation.
  • F) Information is collected on variables like the time of administration, the rate of absorption, the estimated bioavailable quantity, the temperatures reached and some user inputs on possible discomfort or chosen area, in order to calibrate the frequencies, times and alternations used and adapt them to the type of skin and thickness found to improve administration in the next cycle.

Abstract

The present invention relates to a device for use in the treatment of diseases comprising a transdermal substance delivery apparatus which allows a non-invasive distribution and absorption of substances by transdermal meanings automatically guided by an algorithm or manually by the final user, through a user interface or acting directly on the transdermal substance delivery apparatus. The present invention also relates to a method of treatment of diseases that comprises a step of applying a non-invasive distribution of at least one substance for the administration of the at least one substance to the user.

Description

DEVICE FOR USE IN THE TREATMENT OF DISEASES
DESCRIPTION
OBJECT OF THE INVENTION
The present invention relates to a device for use in the treatment of diseases comprising a transdermal substance delivery apparatus which allows a non-invasive distribution and absorption of substances by transdermal meanings automatically guided by an algorithm or manually by the final user, through a user interface or acting directly on the transdermal substance delivery apparatus.
The present invention also relates to a method of treatment of diseases that comprises a step of applying a non-invasive distribution of at least one substance for the administration of the at least one substance to the user.
TECHNICAL FIELD
The invention belongs to the group of biomedical devices and methods and more specifically to that of transdermal substance delivery devices and methods.
BACKGROUND OF THE INVENTION
Diabetes is an illness where the body is unable to supply sufficient amounts of insulin to maintain blood sugar within a healthy range. Managing diabetes typically involves the intermittent or continuous measurement of blood glucose levels followed by the administration of insulin in response to the measured blood glucose levels. Insulin may be administered by syringe or by a pump that reliably administers desired quantities of insulin.
The invasive system with needles and catheters is an outdated model that causes patients to prick themselves, have a catheter introduced into the body 24 hours a day (which favors infectious processes), and to be limited economically (sleep impediment, limitation to practice certain sports, difficulty in maintaining discretion regarding the use of equipment). These disadvantages increase the awareness of disease and decrease the quality of life. Insulin pumps are complex systems aimed at more experienced patients, leaving a large segment of the population without the possibility of automating treatment and reducing concerns. It is also a system that involves an enormous expense because of the associated materials (needles, catheters, pump purge elements, etc.).
Traditional pumps are a clear example of this. They remain as a generally uncomfortable and indiscreet system, with problems well known to the community of patients with diabetes or other diseases, which cannot be solved with the same technological tools. An improved pump is a breakthrough, but it is not innovation.
The device for use in the treatment of diseases and the related method of the present invention has a configuration which makes it possible to resolve all the aforementioned drawbacks.
DESCRIPTION OF THE INVENTION
The present invention relates to a device for use in the treatment of diseases comprising a non-invasive transdermal substance delivery apparatus which allows a non-invasive distribution of at least one substance for the administration of the at least one substance to the user automatically guided by an algorithm or manually by the final user, through a user I/O interface or acting directly on the non-invasive transdermal substance delivery apparatus.
The skin, unlike other organs and structures such as intestinal epithelium, is not designed for the absorption of substances useful to the body. The permeability through the skin is very low because it is formed by several layers, some of them very thick, and with a very little blood supply.
In a simplified way we can divide the skin into the following layers. The epidermis (the most superficial layer of the skin) is formed by a series of layers, the first being the stratum corneum, which, being impermeable to most substances, is the main barrier for the administration of substances (like drugs) through the skin. It prevents molecules larger than 500 Da from entering through it and is between 10-15 μηη thick. Next are the remaining layers of the epidermis and then there is the dermis, 1 -2 mm thick.
For a substance to be absorbed through the skin it must diffuse through the stratum corneum and the other layers of the epidermis. The transport through the skin is mainly by simple diffusion since this organ does not have mechanisms of active transport.
There are a large number of capillary vessels in the upper layer of the dermis, which facilitate the diffusion of the substance throughout the circulatory system, so it is interesting that the substance reaches that depth.
The main causes for considering the skin as a possible system for substance
(like drugs) delivery without the use of needles are the possibility of avoiding problems with pH, intestinal issues or deactivation by the enzymes associated with the gastrointestinal tract.
In order to increase the absorption capacity of the substance by the skin, several studies have shown how, thanks to the action of various ultrasonic waves with certain characteristics, they have succeeded in varying the structure of the most superficial layers of the skin favouring different processes of substance distribution.
The studies performed years ago were mainly around high frequency ultrasonic waves or therapeutic frequencies, until it was discovered that the formation of microducts near the cutaneous surface was inversely related to the frequency of the ultrasound. Since then, several investigations have been made in low-frequency sonophoresis. These low frequency ultrasonic waves are mainly used for the formation of the microducts named above, which serve as a mean of passing the molecules of the substance to be supplied to internal layers capable of absorbing them.
Complementary to this effect, the study of high-frequency ultrasound was not abandoned, but it was observed that its application in certain means achieved the generation of cavitation, a great ally in transdermal absorption. This phenomenon consists in the creation of small bubbles which when exploded; create a great increase of localized pressure that causes the disappearance of part of the aforementioned stratum corneum.
By removing part of the upper layers of the skin, which are those with greater adversity to the desired absorption, greater ease in transdermal administration is achieved.
One possibility is to use both high and low frequency ultrasounds simultaneously so that the former create the bubbles previously named and the latter, in addition to creating the microducts, help to place the bubbles in areas closer to the surface to be treated, increasing the elimination effect of stratum corneum.
