Microneedle array, actuator, and method of usage

Abstract

To provide a transdermal drug delivery device, such as a microneedle array patch, disposed on a skin for transdermal delivery of a drug.SOLUTION: A transdermal drug delivery device for delivering a biological activator via a skin of a mammal includes an array of microneedles, and means for operating the microneedles. The operating means individually operates the microneedles.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] The present invention relates to transdermal drug delivery devices, and in particular to microneedle arrays, such as microneedle array patches, that are placed on the skin for transdermal delivery of drugs. [Background technology]

[0002] Pharmaceutical compositions can be administered via various routes, including, for example, oral administration or subcutaneous injection.For certain active ingredients in pharmaceutical compositions, more local administration is preferred.This is particularly true for larger active ingredients, such as biologics.Therefore, such larger active ingredients are often administered by injection, whether subcutaneous, intramuscular, or intravenous.

[0003] Examples of active pharmaceutical ingredients that have been administered by injection are, for example, certain hormone treatments in the fertility treatment area, insulin, or many biologics in the oncology and autoimmune treatment areas, such as, for example, antibody or fusion protein treatments.

[0004] Injection administration often requires the assistance of a trained healthcare provider or requires patient training. Many patients perceive injections as a painful and tedious procedure, which can lead them to withhold, discontinue, or infrequently inject the active ingredient of the medication. This can result in significant impairment of adherence to the treatment plan. Furthermore, the use of injection devices with exposed needles poses a risk of needlestick injuries, and from a safety perspective, this risk must be minimized as much as possible.

[0005] Microneedle technology integrated into an array in a transdermal patch has offered an attractive alternative to the more common method of injection administration. A typical microneedle array for transdermal administration is in the form of a patch applied to a patient's skin. A pharmaceutical composition containing a pharmaceutically active ingredient is delivered to a patient via the array of microneedles, which are coated with a pharmaceutical composition or partially dissolvable and constructed of a solid pharmaceutical composition. Once the active pharmaceutical ingredient has been administered via the transdermal patch equipped with the microneedle array, the transdermal patch can be removed.

[0006] Thus, conventional transdermal patches deliver active pharmaceutical ingredients in a single dose, which can be either an immediate-release or sustained-release composition. A drawback of such transdermal patches is that they are designed for single administration. However, certain treatments require multiple doses of the active pharmaceutical ingredient at predetermined intervals over a period of time. For example, certain treatments require a single injection per day for, say, two weeks. While it is possible to remove the transdermal patch at the end of each dose and replace it with another transdermal patch before the next dose, this remains very inconvenient for patients and does not improve the likelihood of patients not adhering to the treatment plan.

[0007] There is therefore a need to provide a convenient, easy-to-use device for administering injectable active pharmaceutical ingredients to a patient, particularly where the treatment consists of multiple doses delivered over a period of time at predetermined time intervals. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention relates to a device for transdermal delivery of an active pharmaceutical ingredient. The device of the present invention is convenient and easy to use for administering a treatment using an active pharmaceutical ingredient to a patient, where the treatment requires multiple administrations at predetermined time intervals over a period of time. The transdermal microneedle array patch device of the present invention includes an actuator mechanism for individually addressing one or more microneedles in the array. As a result, a single microneedle array transdermal patch device can be used for multiple administrations over a period of time. Thus, the device of the present invention provides a solution to the above-mentioned technical problem by enabling actuation of one or more individual needles in a microneedle array, thereby enabling a microneedle array patch device that can be used for multiple administrations over a period of time according to a specific dosing regimen of an active pharmaceutical ingredient. Furthermore, such a device significantly improves patient convenience, particularly in patients self-administering at home, and increases the likelihood of compliance with a preset dosing regimen. [Means for solving the problem]

[0009] According to one embodiment of the present invention, there is provided a device for delivering a bioactive agent, which is an active pharmaceutical ingredient, through mammalian skin, comprising an array of microneedles and means for actuating the microneedles, wherein the actuation means actuates the microneedles individually. According to a preferred embodiment, the actuation means actuates a subset of the array of microneedles simultaneously. According to some embodiments of the present invention, the microneedles comprise a dissolvable portion comprising the active pharmaceutical ingredient or a composition comprising the active pharmaceutical ingredient.

