Methods and systems for delivering drugs through the skin of the body

Abstract

A transdermal permeant delivery system for delivering at least one permeant to a tissue membrane of an individual comprises: a filament array having a plurality of filaments disposed in a perforated region and configured to deliver thermal energy to the tissue membrane to form a plurality of micropores; an applicator electrically connected to the filament array and configured to supply electrical energy to the filaments to generate the plurality of micropores in the micropore region; and a patch configured to be applied to the micropore region and releasably containing at least one permeant. A method of treatment comprises administering the permeant in the form of a drug to an individual in need thereof using the transdermal permeant delivery system.

Description

Technical Field

[0001] Transdermal patches can be used to maintain drug release and control the delivery of drugs or compounds in vivo. Transdermal patches generally include a reservoir containing an active penetrant (e.g., a drug). Patch is typically attached to the skin of the body so that the drug or compound must pass through the skin. Like this, the stratum corneum of the skin provides or serves as a barrier for drug or compound delivery to the body.

[0002] The present disclosure relates to delivering drugs or other compounds through the skin. More particularly, the present disclosure relates to enhancing the delivery of drugs or compounds through the skin to improve delivery from transdermal patches.

[0003] background

[0004] Transdermal patches deliver molecules of a drug or compound from a reservoir (e.g., a polymer matrix system) through the body's skin. However, the different layers of the skin can act as a barrier to molecule delivery, limiting drug delivery in terms of molecular weight (e.g., molecular weight greater than 500 Da). For such passive transdermal drug delivery systems, the skin also creates a limitation on optimal hydrophobic properties.

[0005] Minimally invasive technologies and methods exist to improve the ability of transdermal patches to deliver larger molecular weight drugs. For example, microneedles embedded in the transdermal patch and / or in the skin and / or micropores of the skin can help improve drug delivery and / or increase the molecular weight of molecules transported through the skin between the transdermal patch and the body. Thus, this technology improves the delivery of large molecules and alters the drug delivery characteristics of the transdermal patch.

[0006] However, these technologies may still impose limitations on drug delivery from a transdermal patch through the skin to the body. For example, a transdermal patch used in conjunction with microneedle technology may have limitations on controlled delivery and / or drug loading, which are often desirable features of a transdermal patch. Therefore, the use of a transdermal patch in conjunction with microporation technology is often preferred because this combination provides more flexible drug delivery than using a transdermal patch with microneedle technology.

[0007] There are heat, radio frequency (RF) and laser microperforation technologies. However, existing systems and methods cannot utilize and / or produce micropores with optimal characteristics and / or parameters for delivering drugs between transdermal patches and the body via the skin. On the contrary, such systems can only produce micropores in the skin, and although it is known that such micropores improve drug delivery, it is not known and / or understood how to produce the best micropores for delivering drugs including macromolecules. Therefore, there is a need for a better system and method for producing micropores that improve drug delivery including macromolecules. In some embodiments, micropores are produced using microperforation, thermal ablation or flash evaporation, and the micropaths in a biofilm or tissue (e.g., skin) can enhance the delivery of a drug or compound to the body. Summary of the Invention

[0008] The methods and devices or apparatus disclosed herein each have several aspects, no single aspect of which is solely responsible for its desirable properties. Without limiting the scope of this disclosure (e.g., as expressed by the appended claims), its more salient features will now be briefly discussed. After considering this discussion, and particularly after reading the section entitled "Detailed Description of the Invention," one should understand how the described features provide advantages, including data authentication services.

[0009] One innovation is a transdermal permeant delivery system for delivering at least one permeant into a tissue membrane of an individual. The transdermal permeant delivery system may include a) a substrate having an upper substrate surface and defining a perforated area, the substrate comprising a filament array having a plurality of filaments disposed in the perforated area, wherein each filament is capable of conductively transferring thermal energy via direct contact with the tissue membrane to form a plurality of micropores in the microporous area of ​​the tissue membrane, the microporous area being 1% to 20% of the perforated area; b) an applicator electrically connected to the filament array and configured to supply a controlled amount of electrical energy to the filaments so as to generate a plurality of micropores in the microporous area of ​​the tissue membrane by heating the filaments; and c) a patch configured to be applied over the microporous area and releasably containing the at least one permeant, the patch comprising a gel having a thermal conductivity of less than 10 mg / cm 2 A matrix having a water-retaining capacity and at least one penetrant dispersed in the matrix.