The device for use in the treatment of diseases of the present invention allows adapting the health care recommendations to the individual needs of the user and the controlled delivery of substances by transdermal procedures, ie without needles and through the skin. The device has a non-invasive medical apparatus which purpose is to facilitate the automated or manual needle-free administration of substances through the skin, for example, in the day-to-day of patients suffering from some type of chronic pathology that needs to be medicated daily, keeping a constant follow-up of the disease (like diabetes).
The device also comprises a control unit that predicts the evolution of the disease based on the association of various parameters and optionally analyses the risk of certain situations to make personalized recommendations relevant to the disease and lifestyle.
Optionally, the device also comprises a user I/O interface comprising output data means for showing relevant information for the user and/or input data means for entering data by the user.
The device also comprises at least one sensor for measuring various parameters to be supplied to the control unit.
Optionally, the device also comprises a cloud computing system in communication with the control unit and the user I/O interface.
The non-invasive transdermal substance delivery apparatus optionally comprises means for applying ultrasonic waves in areas close to the skin of the user, preferably in such a way that part of the upper layers of the skin, in particular part of the stratum corneum, can be removed by means of high frequency ultrasonic waves and in such a way that microducts are opened by means of the application of low frequency ultrasonic waves. Also optionally, the non-invasive transdermal substance delivery apparatus comprises means for applying laser in areas close to the skin of the user. The non-invasive transdermal substance delivery apparatus is capable of adapting to different skin types and desired outcomes the sequential, simultaneous or alternating generation of these waves, in an orderly and controlled way to allow an increase in the absorption capacity of the skin and the diffusion of the substance through it.
The device can be operated manually, but thanks to the mass collection of data and their aggregation, the analysis may be able to obtain conclusions about the relationships between variables studied and recommend calculated doses of substance to be administered so the device can work autonomously.
The device optionally comprises wireless means for exchanging information with external sources in a bilateral way.
The device comprises supply means, preferably a battery, to supply energy to the components of the device.
Preferably, the non-invasive transdermal substance delivery apparatus optionally comprises attachment means for attaching the apparatus to the user, being preferably adhesive means.
Preferably, the non-invasive transdermal substance delivery apparatus optionally comprises at least one reservoir for collecting the substance to administrate.
Through the analysis and processing of the information of the external sources, an algorithm executed by the control unit is able to anticipate the user's needs with a predetermined time horizon. Based on these forecasts, an order is sent to the device to increase or reduce the substance supply. The delivery must be controlled and fast, avoiding high dead times during a dose administration. To do this, it is in communication with the user I/O interface authorized for the task, which is responsible for reporting the dose of the substance to be supplied and the time at which it should be provided. The substance in question is acquired and charged in the device by the user, with the periodicity necessary for the administration.
The medical device so constituted achieves a non-invasive substance supply, completely free of needles, while being easily concealable and handled from a discrete portable terminal and other user interfaces like the one incorporated in it. The apparatus is placed on the skin, having the device the following characteristics:
- It is modular in order to facilitate its use, rotation of administration zone and changing of rechargeable parts (battery, adhesive and charge of substance).
- It is hypoallergenic, thin, discreet and comfortable.
- It works without needles, increasing the quality of life and decreasing adverse events such as infections.
- It is controllable from an external source through the user I/O interface that also allows representing recommendations, internal device failures and how to solve them.
- It is automated thanks to a precise algorithm that informs about the needs at any time and asks for confirmation when making an intervention.
- For safety it can also operate manually in case of electronic failure, battery discharge or communication error with the user I/O interface, acting like a needle-free syringe. - It has a confirmation layer that prevents malicious activation thanks to a mechanical button necessary to confirm the administration of the dose.
The invention also relates to a method of treatment of diseases using the device explained above, the method comprising:
a step of prediction of the evolution of the diseases based on the association of various parameters;
a step of measuring the various parameters to be supplied to the control unit; and
a step of non-invasive distribution of at least one substance for the administration of the at least one substance to the user.
The method further comprises a step of showing relevant information for the user and/or a step of entering data by the user.
The method further comprises a step of communication between a cloud computing system and the control unit prior to the step of showing relevant information for the user and/or after the step of entering data by the user.
The method further comprises a step of applying ultrasounds in areas close to the skin of the user.
The method further comprises a step of exchanging information with external sources in a bilateral way.
The method further comprises a step of supplying energy to the components of the device.
The method further comprises a step of attaching the apparatus to the user. The method further comprises a step of collecting the substance to administrate.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows one embodiment of the device for use in the treatment of diseases of the present invention.
Figure 2 shows a diagram of the cloud computing system of the device for use in the treatment of diseases of the present invention.
Figure 3 shows a diagram of a predictive and managing algorithm executed in the cloud computing system that receives data from the user I/O interface and transmits it in return.
Figure 4 shows a scheme of the non-invasive transdermal substance delivery apparatus of the device for use in the treatment of diseases of the present invention according to a first preferred embodiment.
Figure 5 shows an algorithm flow chart of the predictive and managing algorithm shown in Figure 3.
Figure 6 shows a view of a central assembly of the non-invasive transdermal substance delivery apparatus of the device for use in the treatment of diseases of the present invention with all parts attached according to a second preferred embodiment.
Figure 7 shows an exploded view of all parts of the central assembly, including the substance container according to a second preferred embodiment.
Figure 8 shows a view of all parts of the central assembly, including the substance container and attachable pieces which can be connected to the central assembly by means of adapters.
Figure 9 shows an exploded view of Figure 8.
Figure 10 shows a bottom view of the central assembly allowing to observe the fit of the pieces being prepared for its use.
Figure 1 1 shows a top view of the central assembly with a piece removed from one attachable piece.
Figure 12 shows a filler cut with all parts assembled and channels closed. Figure 13 shows a schematic view of the activation of the device for use in the treatment of diseases acting as insulin supplier, generating high frequency ultrasound and low frequency ultrasound.