[0010] According to one embodiment of the present invention, there is provided an apparatus for delivering a bioactive agent through mammalian skin, comprising an array of microneedles and means for actuating the microneedles, wherein the actuating means separately actuates the microneedles and comprises one or more heating elements and a thermally expandable actuating medium.

[0011] According to another embodiment of the present invention, there is provided a device for delivering a bioactive agent through mammalian skin, comprising an array of microneedles and means for actuating the microneedles, wherein the actuating means separately actuates the microneedles and comprises an actuator and a spring on a disk with a helical guide track.

[0012] According to another embodiment of the present invention, there is provided a method of administering a bioactive agent to a mammal using an apparatus for delivering a bioactive agent through the skin of the mammal, the apparatus comprising an array of microneedles and means for actuating the microneedles, wherein the actuating means separately actuates the microneedles.

[0013] Further objects and advantageous features of the present invention will become apparent from the claims, detailed description, and accompanying drawings. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 shows a cutaway top view of a transdermal patch with a microneedle array containing an actuation mechanism.

[0015] [Figure 2] FIG. 2 shows a transdermal patch with a microneedle array with a thermally expandable actuation medium (here wax) as the actuation means.

[0016] [Figure 3] FIG. 3 shows a schematic diagram of a wax actuator for microneedle actuation in a microneedle array for a transdermal patch.

[0017] [Figure 4] FIG. 4 shows a detailed schematic diagram of the needle tip and skin contact surface.

[0018] [Figure 5] FIG. 5 shows a schematic diagram of a disk with a spiral guide track for use as an actuator and actuation spring mechanism.

[0019] [Figure 6] Figure 6 shows actuation using an actuator and spring mechanism, where in the first stroke, the actuator pin / puck is in the active position and pushes a needle out of the transdermal microneedle array patch (Figure 6A), while progression on an inclined ramp primes the actuator pin / puck for pushing the subsequent needle out of the transdermal microneedle array patch (Figure 6B).

[0020] [Figure 7] Figure 7 shows mechanisms for advancing pins / pucks over successive microneedles in a microneedle array; in the first mechanism, a SMA (shape memory alloy) spring is used to incrementally advance a rotating disk to the next increment (Figure 7A), and in the second mechanism, the rotating disk is incrementally advanced using a rotating spindle (Figure 7B). DETAILED DESCRIPTION OF THE INVENTION

[0021] According to one aspect, the devices and methods described herein are directed to transdermal devices, including intraepidermal delivery devices, for administering active pharmaceutical ingredients to a patient. According to one exemplary embodiment, the systems and methods provide a delivery device for administering an active pharmaceutical ingredient into or below the corneal layer of a patient's skin. As used herein, transdermal refers to the exchange of a substance, such as an active pharmaceutical ingredient (biologic) or a vaccine, through one or more layers of the skin.

[0022] The devices and methods are particularly suitable for use in administering various active agents / ingredients (bioactive agents) to patients, particularly human patients. Active agents / ingredients include biologically active substances that can be delivered through the skin. Examples include antibiotics, antivirals, analgesics, anesthetics, anorexics, anti-arthritics, antidepressants, antihistamines, anti-inflammatory agents, anti-tumor agents, vaccines, including DNA vaccines, adjuvants, and biologics. Other substances that can be delivered intradermally to patients include proteins, peptides, and fragments thereof. Proteins and peptides can be naturally occurring, synthetic, or recombinantly produced. Suitable examples of active agents / ingredients include insulin or fertility hormones, such as recombinant gonadotropins (e.g., recombinant human FSH).

[0023] The microneedle array devices for transdermal delivery described herein are advantageous in that they provide a convenient, easy-to-use device for transdermal administration of active agents. It is also convenient for patients that the devices described herein can be used for treatments requiring multiple administrations over a period of time at specific, pre-determined times within that period. Patients do not need to change microneedle devices or inject multiple different devices each time during the course of treatment. As such, the devices and their use in treatment methods also improve patient compliance with such treatment regimens.

[0024] Certain embodiments of the device include a communications module. The communications module can be any communications module capable of transferring data from the device to a central / external server. The transferred data relates to one or more of confirmation of activation of the microneedle array, the number of needles activated, the date and time of activation of the microneedle array, or a change in the number of microneedles activated as part of a dose adjustment. The communications module can transfer data using any number of connections, including, for example, a wireless connection.