[0010] Various embodiments of the transdermal permeate delivery system disclosed herein may include one, all, or any combination of the features in this paragraph, or other features disclosed herein. The predetermined electrical energy for generating a plurality of micropores by heating the filament may be 0.0067 µJ / µm 3 Up to 0.0400 µJ / µm 3 The microporous area can be 1.25% to 10% of the perforated area. The cumulative volume of multiple micropores can be 0.05 mm 3 / cm 2 Up to 0.35 mm 3 / cm 2. The permeate may be a long-acting drug. The long-acting drug may be a GLP-1 antagonist, an Fc protein, an antibody or a derivative thereof with an extended half-life. In some embodiments, the long-acting drug acts for more than 24 hours. In some embodiments, the long-acting drug may act for 1 day to 7 days. In some embodiments, the long-acting drug acts for more than 7 days. The patch may be configured to release the permeate for more than 24 hours. The system may include a backing layer having at least a partial adhesive. The filament may include a conductive layer of copper and an underlying resistive layer of stainless steel. The applicator may be configured to supply a predetermined electrical energy of 2 mJ / filament to 12 mJ / filament, preferably 2 mJ / filament to 8 mJ / filament, more preferably 3 mJ / filament to 6 mJ / filament to the filament. The applicator may be configured to supply the predetermined electrical energy to the filament for a period of 2 ms to 16 ms, preferably 2 ms to 12 ms. The plurality of micropores in the microporous area are arranged at approximately 20 micropores / cm 2 Up to about 500 micropores / cm 2 , preferably about 50 micropores / cm 2 Up to about 400 micropores / cm 2 The cumulative depth of the plurality of micropores may be about 2500 μm / cm 2 to approximately 30,000 μm / cm 2 The matrix comprises at least one fiber. The matrix may comprise a laminate comprising fibers and a film. The fibers may have a thickness of less than 300 μm, preferably less than 200 μm. The basis weight of the fibers in the matrix may be less than about 100 g / m 2 , preferably less than 20 g / m 2 The fibers may be nonwoven fibers. The permeate may be about 0.01 mg / cm 2 to about 20 mg / cm 2 In various embodiments, the permeant is a small molecule, a peptide, a protein, an oligonucleotide, or a combination thereof.

[0011] Another innovation includes a transdermal permeant delivery system for delivering at least one permeant into a tissue membrane of an individual, the transdermal permeant delivery system comprising a substrate having an upper substrate surface and defining a perforated region, the substrate comprising a filament array having a plurality of filaments disposed in the perforated region, wherein each filament is capable of conductively delivering thermal energy via direct contact with the tissue membrane to form a plurality of micropores in the microporous region of the tissue membrane; and an applicator electrically connected to the filament array and configured to provide controlled electrical energy to the filaments to generate the plurality of micropores in the microporous region of the tissue membrane by heating the filaments. The controlled electrical energy to generate the plurality of micropores by heating the filaments is 0.0067 µJ / µm 3 Up to 0.0400 µJ / µm 3In some embodiments, the controlled electrical energy is a predetermined amount. In some embodiments, the controlled electrical energy is based at least in part on sensed information.

[0012] Another innovation includes a method for treating an individual in need thereof. The method can include identifying an individual suffering from a condition requiring treatment with a selected drug, opening a plurality of micropores in the individual's skin by applying an applicator of any transdermal permeant delivery system disclosed herein to the individual, and applying a patch of the transdermal permeant delivery system disclosed herein to the individual's skin for a period of time over the micropores, wherein a permeant dispersed in a matrix of the patch comprises the selected drug. The period of time can be selected to deliver a therapeutically effective amount of the selected drug through the plurality of micropores. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] These drawings and the associated description herein are provided to illustrate specific embodiments of the invention and are not intended to be limiting.

[0015] Figure 1 is a functional block diagram of a control unit 110 of a microporation drug delivery system, such as the microporation drug delivery system of US Pat. No. 8,116,860 (indicated using reference numeral “ 10 ” therein).

[0016] Figure 2A is a perspective view of a filament 200 of a filament array of a microperforated drug delivery system.

[0017] Figure 2B yes Figure 2A 2 is a perspective view of a filament 200 showing a cross-sectional area 208 and a current flow direction 210 .

[0018] Figure 3A It includes multiple Figure 2A and Figure 2B FIG2 is a top view of a representative filament array of a microperforated drug delivery system of filaments 200 .

[0019] Figure 3B is experiencing one or more filament failures 302 and 304 Figure 3A Top view of the filament array.

[0020] Figure 4 Graph 400 shows a pulse profile showing TEWL versus energy delivered via pulses to a filament array of a microporation drug delivery system, while graph 450 shows delivered energy versus TEWL for a high power applicator (HPA) generating approximately 400 pathways.

[0021] Figure 5 is a graph 500 showing pulse TEWL as a function of pulse length for a given energy per filament.

[0022] Figure 6 There is a graph 600 showing TEWL as a function of total path depth, a graph 640 showing TEWL as a function of total path area, and a graph 680 showing TEWL as a function of total path volume.

[0023] Figure 7 A top perspective view 700 of the transdermal patch 102 is shown.

[0024] Figure 8 is a graph 800 showing sucrose content relative to the amount of exudate extracted from patch 102, and a graph 840 showing the amount of exudate extracted comparing two sucrose patch formulations under different applicator conditions.

[0025] Figure 9 is a graph 900 showing how the weight density of a water retaining material affects the WHC of the water retaining material and a graph 940 showing how the thickness of a water retaining material affects the WHC of the water retaining material.

[0026] Figure 10 A graph comparing the blood concentration of long-acting peptides for each of Groups 1 to 3 in Tables 1 and 2 using microporation parameters and patch 102 parameters is shown, as well as a graph comparing the in vivo concentration of long-acting peptides for each of Groups 4 to 6 using time.

[0027] Figure 11 A graph comparing the blood concentrations of the long-acting proteins in Groups 1 to 5 of Tables 4 to 6 is shown.

