Patent Description:
A variety of diseases exists that require regular treatment by injection of a medicament. Such injection can be performed by using hypodermic injection devices, which are applied either by medical personnel or by patients themselves. As an example, type-<NUM> and type-<NUM> diabetes can be treated by injection of insulin doses, for example once or several times per day, using an insulin injection device. This type of devices typically comprises a insulin pump connected to cannula or an hypodermic injection needle through which the insulin can flow towards the patient's skin.

Despite significant advances, this type of devices still have disadvantages. One such disadvantage is that the use of an hypodermic needle to inject medicament into the patient's skin unavoidably involves making a hole into the injection site, thereby causing tissue injury. In addition, it is known that penetration of the injection needle into the skin can be painful for the patient, in particular for a child. Moreover, the needle may have to be permanently inserted into the patient's body. This may be unpleasant and uncomfortable for the patient and may lead to irritations and complications.

Transdermal delivery devices represent an attractive alternative to hypodermic injection devices, as transdermal medicament delivery is less painful, non-invasive and can be more easily administered by the patients themselves. This type of devices can also provide medicament release for long periods of time without causing irritations.

A challenging aspect with transdermal delivery devices relates to the barrier properties of the skin. The barrier properties of the skin are due in large part to the stratum corneum, i.e. the outer epidermal layer in contact with the environment. The stratum corneum consists of corneocytes surrounded by lipids organized in multiple lamellar bilayers. These structured lipids not only prevent excessive loss of water from the body, but also block the penetration of most topically applied drugs, other than those that are lipid-soluble and of low molecular weight. This results in a significant challenge for administering medicament via the skin.

Medicament delivery systems which use a pair of electrodes to generate an electric field to drive medicament towards a patient's skin through microneedles are known, such as the system disclosed in <CIT>.

At least in certain embodiments, the present invention sets out to overcome or alleviate at least some of the problems mentioned above. In particular, the present invention sets out to provide a device for delivery of medicament which improves the transport of the medicament through the skin of the patient, whilst reducing the discomfort induced by the introduction and/or presence of a needle into the skin of the patient.

Aspects of the present invention relate to a medicament delivery device.

According to a further aspect of the present invention, there is provided a medicament delivery device comprising at least one microneedle for delivering a medicament to a patient; and a system configured to enhance the penetration of the medicament into the patient's skin, wherein the system comprises a first electrode, a second electrode, and a power supply connected to the first and second electrodes, the system being configured to generate an electric field between the first and second electrodes, the first and second electrodes being arranged such that, in use, the electric field generated between the first and second electrodes drives the medicament towards the patient's skinThe second electrode is permeable such that, in use, medicament driven by the electric field flows through the second electrode towards the patient's skin.

The second electrode may comprise a perforated plate.

The system may be configured to generate a pulsed electric field between the first and second electrodes.

The system may comprise a heating element configured to heat the patient's skin.

The heating element may be permeable such that, in use, medicament flows through the heating element towards the patient's skin. The heating element may comprise a perforated heating foil.

The system may comprise a heat controller for controlling the heating element.

The system may be configured to deliver a chemical penetration enhancer into the patient's skin.

The system may comprise a mechanism for mixing the chemical penetration enhancer to the medicament prior to the medicament delivery into the patient's skin.

The medicament delivery device may comprise a porous membrane arranged adjacent to the at least one microneedle, and the porous membrane may be configured to retain the medicament.

The medicament delivery device may comprise a medicament pump mechanism for pumping the medicament towards the at least one microneedle.

The medicament delivery device may comprise a reusable part and a disposable part, and the medicament pump mechanism may be located in the disposable part. In an alternative emboidment, the medicament pump mechanism may be located in the reusable part.

The medicament delivery device may comprise a plurality of microneedles.

The medicament delivery device may comprise a cartridge of medicament.

The medicament delivery device may be an insulin delivery device.

The medicament delivery device may be a wearable device. The medicament delivery device may comprise a a bottom surface configured to removably attach to the patient's skin.

The medicament delivery device may comprise a controller for controlling the medicament delivery to the patient.

The medicament delivery device may comprise a blood glucose sensor configured to send data relating to the blood glucose of the patient to the controller so that the controller controls the insulin delivery to the patient.

The medicament delivery device may comprise a wireless communication unit configured to transmit and/or receive information to/from another device in a wireless fashion.