DETAILED DESCRIPTION OF THE INVENTION
Below, the device for use in the treatment of diseases of the present invention, the disease being preferably diabetes, is described in detail.
The main components of the device are interconnected with WIFI, mobile networks and/or Bluetooth technology and include: 1 - A user I/O interface, preferably a mobile app, comprising output data means for showing relevant information for the user and/or input data means for entering data by the user (e.g., meals, time performing activities, sickness/fever, and special events) and otherwise supplied by sensors explained below, issuing commands controlling the administration of a substance, preferably insulin, and offloading data to other computing resources for processing. The mobile app may execute on a smartphone, tablet, phablet, laptop, desktop computer, NUC, etc.
In various embodiments, the mobile app provides a variety of functions, including but not limited to:
Data display: showing relevant information for the user (current and average glucose, trends, carbs intake, sports time, insulin units needed, predicted glucose and behavior advice, % of measured values within target range).
Events diary: logbook of daily events (meals, sports, insulin injection). Day selection through calendar.
Advice on how to act: (inject insulin/take sugar/run 10 minutes/rest 15 minutes...), therapy modification, physician's personal advice.
Charts of glucose levels over days/weeks/months. Overlaid appear events from the diary (moments of insulin injection, sports, meals)
Chatbot feature: chat-like interface to present and request information in an automated fashion.
2- Sensors for measuring various parameters to be supplied to a control unit that commands the mobile app and/or the non-invasive transdermal substance delivery apparatus. Exemplary sensors that may be used include but are not limited to:
Glucometer or continuous glucose monitor (invasive or non-invasive) for measuring blood/interstitial glucose level. Smartwatch or fitbands with different sensors: Heart rate, blood pressure, body and ambient temperature, galvanic skin response, accelerometer.
3- Cloud computing system, illustrated further in Fig.2, is in communication with the control unit and mobile app, offering a variety of functions:
Predictive and managing algorithm (illustrated in Fig. 3) executed in the cloud computing system or in other technological support related to the device, receiving data from the mobile app and transmitting results in return.
Big data traffic management.
- Access to the data of the mobile app (user I/O interface), generation of charts and relation between parameters).
Encrypted database.
4- Non-invasive transdermal substance delivery apparatus. In one embodiment, this entails the opening of a micro-pore (micro-duct) on the upper layers of the skin, as illustrated in figure 4.
4.1 . Full smart patch: non-invasive substance administration.
4.2. Support platform
4.2.1. Elastic and resistant material as patch covering.
· 4.2.2. Dots represent sticky material to increase skin adherence (must be hypoallergenic material to avoid dermatitis). (Facing the skin).
4.2.3. Hole to place a delivery system module, allowing patch dressing change.
4.3. Delivery system module.
4.3.1 . Electronic module: receiver + transmitter. Unique device identifier.
· 4.3.2. LED to inform about system status (green= okay, red= system failure, orange= visit app logbook for information). (Not facing the skin).
4.3.3. Hole for substance infusion through the pre-opened micro-pore. (Facing the skin).
4.3.4. Pore-opening and delivery module: Laser and/or ultrasound technology to open a micro-pore on the upper layers of the skin that allows non-invasive substance infusion.
4.3.5. substance reservoir (separated chambers for different substances). It needs to be replaced when it runs out of substance. Different to current pumps reservoirs, connected to the hole for substance infusion.
Following this design, the delivery system can be extracted from the support platform whenever it loses stickiness and be placed on another one.
This modular design allows the different parts of the device to be positioned so that they fit better into the user's body contours, avoiding discomfort and being easily concealed. It also facilitates the localization of future device problems and the improvement of the different parts without greatly modifying the rest of the non-invasive transdermal substance delivery apparatus.
A series of elements are needed to be changed each given time period so the device can keep operating, amongst them are supply means to supply energy to the components of the device, preferably being a battery that can be separated from the rest of the apparatus easily. In addition to this element, we can find those considered as disposable, which are composed of adhesives, to allow anchorage of the device to the user's skin, and at least one reservoir for collecting the substance to administrate.
The latter is in charge of containing a series of holes that house the substance to be distributed. To fill them, the user has a two-way coupling system but not attached to the device (The filler). Rotating certain parts of it to certain positions, the desired substance can be collected and, after another series of rotations, injected into the holes and get the reservoir/s sealed.
To increase the absorption capacity of the substance by the skin, a series of ultrasounds are applied in areas close to the skin. These are divided into two groups according to their capacities, being high and low frequency. Those of low frequency (40-300kHz) are placed so that the advance of the wavefront created is perpendicular to the skin and allows the creation of micro-paths (micro-ducts) in the skin, through which the molecule can circulate. Those of high frequency (1 -3 MHz) are placed so that their advance is parallel to the skin and are in charge of eliminating certain parts of the more superficial layers of the skin, in part thanks to the cavitation effect.
The powers and waveforms of both groups avoid any discomfort or damage to the user's skin that would be annoying or undesirable such as excessive redness or excessive removal of the upper layers of the skin.
Further designs of the device for use in the treatment of diseases will be now explained according to figures 6-1 1 , with a delivery system being the central assembly shown in fig. 6 and attachment means for attaching the apparatus to the user, being an adhesive (10.3). As already indicated above, the device is intended to deliver substances to the user by transdermal methods. For this, the device is composed of a series of assemblies, each in charge of a particular function and interconnected to each other. First, there is a user I/O interface through which communication between the device and the user is established; secondly, a non-invasive transdermal substance delivery apparatus with the reservoirs and the delivery substance system; and finally, the electronics assembly, in which the power supply, unit control and ultrasound system are grouped together.
