Microneedle array, actuator and methods of use

Abstract

Described herein are transdermal drug delivery devices, such as microneedle array patches, that are placed on the skin for transdermal delivery of a medicament. Transdermal drug delivery devices for delivering a biologically active agent through the skin of a mammal include a microneedle array and a means for actuating the microneedles, wherein the actuating means causes the microneedles to be actuated individually.

Description

Technical Field

[0001] This invention relates to transdermal drug delivery devices. Specifically, this invention relates to microneedle arrays (such as microneedle array patches) placed on the skin for transdermal delivery of pharmaceutical agents. Background Technology

[0002] Drug components can be administered via various routes, including, for example, oral administration or subcutaneous injection. For certain active ingredients in a drug component, more localized administration is preferred, especially for larger active ingredients (such as, for example, biologics). Therefore, larger active ingredients are typically administered by injection (subcutaneous, intramuscular, or intravenous).

[0003] Examples of active pharmaceutical ingredients administered by injection include, for instance, certain hormone therapies in the field of fertility treatment, insulin, or many biologics in the fields of tumor and autoimmune therapy, such as antibody or fusion protein therapies.

[0004] Injectable medications typically require the assistance of trained healthcare professionals or patient training. Many patients perceive injections as a painful and cumbersome process, and in some cases, they may forgo, stop, or infrequently receive injections of the active pharmaceutical ingredient. This can significantly impact adherence to a treatment plan. Furthermore, the use of injection devices with exposed needles carries a risk of needlestick injury, which should be minimized as much as possible from a safety perspective.

[0005] Microneedle technology, incorporated as an array into a percutaneous patch, offers an attractive alternative to more traditional injection-based drug delivery methods. A typical microneedle array for percutaneous drug delivery is in the form of a patch applied to a patient's skin. A drug component, including an active pharmaceutical ingredient, is delivered to the patient via the microneedle array, which may be coated with the drug component or partially soluble and constructed from a solid drug component. Once the active pharmaceutical ingredient has been administered via the percutaneous patch with the microneedle array, the patch can be removed.

[0006] Therefore, traditional percutaneous patches deliver the active pharmaceutical ingredient in a single-dose manner, which can be an immediate-release or sustained-release component. A disadvantage of these percutaneous patches is that they are designed for a single dose. However, some treatments require multiple administrations of the active pharmaceutical ingredient at predetermined intervals over a period of time. For example, some treatments require daily injections over, say, a two-week cycle. While the percutaneous patch can be removed at the end of each administration and replaced with another patch before subsequent administrations, this remains highly inconvenient for patients and does not increase their likelihood of adhering to the treatment plan.

[0007] Therefore, there is a need for a convenient and easy-to-use device for administering injectable active pharmaceutical ingredients to a patient, particularly where the treatment involves delivering multiple doses at preset time intervals over a period of time. Summary of the Invention

[0008] This invention relates to a device for the transdermal delivery of an active pharmaceutical ingredient. The device of the present invention is convenient and easy to use for administering an active pharmaceutical ingredient to a patient undergoing treatment, wherein the treatment requires multiple administrations at preset 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 within the array. Therefore, 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 aforementioned technical problems by allowing actuation of one or more individual needles within the microneedle array, thereby realizing a microneedle array patch device that can administer multiple doses over a period of time according to a specific dosage regimen for an active pharmaceutical ingredient. Furthermore, the device greatly improves patient convenience, particularly the convenience of home self-administration, and increases the likelihood of adhering to a preset dosage regimen.

[0009] In one embodiment of the invention, an apparatus is provided for delivering an active pharmaceutical ingredient and a bioactive agent through mammalian skin. The apparatus includes an array of microneedles and a device for actuating the microneedles, wherein the actuating device actuates the microneedles individually. In a preferred embodiment, the actuating device simultaneously actuates subgroups of the microneedle array. In some embodiments of the invention, the microneedles include a soluble portion containing the active pharmaceutical ingredient or a component comprising the active pharmaceutical ingredient.