According to a further aspect of the present invention there is provided a method of enhancing the penetration of a medicament into a patient's skin, comprising using a medicament delivery device comprising at least one microneedle for delivering the medicament to a patient and a system configured to enhance the penetration of the medicament into the patient's skin.

The system may comprise a first electrode, a second electrode, and a power supply connected to the first and second electrodes, and the method may comprise generating an electric field between the first and second electrodes to drive the medicament towards the patient's skin.

The system may comprise a heating element and the method may comprise using the heating element to heat the patient's skin.

The method may comprise delivering a chemical penetration enhancer into the patient's skin. The method may comprise mixing the chemical penetration enhancer to the medicament prior to the medicament delivery into the patient's skin.

The method may comprise controlling delivery of the medicament to the patients skin by a controller.

The method may comprise the use of a wireless communication unit provided in the device transmitting and/or receiving information representative of the medicament and/or dose to be administered.

The method may comprise the controller controlling operation of the medicament delivery device dependent on the information received by the wireless communication unit.

The terms "drug" or "medicament" which are used interchangeably herein, mean a pharmaceutical formulation that includes at least one pharmaceutically active compound.

The term "medicament delivery device" shall be understood to encompass any type of device, system or apparatus designed to immediately dispense a drug to a human or non-human body (veterinary applications are clearly contemplated by the present disclosure). By "immediately dispense" is meant an absence of any necessary intermediate manipulation of the drug by a user between discharge of the drug from the drug delivery device and administration to the human or non-human body. Without limitation, typical examples of drug delivery devices may be found in injection devices, inhalers, and stomach tube feeding systems. Again without limitation, exemplary injection devices may include, e.g. patch devices, autoinjectors, injection pen devices and spinal injection systems.

Exemplary embodiments of the present invention are described with reference to the accompanying drawings, in which:.

Embodiments of the present invention provide a medicament delivery device comprising at least one microneedle for delivering a medicament to a patient, and a system configured to enhance the penetration of the medicament into the patient's skin. Providing such a medicament delivery device may help towards avoiding the use of an injection needle for delivering the medicament to the patient. Since no injection needle is needed, such a medicament delivery device does not require a needle hole to be created at the injection site and so can help towards avoiding tissue injury, as well as helping to reduce pain and discomfort in the medicament delivery process. In addition, irritations and complications that may occur by the introduction and/or presence of a needle into the skin in a conventional needle injection device may be avoided. Furthermore, the system configured to enhance the penetration of the medicament into the patient's skin may allow the medicament to overcome more easily the skin barrier and to be, therefore, more efficiently administered.

According to some embodiments of the present disclosure, an exemplary drug delivery device <NUM>, herein simply referred to as "device <NUM>", is shown in <FIG>.

In the context of this application, the terms "upstream" and "downstream" are used herein in relation to the direction of medicament flow through the device in normal use. Moreover, the terms "upper", "lower" and so forth are used herein in relation to the orientation of the device shown in the accompanying drawings.

The drug delivery device, as described herein, may be configured to inject a medicament into a patient. Such a device could be operated by a patient or care-giver, such as a nurse or physician. The device in accordance with the present invention includes a large volume device ("LVD") or patch pump, configured to adhere to a patient's skin for a period of time (e.g., about <NUM>, <NUM>, <NUM>, <NUM>, <NUM> minutes or longer) to deliver a "large" volume of medicament (typically about <NUM> to about <NUM> or more).

In combination with a specific medicament, the presently described device may also be customized in order to operate within required specifications. For example, the device may be customized to inject a medicament within a certain time period (e.g. about <NUM> minutes to about <NUM> minutes or longer).

The delivery devices described herein can also include one or more automated functions. For example, the medicament injection can be automated. Energy for one or more automation steps can be provided by one or more energy sources. Energy sources can include, for example, mechanical, pneumatic, chemical, or electrical energy. For example, mechanical energy sources can include springs, levers, elastomers, or other mechanical mechanisms to store or release energy. One or more energy sources can be combined into a single device. Devices can further include gears, valves, or other mechanisms to convert energy into movement of one or more components of a device.

The one or more automated functions of the present drug delivery device may each be activated via an activation mechanism. Such an activation mechanism can include one or more of a button, a lever or other activation component. Activation of an automated function may be a one-step or multi-step process. That is, a user may need to activate one or more activation components in order to cause the automated function. For example, in a one-step process, a user may depress a button or interact with a user interface in order to cause injection of a medicament. Other devices may require a multi-step activation of an automated function.