As for the physical aspect, the non-invasive transdermal substance delivery apparatus is modular, being divided into a series of rigid parts where the main elements are as we can see in Fig.6 and Fig.7. These parts operate by their own, but can be connected to attachable modules by means of semi-rigid units (8.5) enabling them to be partially rotated and moved away from or close to one another and extend functionalities. In this way, a better positioning of the assembly is provided, being adapted to the shape of the surface to which it is attached (reaching the shape seen in Fig.8).
Thanks to this, the device can be placed in different areas of the body of the user suitable for the skin characteristics, including upper arm, abdomen and thigh but not limited to them. In relation to biosecurity, the device must be changed from time to time to avoid possible conditions that may occur on the skin because of the continuous flow or deposit of substance through or on it. The device is designed to be detached from the skin and recharged each time the stipulated days are reached. It is necessary to reset the device once the process is complete. The only items that need to be renewed are the adhesive and the reservoir/s. In terms of power supply, the user has several batteries allowing their exchange and recharge every time the position is changed and there is an extra reserve included in the central assembly for manual activation in case of failure or discharge.
The device has several elements to allow communication with the user in both outgoing and incoming direction:
• First, the device can provide information about the number of reservoirs remaining, the battery charge level, or the condition of the non-invasive transdermal substance delivery apparatus. For this, a series of LEDs and other interfaces are activated with the appropriate message that is wanted to be transmitted to the user. It is only activated for a short time after request, avoiding sending information when it is not needed.
• As an incoming communication channel, the device interfaces include but are not limited to the the apparatus interfaces, these being a series of buttons (6.3) located in the main housing which must be activated by a small sized key (7.4) that is inside the housing and can be removed and inserted at will. These buttons allow the device to be started and reset as well as the supply of a certain number of reservoirs. For the user to be able to make confirmations to the device, a push button (6.2) is placed in an accessible site of the device.
Once the substance delivery process is complete, the system stores and communicates to the user and algorithm both the amount of substance administered and the amount remaining in the device. In this way, a constant bilateral communication between the different parts of the device is established and the information is stored to ensure its correct operation
Any communication with external electronic elements is done by wireless methods which must be accessed through a series of security keys to begin communication. These keys are provided to the user upon obtaining the product.
To be able to contain the substance and to deliver it, several support platforms (like in the shape of disks) (7.3) are used to keep it safe and protected and to allow its controlled delivery. A main support platform comprises a polymeric disk, which has a certain balance between rigidity and flexibility, providing greater ergonomics to the user. Within the disk are pluralities of holes or reservoirs (10.1 ) into which a certain amount of substance may be introduced.
This disk is between two layers that prevent the exit of the substance, allowing some internal pressure. The upper layer, made of a material biocompatible with the substance, makes the sealant of the non-invasive transdermal substance delivery apparatus reservoir after filling, having dimensions that allow its coupling to the main disk.
The substance is expelled from the support platform through the bottom of each hole or reservoir by an individual channel. In order to control the passage, an impermeable sheet formed by very thin layers of various metals is placed covering the hole floor. Upon receipt of the substance delivery order, an electric current is generated between two of the ends of the metal sheet, acting as a fuse, breaking and letting the dose of substance pass to the skin. To do this, a series of conductive tracks are coupled to a thin layer of silicon deposited on the underside of the disk.
All this is done so that the amount of metallic waste generated that can reach the bloodstream is not harmful.
In order to prevent the substance from deteriorating during the time it is stored in the reservoirs, they are covered on the inside by a thin layer of a polymer biocompatible with the specific substance, being capable of maintaining the chemical stability of the whole. The biocompatible nature of this surface also prevents a phenomenon of adsorption of the substance in the walls of the reservoir. The substance may remain in the reservoir the established days without risk of changes in structure and effectiveness. In addition, the morphology of the hole prevents the remaining of substance inside after being activated, facilitating the arrival of the same to the skin without losses.
In order to be able to be contained in the central assembly, allowing its use and avoiding movements with respect to the rest, an anchorage (7.6) is made that allows its easy extraction and introduction in the central assembly holes of the device (7.5).
This central structure or piece (6.1 ) is composed of two pieces which can be joined by joining means that can include threads but are not limited to them, so that there is an upper (7.1 ) and a lower (7.2) piece, taking into account the skin as ground height. At the top is the circuitry required for the activation of the piezoelectric devices in charge of generating the ultrasounds as well as other elements such as buttons and LEDs for interaction with the user, additional electronics, sensors and it may also contain the power supply necessary for its operation. Furthermore, it contains several holes (7.5) in which the support platform of the substance is fitted, being immobilized by screwing or fitting the lower part (7.2). To avoid rotation of the support platform, a series of notches are made into which the teeth (7.6) of the reservoir container are inserted. These teeth also make an additional stop so that together with the lower part prevent axial movements of the support platform.
To fill the reservoir container, the lower part of the central module is unscrewed or unfitted and the container disk with the reservoirs is removed. Once removed, a filler (Fig.12) operates as a two-way system. Thus, with a few turns of the whole, the substance can be absorbed from its usual container, and with another turn injected into the reservoirs, which are sealed with pressure when the lid is placed. Finally, the disk is inserted again in the central module and the lower part is screwed or fitted. The reservoirs must be filled by the user when he changes the position of the device.
The filler operates as follows:
A. It is checked that the container of reservoirs is well placed in the filler so that it is fitted.
B. An upper part (12.1 ) and a lower part (12.4) are rotated to a series of marks indicating that the top hole is open and the bottom hole closed. To better indicate that the position has been reached, some mechanical resistance is applied to leave this position.
C. The assembly is then used as if it were a syringe absorbing the substance through the upper hole (12.5, 12.6), remaining between connectors (12.2, 12.3).