[0010] In one embodiment of the invention, an apparatus for delivering a bioactive agent through mammalian skin is provided, the apparatus comprising an array of microneedles and a device for actuating the microneedles, wherein the actuating device actuates the microneedles individually and includes one or more heating elements and a thermally expandable working medium.

[0011] In another embodiment of the invention, an apparatus for delivering a bioactive agent through mammalian skin is provided, the apparatus comprising an array of microneedles and a device for actuating the microneedles, wherein the actuating device actuates the microneedles individually and includes a spring and an actuator located on a disc with a helical guide track.

[0012] In another embodiment of the invention, a method for administering a bioactive agent to a mammal is provided, the method using a device for delivering the bioactive agent through the mammalian skin, the device comprising an array of microneedles and a device for actuating the microneedles, wherein the actuating device actuates the microneedles individually.

[0013] Other objects and advantageous features of the invention will be apparent from the claims, detailed description and drawings. Attached Figure Description

[0014] Figure 1 A cross-sectional top view of a percutaneous patch with an array of microneedles, including an actuation mechanism, is shown.

[0015] Figure 2 A transdermal patch with a microneedle array is shown, which has a thermally expandable working medium (here, wax) that can be used as an actuator.

[0016] Figure 3 A schematic diagram of a wax actuator is shown, which is used for microneedle actuation in a microneedle array of a transdermal patch.

[0017] Figure 4 A detailed schematic diagram of the needle tip and the skin contact surface is shown.

[0018] Figure 5 A schematic diagram of a disc with a spiral guide rail is shown, which is used as an actuator in an actuator and spring mechanism.

[0019] Figure 6 illustrates actuation using an actuator and spring mechanism, wherein in the first step, the actuator pin / puck is in the triggered position, thereby pushing the needle out of the percutaneous microneedle array patch. Figure 6A The travel on the inclined ramp initiates the actuator pin / disc to push subsequent needles out of the percutaneous microneedle array patch. Figure 6B ).

[0020] Figure 7 illustrates the mechanism that advances the pin / disc along a series of microneedles in a microneedle array. In the first mechanism, an SMA (shape memory alloy) spring is used to advance the rotating disk incrementally to the next increment. Figure 7A In the second mechanism, a rotating spindle is used to advance the rotating disk in an incremental manner. Figure 7B ). Detailed Implementation

[0021] In one aspect, the apparatus and methods described herein are directed to percutaneous devices, including intradermal delivery devices for administering an active pharmaceutical ingredient to a patient. In one exemplary embodiment, the systems and methods provide delivery devices for administering an active pharmaceutical ingredient into or beneath the stratum corneum of a patient's skin. As used herein, percutaneous refers to the exchange of substances such as active pharmaceutical ingredients (biological agents) or vaccines through one or more layers of skin.

[0022] The described apparatus and method are particularly suitable for administering various active pharmaceutical agents / ingredients (bioactive agents) to patients, especially human patients. Active pharmaceutical agents / ingredients include biologically active substances that can be delivered through the skin. Examples include antibiotics, antiviral agents, analgesics, anesthetics, anorectants, anti-arthritis agents, antidepressants, antihistamines, anti-inflammatory agents, antitumor agents, vaccines (including DNA vaccines), adjuvants, biologics, etc. Other substances that can be delivered to patients intradermally include proteins, peptides, and fragments thereof. Proteins and peptides can be naturally occurring, synthetic, or recombinant. Suitable examples of active pharmaceutical agents / ingredients include insulin or reproductive hormones, such as recombinant gonadotropins (e.g., recombinant human FSH).

[0023] The advantages of the microneedle array device for percutaneous delivery described herein are that it provides a convenient and easy-to-use device for the percutaneous administration of active pharmaceutical preparations. This is also convenient for patients, as the device described herein can be used for treatments requiring multiple administrations over a predetermined period of time. During treatment, patients do not need to change microneedle devices or use different devices for multiple injections each time. Therefore, the device and its use in treatment methods also improve patient adherence to the treatment regimen.