Referring to <FIG>, the device <NUM> includes a body or housing <NUM> which typically contains a medicament reservoir or cartridge <NUM> pre-filled with liquid medicament to be injected, and the components required to facilitate one or more steps of the delivery process. The device <NUM> can include a cover or lid 11a which can be removed when the medicament cartridge <NUM> needs to be changed or refilled. The device <NUM> can also include a protective cover <NUM> that can be detachably adhered to a bottom surface of the device <NUM>. Typically, when using the device <NUM> for the first time, a user must remove the protective cover <NUM> from the housing <NUM> before the device <NUM> can be operated.

The device <NUM> is intended to be placed on the skin of the patient, e.g. on the abdomen of the patient. The device <NUM> is preferably a wearable device. Such devices are commonly referred to as "patch pumps" or "skin patches" due to their nature of being worn or affixed to the patient's skin. The device <NUM> comprises a device holding element <NUM> e.g. in the form of an adhesive tape or pad <NUM> configured to adhere to the patient's skin. The adhesive pad <NUM> is attached to the bottom side or skin attachement side of the device <NUM> and covered by the protective cover <NUM> prior to the first use of the device <NUM>. The adhesive pad <NUM> ensures the adhesion of the device <NUM> onto the skin so that in use, the device <NUM> does not detach from the skin. Alternatively, the device <NUM> comprises a device holding element operating with vacuum to adhere the device <NUM> to the skin.

The device <NUM> includes a medicament receiving element <NUM> configured to receive the medicament flowing from the medicament reservoir <NUM>. In the embodiment described herein, the medicament receiving element <NUM> is in the form of a porous membrane, e.g. a fleece or absorbant pad <NUM>. The absorbant pad <NUM> allows for a substantially continuous controlled delivery of the medicament to the patient.

The device <NUM> further comprises a microneedle assembly including a plurality of microneedles <NUM> arranged in an array <NUM>. The microneedle assembly is configured to transdermally deliver medicament to the patient. The array <NUM> is disposed downstream of the absorbant pad <NUM>, and is configured to deliver to the patient the medicament flowing from the absorbant pad <NUM>. The microneedles <NUM> extend substantially downwardly from a structure or support <NUM>. The support <NUM> may be made from a rigid or flexible sheet of metal or plastic. The support <NUM> is perforated so that medicament can flow through the support <NUM> towards the microneedles <NUM>. It should be understood that the number of microneedles <NUM> shown in the figures is for illustrative purposes only. The actual number of microneedles <NUM> used in the device <NUM> may, for example, range between around <NUM> and around <NUM> microneedles, depending on the area of the bottom surface of the device <NUM>. The size and shape of the microneedles <NUM> may also vary as desired. For example, the microneedles <NUM> may have an overall conical shape, an overall pyramidal shape or a cylindrical portion upon which is positioned a conical portion having a tip. The microneedles <NUM> are typically of a length sufficient to penetrate the stratum corneum and pass into the epidermis. In certain embodiments, the microneedles <NUM> have a length ranging between around <NUM>,<NUM> and around <NUM> millimeters. The microneedles <NUM> help to overcome the skin barrier by creating pores in the skin, thereby enhancing the penetration of the medicament through the skin. The microneedles <NUM> perforate the outer skin layer and ensure that the medicament diffuses in the pores thereby created. The uptake of the medicament through the skin works by diffusion, i.e. the medicament flows down a gradient of concentration, from the absorbant pad <NUM> towards the patient's skin. Once absorbed, the medicament is transported into the blood e.g. with the lymph. The medicament uptake by the patient's body via microneedles has been shown to be better than subcutaneously, e.g. via an hypodermic injection needle, in particular in the case of insulin.

The device <NUM> comprises a tube or hose dispatcher or manifold <NUM> in fluid communication with the medicament reservoir <NUM>. The manifold <NUM> includes an inlet 19a connected to the medicament reservoir <NUM> and a dispense outlet 19b connected to the absorbant pad <NUM>. The manifold <NUM> is arranged such that, in use, medicament flows from the medicament reservoir <NUM> through the manifold <NUM> via the inlet 19a, and towards the absorbant pad <NUM> via the dispense outlet 19b. The dispense outlet 19b is disposed upstream of the absorbant pad <NUM> and is configured such that medicament flowing from the manifold <NUM> is distributed substantially uniformly in the absorbant pad <NUM>. For example, and as visible in <FIG>, the absorbant pad <NUM> faces the dispense outlet 19b and the area of the absorbant pad <NUM> is substantially similar to the area of the cross-section of the dispense outlet 19b.