[0025] FIG. 1 generally illustrates an embodiment of a device for delivering a bioactive agent through mammalian skin, including an array of microneedles and a means for actuating the microneedles, where the actuation means independently actuates the microneedles. In FIG. 1, the device (1) is a transdermal patch device, i.e., a device that adheres to a patient's skin (an on-skin device) and includes a mechanism for delivering an active agent through the patient's skin. The device (1) includes a body or case (2) that includes a microneedle array (3) (a support structure containing multiple microneedles) and an actuation means (4). The body or case (2) further includes a controller (5) and a battery (6). Attachment to the skin can be achieved by any suitable means (7) for securing the device to the patient's skin. Examples of suitable means (7) for securing the device to the patient's skin include an adhesive layer (illustrated in FIG. 1) or a belt or elastic band.

[0026] Figure 2 provides a more detailed structure of an embodiment of the device of the present invention. According to such an embodiment, the means for actuating the microneedles (8) comprises a thermally expandable actuating medium (9), such as a wax layer. The device body or case (2) includes a battery (6), a controller (5), a thermally expandable actuating medium (such as a wax layer) (9), and a microneedle array (3), which includes many microneedles (8). The device further includes a means (7) for securing the device to the patient's skin, which is suitably an adhesive layer, as shown in Figure 2.

[0027] The actuation means (4) for actuating the microneedles can be any suitable actuation means that allows the microneedles to penetrate the skin. The actuation means of the present invention is characterized by allowing individual actuation of each microneedle. Preferred means for actuating the microneedles include the use of a thermally expandable actuation medium or the use of a spring and actuator pin.

[0028] The thermally expandable actuation medium can be any actuation medium that expands as a result of an increase in temperature. Such an actuation medium would need to expand in a manner that provides sufficient force to the microneedles. Each microneedle in the microarray needs to be able to penetrate the skin and move to a sufficient depth, e.g., subcutaneously, for transdermal drug delivery. Considering that the microneedles are typically coated with a drug or contain a drug in biodegradable form at the distal end of the microneedle tip, the microneedles should be moved so that the drug-containing distal tip crosses the skin and, after actuation, is positioned, e.g., subcutaneously. Therefore, when the actuation means includes a thermally expandable medium, a suitable thermally expandable medium has a sufficient expansion amount to exert a force of at least 1 N over the entire range of movement of the microneedle. Preferably, this force is about 1 N to about 5 N. Upon such expansion, the resulting force should be sufficient to cause the microneedle to have a stroke distance of at least 0.5 mm, suitably at least 0.65 mm, and preferably about 1 mm to about 5 mm (see Figure 4). FIG. 4 illustrates an embodiment of a microneedle included in a microneedle array. Here, prior to actuation, the needle tip (11) is positioned within the device and protected from the external environment by a barrier (12) (e.g., foil). Such a barrier (12) maintains the sterility of the microneedle (8) within the device. To maintain sterility, the environment surrounding the microneedle is sealed by a sterile seal, such as a barrier (12). According to certain embodiments, the microneedle (8) may be individually sealed with such a barrier (12). Therefore, actuation of the microneedle also requires penetration of this barrier (12) for transdermal administration of the active agent. The barrier (12) is preferably positioned between the microneedle array and the means (7) for adhering the device to the skin (e.g., an adhesive layer). Considering in FIG. 4 that the length of the needle tip (11) is 500 μm as an example, the clearance between the needle tip (11) and the barrier (12) is 50 μm, and in this example, with both the barrier (12) and the skin adhesive means (7) having a thickness of 50 μm, the required minimum stroke is at least 0.65 mm.