D. After observing that there is no air inside, a transversal piece (12.1 ) turns and the interior is sealed.
E. The upper part (12.4) is rotated until lower holes (12.7, 12.8) are open and the reservoirs can be filled.
F. After making sure that all the substance has been injected, the reservoir container is closed by turning it so that the top cap engages.
G. The container is removed from the filler and ready for use.
In order to facilitate the correct positioning of the rotating parts, certain drawings are included on them, helping to know in which position it is.
The container disk and the filler are for single use and are manufactured with a series of biocompatible polymers for each of the substances to be used. The container can also be filled with the current administration systems such as syringes or pens / medicine pens.
Depending on each user, different types of substance may be supplied. The number of reservoirs in the device determines the dose ranges that can be administered. Depending on the quantity and type of substance required, a given number of reservoirs are activated automatically (algorithm-guided) or manually (user- guided).
With the possibility of filling with different types of substances at the same time, various modifications are made in the filler and container disk to allow it. These may include separation of the internal compartment or creation of more holes for the passage of the substance.
Once the substance has been introduced into the reservoirs, they are covered with the above-named top cap being formed of a polymer sheet, coated with the same biocompatible material as the inner faces of the reservoir.
To fit the entire assembly to the skin, a bandage (10.3) in the form of a circular crown is used to adhere comfortably, but without covering the holes in the reservoirs, which are arranged in an orderly manner over the entire surface of the support platform. Its function is to keep the device as still as possible with respect to the specific area of the skin of the user that has been selected as the absorption zone. Its shape allows a correct grip of the whole to the user and contemplates evolutions of it and the complete apparatus towards more ergonomic designs that allow adaptation to the body morphology and are flexible.
The adhesive is hypo-allergenic, thus avoiding allergic reactions on the skin that can lead to dermal problems. Since each skin is different, there may be users with skins that generate some type of reaction, in which case they should consult their dermatologist. In addition, it is characterized by its water resistance, elasticity and permeability, facilitating removal of the exudate.
The adhesive is changed every time the device is detached so as to prevent it from losing its effectiveness and being peeled off the skin.
The electronics of the device can be separated into three different modules differentiated by their use and operation. The first module is the power supply, a second module is the control part of the circuit whose operation coordinates all the apparatus and finally the ultrasonic module, which facilitates the absorption of the substance. These modules are integrated into a single electronic module that encompasses all the circuitry of the device and is housed in the central assembly (6.1 ).
The circuitry is designed so that it does not reach temperatures or powers that could endanger the health of the user or the stability of the components of the device, including in this section the substance.
The battery module is responsible for powering the entire device. Thanks to its load, it is possible to use the whole device for a long time without the need to recharge. In order to be able to connect it as an attachable module to the central module, an attachable piece (8.3) is made, which can be connected to the attachable module by means of adapters, such as that seen at (8.2), with the suitable connectors (1 1.3). Certain movements for extraction may be made thanks to various mechanical systems (9.1 , 1 1.2), preferably connectors, in addition to systems to prevent their exit (8.4, 9.2, 1 1.1 ). It can be found as an accessory piece or forming part of the central assembly. If connected as an accessory piece to the central module (attachable module), it is done through the previously mentioned semi-rigid structures (8.5).
It also has a charge input to be able to recharge it by the connection to the electric network or supply devices. To protect the battery in both charge and discharge mode, a series of protection circuits are implemented.
The control unit of the apparatus is responsible for controlling and coordinating all circuits in the apparatus. To do this, it processes the information received from external sources such as the algorithm and sensors, makes the necessary control orders and finally, applies them on the apparatus. The calculation power is not high because of the low device requirements. There are two possible ways to give an action order to the device: an electronic way through wireless communication and a physical path.
The wireless communication module receives and processes the different signals so that they can be interpreted by the control unit. As a security measure, it carries a predefined address and key, thus avoiding possible manipulation by others than the user.
The main barrier to overcome for the substance in order to reach the bloodstream is the stratum corneum. It is the most superficial layer of the skin and consists of dead cells that greatly limit its permeability. In order to facilitate absorption, an ultrasound field is applied to the surface on which the substance is deposited.
An electric current with a certain frequency, which is amplified to the required voltages, is generated by a series of resonator circuits for the production of ultrasounds. These currents reach a series of piezoelectric elements, responsible for producing a vibration and, consequently, a series of mechanical waves in the spectrum of the ultrasounds. These ultrasounds are divided into two categories, the low frequency ultrasounds (10.2) being those whose oscillation frequency is less than 1 MHz and high frequency ultrasounds (7.7) those with values greater than 1 MHZ.
The low frequency ultrasounds (10.2) are located in the upper part of the central module, the furthest from the skin, at the lower end of columns that pass through the support platform of reservoirs. The main direction of advance of the waves generated in this case is perpendicular to the plane of the skin. This type of wave is used to generate microducts in the surface allowing large molecules, such as those that can be part of a substance or drug, to reach the inner layers of the skin.
The high frequency ultrasounds (7.7) are placed in the shape of small piezoelectrics at a very small distance from the skin in the walls of the cavity left by the central assembly's casing to deposit the substance, being part of the lower part of the central module (7.2), so that the main direction of movement of the waves is parallel to the plane of the skin. The use of high frequency ultrasound for the generation of cavitation is a great ally in the effect of transdermal absorption. This effect consists on the generation of small bubbles that explode upon colliding with the skin, resulting in a considerable increase of local pressure, thus eliminating part of the stratum corneum.
The addition of these two effects increases the absorption capacity of the substance by the skin.
Thanks to the placement of various ultrasonic generators and a possible control over them, the state of various areas of the skin can be managed at all times. They are placed in areas close to the place of deposition of the substance. With this system, the substance penetrates the skin in a non-invasive way reaching the cutaneous capillaries from where it is incorporated into the circulatory system.