A pump mechanism <NUM> is provided to cause the medicament to flow from the medicament reservoir <NUM> through the manifold <NUM>. The pump mechanism <NUM> includes a motor <NUM>, a thumb screw <NUM> and a plug or piston <NUM>. In use, the motor <NUM> rotates the thumb screw <NUM>, which drives the piston <NUM> within the medicament reservoir <NUM> towards the manifold <NUM>. While driven by the motor <NUM>, the piston <NUM> pushes the medicament out of the reservoir <NUM> through the manifold <NUM> via the inlet 19a, and towards the absorbant pad <NUM> via the dispense outlet 19b. The absorbant pad <NUM> allows for a uniform distribution of the medicament and therefore ensures that the medicament is homogeneously distributed on on the array <NUM>. The medicament flows from the absorbant pad <NUM> through the array <NUM> of microneedles <NUM>, and diffuses through the skin.

The device <NUM> further comprises a controller <NUM> for monitoring and/or controlling the operation of the device <NUM>. The controller <NUM> includes memories such as a Random Access Memory and/or a Read-Only Memory, and a firmware configured to control the motor <NUM> such that the flow or amount of medicament delivered can be varied, e.g. so that the medicament is pumped at a rate which enables the skin to absorb the medicament. The device <NUM> also comprises a power supply <NUM>, a user interface <NUM> and a wireless communication unit <NUM>.

<FIG> is a block diagram schematically showing the electronic components of the device <NUM> of <FIG>. The power supply <NUM> includes a disposable or rechargeable battery 25a, a power controller 25b, and a supply contact 25c. The supply contact 25c is configured to enable the device <NUM> to be connected to an external power source for powering the device <NUM> or for recharging the battery 25a. The power supply <NUM> is connected to the controller <NUM> and to the wireless communication unit <NUM> to supply power to each.

The power supply <NUM> is connected to the motor <NUM> via a pulse width modulation <NUM> for powering the motor <NUM>. The controller <NUM> is connected to the pulse width modulator <NUM> to control the drive of the motor <NUM>. The controller <NUM> is also connected to the wireless communication unit <NUM> and with the user interface <NUM> to control and receive signal input from each. The pump mechanism <NUM> and/or reservoir <NUM> comprise an encoder <NUM>, such as a linear transducer. The encoder <NUM> is connected to the controller <NUM> and is configured to send a signal indicative of the position of the piston <NUM> to the controller <NUM>. Alternatively, or in addition, the encoder <NUM> is a rotational transducer and is configured to send a signal indicative of the number of rotations of the thumb screw <NUM> to the controller <NUM>. The controller <NUM> and the pulse-width modulation <NUM> are powered by the power supply <NUM>.

The wireless communication unit <NUM> is configured to transmit and/or receive information to/from another device in a wireless fashion. Such transmission may for instance be based on radio transmission or optical transmission. In some embodiments, the wireless communication unit <NUM> is a Bluetooth transceiver or NFC transceiver. Alternatively, the wireless communication unit <NUM> may be substituted or complemented by a wired unit configured to transmit and/or receive information to/from another device in a wire-bound fashion, for instance via a cable or fibre connection. When data is transmitted, the units of the data (values) transferred may be explicitly or implicitly defined. For instance, in case of an insulin dose, always International Units (IU) may be used, or otherwise, the used unit may be transferred explicitly, for instance in coded form.

The controller <NUM> may be programmed to cause a flow of medicament through the manifold <NUM> towards the patient's skin based on instructions from a separate, remote device. As illustrated in <FIG>, the wireless communication unit <NUM> may be configured to receive instructions from a remote device D, such as a smartphone or tablet running a specific application. The wireless communication unit <NUM> is configured to deliver the received instructions to the controller <NUM>. In one embodiment, the remote device D may be in wireless connection with a continuous blood glucose monitoring ("BGM") device G and/or with a test strip-based BGM device S. The test strip-based BGM device S and/or the BGM device G may send data relating to the blood glucose of the patient to the remote device D. The remote device D may then communicate with the controller <NUM>, via the wireless communication unit <NUM>, to control the pump mechanism <NUM> and thereby the insulin delivery to the patient depending on e.g. the blood glucose level of the patient. For example, a blood glucose sensor as described in <CIT> may be used. Alternatively, the user interface <NUM> can be used by the patient X or a healthcare professional ("HCP") to directly program the device <NUM>. In addition, the healthcare professional HCP, the patient P or a dispensing phamacy P may be able to upload data relating to the patient's medicament requirements, to a cloud-based server, and the remote device D may be able to communicate with the cloud-based server to retrieve such information and control the operation of the device <NUM> accordingly. For example, a healthcare professional may adjust the medicament regime for a patient X depending on their latest health test or recent BGM results, and upload such data to the cloud-based server. The pharmacy P may be able to upload the specifics of the dispensed medicament to the cloud-based server, such as medicament concentration, advised delivery rate and/or volume.

