WO2012089627A1

WO2012089627A1 - Needle apparatus for the transdermal administration of drugs

Info

Publication number: WO2012089627A1
Application number: PCT/EP2011/073859
Authority: WO
Inventors: Furio Gramatica; Elena Forvi; Marzia Bedoni; Domenico Giorgio Cassara'; Michele Casella
Original assignee: Fondazione Don Carlo Gnocchi Onlus
Priority date: 2010-12-27
Filing date: 2011-12-22
Publication date: 2012-07-05
Also published as: ITMI20102414A1; IT1403293B1

Abstract

There is described an apparatus (1) with microneedles (12) for the transdermal administration of a drug comprising an interchangeable cartridge (12) and an applicator device (3). The applicator is capable of causing piercing of the skin and of actuating, after piercing has taken place, controlled emptying of the reservoir for the drug present in the cartridge. The device is such as to infuse, through the microneedles, the drug in the tissue in a continuous or even pulsatile manner, but always controlled. The applicator is ergonomic and wearable.

Description

NEEDLE APPARATUS FOR THE TRANSDERMAL ADMINISTRATION OF DRUGS

DESCRIPTION

The present invention relates to a needle apparatus for the transdermal delivery of drugs, made of an applicator device and a cartridge uniquely usable with said applicator.

Drugs are administered through the skin, a body organ which performs a plurality of functions, including that of separating and isolating the body from the outside environment. This barrier function is produced in particular by the stratum corneum, i.e. the outermost layer of the skin, about 10-20 μιη thick, which is characterized as a pavement epithelium of hexagonal cells, closely packed and keratinized, without any nucleus, embedded in a lipid matrix. The stratum corneum consists of 15% water, 15% lipids and 70% proteins: it can be described according to the "brick and mortar" model, in which the cells (bricks) form the protein domain, while the extracellular matrix forms the lipid domain (mortar). Due to this composition and structure, the stratum corneum acts as a physical and chemical barrier, limiting the diffusion of molecules into the skin, starting from those with a molecular weight of over 500 Da [Donnelly R.F. et al., 2010].

It is difficult for substances that are pharmacologically active like hormones or proteins, such as insulin (5800 Da), to penetrate the stratum corneum and then spread through the layers of the vital epidermis, dermis and hypodermis, to reach the microcirculation and, finally, the systemic circulation.

Currently, many pathologies are treated through the transdermal administration of drugs; however, as the dimensions of the drug molecules are too large to pass effectively through the stratum corneum using patches or other methods, injection therapy is commonly used to offer a better pharmacokinetic profile. For hypodermic injections, the needles used have dimensions in the order of a few millimetres in length and in the order of tenths of millimetre in diameter, making their application somewhat uncomfortable and painful and exposing the patient, operator and/or caregiver to accidental pricking.

In the field of transdermal administration, some types of microneedles have recently been introduced, i.e. needles of micrometric dimensions, with heights between 25 and 2000 μπι and diameters of a few tenths or hundredths of micrometers.

Microneedles, either solid or hollow, are capable of piercing the stratum corneum and, by penetrating only the epidermis or papillary dermis, do not activate the nociceptors, endings of sensory neurons responsible for pain sensation located in the deep dermis and in the hypodermis. Moreover, they create preferential routes into the skin with dimensions more or less equal to their size, making it possible to deliver active substances, and in particular those with high molecular weight. In this way, microneedles are more comfortable for patients who have to repeat therapy several times a day.

Due to their dimensional and structural characteristics, microneedles can be used in four different types of applications for transdermal drug delivery.

The first type of application, based on solid microneedles embedded in a small roller, makes use of the micro-perforations created in the surface layers of the skin to generate preferential routes for passive diffusion of the drug. The drug is contained in a patch, applied after using the roller.

The main problems associated with this application above all relate to the fact that perforations present in the stratum corneum may close up rapidly, limiting diffusion of the drug in the dermis and consequently in the blood circulation; moreover, it is not possible to administer the drug in a controlled manner, as the quantity of drug effectively delivered cannot be determined.

The second type of application uses the possibility of coating solid microneedles with drugs: in this case, a patch, with microneedles coated with the drug projecting from its surface, is applied onto the skin; these needles pierce the skin and the drug is delivered to the deeper layers of the skin.

The third type of application relates to the development of biodegradable solid microneedles: these microneedles are applied to the vital epidermis by means of a patch and, during the degradation process, they release the drug which is absorbed by the epidermis.