[0028] Figure 12 Graphs comparing the blood concentrations of the long-acting proteins of Group 1 and Group 2 shown in Tables 8 to 10 are shown.

[0029] Figure 13 A graph comparing blood drug concentration levels in hairless guinea pigs is shown when polysaccharide is the type of drug formulation applied to patch 102, and a graph showing the average curve for the polysaccharide for 400 passes generated under a 4 ms pulse, as described above.

[0030] Figure 14 A graph comparing blood drug concentration levels in hairless guinea pigs is shown when a peptide is the type of drug formulation applied to the patch 102 and four groups of patches 102 have different patch parameters.

[0031] Figure 15 A graph comparing blood drug concentration levels in hairless guinea pigs is shown when a peptide is the type of drug formulation applied to patch 102 .

[0032] Figure 16 A graph showing blood drug concentration levels in hairless guinea pigs is shown when a peptide (eg, lixisenatide) is the type of drug formulation applied to the patch 102 .

[0033] Figure 17 A graph showing blood drug concentration levels in hairless guinea pigs is shown when a peptide (eg, teriparatide) is the type of drug formulation applied to patch 102 .

[0034] Figure 18 A graph comparing blood drug concentration levels in hairless guinea pigs is shown when a peptide (eg, somatropin) is the type of drug formulation applied to patch 102 .

[0035] Figure 19 A bar graph 1900 and a graph 1920 are shown, indicating serum titer values ​​for seven groups of vaccines administered in rats according to the parameters in Table 20.

[0036] Figure 20 A bar graph 2000 showing the total amount of antibody titers in mice for Groups 1 to 10 vaccines administered according to the parameters in Table 22 and a bar graph 2020 showing the in vivo Th1 cell antibody titers for Groups 1 to 10 are shown.

[0037] Figure 21 A bar graph 2100 showing the total amount of antibody titers in mice for Groups 1 through 6 vaccines administered according to the parameters in Table 22 and a bar graph 2120 showing the in vivo Th1 humoral antibody titers for Groups 1 through 6 are shown. DETAILED DESCRIPTION

[0038] Although certain embodiments and examples are disclosed below, the subject matter of the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or uses, as well as modifications and equivalents thereof. Therefore, the scope of the present application is not limited to any specific embodiment described below. For example, in any method or process disclosed herein, the actions or operations of the method or process can be performed in any appropriate order and are not necessarily limited to any specifically disclosed order. Various operations can be described as multiple discrete operations in a manner that can help understand certain embodiments; however, the order of description should not be interpreted as implying that these operations are sequentially related. In addition, the structures, systems and / or devices described herein can be implemented as integrated components or separate components. For the purpose of comparing various embodiments, certain aspects and advantages of these embodiments are described. It is not necessary for any specific embodiment to achieve all of these aspects or advantages. Therefore, for example, various embodiments can be implemented in a manner that achieves or optimizes one advantage or a group of advantages as taught herein, without having to achieve other aspects or advantages that may also be taught or suggested herein.

[0039] In the following detailed description, reference is made to the accompanying drawings, which form a part of the present disclosure. The exemplary embodiments described in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be employed, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It should be readily understood that the aspects of the present disclosure as generally described herein and shown in the drawings may be arranged, substituted, combined, and designed in a variety of different configurations, all of which are expressly contemplated by the present disclosure and all of which form a part of the present disclosure.

[0040] The terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the present disclosure. It should be understood that if a specific number of claim elements are intended, such intention will be clearly stated in the claims, and in the absence of such statements, such intention does not exist. For example, as used herein, the singular forms "a", "an" and "said" are intended to also include plural forms, unless the context clearly indicates otherwise. As used herein, the term "and / or" includes any combination and all combinations of one or more of the relevant listed items. It should also be understood that the terms "comprises", "comprising", "includes" and "including" indicate the presence of specified features, integers, steps, operations, elements and / or components when used in this specification, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or their groups. Expressions such as "at least one (kind) of ... " modify the entire list of elements when preceding a list of elements, without modifying the individual elements in the list.

[0041] High potency drugs (e.g., long-acting peptides, proteins, and oligonucleotides) are typically administered via injection. Other delivery methods may result in lower drug bioavailability and / or higher drug delivery (e.g., rate, amount, etc.) differences than injection. Such differences may result in higher costs or reduce the safety and / or effectiveness of the drug.

[0042] Long-acting drug formulations developed to minimize injection frequency and / or related patient costs can have high and / or variable effectiveness. Therefore, long-acting drug formulations are usually administered via injection, such as reservoir-type preparations. This injection may be more painful than a typical injection because it may involve a needle larger than a common injection. Once injected, if there is an adverse reaction (different from a patch that can be removed), the injected material cannot be removed. Injection site reactions may also occur. This injection may have a lower compliance than an injection with a smaller-sized needle. Therefore, in order to improve patient compliance, it is necessary to use a needleless and painless delivery and / or administration device for long-acting drug formulations. Needleless and painless delivery devices should also be well controlled to reduce the risk of side effects.