As shown in <FIG>, the device <NUM> comprise an upper or reusable part <NUM>, and a lower or disposable part <NUM>. In use, the reusable part <NUM> and the disposable part <NUM> are assembled together. The reusable part <NUM> may be removably attachable to the disposable part <NUM>, for example when the reusable part <NUM> is designed to include costly components of the device <NUM>. The reusable part <NUM> is mechanically connected to the disposable part <NUM>, e.g. the reusable part <NUM> is clipped to the disposable part <NUM>. The reusable part <NUM> is further connected to the disposable part <NUM> at the manifold <NUM>, which connects the medicament reservoir <NUM> in the reusable part <NUM> to the absorbant pad <NUM> in the disposable part <NUM>. In such an embodiment, a fluid coupling <NUM> may be provided in the manifold <NUM> to fluidly connect first and second sections of the manifold respectively disposed in the reusable part <NUM> and disposable part <NUM> of the device <NUM>. Therefore, when the reusable part <NUM> and disposable part <NUM> of the device <NUM> are mechanically connected together as described above, the fluid coupling makes a fluid tight connection between the first and second sections of the manifold to ensure reliable delivery of the medicament from the reservoir <NUM> to the absorbant pad <NUM>.

This arrangement of the device <NUM> has the advantage that the pump mechanism <NUM> and the array <NUM> can be worn together, thereby allowing to avoid the use of a separate supporting device for the pump mechanism <NUM>. This arrangement also allows for a better control of the pump mechanism <NUM>. In the embodiment shown in <FIG>, the reusable part <NUM> includes the electronic components of the device <NUM>, the pump mechanism <NUM> and the medicament reservoir <NUM>. The disposable part <NUM> includes the absorbant pad <NUM> and the array <NUM>. It should be noted that the invention is not intended to be limited to this particular type of device and other types of device are intended to fall within the scope of the invention. For example, as shown in <FIG>, in an alternative embodiment, the pump mechanism <NUM> and the medicament reservoir <NUM> could be both located in the disposable part <NUM>, and the drive motor <NUM> may be located in the reusable part <NUM>. In the embodiment shown in <FIG>, the pump mechanism <NUM> may be in the form of a peristaltic pump or radial pump. In such an embodiment, a mechanical coupling <NUM> may be provided between a drive output from the motor, and a drive input to the pump mechanism <NUM>. In a further variant, the device <NUM> could comprise a single part, which could be either fully disposable or fully reusable.

As shown in <FIG>, the device <NUM> further comprises a system <NUM> for electrically enhancing the penetration of the medicament into the patient's skin. In the embodiment shown in <FIG>, the system <NUM> comprises a first electrode or upper electrode or anode <NUM>, a second electrode or lower electrode or cathode <NUM>, and a DC voltage generator <NUM> connected to the upper and lower electrodes <NUM>, <NUM>. The upper and lower electrodes <NUM>, <NUM> are separated by an electrically insulating material to avoid short circuits. The absorbant pad <NUM> may play the role of such insulating material. Alternatively, for example in an embodiment where the absorbant pad <NUM> is omitted, an electrically insulating perforated sheet, e.g. in plastic, may be disposed between the upper and lower electrodes <NUM>, <NUM>. In a further alternative, the electrical insulation between the upper and lower electrodes <NUM>, <NUM> may be created by means of a plurality of insulating balls, e.g. in plastic or covered with a plastic material having electrical insulating properties. The system <NUM> is configured to generate between the upper and lower electrodes <NUM>, <NUM> an electric field for driving or accelerating the medicament towards the patient's skin. Specifically, the system <NUM> is configured to generate between the upper and lower electrodes <NUM>, <NUM> pulses of electric current between the upper and lower electrodes <NUM>, <NUM> for driving or accelerating the medicament towards the patient's skin.