[0024] In some embodiments of the device, a communication module is included. The communication module can be any communication module capable of transmitting data from the device to a central server / external server. The transmitted data relates to one or more of the following: confirmation that the microneedle array has been triggered, the number of triggered needles, the time and date the microneedle array was triggered, or changes in the number of microneedles to be triggered as part of dosage adjustment. The communication module can use any number of connections to transmit data, including, for example, wireless connections.

[0025] Figure 1 Embodiments of a device for delivering bioactive agents through mammalian skin are generally described, the device comprising an array of microneedles and a device for actuating the microneedles, wherein the actuating device actuates the microneedles individually. Figure 1 In this context, device (1) is a percutaneous patch device, i.e., a device to be attached to a patient's skin (on-skin device), which surrounds a mechanism for delivering an active pharmaceutical preparation through the patient's skin. Device (1) includes a body or housing (2) that surrounds a microneedle array (3) (which is a support structure comprising multiple microneedles) and an actuating device (4). The body or housing (2) also surrounds a controller (5) and a battery (6). Attachment to the skin can be achieved by any suitable device (7) for securing the device to the patient's skin. Examples of suitable devices (7) for securing the device to the patient's skin include adhesive layers (such as... Figure 1 (as shown) or belt or rubber band.

[0026] Figure 2 A more detailed structure of an embodiment of the device of the present invention is provided. In this embodiment, the device for actuating the microneedles (8) includes a thermally expandable working medium (9), such as a wax layer. The body or housing (2) of the device surrounds the battery (6), the controller (5), the thermally expandable working medium (such as a wax layer) (9), and the microneedle array (3), wherein the microneedle array includes a plurality of microneedles (8). The device also includes a device (7) for securing the device to the patient's skin, the device being suitably such as Figure 2 The adhesive layer shown.

[0027] The actuation device (4) for actuating the microneedles can be any suitable actuation device that allows the microneedles to penetrate the skin. The actuation device of the present invention is characterized in that it allows individual actuation of each microneedle. Preferred devices for actuating the microneedles include those using a thermally expandable working medium or those using a spring and actuator pin.

[0028] The thermally expandable working medium can be any working medium that expands due to temperature rise. The working medium will need to expand in a manner that provides sufficient force to the microneedles. Each microneedle in the microarray is required to pierce the skin and needs to be displaced to a sufficient depth for transdermal (e.g., subcutaneous) drug delivery. Given that microneedles are typically either coated with a drug or have a distal tip containing a biodegradable form of the drug, the microneedles are displaced so that the distal tip containing the drug penetrates the skin and is positioned subcutaneously after actuation. Therefore, in cases where the actuating device includes a thermally expandable medium, a suitable thermally expandable medium has an expansion volume sufficient to apply a force of at least 1 N over the entire displacement range of the microneedle's travel. This force is preferably from about 1 N to about 5 N. In the case of such expansion, the resulting force must be sufficient to give the microneedle a travel distance of at least 0.5 mm, suitably at least 0.65 mm, and preferably from about 1 mm to about 5 mm (see...). Figure 4 ). Figure 4 An embodiment of the microneedles is depicted when they are included in a microneedle array. Here, prior to actuation, the needle tip (11) is positioned within the device and protected from external environmental influences by a barrier (12) (e.g., foil). The barrier (12) keeps the microneedles (8) within the device sterile. To maintain sterility, the environment around the microneedles is hermetically sealed by a sterile seal such as the barrier (12). In some embodiments, the microneedles (8) may be sealed separately by the barrier (12). Therefore, actuation of the microneedles also requires penetration of the barrier (12) for transdermal administration of an active pharmaceutical ingredient. The barrier (12) is preferably located between the microneedle array and a device (7) (e.g., an adhesive layer) for attaching the device to the skin. Considering that in Figure 4 In this example, the needle tip (11) is 500 μm long, the gap between the needle tip (11) and the barrier (12) is 50 μm, and the thickness of the barrier (12) and the skin attachment device (7) is 50 μm. Therefore, the minimum stroke required in this example is at least 0.65 mm.