[0029] Suitably, such a thermally expandable working medium is preferably a wax. Suitable waxes include, for example, paraffin wax, thermostatic wax, polyethylene glycol, or mixtures thereof. Such a suitable thermally expandable medium has a relatively high melting point and a high thermal expansion. High thermal expansion refers to any paraffin or thermostatic wax that can exert a force of at least 1 N upon expansion within an expansion range of 0.5 mm to 5 mm. For example, the expansion range in each direction is 0.5 mm to 5 mm. Relatively high melting point refers to paraffin wax and thermostatic wax that have a melting point significantly higher than body temperature, but not so high as to adversely affect other elements of the device or the patient to whom the device is applied. Suitably, the melting temperature of the paraffin wax or thermostatic wax is 50°C to 90°C, more suitably 60°C to 80°C, e.g., 65°C to 75°C. Suitably, the paraffin wax or thermostatic wax has a narrow range of carbon chain lengths, as a wide range of carbon chain lengths for paraffin wax or thermostatic wax may result in a wide range of melting temperatures, while a defined melting temperature is more suitable for applications for use in devices such as those described in the present invention. An example of a thermally expandable working medium includes 60% hexatriacontane and 40% paraffin wax. Suitable examples of thermally expandable media include waxes such as Kerax 1303 and Alfa 1260.

[0030] Such a thermally expandable working medium is in intimate contact with a heat source (13), as shown in FIG. 3. Such a heat source (13) is in direct contact with the thermally expandable working medium (9) and is controlled by the controller (5). Each microneedle (8) of the microneedle array (3) is actuated by a dedicated heat source (13). To actuate an individual microneedle (8), that microneedle's dedicated heat source (13) generates sufficient heat to expand the thermally expandable working medium (9). According to certain embodiments, such a heat source (13) may be an integral part of, for example, a printed circuit board (PCB) included in the controller (5). According to suitable embodiments, each heat source (13) is an electrical heat source, such as a resistor on the PCB.

[0031] Heating the thermally-expandable actuating medium (4) forces each microneedle (8) through its opening, the sterile barrier (12), and the patient's skin, delivering the drug. In an exemplary embodiment shown in FIG. 3, a printed circuit board (PCB) includes a heat source (13) for each microneedle (8) in the microneedle array (3). The thermally-expandable actuating medium (9) is in intimate contact with each heat source (13), and a controller (5) on the PCB (not shown) activates the individual heat sources to actuate each microneedle (8). Each microneedle (8) is positioned in an opening (14). Such openings (14) can be formed from a support plate (15). The support plate (15) can include one or more layers. If the support plate (15) is composed of multiple layers, such layers are separated by spacers (see FIG. 3). According to a preferred embodiment, the support plate (15) comprises two layers (15a, 15b) separated by a spacer (16). Such a spacer (16) reduces potential friction at the openings (14), which may increase the force required to actuate the microneedles (8) for transdermal delivery of a drug or active agent.

[0032] According to a suitable embodiment, the microneedles (8) have a diameter of 0.3 to 0.5 mm, preferably about 0.4 mm. Microneedles suitable for application in the microneedle arrays of the present invention are intended to administer an active drug / bioactive agent to a patient. As such, each microneedle (8) contains a dose or sub-dose of the bioactive agent to be administered. Activation of the microneedles (8) administers the dose or sub-dose to the patient. Thus, the microneedle array (4) of the delivery device of the present invention contains either one or multiple doses of the bioactive agent to be administered to the patient. If the microneedle array (4) contains multiple doses of the bioactive agent, the controller (5) can initiate activation of a subset of the microneedles (8) to administer the appropriate doses according to a treatment plan.

[0033] The bioactive agent can be any of the active agents described, including, for example, an agent selected from a small molecule, peptide, protein, antibody, fusion protein, DNA, and RNA. According to one embodiment, the bioactive agent is an infertility treatment drug such as Gonal-F® (recombinant gonadotropin). According to another embodiment, the bioactive agent is insulin. According to yet another embodiment, the bioactive agent is a cancer treatment drug. Any such agent can be incorporated into the pharmaceutical composition as the sole active pharmaceutical ingredient or as part of a combination of pharmaceutically active ingredients in the same pharmaceutical formulation.