[0043] Microporation (e.g., using laser, RF, and / or heating elements) can be controlled based on variations in the number of holes, pulse duration (hole quality), and treatment area. However, variations in the skin (e.g., between different patients, between different locations on the patient's body, the patient's environment, the characteristics of the patient's skin, etc.) may result in differences in the micropores produced in different conditions or patients (regardless of the microporation method implemented). Such differences may result in ineffective, inconsistent, unsafe, and / or variable drug delivery using transdermal patches in combination with known microporation methods.

[0044] One embodiment of microporation utilizes thermal ablation to create the micropores. Although the examples provided in this disclosure may focus on microporation via such thermal ablation, the systems and methods described herein are equally applicable to other microporation methods and systems (eg, RF, laser, etc.).

[0045] During perforation of the skin, a metal filament heated to a high temperature is used to ablate the skin by introducing electrical energy through the filament and into the skin. The rapid introduction of energy into the skin causes a rapid increase in the temperature of the outer layer of the skin and results in ablation of at least a portion of the skin. The instantaneous ablation ensures that the stratum corneum (the outermost protective layer of the skin that prevents foreign matter from entering the body protected by the skin and prevents the loss of body fluids) is removed from the skin. The removal of the stratum corneum provides an opening (i.e., a pore) whose depth is proportional to the energy introduced through the metal filament and into the skin.

[0046] If the energy introduced through the metal filament is large enough and delivered quickly enough, the stratum corneum is ablated, exposing the epidermis (the layer of skin that is hydrated and can serve as a conduit for the formulated active pharmaceutical ingredient). Introducing more energy into the skin will cause more epidermis (i.e., water) to evaporate and create deeper pores. Deeper pores will facilitate or provide a higher flux rate of the formulated active drug, thereby providing a sufficiently desirable supply or concentration of the formulated active drug through the skin.

[0047] The basic configuration of microperforation drug delivery system is well known to those skilled in the art, so this paper does not need to elaborate again.For example, in No. 8,116,860 United States Patent (USP), transdermal permeate delivery system is described, described patent is incorporated to accordingly by reference, particularly for the purpose of describing the various features of this microperforation drug delivery system.As described herein, the microperforation drug delivery system of No. 8,116,860 United States Patent (wherein using reference numeral " 10 " expression) comprises basic feature, and described basic feature comprises and is configured to produce the filament array (wherein using reference numeral " 70 " expression) of one or more paths or micropores in patient's skin and one or more transdermal patches (wherein using reference numeral " 100 " expression) containing at least one pharmaceutical preparation.Other similar microperforation drug delivery systems comprising this basic feature are well known to those skilled in the art.Various microperforation drug delivery systems with this basic feature are well known to those skilled in the art, and can be used or adaptive use under the guidance of the teaching provided herein by those skilled in the art.

[0048] In some embodiments, a microporation device can be defined by the total area of ​​the paths (e.g., micropores) created by one or more filaments in the skin and the total energy delivered to the one or more filaments to create the paths. In some embodiments, the microporation device creates paths such that the total area of ​​the paths in the skin is about 1% / square centimeter (cm) to 20% / cm 2 In some embodiments, for each square centimeter of skin exposed to the microporation device, the pathways in the skin may preferably occupy between about 1.25% and 10% of the skin. In some embodiments, 1.25% / cm of the skin 2 Up to 10% / cm 2 The ratio provides effective drug delivery for drug formulations having molecular sizes within a specific range or within a specific range. In some embodiments, the total energy delivered to the one or more filaments is related to the characteristics of the resulting pathway based on the transepidermal water loss (TEWL) value of the skin.

[0049] In some embodiments, the energy delivered to one or more filaments to create a path can be 0.0067 µJ / µm 3 Up to 0.0400 µJ / µm 3 The energy delivered to the one or more filaments can be delivered in pulses of 2 milliseconds (ms) to 12 ms for delivering sufficient energy to produce a consistent path.

[0050] The characteristics of the path for effectively and safely delivering drugs through the skin (e.g., from a transdermal patch) can vary between in vitro and in vivo embodiments. For example, in some embodiments, one or more filaments generate a path when an energy of 2 mJ / filament to 12 mJ / filament is applied to one or more filaments in a pulse of 2 ms to 16 ms. In some embodiments, the energy applied to one or more filaments to generate the path is 2 mJ / filament to 8 mJ / filament or 3 mJ / filament to 6 mJ / filament, and the duration of the pulse is 2 to 12 ms. In such embodiments, the one or more filaments can comprise stainless steel or be substantially formed of stainless steel, and for 2 mJ / filament to 12 mJ / filament, the volume (V) is 300,000 μm 3 (0.0067 µJ / µm 3 Up to 0.0400 mJ / µm 3 ). In some embodiments, one or more filaments arranged in a filament array can produce a 2 20 to 500 pathways of a biofilm (e.g., skin) exposed to one or more filaments. In some embodiments, one or more filaments arranged in a filament array can generate 20 to 500 pathways of biofilm (e.g., skin) exposed to one or more filaments. 2 50 to 400 pathways of skin exposed to one or more filaments.

[0051] In some embodiments, the cumulative (or total) depth of all paths formed by the one or more filaments is about 2500 to 30000 μm per square centimeter of skin exposed to the one or more filaments. In some embodiments, the cumulative or total volume of all paths formed by the one or more filaments is about 0.05 to 0.35 mm per square centimeter of skin. 3 .