The limits related to the second and third types of application are substantially technological: the main problem for the second type of application consists in creating a stable and homogeneous interface between the coating and the array of microneedles, while for the third type, it is the possibility of enriching a biodegradable matrix with a drug, without altering its chemical-physical properties during production processes, which normally require the use of heat.

Further, in both applications the dosage of the drug is limited by the volumes and by the dimensions of the coatings or of the microneedles themselves.

Finally, microneedles coated or made entirely of polymers do not have the same mechanical properties as metal or silicon microneedles and are not as sharp as these latter: this leads to an increase in the force required to pierce the SC and consequently the possibility of stimulating the mechanoreceptors and, in cascade, the nociceptors of the dermis.

The fourth type of application relates to the use of hollow microneedles which infuse the drug in proximity of the blood microcirculation present in the papillary dermis. The conduit they provide places a reservoir in direct fluid communication with the papillary dermis and with the capillaries present therein. The main limit of these microneedles is linked to the possibility of occlusion during perforation of the skin.

As described in US2007/0161964, emptying of the reservoir, placed in communication with the microneedles, can take place manually by compressing a flexible membrane. However, this method does not allow exact quantification of the infused drug, causing losses of the drug and uncontrolled infusion.

Alternatively, as set forth in US2002/0193754, the reservoir is emptied by the actuating mechanisms which, as opposed to manual mode, allow controlled dosage of the drug and regulation of the flow through the skin, respecting the acceptance and compliance of the receiving tissue.

Ultimately, a microneedles base device has to satisfy some requirements to infuse drug through the skin, the first of which is perforation of the SC, the success of which is determined by the method with which the microneedles come into contact with the skin: in the literature we find many microneedle applicators for transdermal use which attempt to satisfy this requirement.

The patent application US2008/0114298A1 describes an applicator in which the array of needles is integral with a flexible membrane and is capable of changing concavity by applying pressure: in this way, the array of needles is pushed towards the skin, piercing it. In this applicator it is not possible to achieve high penetration reproducibility of the stratum corneum as it does not disclose that the change in the concavity of the device is controlled by mechanisms. Due to its structure the device is designed for applications to deliver drugs through microneedles for one of the three types of application described above, which do not include the presence of a reservoir and of a mechanism to regulate the emptying of this reservoir, and therefore do not allow either quantification of the drug infused or control of the flow of drug through the skin. Moreover, the contact with skin is produced by means of an adhesive ring, which over time can cause loss of adherence of the device to the tissue.

US2005/0261631A1 and US2010/0222743 describe two applicators wherein the needles array or patch are inserted into the human skin by releasing a leaf spring in the first case and a torsion spring along an arcuate path in the second case, to ensure velocities of around 4-10 m/s, making it possible to exert greater insertion forces and consequently facilitate piercing of the stratum corneum.

The device described in US2005/0261631A1 provides for a pressure collar to ensure adhesion of the device to the skin during application, while the system described in US 2010/0222743 considers the possibility of keeping the applicator separate from the microneedle patch, making it possible to re-utilize the former and replace the latter.

US2007/0161964A1 describes the applicator of a needle patch in which application of the patch to the skin takes place by manually depressing a button on the applicator. The presence of a roller, rolled over the patch after it has been placed on the skin, promotes the complete insertion of the microneedles into the skin, increases the adhesion of the patch to the skin and, through pressure, induces the delivery of the drug from a reservoir present in the patch to the microneedles and then into the skin. This device does not guarantee penetration reproducibility in the stratum corneum or delivery of all of the drug contained in the reservoir, as stated previously.

US2002/0193754A1 describes a device for controlled drugs delivery consisting in a portable system which combines a control unit with a disposable cartridge, provided with microneedles and applied to the skin. Using a display and a keypad, the control unit allows the infusion parameters to be set: in this way, it is possible to regulate the flow of drug from the reservoir present in the unit toward the reservoir present in the cartridge and from this toward the microneedles. These needles, after piercing the skin by pressure exerted manually or through a spring, allow diffusion of the drug. Delivery of the drug is controlled by a closed loop system, due to the presence of flow sensors present in the cartridge, which send the signal to the control unit via an electrical line. The disadvantages of the system described consist in its size, due to the presence of the control unit; moreover, sudden movements by the subject could cause the fluid and electrical lines between control unit and cartridge to detach, not guaranteeing continuity of communication. Finally, no solutions to maintain contact between the transdermal cartridge and the skin of the subject are disclosed.