[0029] Suitablely, the thermally expandable working medium is preferably a wax. Preferred waxes include, for example, paraffin wax, thermostat wax, polyethylene glycol, or mixtures thereof. The suitable thermally expandable medium has a relatively high melting point and high thermal expansion. High thermal expansion means that any paraffin wax or thermostat wax can exert a force of at least 1 N within an expansion range of 0.5 mm to 5 mm during expansion. For example, the expansion range in each direction is 0.5 mm to 5 mm. A relatively high melting point means that paraffin wax and thermostat wax have melting points significantly higher than body temperature but not high enough to reach a melting temperature that would adversely affect other components of the device or the patient using the device. Suitablely, the melting temperature of paraffin wax or thermostat wax is 50°C to 90°C, more preferably 60°C to 80°C, for example 65°C to 75°C. Suitablely, paraffin or thermostatic wax has a narrower range of carbon chain lengths because a wider range of carbon chain lengths in paraffin or thermostatic wax can result in a wider range of melting temperatures; however, a limited melting temperature is more suitable for applications using the apparatus described in this invention. Examples of thermally expandable working media include 60% hexadecane and 40% paraffin. Suitable examples of thermally expandable media include waxes such as Kerax 1303 and Alfa 1260.

[0030] The working medium that can expand thermally is in close contact with the heat source (13), such as Figure 3 As shown. The heat source (13) is in direct contact with the thermally expandable working medium (9) and is regulated by the controller (5). Each microneedle (8) in the microneedle array (3) is actuated by a dedicated heat source (13). To actuate each individual microneedle (8), the heat source (13) dedicated to that microneedle generates sufficient heat to cause the thermally expandable working medium (9) to expand. In some embodiments, the heat source (13) may be an integral part of, for example, a printed circuit board (PCB) included in the controller (5). In suitable embodiments, each heat source (13) is an electrothermal source, such as, for example, a resistor on the PCB.

[0031] When the working medium (4) that can expand thermally is heated, each microneedle (8) is pushed through its orifice, through the sterile barrier (12), and through the patient’s skin to administer the drug. Figure 3An exemplary embodiment is shown, wherein a printed circuit board (PCB) includes a heat source (13) for each microneedle (8) in a microneedle array (3). A thermally expandable working medium (9) is in close contact with each heat source (13), and a controller (5) on the PCB (not shown) actuates each individual heat source to actuate each microneedle (8). Each microneedle (8) is positioned in an aperture (14). The aperture (14) may be formed from a support plate (15). The support plate (15) may include one or more layers. In the case where the support plate (15) includes more than one layer, these layers are separated by spacers (such as... Figure 3 (as shown). In a preferred embodiment, the support plate (15) comprises two layers (15a, 15b) separated by spacers (16). The spacers (16) reduce potential friction in the orifice (14), which could increase the required force for actuating the microneedles (8) for transdermal administration of a drug or active pharmaceutical preparation.

[0032] In suitable embodiments, the microneedles (8) have a diameter of 0.3 to 0.5 mm, preferably about 0.4 mm. Microneedles suitable for use in the microneedle array of the present invention are used to administer an active pharmaceutical preparation / bioactive agent to a patient. Therefore, each microneedle (8) includes a dose or partial dose of bioactive agent to be administered. Triggering of the microneedle (8) administers a dose or partial dose to the patient. Thus, the microneedle array (4) of the delivery device of the present invention contains one or more doses of bioactive agent to be administered to a patient. In the case where the microneedle array (4) includes multiple doses of bioactive agent, a controller (5) can initially actuate a subgroup of microneedles (8) to administer an appropriate dose according to the treatment regimen.

[0033] The bioactive agent can be any active pharmaceutical preparation as described, including agents selected from small molecules, peptides, proteins, antibodies, fusion proteins, DNA, and RNA. In one embodiment, the bioactive agent is a fertility agent, such as... (Gonal (A recombinant gonadotropin). In another embodiment, the bioactive agent is insulin. In yet another embodiment, the bioactive agent is a cancer therapeutic agent. Any of the said agents are formulated as a pharmaceutical component either as the sole active pharmaceutical ingredient or as part of a combination of pharmaceutically active ingredients in the same pharmaceutical formulation.