The upper and lower electrodes <NUM>, <NUM> are in the form of parallel metallic plates disposed subtantially parallel to each other to form a capacitor. The upper and lower electrodes <NUM>, <NUM> are respectively disposed upstream and downstream of the absorbant pad <NUM>. Alternatively, as shown in <FIG>, the upper and lower electrodes <NUM>, <NUM> are disposed upstream of the absorbant pad <NUM>. For example, the upper and lower electrodes <NUM>, <NUM> are disposed in the dispense outlet 19b. The upper and/or lower electrodes <NUM>, <NUM> are permeable such that, in use, medicament flows through the upper and/or lower electrodes <NUM>, <NUM> towards the absorbant pad <NUM>. For example, the upper and/or lower electrodes <NUM>, <NUM> are in the form of a perforated plate or hole mask.

The DC voltage generator <NUM> is configured to generate a voltage difference between the upper and lower electrodes <NUM>, <NUM>. In the embodiment shown in <FIG>, the DC voltage generator <NUM> is located in the disposable part <NUM> of the device <NUM>. However, the DC voltage generator <NUM> could be located at a different location in the device <NUM>, e.g. in the reusable part <NUM>.

The upper electrode <NUM> and the lower electrode <NUM> are arranged relative to each other such that the strength of the electric field between the upper and lower electrodes <NUM>, <NUM> is optimised. The relation between the electric field generated and the distance between the upper and lower electrodes <NUM><NUM> is defined as follows : <MAT> where E is the electric field, V is the voltage differential between the upper and lower electrodes <NUM>, <NUM>, and d is the distance between the upper and lower electrodes <NUM>, <NUM>. Therefore, it is desirable to have a distance d between the upper and lower electrodes <NUM>, <NUM> as small as possible in order to generate an electric field having a strength as high as possible.

The system <NUM> is configured to generate high voltage and short duration pulses between the upper electrode <NUM> and the lower electrode <NUM>. The voltage differential between the upper and lower electrodes <NUM>, <NUM> preferably ranges around <NUM> volts. The duration of the pulses is preferably around one or more seconds.

In use, the medicament flows from the reservoir <NUM> into the manifold <NUM>, towards the dispense outlet 19b and between the upper and lower electrodes <NUM>, <NUM>. The medicament flows between the upper and lower electrodes <NUM>, <NUM> e.g. by means of a capillary force. The pulsed electric field generated between the upper and lower electrodes <NUM>, <NUM> accelerates molecules in the medicament, e.g. insulin molecules in the case where the device <NUM> is an insulin delivery device, or more generally polar molecules that are present in the medicament, towards the lower electrode <NUM> and towards the patient's skin. This process, also known as electroporation, ensures that the medicament is optimally transported through the patient's skin. As shown in <FIG>, he electric field generated between the upper and lower electrodes <NUM>, <NUM> ionizes the molecules of air present between the upper and lower electrodes <NUM>, <NUM>. The ions generated are accelerated by the electric field towards the lower electrode <NUM>. The ions allows to further open the skin pores, thereby further enhancing penetration of medicament through the skin. Ventilation means such as a fan could be provided in the device <NUM> to further accelerate the medicament towards the patient'skin.

The high voltage, short duration pulses applied to the patient's skin allow to effectively enhance skin penetration of molecules and water based compounds of the medicament into the skin. For example, the number of transdermal pathways available via electroporation is over <NUM> times more than the number of transdermal pathways available via iontophoresis. The pulsed electric field generated creates pathways in lipid bilayer membranes of the skin, thereby making the penetration of the medicament through the skin easier. The device <NUM> therefore allows to increase the permeability of the patient's skin. Specifically, the device <NUM> allows to transport through the skin a higher volume of medicament than a conventional transdermal medicament delivery device. The system <NUM> also allows to transport through the skin molecules of higher molecular weight than with a conventional transdermal medicament delivery device. In particular, the combination of the system <NUM> and the array <NUM> of microneedles <NUM> allows to overcome more easily the skin barrier and therefore to administer the medicament more efficiently than with a conventional medicament delivery device.

A medicament injection device <NUM> according to a further embodiment of the present invention is shown in <FIG>. The further embodiment corresponds closely to the first embodiment and like reference numerals have been used for like components. Differences in relation to the first embodiment are described below.