US7678079B2 describes a device based on microneedles for controlled delivery of drugs in which the user, by simply removing an interlock, allows a disk or spring to apply a constant pressure to the content of a reservoir, receiving audible or tactile feedback. Removal of the interlock also allows the device to be applied to the skin by means of an adhesive. An activation button present on the device can be actuated to release, through springs, some microneedles in communication with the content of the pressurized reservoir into the subject's skin. In this way, infusion of the drug into the skin is promoted. However, this system is not equipped with elements that create a stable interface between the skin and the device, as contact is produced simply by means of an adhesive.

US 2003/0187395 describes an applicator for contacting the skin surface dimensioned to receive a cartridge. This cartridge contains a drug reservoir, a fluidic channel, and an array of microneedles to penetrate the skin.

After having applied the applicator to the skin, the cartridge is inserted into the applicator: the closing of the applicator fixes the position of the cartridge in respect of the skin, activates the fluidic communication between the reservoir and the microneedles and allows for the emptying of the reservoir by means of a spring, coupled with the applicator. This device does not show a reliable mechanism to obtain a successful and repeatable piercing of the skin; in addition the spring-based mechanism for emptying the reservoir does not allow the control of the drug infusion in terms of not uniform injection rate and incomplete drug delivery due to dead volumes.

The device is not equipped with a mechanism to retract the needles at the end of the infusion and is not provided with a system to cover needles after their use to avoid accidental pricking. US 1990/4894054 describes a device which consists of a preloaded syringe for hypodermal injections, which contains a reservoir and a needle. The syringe is provided with a button: when the button is pushed, a spring is activated.

The springs pushes a needle toward the skin surface in order to obtain the piercing and, at the same time, the spring activates a piston mechanism to empty the reservoir, in fluidic connection with the needle, delivering the drug into the skin. In this device the mechanism to empty the reservoir, which involves the button, the spring and the piston, does not guarantee for a controlled and uniform infusion of the drug.

The device in addition is not provided with a mechanism to retract the needle at the end of the infusion, preventing accidental pricking.

It would therefore be desirable to provide a transdermal device for the controlled delivery of drugs based on microneedles capable of ensuring penetration of the SC before starting to infuse the drug in a reproducible manner, to control the effective dosage of the infused drug, to guarantee contact between the microneedles and the skin for the entire duration of infusion and to ensure a high level of safety for the entire application of this device.

The object of the present invention is therefore to provide a device that meets the aforesaid requirements and, moreover, is easy to use, ergonomic, comfortable, miniaturized and wearable.

In particular, an object of the present invention is to provide an apparatus for the transdermal administration of drugs which is capable of receiving a prefilled cartridge, equipped with microneedles, from which a covering and a protective cap can be removed. The apparatus should also be capable of indicating to the user that the cartridge has been inserted.

Another object of the present invention consists in providing an apparatus for the transdermal administration of drugs which can be positioned in the recommended sites for intradermal or hypodermal injection of the drug, such as the lateral surface of the arm, the medial surface of the forearm, the ventral surface of the thigh and the periumbilical region of the abdomen. It should be possible to maintain the apparatus adherent to the skin through a band, adjustable by means of Velcro or strap, provided with a pocket or suitable mechanism for placing the cap of the cartridge. The apparatus should also be capable of indicating correct positioning to the user.

A further object of the present invention is that of providing an apparatus for the transdermal administration of drugs capable of accelerating the cartridge with the microneedles towards on the skin by means of manually activated mechanisms, reaching insertion forces and velocities such as to guarantee piercing of the skin by the microneedles in a reproducible manner. The apparatus must be capable of preventing application of the drug in the case of loss of sterility of the cartridge, as a consequence of exceeding a given time threshold.

Yet another object of the present invention is to provide an apparatus for the transdermal administration of drugs which, by means of an automatic activation mechanism, is capable of emptying the reservoir contained in the cartridge in a controlled manner, delivering the drug into the skin through the microneedles.

A further object of the present invention is to provide an apparatus for the transdermal administration of drugs capable of retracting, by means of automatic activation mechanisms, the spent cartridge with the microneedles from the skin, after infusion, so that the microneedles are not visible to the user and accidental pricking is prevented.

Another object of the present invention consists in providing an apparatus for the transdermal administration of drugs capable of indicating the development of automatic operations to the user, such as acceleration of the cartridge movement, emptying of the reservoir and retraction of the microneedles from the skin, as well as completion of these operations.