[0034] The pharmaceutical formulation comprising a bioactive agent is applied to the microneedles (8) of the microneedle array (3) to produce a single dose or multiple doses of the bioactive agent in the microneedle array. The microneedles (8) can be applied in any suitable manner so that each microneedle contains a single dose or a partial dose of the bioactive agent. In one embodiment, the microneedle (8) is a solid microneedle coated with a pharmaceutical formulation comprising a bioactive agent. In another embodiment, the pharmaceutical formulation comprising a bioactive agent is a solid formulation with sufficient consistency and strength to form a portion of the microneedle (8). The suitable solid formulation comprising the bioactive agent forms a portion of the needle tip (i.e., the distal end of the microneedle (8)) for administration to the patient upon microneedle actuation. Once injection is performed, the bioactive agent is released from the formulation. In some embodiments of the invention, the microneedles (8) of the microneedle array (4) are soluble microneedles that dissolve upon contact with a fluid after being actuated and injected through the patient's skin. Suitable soluble needles are described, for example, in U.S. Patent Application No. 2017 / 0296465.

[0035] In an alternative embodiment, the actuating device (4) includes an actuator and a spring (such as...). Figure 5 As shown). In such Figure 5 In one such embodiment shown, the microneedle array (4) is arranged concentrically. In this embodiment, the actuating device (4) includes a cog wheel (15) having a concentric helical track (16), on which a disk (17) advances around the helical track (16) to actuate one or more microneedles (8). The disk (17) includes an actuator and a spring (as shown in Figure 6).

[0036] The advance of the disk (17) around the helical track (16) sequentially actuates one or more microneedles (8) to deliver a dose. Figure 6A and Figure 6B As shown, the disk (17) includes an actuator (18) and a spring (19). The helical track (16) includes a series of ramps, each ramp (20) followed by a hole (21) before the next ramp (20). The advance of the disk (17) along the ramps (20) pushes the actuator (18) upward against the spring (19), thereby generating spring force potential energy (as shown in the figure). Figure 6A As shown). Further advance of the disk (17) above the hole releases the spring force potential energy and triggers the spring (19), thereby actuating the actuator (18) to push the microneedle (8) downward with sufficient force (as shown). Figure 6BAs shown), the disc (17) penetrates the sterile barrier (12) and the patient's skin (not shown here). The advance of the disc (17) along the spiral track repeats this cycle, i.e., actuating the spring (19) with spring force potential energy and releasing the spring (19) to actuate the actuator (18), thereby pushing the microneedle (8) downward to administer the bioactive agent to the patient. The spring (19) can be of any shape capable of releasing spring force potential energy onto the actuator (18). The spring (19) is suitably a spring having 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 disk (17) can move around the spiral track (16) in any suitable manner. Figure 7A and Figure 7B Examples of alternative mechanisms for advancing a disk (17) around a helical track (16) are provided. In both examples, the helical track (16) is stationary, while the disk (17) is slidably connected to a gear (15). Rotation of the gear (15) causes the disk (17) to advance around the helical track (16). This advance of the disk (17) is based on incremental advances of the number of microneedles (8) to be injected for each dose. The incremental advance of the disk (17) around the helical track (16) is controlled by the incremental rotation of the gear (15). The rotation of the gear (15) is achieved by the action of, for example, a shape memory alloy (SMA) spring (22), such as... Figure 7A As shown. In another example ( Figure 7B In this process, the rotation of the gear (15) is achieved by using a spindle (23). The spindle (23) is rotated by an external force that increments in steps, causing the gear (15) to rotate. The external force can be provided by any force that rotates the spindle (23), such as, for example, a stepper motor or a brushless motor.