[0052] In some embodiments, a transdermal patch, in combination with the pathways created by a microporation device, can have one or more properties that enhance optimal drug release and diffusion of a drug formulation into the body. For example, a transdermal patch can include one or more of the following properties:

[0053] a polymer matrix comprising at least fibers;

[0054] a polymer matrix comprising nonwoven fibers;

[0055] a polymer matrix of the laminate comprising the film and the fibers;

[0056] A polymer matrix comprising fibers having a thickness of less than 200 μm or 300 μm;

[0057] Contains less than 20 g / m 2 or less than 100 g / m 2of the fiber weight of the polymer matrix;

[0058] ·With a range of about 0.01 to 20 mg / cm 2 weight of the permeate; and / or

[0059] Less than 20 mg / cm 2 The water-retention capacity of the permeate.

[0060] Improvements to microperforation devices and transdermal patches as described herein enable microperforation drug delivery systems to effectively and safely provide the delivery of long-acting drugs in a controlled manner. The embodiments of microperforation drug delivery systems as described herein can provide improved patient compliance and enhanced drug delivery capabilities. The embodiments of microperforation drug delivery systems can also provide the risk of adverse effects caused by uncontrolled delivery for the patient, and reduce the development cycle and the cost of medicine. The embodiments of microperforation drug delivery systems also enable the patient to painlessly cut and needle-free at the position selected by the patient, which results in improved compliance and the cost (less access to health care professionals) of reduction. The embodiments of microperforation drug delivery systems as described herein can be used for patients with skin types, illnesses, etc. of a wide range, and are less different to individual drug delivery results. The embodiments of microperforation drug delivery systems can be applicable to a variety of pharmaceutical preparations, such as high-efficacy drugs, high molecular weight drugs, and biological preparations, etc. The embodiments of microperforation drug delivery systems also enable to deliver drugs with higher utilization (compared with current transdermal patches) in an effective and controlled manner, thereby improving the bioavailability of drugs in patients.

[0061] Figure 1 is a functional block diagram of a control unit 110 of a microporous drug delivery system (e.g., the microporous drug delivery system 10 of U.S. Patent No. 8,116,860). The control unit 110 is an example of a hardware device or circuit that can implement the various methods described herein and provide control and power to one or more filaments of a microporous drug delivery system (e.g., the filament array 70 of U.S. Patent No. 8,116,860). In some embodiments, the control unit 110 does not include Figure 1 In some embodiments, the control unit 110 includes Figure 1 Additional components not shown.

[0062] The control unit 110 includes a processor 112 that controls the operation of the control unit 110. The processor 112 may also be referred to as a central processing unit (CPU) or a hardware processor. The control unit also includes a memory unit 114, which may include read-only memory (ROM) and random access memory (RAM), and may provide instructions and / or data to the processor 112 and may serve as a repository for storing instructions and / or data from the processor 112. A portion of the memory unit 114 may also include non-volatile random access memory (NVRAM). The processor 112 typically performs logical and arithmetic operations based on program instructions stored in the memory unit 114 or received instructions and / or data. The instructions in the memory unit 114 may be executable to implement the methods described herein. In addition, the control unit 110 may utilize the memory unit 114 to store information about other components in the microporous drug delivery system to enable the use of certain methods described below, for example, to store specific set points and / or operating characteristics of components in the microporous drug delivery system. The control unit 110 may then utilize the processor 112 associated with the memory unit 114 to analyze the stored data and determine and / or identify various settings, categories, characteristics, etc. of one or more other components in the microporation drug delivery system.

[0063] Processor 112 may include or be a component of a processing system implemented by one or more processors. The one or more processors may be implemented using any combination of general-purpose microprocessors, microcontrollers, digital signal processors (DSPs), field programmable gate arrays (FPGAs), programmable logic devices (PLDs), controllers, state machines, gated logic, discrete hardware components, dedicated hardware finite state machines, or any other suitable entities that can perform computations or other manipulations of information.

[0064] The processing system may also include a non-transitory machine-readable medium for storing software. Software should be broadly interpreted to mean any type of instructions, whether referred to as software, firmware, middleware, microcode, hardware description language, or other. Instructions may include code (e.g., in source code format, binary code format, executable code format, or any other suitable code format). The instructions, when executed by one or more processors, cause the processing system to perform the various functions described herein. Processor 112 may also include a data packet generator to generate data packets for control operations and data communications.

[0065] The control unit 110 may include networking components, such as a transmitter 116 and a receiver 118 that allow data to be sent and received between the control unit 110 and a remote location or device. The transmitter 116 and the receiver 118 may be combined into a transceiver or network interface 120. The network interface 120 (and / or the transmitter 116 and the receiver 118) may communicate via a communication link 122, which may include a wireless or wired communication link. In some embodiments, the communication link 122 may include a link to a mobile device or other user device for monitoring and / or tracking the use of the control unit 110 and / or the microporation drug delivery system. The network interface 120 works in conjunction with the processor 112 to communicate via the communication link 122.