[0034] Such a pharmaceutical formulation containing a bioactive agent is applied to microneedles (8) in the microneedle array (3) to provide a single or multiple doses of the bioactive agent within the microneedle array. Application to the microneedles (8) can be by any suitable method to provide each microneedle with a single dose or a fraction of a dose of the bioactive agent. According to one embodiment, the microneedles (8) are solid microneedles coated with the pharmaceutical formulation containing the bioactive agent. According to another embodiment, the pharmaceutical formulation containing the bioactive agent is a solid formulation having sufficient consistency and strength to form part of the microneedle (8). Such a suitable solid formulation containing the bioactive agent forms part of the needle tip, i.e., the distal end of the microneedle (8) that is administered to a patient upon actuation of the microneedle. Upon injection, the bioactive agent is released from the formulation. According to certain embodiments of the present invention, the microneedles (8) of the microneedle array (4) are dissolvable microneedles that dissolve upon contact with fluid after being actuated and injected through a patient's skin. Suitable dissolvable needles are described, for example, in U.S. Patent Application No. 2017 / 0296465.

[0035] According to an alternative embodiment, the actuation means (4) comprises an actuator and a spring (as shown in FIG. 5). According to one embodiment as in FIG. 5, the microneedle array (4) is arranged concentrically. According to such an embodiment, the actuation means (4) comprises a gear (15) comprising a concentric spiral track (16), on which a puck (17) advances around the spiral track (16) to actuate one or more microneedles (8). The puck (17) is comprised of an actuator and a spring (see FIG. 6).

[0036] As the puck 17 advances around the spiral track 16, one or more microneedles 8 are actuated in sequence to deliver a dose. As shown in Figures 6A and 6B, the puck 17 is comprised of an actuator 18 and a spring 19. The spiral track 16 is comprised of a series of ramps, with each ramp 20 immediately followed by a hole 21 before the next ramp 20. As the puck 17 advances along the ramps 20, the actuator 18 presses against the spring 19, creating a spring force potential (see Figure 6A). As the puck 17 advances further over the hole, the spring force potential is released, actuating the spring 19, which activates the actuator 18 and depresses the microneedles 8 with enough force to penetrate both the sterile barrier 12 and the patient's skin (not shown) (see Figure 6B). Advancement of the puck (17) along the spiral track primes the spring (19) with a spring force potential, which then releases the spring (19) to actuate the actuator (18), depressing the microneedle (8) and administering the bioactive agent to the patient, repeating this cycle. The spring (19) can be any shape of spring capable of releasing a spring force potential to the actuator (18). Such a spring (19) suitably has a K value in the range of about 0.01 N / mm to about 10 N / mm. Suitably, the spring has a K value of 1 N / mm.

[0037] The puck 17 can be advanced around the helical track 16 in any suitable manner. Figures 7A and 7B show examples of alternative mechanisms for advancing the puck 17 around the helical track 16. In both examples, the helical track 16 is stationary, but the puck 17 is slidably connected to a gear 15. Rotating the gear 15 advances the puck 17 around the helical track 16. This advancement of the puck 17 increases incrementally based on the number of microneedles 8. The incremental advancement of the puck 17 around the helical track 16 is controlled by incremental rotation of the gear 15. Rotation of the gear 15 is accomplished using, for example, the action of a shape memory alloy (SMA) spring 22, as shown in Figure 7A. In another example (Figure 7B), rotation of the gear 15 is accomplished using a spindle 23. Rotating the spindle 23 stepwise via an external force rotates the gear 15. The external force can be provided by any force that rotates the spindle 23, such as a step motor or a brushless motor.

[0038] Whether microneedle actuation is performed using a wax motor or by moving a puck around a spiral track, the number of microneedles (8) injected is preset based on a particular bioactive agent dosing regimen. The device's controller (5) activates a preset number of microneedles (8) based on the dosing regimen at one or more preset times during the treatment period. The controller (5) can be configured with a preset schedule for administering the bioactive agent, for example, by initiating the device when or shortly before the device is placed on the patient. The dosage (i.e., the number of microneedles (8) injected) can also be adjusted over time by adjusting the configuration of the controller (5) after the device is placed on the patient. The controller (5) can be configured directly on the device (e.g., via a user interface) or remotely. The controller (5) suitably includes a processing module and a communication module. Such a communication module can be connected to an external server via any suitable means, such as a fixed or wireless connection. In such devices, where the controller (5) is connected to a remote server, dose adjustment can be performed remotely via the communication module of the controller (5), and after remote adjustment, the controller (5) can be configured with the adjusted dosing regimen.