Because of the difference between different skins characteristics and the locations where the assembly can act, it is possible to control and adapt the times between ultrasound application pulses in addition to the frequencies and the times of application. These inputs are limited between certain ranges to avoid the possibility of damaging the skin in a poor configuration.
In this way a more offensive or delicate action towards the skin can be obtained, achieving an increase or decrease in the absorption capacity of the most superficial layers of the skin, besides eliminating more or less amount of stratum corneum,
The performance of both types of ultrasound is possible as its operation is independent of one another. The performance of high frequency ultrasounds is less in terms of time than the low frequency ones since their effect is more pronounced and the regeneration of the removed stratum corneum may be slower than the time between two activations of the low ones. In addition, this avoids problems or discomforts that could create slight injuries to the skin. However, the activation of the low frequency is more common, since the disappearance of microducts is faster.
The activation of the high frequency ultrasounds must occur while the low are activated to maximize the effect of cavitation. And above all, the activation of either type should be performed after the deposition of the substance. An example of use is that observed in Fig.8, but it can vary depending on skin types, locations and desired outcomes.
While the foregoing discussion has been focused on diabetes treatment, one of ordinary skill would recognize that embodiments of the present invention are suited to the delivery of substances generally in response to parameters measured by one or more sensors, as well as the treatment of other illnesses. The method of treatment of diseases that comprises a step of applying a noninvasive distribution of at least one substance for the administration of the at least one substance to the user is explained below.
The app receives measurements of blood/interstitial glucose levels and one or more other parameters (including but not limited to heart rate, blood pressure, temperature, galvanic skin response, activity) from external devices such as continuous glucose monitoring sensors, smartwatches or fitbands and inputs entered by users using the app (meals and sports quantity and quality, sickness, fever, special events like the period or extreme focus).
Then, these parameters are processed (potentially in the cloud or, if the user is without internet connection and the user's hardware is sufficiently powerful, then processing may be performed on the app or the non-invasive administration apparatus). The learning algorithm gathers the data for the analysis, makes predictions of future parameter (like glucose) levels and risky events and, according to that, it gives personalized management advice and tells the user the amount of insulin (and/or any other substance) they need and at what time. If low time within optimal parameter (like glucose) range is detected over a week, therapy changes will be implemented (like insulin increase/decrease/ redistribution of daily doses).
Using the extra parameters, the algorithm detects specific situations and triggers alarms when appropriate (for example: combination of accelerometer, temperature and heart rate data can indicate sport activity; combination of blood pressure, heart rate and galvanic skin response can indicate stress). These situations vary the parameter-substance (like glucose-insulin) kinetics and therefore, user's needs. Identifying them allows the measured parameter (like glucose) values, the advice given, and/or the substances to be administered to be adjusted to address the situations affecting the user and better manage the studied parameter (like glucose).
The multi-parameter approach allows personalization of the analysis for each user at any given moment of daily activity. It establishes different categories depending on the user's parameters (weight, height, sex, age, years from diagnosis, standard glucose levels recommended for each user) and measured parameters (glucose, etc.). Based on these categories and the current measurements, it gives personalized advice on how to act.
Then, if substance delivery is needed, the algorithm sends the trigger to the non-invasive transdermal delivery apparatus through the app, for example specifying how much insulin and/or glucagon it should deliver and the speed of infusion; when the algorithm detects a glucose decreasing trend, it sends a signal to the non-invasive transdermal delivery apparatus to stop infusion of insulin and might initiate glucagon delivery, i.e., similar to when the user has hypoglycemia.
The data and the results of the algorithm may be accessed not only by means of the device of the invention, but also remotely by the user's personal choice (himself or others). When the information has been processed, it is sent back to the app to inform the user. The doctor can use the cloud computing platform to inform the user about specific needs for him.
The proposed algorithm is an innovative, computing system that allows for a personalized real-time treatment of diabetes users and for a lifestyle intervention. The algorithm features include
• Personalizing the treatment based on past patterns of measured parameters for each user;
• An innovative multi-level set up which provides real-time forecasts of future parameter (like glucose) levels, associated risk of special situations (like hypo- or hyperglycemia episode), and concrete treatment/advice for each future need;
• Detecting special events (e.g., stress situation) and behavioral habits (e.g., sport activity) through combination of physical (e.g., temperature), biological (e.g., heart rate), and behavioral parameters (e.g., habits);
As illustrated in next table, the algorithm, in one embodiment, includes various levels for processing measured values.
Main features of four level components
Feature Zero level First level Second level Third level component component component component
Aim Send an Forecasting Making decisions Modeling insulin alarm glucose level about hyper- or metabolism (+/- immediately hypoglycemia glucagon) due to a episode
sudden high occurrence
risk
Initializing Always Always working When first level When second working output surpass a level output given threshold surpass a given threshold
Inputs App App measures Forecasted Forecasted measures glucose level glucose level
- Past values of - Past values of app measures app measures
- Risk of episode occurrence
Outputs Alarm + Forecasted Risk of episode Alarm + trigger trigger glucose level for occurrence
different horizons One or more of the levels will typically operate at the same time, potentially providing their outputs to other levels:
Zero Level: Immediate actions algorithm:
This level monitors if the parameter (like glucose) levels go critically high or low in a short period of time that couldn't have been predicted. It takes as inputs the measured values and throws as output one or more alarms for the following situations:
Very high parameter (like glucose) levels: alarm that alerts about the immediate need of substance (like insulin) to be administered to decrease parameter (like glucose) levels.