[0066] The control unit 110 is covered by a housing unit or casing 124. The housing unit 124 may protect the control unit 110 and / or components of the micro-poration device from the environment and provide a package that is safe to operate and simple and convenient for the user.

[0067] The control unit 110 also includes one or more energy storage devices 126. The energy storage devices 126 may include one or more batteries, capacitors, or similar energy storage components. When the control unit 110 is in operation (e.g., operating in a microporous drug delivery system), the energy storage devices 126 provide energy to the components of the control unit 110.

[0068] In some embodiments, control unit 110 includes one or more circuits or sensors 128 configured to monitor the operation or condition of one or more components of control unit 110. For example, sensor 128 can detect the charge state and / or health state of energy storage device 126. Additionally and / or alternatively, sensor 128 can detect conditions of one or more components of control unit 110 that indicate a fault in control unit 110. For example, sensor 128 can detect when one or more filaments are "blown," or in an open circuit state, or are degrading and approaching an open circuit state. Alternatively or additionally, sensor 128 can detect when too much or too little voltage or current is delivered to a filament and / or when the temperature of a filament is above, below, or at a desired threshold. In some embodiments, sensor 128 can be configured to monitor the operation of processor 112. If sensor 128 detects an overvoltage or overtemperature condition or determines that processor 112 is unresponsive, sensor 128 can generate an output. In some embodiments, the output from sensor 128 can be communicated via transmitter 116 or network interface 120 over communication link 122. In some embodiments, output from the sensor 128 may be communicated internally to other components of the control unit 110 , such as the processor 112 or the user interface 132 , as will be described further below.

[0069] In some embodiments, when the control unit 110 is initialized and / or when the microporation drug delivery system is started, the sensor 128 performs an initial check to ensure that all connections are correct and that all components of the microporation drug delivery system are in normal working condition. Thus, the control unit 110 can perform an initial check of the microporation drug delivery system to determine if there are any faults. If no fault is detected in or by the control unit 110, the control unit 110 begins to supply current to the filament. If a fault is detected, the control unit 110 can be prevented from supplying current to the filament. Thus, the sensor 128 can function as or act as a safety circuit and prevent the microporation drug delivery system from operating in a faulty state.

[0070] In some embodiments, the sensor 128 and / or the processor 112 can monitor the temperature of the conductive member. The processor 112 can also control the temperature of the conductive member to prevent filament failure, wherein filament failure causes one or more filaments to melt or fail into an open circuit state. In some embodiments, the temperature is determined based on the sensor 128 identifying the resistance of the conductive member, and wherein controlling the temperature to prevent filament failure includes controlling the temperature to prevent filament failure when the conductive member is in contact with at least one of the skin surface and air.

[0071] The control unit 110 also includes a current generator 130. The current generator 130 generates a current signal that is communicated via the filaments, as described herein. In some embodiments, the current signal includes one or more pulses. In some embodiments, the pulses are modified to have one or more durations, amplitudes, etc. to control the temperature of the filaments and create holes in the skin. In some embodiments, the current signal can be a periodic pulse or a constant amplitude and frequency signal. For example, the current generator 130 can generate current signals with different properties during different time periods, which are transmitted to the filament array via the control unit 110. During a first time period, or for a first duration, a current signal with a first set of properties can be generated, for example, as a single pulse or with a constant amplitude. During a subsequent second time period, a current signal with a second set of properties can be generated, for example, with a specific periodicity and a specific amplitude.

[0072] In some embodiments, processor 112 enables or disables generation and delivery of a current signal to the filament based on conditions detected using sensor 128 or commands from processor 112. In some embodiments, disabling generation and delivery of a current signal includes terminating the current signal or reducing the current signal.

[0073] In some aspects, the control unit 110 further includes a user interface 132. The user interface 132 may include a keyboard and / or a display. The user interface 132 allows a user to control the operation of the control unit 110 and / or the microporation drug delivery system. The user interface 132 may include any element or component that conveys information to a user of the control unit 110 and / or receives input from the user.

[0074] The control unit 110 also includes an input / output (I / O) circuit assembly 134. In some embodiments, the I / O circuit 134 can include components that allow the control unit 110 to be coupled to one or more other components (e.g., filaments) in the microporation drug delivery system. In some embodiments, the I / O circuit 134 includes a connector (e.g., a universal serial bus (USB) connector, a proprietary connector, or any other connector) that physically connects the control unit 110 to the other components. In some embodiments, the I / O circuit 134 includes components that detect improper connections between the control unit 110 and / or other components.

[0075] The various components of the control unit 110 can be connected together via a bus system 136. The bus system 136 may include, for example, a data bus and, in addition to the data bus, a power bus, a control signal bus, and a status signal bus. Those skilled in the art will appreciate that the various components of the control unit 110 may be connected together or receive or provide input to each other using some other mechanism.

[0076] Despite Figure 1 Although multiple individual components are shown, those skilled in the art will appreciate that one or more of these components can implement not only the aforementioned functions, but also the functions of the other components described above. For example, the processor 112 can be used to implement not only the functions of the processor 112 described above, but also the functions of the current generator 130 and / or the sensor 128 described above. Figure 1 Each component shown in the figure may be implemented using multiple individual elements.