A further object of the present invention is to provide an apparatus for the transdermal administration of drugs which allows the spent cartridge to be extracted from the applicator in a safe manner, the applicator to be put away and the spent cartridge to be eliminated, guiding the user in the performance of these actions.

The aforesaid objects are achieved by an apparatus for the transdermal administration of drugs comprising a cartridge containing the drug to be administered and an applicator device couplable to said cartridge, characterized in that:

said cartridge comprises:

a reservoir for the drug, one or more hollow needles in communication with said reservoir for the drug,

- means for emptying said reservoir,

- means for connecting said cartridge to said applicator device,

a removable cap,

a protecting covering,

said means for emptying the reservoir comprise a piston coupled to a seal element, said piston being capable of moving from a first non-operating position to a second operating position to allow emptying of the drug from said reservoir.

Said applicator device comprises:

an enclosure,

a support for said cartridge provided with means for connection to said cartridge, an elastic mechanism coupled to said support for translation thereof from a first non- operating position to a second operating position in which said cartridge is in contact with the skin of a user,

a rod acting on a means for emptying the reservoir of said cartridge,

- first means for translation of said rod coupled to said enclosure,

second means for translation coupled to said enclosure for translation of said cartridge from said operating position to a non-operating position.

Another aspect of the present invention relates to a cartridge for the transdermal delivery of drugs couplable to an applicator device, also called applicator. The cartridge is capable of being easily removed from the applicator and therefore replaced in order to allow the infusion of different drugs or repeated administrations by replacing the spent cartridge.

A further aspect of the present invention is that of providing an applicator device of a cartridge for the transdermal delivery of drugs capable of being coupled to pre-filled cartridges, so as to perform infusions in a simple manner without the assistance of skilled personnel. The applicator device is also easily positioned on the infusion point and maintains its position throughout the whole of the infusion cycle.

Yet another aspect of the invention is that of providing an apparatus for the transdermal administration of drugs which is easy to use, which is controlled by electronic control means adapted to reduce the operations to be performed by the patient and capable to communicate, through digital signals, correct operation of the apparatus or any faults detected during its application.

Another aspect of the present invention relates to an apparatus, in which the applicator is suitable to receive and to host the cartridge in a proper and unique way: the apparatus cannot perform its operations without the cartridge and vice versa. The applicator and the cartridge are two different and complementary components of a same apparatus, both necessary for the functioning of this latter.

Further characteristics and advantages of the present invention will be more apparent from the description of preferred embodiments, illustrated purely by way of non-limiting example in the accompanying figures, wherein:

- Fig. 1 shows a section of a cartridge suitable to be associated with an applicator device for the transdermal administration of drugs according to the invention;

- Fig. 2 is an exploded perspective view of the cartridge of Fig. 1, associated with a protective cap and with its protective covering;

- Fig.3 is a top perspective view of the apparatus according to the invention;

- Fig. 4 is a bottom perspective view of the apparatus of Fig. 3;

- Fig. 5 is a sectional perspective view of the apparatus of Fig. 3, with the cartridge of Fig. 1 mounted therein;

- Fig. 6 is a view of a part of the applicator device and of the cartridge;

- Fig. 7 is a top perspective view of part of the applicator device of the cartridge;

- Fig. 8 is an additional view of the applicator device and of the cartridge;

- Figs.9a - 9b - 9c - 9d - 9e - 9f - 9g - 9h are sectional views of the apparatus of the invention during the phases of use;

- Fig. 10 shows another exploded schematic view of the apparatus of the invention;

- Fig. 11 is a schematic view of the apparatus applied to the arm of a patient; and

- Fig 12 is a flow chart of the sequential operations involving the apparatus of the invention, in order to use it properly for transdermal delivery of drugs.

With reference to the figures described, and in particular to Fig. 1, the apparatus for the transdermal administration of drugs 1, according to a first embodiment, comprises a disposable cartridge 2 provided with a lower wall 11 from which hollow needles 12 project, and with an upper wall 13 which allows contact between the cartridge 2 and an applicator device 3, not shown, which will be described hereunder. The cartridge 2 is provided with a reservoir 15 containing the drug to be administered. The hollow microneedles 12 are in communication with the reservoir 15 to allow outflow of the drug from the cartridge.