Very low parameter (like glucose) levels: alarm that alerts about the immediate need to take or administer a substance (like glucagon) to increase parameter (like glucose) in blood levels. · First level: parameter (like glucose) level forecasting algorithm:
This algorithm monitors and predicts future parameter (like glucose) levels for several predicting horizons up to 90 minutes. It provides an accurate forecast of the parameter (like glucose) levels as output, based on several inputs such as past glucose, blood pressure, heart rate, galvanic skin response, body and external temperature, activity tracking, meals, sickness/fever and special events. This algorithm represents the core component of the device, it returns its output to the next level component, and it would be always working in order to monitor the parameter (like glucose) in real-time.
Second level: Special situations (like Hypo/Hyperglycemia) risk predictor:
A forecasting algorithm for special situations (like hyper- and hypoglycemia) risk. It represents the second level of the device and it receives the first level output (i.e., predicted glucose level) as input and past values of sensor measurements. This component predicts whether a special situation (like hyper- or hypoglycemia) will occur. It would work when the received signal exceeds a pre-specified parameter (like glucose) level threshold, and then computes the risk of the situation occurrence.
Third level: Behavior advice provider and effector trigger (substance delivery/ stop delivery + recommend substance oral or transdermal administration): A mathematical model of substance (like insulin and/or glucagon) metabolism. It receives the first level output, the second level output (like hyper or hypoglycemia episode occurrence), and/or past sensor values as input. This component determines the substance (like insulin and/or glucagon) level that should be administered. It starts when the received input exceeds a pre-specified risk threshold. For example: If the episode is hyperglycemia (high level of parameter situation), it provides advice to reduce levels of glycaemia (medium level of episode risk) or it computes the insulin (substance) quantity that needs to be administered and the period of injection (high level of episode risk). If the episode is hypoglycemia, it returns an alarm to the user about the need to take sugar or meals to increase blood glucose levels or might compute the glucagon quantity that needs to be administered and the period of injection. The mathematical model may be calibrated individually for each user in a training period.
• An extra level for the algorithm will consist on deep learning network acting as a pattern detector module that will be capable of relating user's parameters values, situations, moments, and different inputs in order to identify individually repeated patterns and aggregate them in order to reach conclusions about the disease, market and treatment.
The algorithm is developed in a given programming language such as C/C++. Some simple computations (as data manipulation or matrix algebra operations) might be carried out by invoking open-source libraries.
The following is one example of the execution of the algorithm (Further explained in Fig. 5): 1 . Cloud computing system receives measured values at time t.
1 .1 . If received glucose level is within a pre-specified security interval: go to step 2.
1 .2. Else:
1 . 2. 1. If glucose level is above the upper interval, an alarm alerts about immediate need of insulin.
1 . 2. 2. If glucose level is below the lower interval, an alarm alerts about immediate need to take sugar (and/or glucagon need).
2. Level 1 algorithm is trained based on measured values data stored in the database until time t. Extra parameters are used to correct glucose levels to their real values according to the specific situations that the user is living and his individual biology. 2.1 . Level 1 algorithm is updated for the user (up-to-date training based on past patterns and values) and predictions up to 90-minutes-ahead glucose levels are obtained.
2.2. If all the 90-minutes-ahead predictions are within a pre-specified security interval: go to step 5.
2.3. Else: for all the 90-minutes-ahead predictions
2. 3. 1. If predicted glucose level is above an upper limit: qualify the episode as potential hyperglycemia and show the predicted trend.
2. 3. 2. If predicted glucose level is below a lower limit: qualify the episode as potential hypoglycemia and show the predicted trend.
2. 4. Go to step 3.
3. Level 2 algorithm is trained based on measured values data stored in the database until time t and the 90-minutes-ahead predicted glucose levels.
3.1 . Level 2 algorithm is updated for the user and risk of hyper o hypoglycemia episode for the 90-minutes-ahead moments are obtained.
3.2. If all the 90-minutes-ahead associated risk are below a pre-specified value: go to step 5.
3. 3. Else: for all the potentially risky episode(s) detected in step 2.3
3. 3. 1 . If the associated risk computed in step 3. 1 . is below or above the pre-specified value: qualify the episode as actual hypo or hyperglycemia, respectively.
3. 4. Go to step 4.
4. Compute treatment. Level 3 algorithm is a mathematical model of insulin metabolism (and also Glucagon metabolism mathematical model might be used). It bases drug delivery (trigger) on the output of 3.3.1 ., the anthropometric and therapy parameters of the user (weight, height, sex, years with diabetes, daily insulin shots and quantity, type of insulin), APP MEASURES data stored in the database until time t and the 90- minutes-ahead predicted glucose levels.
4.1 . If episode is qualified as hyperglycemia: The mathematical model computes the insulin quantity and the moment for it to be injected or gives advices to prevent the future problem (for example do sports).
4.2. If episode is qualified as hypoglycemia: It returns an alarm to the user informing him to take sugar or it might compute the amount needed of glucagon to increase blood glucose. 5. Update t = t + 1. Go to step 1. Operationalization of variables:
Measured parameters:
Figure imgf000024_0001
Trigger: activate effector (substance delivery) and give behavior advice. EXAMPLE
A) The device receives an order, wirelessly or manually, to supply a determined number of doses of substance.
A.1 If the order is wireless, it will occur by an order from the algorithm, which communicates the necessary dosages of substance and starts the supply device automatically.
A.2 If the order is manual, the user must select the doses required and activate the device by using the security key (7.4), which will be inserted in one of the side buttons (6.3) of the device to activate a certain number of reservoirs, or by interaction with the activation button (6.2), with which the desired doses can be selected and delivered from the reservoirs.
B) Upon receiving the command, the device activates an electric current that causes the membranes under the reservoirs (10.1 ) to be activated, acting as gates when they break.