[0077] In some embodiments, one or more components of the control unit 110 can provide for locking the control unit 110 so that the microporous drug delivery system is not misused or used incorrectly. Additionally or alternatively, one or more components of the control unit 110 can count the uses or doses provided by the microporous drug delivery system and / or provide reminders about upcoming doses. In some embodiments, the network interface 120 can be used to communicate with a doctor or pharmacy to refill the prepared drug or change the dose as needed, etc. In some embodiments, the user interface 132 can provide for personalization of the microporous drug delivery system and provide voice prompts, guidance lights, etc. to simplify the operation of the microporous drug delivery system.

[0078] In the microporation drug delivery system, the current signal generated by the current generator 130 of the control unit 110 and applied to the filament array causes the filament array to heat up and serve as an energy / heat delivery medium. The filament array provides a sufficient amount of energy / heat to the skin to ablate at least the surface of the skin (i.e., the stratum corneum). In some embodiments, the amount of energy / heat delivered to the skin by the filament array is varied by varying the current delivered to the filament array or by varying the amount of time the filament array delivers energy to the skin. For example, the current generator 130 can vary the amount of time the filament array delivers energy to the skin. In some embodiments, the amount of time can be varied by varying the amount of time the filament array is in contact with the skin and / or by varying the pulse length of the current delivered to the filament array. For example, the current generator 130 can vary the pulse length of the current signal. To perform skin ablation, the current applied to the filament array can cause the temperature of the filament array to be above the melting point of the stratum corneum and epidermis, but below the melting point of the filament array. In various embodiments, a target temperature can be provided for the filament array. In some embodiments, the target temperature for ablation by the filament array can be approximately 123° C. In other embodiments, the target temperature for ablation by the filament array can be, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 degrees of 123° C. In some embodiments, the target temperature for ablation by the filament array can be greater than 123° C.

[0079] Figure 2A It is a perspective view of the filament 200 of the filament array of microperforated drug delivery system. As shown, filament 200 has a three-dimensional shape, with height 202, length 204 and width 206. Filament 200 is formed by conductive material (for example, stainless steel, aluminum, ferrite, or other metals or similar materials with resistance but not insulation) or comprises conductive material (for example, stainless steel, aluminum, ferrite, or other metals or similar materials with resistance but not insulation). In some embodiments, filament 200 can be a microfilament or similar filament. For example, filament 200 can be 50 μm wide, 15 μm thick and 400 μm long. Although shown in the filament 200 has the shape of a roughly rectangular block or prism, filament 200 can have any other shape, for example trapezoidal shape.

[0080] Various factors affect the balance of energy delivered to the filaments 200 and transported to the skin to create a path. For example, the filaments 200 of the filament array can create a path in the skin by transferring enough energy from the filaments 200 to the skin to ablate the stratum corneum to expose the epidermis. The amount of energy transferred from the filaments 200 to the skin can be based on the temperature difference between the skin and the filaments 200, the material of the filaments 200, the properties of the skin (e.g., skin type, morphology, elasticity, hydration, and thermodynamic parameters of the skin layer), and the contact / pressure between the filaments 200 and the skin. In some embodiments, a vacuum can be used to increase the contact between the filaments 200 and the skin. For example, the filament array can include a hole or other structure, and when connected to a vacuum cleaner, the hole or other structure causes the skin to be "sucked toward" the hole or structure, increasing the contact between the filaments 200 and the skin. The amount of energy transferred can also be based on the electrical signal (e.g., one or two of current, voltage, waveform, etc.) transmitted by the filaments 200. The distance between the filaments of the filament array can also affect the amount of energy transferred. The identified electrical parameters or factors can contribute to the supply of energy / heat, while the mechanical parameters can define the drop of energy / heat. The resistance of the filament 200 can depend at least in part on the material used in the filament 200 and the shape of the filament, and affect the energy supplied by the filament 200.

[0081] In some embodiments, the control unit 110, eg, via the sensor 128 and / or the processor 112, can determine whether the pressure applied by the conductive member (eg, the array of filaments) to the skin surface is greater than or equal to a first pressure threshold.

[0082] Figure 2B yes Figure 2A 2 is a perspective view of a filament 200 showing a cross-sectional area 208 and a current flow direction 210. As shown, the cross-sectional area 208 is trapezoidal, and the current flows through the filament 200 in the current flow direction 210. However, the cross-sectional area 208 can be any shape (e.g., square, rectangular, circular, oval, triangular, other polygonal, etc.), and the current flow can be in a direction substantially perpendicular to the cross-sectional area 208 of the filament 200. Based on the current flowing through the filament 200 and the cross-sectional area 208, the current density / flux can be determined according to the following equation 1:

[0083] Current density = I / A

[0084] (Equation 1)

[0085] in:

[0086] I – the current flowing through the filament 200, and

[0087] A – cross-sectional area of ​​the filament 200 .

[0088] As the cross-sectional area of ​​filament 200 increases, the corresponding current must be increased to maintain current density based on Equation 1. As the length of filament 200 increases, the resistance of filament 200 may increase, such that for an increased mass of filament 200, voltage and power increase.