[0038] Regardless of whether the actuation of the microneedles is performed using a wax motor or by moving a disc around a helical track, the number of microneedles (8) to be injected is preset based on a specific bioactive agent dosing regimen. During treatment, the controller (5) in the device actuates a preset number of microneedles (8) one or more preset times based on the dosing regimen. The controller (5) may be configured with a preset schedule for determining the dosage of the bioactive agent, such as in the step of activating the device when it is placed on a patient or just before it is placed on a patient. After the device is placed on a patient, the dosage (i.e., the number of microneedles (8) to be injected) can also be adjusted over time by adjusting the configuration of the controller (5). The controller (5) may 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. The communication module may be connected to an external server in any suitable manner, such as via a fixed connection or via a wireless connection. In the device in which the controller (5) is connected to a remote server, dose adjustment can be performed remotely through the communication module of the controller (5), and after remote adjustment, the controller (5) can be configured with the adjusted dose scheme.

[0039] In addition, the controller (5) may also include a processing module for storing injection or usage dates. A connection via the communication module in the controller (5) to a central or external server allows for the collection of usage and injection data. Usage and injection data can be processed on an external server to provide additional information to healthcare professionals or patients to monitor or correlate any patient outcomes with adherence to a given dosing regimen. It is understood that data using the communication module in the controller (5) can be transmitted via any cloud service or through a dedicated app using a wireless connection.

[0040] While the invention has been shown and described with preferred designs, modifications can be made to the invention within the spirit and scope of this disclosure. Therefore, this application is intended to cover any variations, applications, or modifications thereof that utilize the general principles of the invention. Furthermore, this application is intended to cover deviations that fall within the known or customary practice of the field to which this invention pertains.

Claims

1. A device for delivering a bioactive agent through the skin of a mammal, the device comprising an array of microneedles and an actuation means for actuating the microneedles, wherein, The actuation device actuates the microneedle individually; The actuating device includes an actuator and a spring, and further includes a gear with a concentric helical track, on which a disk advances around the helical track to actuate one or more microneedles; The spiral track includes a series of ramps, each ramp followed by a hole before the next ramp. The forward movement of the disk above the hole releases spring force potential energy and triggers the spring, thereby actuating the actuator to push the microneedle downward.

2. The apparatus of claim 1, wherein, The actuating device simultaneously actuates a subgroup of the microneedle array, the subgroup comprising two or more microneedles.

3. The apparatus of claim 2, wherein, Simultaneously, the subgroups of the microneedle array are actuated over a time period of 1 to 60 seconds.

4. The apparatus of any one of claims 1-3, wherein, The device is a skin-attached device, and the device further includes a means for attaching to mammalian skin, wherein the means for attaching to the skin is selected from adhesives, tapes, and rubber bands.

5. The apparatus according to any one of claims 1-3, wherein, The microneedles include the bioactive agent.

6. The apparatus according to claim 5, wherein, The microneedles are coated with the bioactive agent.

7. The apparatus according to claim 5, wherein, At least a portion of the distal end of the microneedle is a solid formulation containing the bioactive agent.

8. The apparatus according to any one of claims 1-3, wherein, The bioactive agent is a drug selected from small molecules, peptides, proteins, antibodies, fusion proteins, DNA, and RNA.

9. The apparatus according to claim 8, wherein, The bioactive agent is a fertility agent.

10. The apparatus according to claim 9, wherein, The fertility drug mentioned is Gonal-F.

11. The apparatus according to claim 8, wherein, The bioactive agent is insulin.

12. The apparatus according to claim 8, wherein, The bioactive agent is a cancer therapeutic agent.

13. The apparatus according to any one of claims 1-3, wherein, Upon actuation of the microneedle, the microneedle comes into contact with the fluid and dissolves, thereby releasing the bioactive agent to the mammal.

14. The apparatus according to any one of claims 1-3, wherein, The microneedle is actuated with a force of at least 0.5 N and an actuation stroke of at least 0.5 mm.

15. The apparatus according to any one of claims 1-3, wherein, The microneedle is actuated with a force of about 1N to about 5N, and the actuation stroke is about 1mm to about 5mm.

16. The apparatus according to claim 15, wherein, The microneedle is actuated with a force of approximately 1 N.

17. The apparatus according to any one of claims 1-3, wherein, The time interval between each actuation can be controlled.

18. The apparatus according to claim 17, wherein, The time period is from approximately 1 second to approximately 7 days.

19. The apparatus according to claim 17, wherein, The time period is a pre-defined injection cycle.

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