[0039] Additionally, the controller 5 may further include a processing module for storing injection or usage dates. Connection to a central or external server via the controller 5's communications module allows for the collection of usage and injection data. The usage and injection data can be processed on the external server to provide additional information to a medical professional or patient, and to correlate patient outcomes with monitoring or adherence to a particular dosing regimen. It is understood that data using the controller 5's communications module can be transmitted via a wireless connection via any cloud service or dedicated app.

[0040] While this invention has been shown and described as having a preferred design, the invention can be modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the disclosure as come within known or customary practice in the art to which this invention pertains.

Claims

1. A device for delivering a bioactive agent through mammalian skin comprising an array of microneedles and means for separately actuating the microneedles.

2. 10. The device of claim 1, wherein the actuation means simultaneously actuates a subset of the array of microneedles, the subset comprising two or more microneedles.

3. The device of claim 2 , wherein the simultaneous actuation of a subset of the array of microneedles comprises actuation over a period of 1 to 60 seconds.

4. 4. The device of any one of claims 1 to 3, which is an on-skin device further comprising means for adhering to the skin of a mammal, wherein said means for adhering to the skin is selected from adhesive, a belt, and a rubber band.

5. The device of any one of claims 1 to 4, wherein the microneedles comprise a bioactive agent.

6. The device of claim 5 , wherein the microneedles are coated with a bioactive agent.

7. 6. The device of claim 5, wherein at least a portion of the distal end of the microneedle is a solid formulation comprising a bioactive agent.

8. The device of any one of claims 1 to 7, wherein the bioactive agent is an agent selected from a small molecule, a peptide, a protein, an antibody, a fusion protein, DNA, and RNA.

9. The device of claim 8 , wherein the bioactive agent is an infertility treatment drug such as Gonal F.

10. The device of claim 8 , wherein the bioactive agent is insulin.

11. The device of claim 8 , wherein the bioactive agent is a cancer therapeutic agent.

12. 12. The device of any one of claims 1 to 11, wherein the microneedles dissolve upon contact with a liquid after actuation of the microneedles, thereby releasing the bioactive agent into the mammal.

13. The apparatus of any one of claims 1 to 12, wherein the actuation means comprises an actuator and a thermally expandable actuation medium.

14. 14. The device of claim 13, wherein the thermally expandable working medium comprises paraffin wax, thermostatic wax, polyethylene glycol, or a mixture thereof.

15. 15. The apparatus of claim 14, wherein the thermally expansive working medium has a relatively high melting point and high thermal expansiveness.

16. The apparatus of any one of claims 13 to 15, wherein the actuation means further comprises a heat source.

17. 17. The apparatus of claim 16, wherein the heat source is an electrical heat source, such as a resistor, controlled via a printed circuit board.

18. 18. The device of claim 16 or 17, wherein each microneedle in the array is coupled to an individual heat source.

19. An apparatus according to any preceding claim, wherein the actuation means comprises an actuator and a spring.

20. 20. The device of claim 19, wherein the spring is repeatedly primed before the actuator engages each microneedle.

21. 21. The device of claim 19 or 20, wherein the actuator means further comprises a spiral track along which the actuator moves from one microneedle to the next.

22. 22. The device of claim 21, wherein the spiral track includes a plurality of ramps and depressions to prime the spring and actuator with each actuation.

23. 23. The device of any one of claims 1 to 22, wherein the microneedles actuate with a force of at least 0.5 N and an actuation stroke of at least 0.5 mm.

24. 24. The device of any one of claims 1 to 23, wherein the microneedles are actuated with a force of about 1 N to about 5 N, preferably about 1 N, and have an actuation stroke of 1 mm to about 5 mm.

25. An apparatus according to any preceding claim, wherein the period between each actuation is controllable.

26. 26. The device of claim 25, wherein the period of time is from about 1 second to about 7 days.

27. 26. The device of claim 25, wherein the period is a predefined injection cycle.

28. A method of administering a bioactive agent to a mammal using a device according to any one of claims 1 to 27.

29. 29. The method of claim 28, wherein the mammal is a human.

30. 30. The method of claim 29, wherein the human is a female and the bioactive agent is an infertility treatment drug.

31. 30. The method of claim 29, wherein the bioactive agent is insulin.

32. 30. The method of claim 29, wherein the bioactive agent is a cancer therapeutic agent.

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