The cartridge 2 allows the drug to be stored in the reservoir 15 preventing loss thereof, due to the presence of a seal element 16 coupled to a piston 17, the upper side of which also forms the upper wall 13 of the cartridge. The assembly formed by the piston 17 and by the seal element 16 also forms the means for emptying the reservoir, as it is mounted slidingly in the reservoir 15 and is subject to actuator means acting on the upper wall 13, which cause it to translate according to a direction parallel to the lateral surface 14. This translation pushes the drug - present in liquid form - through the needles 12 until the content of the reservoir 15 has been completely emptied.

The cartridge 2 is also provided with a removable cover or cap 20 (Fig. 2), which can be fitted to the cartridge through a threaded coupling 18 of the cartridge 2 adapted to engage a corresponding threaded portion 18' of the cap 20. This coupling allows the cap 20 to be separated from the cartridge 2 by rotation, once this latter has been made integral with an applicator device 3, shown in Figs. 5 and following, by means of a support 51 (Fig. 6) present in the applicator device 3.

The cartridge 2 is provided with a groove 19 to allow said cartridge to be connected to the support 51, also if the cap 20 is present, by means of the concavity 21.

The cartridge 2 is also provided with a protective covering 22, allows the cartridge 2 to remain sterile once it has been inserted into the cap 20 by screwing during manufacture. The covering 22 is removed before insertion of the cartridge 2, integral with the cap 20, into the applicator device 3.

In a second embodiment of the cartridge 2, not shown, coupling between the cartridge and the applicator device is not mechanical, but magnetic. In this case, the cartridge is provided with a support, from the lower surface of which microneedles project. The support is provided in the centre with a solid cylinder, with a magnet at the end; the magnet couples with another magnet contained in the applicator device, allowing cartridge and applicator to become integral. The drug reservoir is formed by a bellows type O-ring, which is inserted in the cylinder, rests on the upper surface of the support and is in contact with the microneedles. The reservoir is emptied by a piston with a hollow centre, to allow insertion thereof, during emptying of the reservoir, into the cylinder of the support.

In a third embodiment of the cartridge, not shown, coupling between the cartridge and the applicator device is once again of magnetic type. In this case, the cartridge is formed by a hollow cylinder, from the base of which the microneedles project. The upper wall of the cylinder is produced in such a manner as to house a magnet which couples with another magnet contained in the applicator, so as to make cartridge and applicator device integral. The drug reservoir is formed by a bellows element which is inserted in the cylinder, rests on the base of the cylinder and is in contact with the microneedles. The piston is inserted in the hollow cylinder and is capable of sliding in the reservoir until its emptying.

With reference to Figs. 3, 4 and 5, the apparatus 1 according to the invention comprises an enclosure 100, the lower wall 31 of which is provided with a cavity 32 forming the housing for the cartridge 2 complete with cap 20 and for the applicator device 3 thereof. In the present description, the apparatus as a whole is indicated with the reference numeral 1, the interchangeable cartridge with 2 and the applicator device with 3, intended as the assembly of both the enclosure 100 and the elements destined to secure the cartridge 2 to the applicator device 3.

A support 51 for the cartridge 2 is contained in the applicator device 3. The support 51 comprises two pairs of bushings 5 and 51 ", with vertical axis, in diametrically opposite position. The two pairs of bushings 51 ' and 51 " provide sliding mounting of the support 51 on two opposed vertical guides 52, integral with the applicator device 3, along which the support 51 can slide vertically.

Manual insertion of the cartridge 2, complete with cap 20, in the applicator device 3 (Fig 9a) takes place by removing the protection 22 and abutting the surface 13 against the lower part of the support 51, pushing this latter upward against the reaction of a spring, described below. This action by an operator takes the cartridge 2 to engage a first pair of mechanical fasteners 45 of the support 51 (Figs. 6, 7, 8). The first pair of mechanical fasteners 45 constrains the cartridge to the support 51 through specific curved clips 46 which are inserted into a horizontal circular groove 19 of the cartridge 2.

Upward translation of the support 51 brings the support 51 to engage - through appropriate recesses, not shown, provided in the upper part thereof - a second pair of mechanical fasteners 48.