C) Upon opening the gate, the substance falls to the skin, without loss, on the selected region for administration. D) Once the substance is on the skin, the ultrasound system is activated, which will facilitate the absorption of the substance. An electric current is generated with a certain frequency, which will be amplified to the required voltages. These currents reach a series of piezoelectric elements responsible for producing a vibration and, consequently, a series of mechanical waves in the spectrum of the ultrasounds. These ultrasounds are divided into two categories whose addition will increase the absorption capacity of the substance by the skin.
D.1 High-frequency ultrasound (7.7) will be activated carrying a direction of propagation parallel to the plane of the skin, generating small bubbles that, upon collision with the skin, explode resulting in a considerable increase in local pressure, thus eliminating part of the stratum corneum.
D.2 Low-frequency ultrasound (10.2) will be activated taking a direction perpendicular to the plane of the skin, generating microducts on the surface that will facilitate the substance passing to deeper layers of the skin.
D.3 The sequential, simultaneous or alternating generation of these waves, in an orderly and controlled way, allows to increase the absorption capacity of the skin and the diffusion of the substance through it.
E) Once the substance delivery process is complete, the device stores and communicates to the user and algorithm both the amount of substance administered and the amount remaining in the device. In this way, a constant bilateral communication between the different parts of the device is established and the information is stored to ensure its correct operation.
F) Information is collected on variables like the time of administration, the rate of absorption, the estimated bioavailable quantity, the temperatures reached and some user inputs on possible discomfort or chosen area, in order to calibrate the frequencies, times and alternations used and adapt them to the type of skin and thickness found to improve administration in the next cycle.

Claims

1. Device for use in the treatment of diseases comprising:
a control unit that predicts the evolution of the disease based on the association of various parameters;
at least one sensor for measuring the various parameters to be supplied to the control unit;
characterized in that the device further comprises:
a non-invasive transdermal substance delivery apparatus which allows a non- invasive distribution of at least one substance for the administration of the at least one substance to the user.
2. Device for use in the treatment of diseases according to claim 1 characterised in that it further comprises a user I/O interface comprising output data means for showing relevant information for the user and/or input data means for entering data by the user.
3. Device for use in the treatment of diseases according to claim 2 characterised in that it further comprises a cloud computing system in communication with the control unit and the user I/O interface.
4. Device for use in the treatment of diseases according to any one of the previous claims characterised in that the non-invasive transdermal substance delivery apparatus comprises means for applying ultrasonic waves in areas close to the skin of the user.
5. Device for use in the treatment of diseases according to claim 4 characterised in that the means for applying ultrasounds in areas close to the skin of the user are high frequency ultrasounds means (7.7) for applying ultrasonic waves, preferably in the frequency range between 1 and 3 MHz and/or low frequency ultrasound means (10.2) for applying ultrasonic waves, preferably in the frequency range between 40 and 300kHz.
6. Device for use in the treatment of diseases according to any one of the previous claims characterised in that the non-invasive transdermal substance delivery apparatus comprises means for applying laser in areas close to the skin of the user.
7. Device for use in the treatment of diseases according to any one of the previous claims characterised in that it comprises wireless means for exchanging information with external sources in a bilateral way.
8. Device for use in the treatment of diseases according to any one of the previous claims characterised in that it comprises supply means to supply energy to the components of the device.
9. Device for use in the treatment of diseases according to any one of the previous claims characterised in that the transdermal substance delivery apparatus comprises attachment means for attaching the apparatus to the user.
10. Device for use in the treatment of diseases according to any one of the previous claims characterised in that the transdermal substance delivery apparatus comprises at least one reservoir for collecting the substance to administrate.
1 1. Device for use in the treatment of diseases according to any one of the previous claims characterised in that it comprises a delivery system configured to deliver the at least one substance to the user by means of the non-invasive transdermal substance delivery apparatus
12. Device for use in the treatment of diseases according to any one of the previous claims characterised in that the non-invasive transdermal substance delivery apparatus is modular.
13. Device for use in the treatment of diseases according to claim 12 characterised in that the non-invasive transdermal substance delivery apparatus comprises a central structure or piece (6.1 ) that in turn comprises two pieces which are joined by joining means so that there is an upper (7.1 ) and a lower (7.2) piece and several holes (7.5) in which a support platform of the substance is fitted.
PCT/EP2017/050823 2016-01-16 2017-01-16 Device for use in the treatment of diseases WO2017121901A1 (en)

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US20060188556A1 (en) * 2005-02-24 2006-08-24 Redding Bruce K Ultrasonically assisted dermal or transdermal delivery substance preparation
US20090149798A1 (en) * 2007-12-05 2009-06-11 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Implant system for chemical modulation of neural activity
US20100298765A1 (en) * 2009-05-22 2010-11-25 Abbott Diabetes Care Inc. Safety features for integrated insulin delivery system
WO2012108938A1 (en) * 2011-02-11 2012-08-16 Abbott Diabetes Care Inc. Software applications residing on handheld analyte determining devices
US20140309615A1 (en) * 2013-04-16 2014-10-16 Bryan Mazlish Discretionary insulin delivery systems and methods

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060188556A1 (en) * 2005-02-24 2006-08-24 Redding Bruce K Ultrasonically assisted dermal or transdermal delivery substance preparation
US20090149798A1 (en) * 2007-12-05 2009-06-11 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Implant system for chemical modulation of neural activity
US20100298765A1 (en) * 2009-05-22 2010-11-25 Abbott Diabetes Care Inc. Safety features for integrated insulin delivery system
WO2012108938A1 (en) * 2011-02-11 2012-08-16 Abbott Diabetes Care Inc. Software applications residing on handheld analyte determining devices
US20140309615A1 (en) * 2013-04-16 2014-10-16 Bryan Mazlish Discretionary insulin delivery systems and methods

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