The device <NUM> comprises a heating system <NUM> for enhancing the penetration of the medicament through the patient's skin. In the embodiment shown in <FIG>, the heating system <NUM> comprises a heating element <NUM> configured to heat the patient's skin. The heating element <NUM> is permeable such that, in use, medicament flows through the heating element <NUM> towards the patient's skin. For example, the heating element <NUM> is in the form of a perforated foil. In a variant, the heating element <NUM> is in the form of a coiled resistance. The heating element <NUM> is preferably electrically insulated. The heating element <NUM> is disposed at the dispense outlet 19b, upstream of the absorbant pad <NUM>. The heating element <NUM> is disposed parallel to the absorbant pad <NUM>. Preferably, the heating element <NUM> extends along a distance greater than half of the length of the absorbant pad <NUM>, so that the absorbant pad <NUM> is efficiently and uniformly heated.

The system <NUM> comprises a heat controller <NUM> for controlling the temperature of the heating element <NUM>. The heat controller <NUM> comprises a temperature sensor. The temperature sensor is for example in the form of a NTC thermistor, a PTC thermistor, a semiconductor or a thermocouple working with the Seebeck effect.

In use, the heating system <NUM> heats the medicament as well as the injection site. The heating allows to increase the blood flow in the patient's body, proximate the injection site, which enhances the medicament diffusion process. The heating allows to enhance microcirculation in the area of the injection site, thus facilitating medicament transfer into the patient's body.

In use, the temperature of the heating element <NUM> should be sufficiently high for enhancing efficiently the medicament diffusion process. However, the temperature should not be too high to avoid sweating of the skin, which could decrease the efficiency of the medicament absorption and cause detachment of the device <NUM> from the skin. In use, the temperature of the heating element <NUM> is preferably around five degrees higher than the temperature of the patient's skin. A temperature sensor may be provided in the device <NUM> to maintain the heating element <NUM> at such temperature. Alternatively, a sensor may be provided in the device <NUM> to measure the temperature of the room in which the medicament delivery is performed, such that the temperature of the heating element <NUM> is maintained at a higher value than the temperature of the room, e.g. around five degrees higher than the temperature of the room.

The device <NUM> comprises a system <NUM> for chemically enhancing the penetration of the medicament into the patient's skin. In the embodiment shown in <FIG>, the system <NUM> is configured to deliver a support agent or pore opener or chemical penetration enhancer to the patient. As shown in <FIG>, the system <NUM> comprises a mechanism for mixing the chemical penetration enhancer to the medicament prior to the medicament delivery into the patient's skin. The mechanism comprises a reservoir <NUM> for storing the chemical penetration enhancer and a pump <NUM> for pumping the chemical penetration enhancer into the manifold <NUM> where the chemical penetration enhancer contacts the medicament.

The chemical penetration enhancer is, for example, Dimethyl sulfoxide (DMSO). Mixing the medicament with DMSO allows to efficiently improve the medicament absorption through the skin. In a variant, alcohol such as ethanol can be added to the medicament prior to the medicament delivery. In a further variant, a solution may be added to the medicament to lower the pH value of the medicament such that the medicament has a pH lower than the pH of the patient's skin. For example, a saline solution may be used. The resulting pH gradient between the medicament and the skin results in a chemical force which drives the medicament through the skin and ensures that the medicament is efficiently absorbed. In further alternatives, other substances, such as a fat subtance, or urea, can also be added to the medicament to chemically increase the permeability of the skin. The chemical penetration enhancer is chosen depending on the medicament to be delivered.

In one embodiment, the medicament is mixed with an agent to ensure that the salt concentration in the patient's skin and body is greater than the salt concentration in the liquid medicament, so that the osmotic pressure created by the gradient of salt concentration between the patient's skin and the medicament draws the medicament towards the patient's skin.

Alternatively, or additionally, the chemical penetration enhancer may be provided at the bottom surface or skin attachement side of the device <NUM>. The bottom surface may for example comprise a layer of chemical penetration enhancer. In one embodiment, the bottom surface includes a layer of water-based substance. Increasing the amount of water at the skin surface allows to moisturize the skin surface and to consequently open skin pores at the injection site, thereby enhancing the permeability of the skin. Alternatively, a layer of oil-based substance may be provided at the bottom surface of the device <NUM>.

The term "drug delivery device" shall encompass any type of device or system configured to dispense a drug or medicament into a human or animal body. Without limitation, a drug delivery device may be an injection device (e.g., pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for intraocular, subcutaneous, intramuscular, or intravascular delivery), skin patch (e.g., osmotic, chemical), inhaler (e.g., nasal or pulmonary), an implantable device (e.g., drug- or API-coated stent, capsule), or a feeding system for the gastro-intestinal tract.