The second pair of mechanical fasteners 48 comprises a pair of curved clips 49 mounted superiorly around pins 4 housed in appropriate seats of the enclosure 100 (Fig. 6). The pair of fasteners 48 secures the support 51 and determines its upper stroke end position. This securing of the support 51 by the second pair of fasteners 48 is produced by inserting the curved clips 49 in corresponding recesses provided in the upper part of the support 51. The curved clips 49 are pressed against the support 51 by springs reacting against the walls of the cavity 32 of the enclosure 100. In this position, after insertion of the cartridge 2 in the applicator device 3, the support 51 compresses a spring 44, housed in an upper cavity 53 of the support 51 (Fig 9b). If insertion takes place correctly, an electrical contact is produced between two appropriate surfaces of the applicator device, not shown in the accompanying figures.

At this point, the cap 20 can be unscrewed from the cartridge (Fig 9c).

Adherence of the apparatus 1 to the skin is ensured by a positioning means adapted to guarantee contact with the surface of the skin. According to the present embodiment the positioning means is a specific elastic band 60, adjustable and adaptable, according to the application position, by means of specific securing means 35 present on the lateral surface 34 of the apparatus 1 (Figs. 3, 10 and 11). This band 60 is provided with a pocket 61 or other means suitable to house the cap 20 of the cartridge 2, after it has been removed therefrom. Correct positioning of the apparatus 1 on the skin during use is detected by an electrical impedance sensor 33 (Fig. 4) housed in the lower part 31, capable of detecting the conductivity of the surface with which it is in contact. Calibration of the apparatus allows conductivity values corresponding to correct contact, or to inadequate contact, to be detected. When the apparatus 1 is correctly positioned on the skin it is possible to perform transdermal administration of the drug contained in the cartridge 2.

Activation of the sequence of events that determine administration is determined by activation of a pair of electromagnets 43 provided in the walls of the cavity 32 of the applicator device. These electromagnets are located aligned with the second pair of fasteners 48, in particular aligned with a pair of magnets 50 present on the clips 49 of the fasteners 48, inside the springs 5 (Fig. 6). The electromagnets 43 attract the magnets 50 and the clips 49, releasing the support 51 from the fasteners 48. Consequently, the spring 44 extends, decompresses, and pushes the support 51 downward, along the vertical guides 52. The support 51 in turn carries the cartridge 2 toward the patient's skin, causing penetration of the microneedles 12 therein (Fig. 9d).

Preferably, the total movement of the cartridge 2 from the position of coupling to the applicator device 3 - with the spring compressed - to decompression of the spring, is no greater than 10 mm, more preferably 5 mm, to obtain a translation velocity of 5 m/s, even more preferably 2 or 3 m/s.

After actuation, the cartridge 2 remains integral with the applicator device by means of the first pair of fasteners 45 of the support 51.

Subsequently, a first motor 54 is activated to rotate a shaft on which a pinion 55 is mounted, engaged on a threaded rod 56 provided inferiorly with a plunger 256 in contact with the upper surface 13 of the cartridge 2, in particular with the piston 17 (Figs. 5, 7, 9, 10). The rod 56 and the plunger 256 form actuating means of the piston 17 of the cartridge 2. Rotation of the pinion 55 causes vertical translation of the rod 56, due to the threaded coupling. At the end of the kinematic chain, the piston 17 is pushed by the plunger 256 into the reservoir 15 determining controlled emptying thereof and consequent transdermal infusion of the drug (Fig. 9e). Preferably, each infusion step lasts less than 10 minutes, more preferably between 1 and 5 minutes, repeatable if necessary, and the quantity of fluid injected in each infusion is between 1 μΐ and 5 ml.

Reversal of the direction of motion of the motor 54 returns the rod 56 and the plunger 256 to their initial position (Fig. 9f).

At the end of the infusion cycle, two second motors 57 are activated; these motors are integral with two cams 58, which act on two projecting elements 59 of the support 51 of the applicator 3. Rotation of the motors 57 causes rotation of the cams 58 which, acting on the elements 59 of the support 51, retract this support 51 and the cartridge 2 coupled to it inside the cavity 32 of the applicator, in such a manner as to extract the microneedles 12 from the skin before the user removes the elastic band 60 of the applicator 3 (Fig. 9g).

Following removal of the applicator 3 from the injection site, through removal of the elastic band 60, the cartridge 2 is extracted from the applicator 3. This operation is performed first by repositioning the cap 20, previously placed in a pocket 61 or in another suitable means, on the cartridge 2 through the specific threaded coupling 18, 18'. Removal of the cartridge 2 from the support 51 takes place by pulling the cartridge downwards, in such a manner as to overcome the opposing force of the clips 46 of the first pair of mechanical fasteners 45 to the cartridge 2 (Fig 9h). In this way the applicator goes back to its original status (Fig 9a), ready for another cycle of infusion.

In the case in which the user, after terminating the application, is no longer in possession of the cap 20 required to extract the cartridge 2 from the applicator 3, the applicator is provided on the lateral surface 34 with a pair of recessed buttons 36, which act as emergency device for releasing the spent cartridge 2. These buttons 36, which are preferably only used if the applicator is not in the injection site, are activated manually and simultaneously and act on springs 47 positioned inside the clips 46 of the first pair of mechanical fasteners 45, which make the cartridge 2 integral with the support 51 of the applicator 3 (Fig. 7). Pressure on the buttons 36 compresses the springs 47 releasing the clips 46 from the grip of the cartridge. The applicator 3 is also provided with an interchangeable battery 38 (Fig. 4), housed in the enclosure 100 in the lower surface 31 thereof, and with buttons 40, LEDs 41 and a display 42 (Fig. 3). The battery 38 is capable of activating an electronic control system which automatically actuates the apparatus 1, in such a manner as to reduce the operations performed by the user to a minimum, making the apparatus easy to use even in a domestic environment and by personnel without specific training.

The electronic control system of the apparatus is able of analysing external signals and communicating with the user, guiding him/her directly in executing easy operations by means of acoustic and/or visual signals. Other operations are automatically carried out by the electronic system, ever informing the user with feedbacks. Finally, the electronic control system is also able to detect such abnormalities in the functioning of the apparatus and to inform the user.

The proper sequence of operations that the user has to perform guided by the apparatus or those the apparatus executes automatically without any intervention of the user, are reported in the flow chart of the Figure 12, now described.

It has to be high lightened that this sequence of operations can be executed only if the two main components of the apparatus (1) are present: the cartridge (2) coupled with the applicator (3).

The cartridge 2, contained in the cap 20 and without the protective covering 22, is inserted manually in the applicator 3, previously switched on by means of a button 40.

Initial switch-on of the applicator device, accompanied by activation of a fixed green LED, must take place in order to view some messages that appear on the display of the applicator, including a welcome message and a message asking the user to insert the cartridge in the applicator.

Correct insertion of the cartridge activates an electrical contact between two elements present in the applicator, sending a signal to the electronic control system. The system causes a green LED to flash and some messages to be displayed on the display of the applicator. At this point a timer is activated for sterilization and safety reasons, as discussed hereafter. The user, after ensuring that correct contact has taken place, is asked to remove the cap from the cartridge by unscrewing it, to place it in the specific housing for subsequent re-use during removal of the spent cartridge, and to position the applicator on an infusion site of his or her body.

The applicator is made to adhere to the skin in the area for delivery of the drug by means of an elastic band. An electrical contact, positioned on the lower surface of the applicator, checks the contact established between the skin and the surface of the applicator, sending a confirmation signal to the control system. The system displays a message and activates a fixed yellow LED on the display of the applicator, informing the user of correct positioning and indicating that it is possible to press a button located on the display of the applicator. If the applicator is positioned on a conductive surface other than the skin, three LEDs flash: a red LED, a green LED and a yellow LED, indicating an improper positioning.

After the applicator correctly has been positioned, a message on the display invites the user to press a button located on this display. If at that time the timer has exceeded the predetermined time threshold for sterility of the cartridge, the three LEDs flash, while some messages on the display indicate that the functions of the applicator have been blocked and that the user must replace the old cartridge with a new one, removing the applicator from the skin and eliminating the old cartridge by means of its cap.

If the time threshold has not been exceeded, the button pressed sends a signal to the control system, which activates the fixed red LED located on the display.

Through the spring mechanism, activated by pressing the button, the cartridge and its support are actuated toward the skin, causing perforation of the tissue by the microneedles. Movement of the cartridge produces electrical contact between two elements present in the applicator, sending a signal to the control system, which maintains on the fixed red LED and displays a message on the display.

After the cartridge has moved, the piston present in the applicator is automatically actuated by the motor toward the upper surface of the cartridge, determining emptying of the reservoir. The drug is delivered through the microneedles inserted in the skin.

The infusion step is indicated to the user by the fixed red LED and a message on the display of the applicator.

At the end of infusion, the piston is automatically returned to its initial position by the motor and, through activation of two further motors, the cartridge overcomes the opposing force of the spring and is returned inside the applicator for a stroke that fully retracts the microneedles inside the apparatus. At this point, the system activates the fixed yellow LED, to indicate to the user that all operation are finished and thus the applicator can be removed, also displaying a message on the display of the applicator.