The drug container may be, e.g., a cartridge, reservoir, or other solid or flexible vessel configured to provide a suitable chamber for storage (e.g., short- or long-term storage) of one or more drugs. In some instances, the drug container may be or may include a dual-chamber cartridge configured to store two or more components of the pharmaceutical formulation to-be-administered (e.g., an API and a diluent, or two different drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components prior to and/or during dispensing into the human or animal body.

The drugs or medicaments contained in the drug delivery devices as described herein can be used for the treatment and/or prophylaxis of many different types of medical disorders. Examples of disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further examples of disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs and drugs are those as described in handbooks such as <NPL>, for example, without limitation, main groups <NUM> (antidiabetic drugs) or <NUM> (oncology drugs), and<NPL>on.

Examples of APIs for the treatment and/or prophylaxis of type <NUM> or type <NUM> diabetes mellitus or complications associated with type <NUM> or type <NUM> diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-<NUM>), GLP-<NUM> analogues or GLP-<NUM> receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-<NUM> (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the terms "analogue" and "derivative" refer to any substance which is sufficiently structurally similar to the original substance so as to have substantially similar functionality or activity (e.g., therapeutic effectiveness). In particular, the term "analogue" refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, by deleting and/or exchanging at least one amino acid residue occurring in the naturally occurring peptide and/or by adding at least one amino acid residue. The added and/or exchanged amino acid residue can either be codable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues. Insulin analogues are also referred to as "insulin receptor ligands". In particular, the term "derivative" refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, in which one or more organic substituent (e.g. a fatty acid) is bound to one or more of the amino acids. Optionally, one or more amino acids occurring in the naturally occurring peptide may have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or amino acids, including non-codeable, have been added to the naturally occurring peptide.

Examples of insulin derivatives are, for example, B29-N-myristoyl-des(B30) human insulin, Lys(B29) (N- tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®); B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-gamma-glutamyl)-des(B30) human insulin, B29-N-omega-carboxypentadecanoyl-gamma-L-glutamyl-des(B30) human insulin (insulin degludec, Tresiba®); B29-N-(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyhepta¬decanoyl) human insulin.

Examples of GLP-<NUM> , GLP-<NUM> analogues and GLP-<NUM> receptor agonists are, for example, Lixisenatide ( Lyxumia®, Exenatide (Exendin-<NUM>, Byetta®, Bydureon®, a <NUM> amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide (Victoza®), Semaglutide, Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®), rExendin-<NUM>, CJC-<NUM>-PC, PB-<NUM>, TTP-<NUM>, Langlenatide/ HM-11260C, CM-<NUM>, GLP-<NUM> Eligen, ORMD-<NUM>, NN-<NUM>, NN-<NUM>, NN-<NUM>, Nodexen, Viador-GLP-<NUM>, CVX-<NUM>, ZYOG-<NUM>, ZYD-<NUM>, GSK-<NUM>, DA-<NUM>, MAR-<NUM>, MAR709, ZP-<NUM>, ZP-<NUM>, TT-<NUM>, BHM-<NUM>. MOD-<NUM>, CAM-<NUM>, DA-<NUM>, ARI-<NUM>, ARI-<NUM>, Exenatide-XTEN and Glucagon-Xten.

An example of an oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia.

Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab')<NUM> fragments, which retain the ability to bind antigens. In some embodiments, the antibody has effector function and can fix a complement. The term antibody also includes an antigen-binding molecule based on tetravalent bispecific tandem immunoglobulins (TBTI) and/or a dual variable region antibody-like binding protein having cross-over binding region orientation (CODV).

Claim 1:
A medicament delivery device (<NUM>, <NUM>, <NUM>) comprising:
at least one microneedle (<NUM>) for delivering a medicament to a patient; and
a system (<NUM>, <NUM>, <NUM>) configured to enhance the penetration of the medicament into the patient's skin,
wherein the system (<NUM>) comprises a first electrode (<NUM>), a second electrode (<NUM>), and a power supply (<NUM>) connected to the first and second electrodes, the system being configured to generate an electric field between the first and second electrodes, the first and second electrodes being arranged such that, in use, the electric field generated between the first and second electrodes drives the medicament towards the patient's skin, and
characterised in that
the second electrode (<NUM>) is permeable such that, in use, medicament driven by the electric field flows through the second electrode (<NUM>) towards the patient's skin..