After the applicator has been removed, the electronic control system informs the user that the spent cartridge must be removed from the applicator by activating the flashing green LED and through a message that appears on the display.

The spent cartridge can be removed from the applicator using the cap previously placed in a pocket, or in a suitable means provided on the elastic band.

If the user, after the application, is no more in possession of the cap, he/she can eject the cartridge by means of the emergency buttons on the lateral surface of the applicator. Otherwise, once the cap is inserted in the applicator and screwed on the cartridge, it becomes integral with the cartridge and can be pulled downwards, overcoming the fastening devices constraining the cartridge to the applicator: the cap at this point is removed, together with the spent cartridge, eliminating the risk of accidental pricking of the user or of operators responsible for waste disposal. Finally, the electronic control system activates the fixed green LED and a message appears on the display, asking the user to eliminate the spent cartridge.

If the previous operation for removal of the spent cartridge is not completed, the applicator remains on and reminds the user that the cartridge must be disposed of, both with an acoustic signal and visually, through continuous flashing of the green LED and a message on the display.

Finally, through activation of the fixed green LED and messages on the display, the user is asked to eliminate the spent cartridge, to switch off the applicator by pressing the button and to replace it in its case.

Moreover, another embodiment of the apparatus provides for the presence of acoustic stimuli and voice messages in addition to and not in place respectively of the coloured LEDs and of the messages on the display, for visually impaired users.

The cartridge and the applicator described can be used for different therapeutic treatments. In fact, by acting on parameters, such as the length of the needles, the length of the spring and its elastic constant, piercing of the skin to different depths can be obtained, making it possible to deliver different drugs to different regions of the skin.

Claims

An apparatus for the transdermal delivery of drugs comprising a cartridge (2) couplable to an applicator device and an applicator device (3),

characterized in that said cartridge (2) comprises:

a reservoir for the drug (15),

one or more hollow needles (12) placed in communication with said reservoir for the drug (15),

- means for emptying (17, 16) said reservoir (15) comprising a piston (17) coupled to a seal element (16), said piston (17) being capable of moving from a first non- operating position to a second operating position to allow emptying of the drug from said reservoir (15)

- means for connecting (19) said cartridge (2) to said applicator device (3),

a removable cap (20),

a protecting covering (22),

and characterized in that said applicator device (3) comprises:

an enclosure (100);

a support (51) for a cartridge (2) containing a drug to be administered, said support being provided with means for connection (45) to said cartridge (2);

an elastic mechanism (44) coupled to said support (51), for translation thereof from a first non-operating position to a second operating position in which said cartridge (2) is in contact with the skin of a user;

a rod (56) associated with a plunger (256) adapted to act on a means for emptying the reservoir of said cartridge (2);

- first means for translation (54, 55) of said rod (56) coupled to said enclosure (100); second means for translation (57, 58, 59) coupled to said enclosure (100) for translation of said support (51) of said cartridge (2) from said operating position to a non-operating position.

The apparatus according to claim 1, characterized in that said means for connecting said cartridge (2) to said applicator device (3) comprise a groove (19) provided on the upper part of the cartridge (2).

The apparatus according to claim 1, characterized in that said support (51) of said applicator device (3) is provided with a seat (53) suitable to house said elastic mechanism (44), said support (51) being movable inside said enclosure.

The device according to one or more of the previous claims, characterized in that said means of said applicator device (3) for connection (45) of said cartridge to said support (51) comprise curved clips (46).

The apparatus according to one or more of the previous claims, characterized in that said first means for translation (54, 55) of said rod (56) of said applicator device (3) comprise a threaded portion of said rod coupled to a gear (55) actuated by first motor means (54).

The apparatus according to one or more of the previous claims, characterized in that said second means for translation of said cartridge (2) of said applicator device (3) comprise second motor means (57) coupled to cams (58).

The apparatus according to one or more of the previous claims, characterized in that said applicator device (3) it comprises an electrical impedance sensor (33) positioned on the lower surface (31) of said device (3).

The apparatus according to one or more of the previous claims, characterized in that said applicator device (3) it comprises positioning means suitable to ensure contact with the surface on which inoculation of the drug takes place.

The apparatus according to claims 8, characterized in that the positioning means of said applicator device (3) comprise an elastic band (60) coupled to said enclosure.