[0089] The current density of the filament 200 can be used to identify the operational range of the filament array to produce viable holes without causing pain or damaging the filament array, as will be described in further detail below. The depth of the hole produced in the skin is proportional to the energy delivered to the skin via the filament 200.

[0090] In some embodiments, the control unit 110 (eg, via the processor 112) determines a supply ratio of the current signal to the cross-sectional area of ​​the filament 200. The control unit 110 further controls the supply ratio to be between a first threshold and a second threshold, the second threshold being greater than the first threshold.

[0091] Figure 3A A top view of a representative filament array of a microporous drug delivery system, comprising multiple Figure 2A and Figure 2B The filament array includes a plurality of filaments 200 disposed between conductive support members or structures. Figure 3A Not shown, but the conductive support member can be coupled to a power source.

[0092] In some embodiments, the conductive support member is made of copper or a similar conductive material. In some embodiments, the conductive support member is a different material than the filament 200. Figure 3B As shown in FIG, the conductive support member 300a includes fingers or similar protrusions 301, and the filaments 200a to 200k are arranged between the fingers or similar protrusions 301, where l<k. Although not shown, the corresponding conductive support member may have fingers 301 that are interleaved with the fingers 301 of the conductive support member 300a.

[0093] The conductive support member provides structural support for the filament 200 by holding the filament 200 in place between the fingers of the conductive support member. Additionally and / or alternatively, the conductive support member conductively couples the filament 200 to a power source.

[0094] In some embodiments, using one or more components of the microporous drug delivery system to control or vary the amount of time that the filament 200 delivers energy to the skin can be simpler and more efficient than controlling the current delivered by the filament 200. For example, such control of the amount of time can utilize fewer components than a system that controls or varies the current delivered to the filament 200. However, when controlling or varying the amount of time that the filament 200 delivers energy to the skin, the control unit 110 can prevent a slow increase in skin temperature, which can "bake" and / or damage or dry out the top layer of the skin (e.g., the stratum corneum and / or epidermis). This baking and / or drying of the top layer of skin can produce a charred / dried layer of dead skin tissue. This layer of dead tissue can hinder the distribution of heat from the filament 200 into the deeper layers of the skin (e.g., the epidermis) and prevent the creation of viable pores for delivering the formulated active drug. In addition, the baking and / or drying of the top layer of skin (i.e., exposure of the skin to heat) can trigger a neural response in the skin that causes or is interpreted as pain. Therefore, the duration of the heat pulse or the duration that the filaments 200 are in contact with the skin is less than the time that would bake or dry the top layer of the skin.

[0095] Additionally, increasing the current passing through the filament allows the filament to reach the target temperature in a shorter period of time (i.e., heat very quickly) compared to a relatively lower current passing through the filament. Furthermore, the increased current shortens the time required to produce the desired pore size, thereby reducing or eliminating the risk of a nerve reaction to the heat and reducing or eliminating pain associated with ablation.

[0096] When current generator 130 and control unit 110 provide high current to the filament array, individual filaments 200 in the filament structure experience a rapid increase in temperature. This increase in temperature of filaments 200 (and, consequently, the filament array) can shorten the time required to achieve a target pore size. Consequently, the risk of neural reactions to heat due to baking and / or drying is reduced or eliminated, and pain associated with ablation can be reduced or eliminated.

[0097] As described above, the filaments 200 in the filament array will be electrically connected to a power source (e.g., Figure 1 The energy / heat of the control unit 110 of the current generator 130 is transferred to the skin. Each filament 200 has one or more properties that may affect the energy / heat transfer to the skin. For example, the filament 200 has a resistance that depends on the material used for the filament and the mechanical shape of the filament. The amount of energy supplied to and by the filament is based on the current applied to the filament 200 (i.e., based on the current generated by the current generator 130), the resistance of the filament 200, and the size of the filament. The energy supplied to the filament can be calculated using the following equations 2 and 3:

[0098] E=P t=I U t=I 2 R f t=U 2 / R f t

[0099] (Equation 2)

[0100] R f = l / (w h)

[0101] (Equation 3)

[0102] in:

[0103] E – Energy,

[0104] P – power,

[0105] t – time,

[0106] I – current flowing through the filament 200,

[0107] U – voltage at the end of the filament 200 ,

[0108] ·R f – the resistance of the filament 200,

[0109] · – the specific material resistivity of the filament 200,

[0110] l – length of the filament 200,

[0111] w – the width of the filament 200, and

[0112] h – height (thickness) of the filament 200 .

[0113] The amount of energy supplied to and by the filament array is based on the current applied to the filament array (i.e., based on the current generated by the current generator 130) and the total resistance of the filament array. The total resistance of the filament array is determined by averaging the filaments 200 of the filament array. The energy supplied to and by the filament array can be calculated using the following equations 4 and 5:

[0114] E=P t=I U t=I 2 R a t=U 2 / R a t

[0115] (Equation 4)

[0116] R a = R f / N fb N b

[0117] (Equation 5)

[0118] in:

[0119] E – Energy,

[0120] P – power,

[0121] t – time,

[0122] I – the current flowing through the filament array,

[0123] U – the voltage across the filament array contacts, and

[0124] ·R a – Average resistance of the filament array (depends on row and array configuration).

[0125] Figure 3B is experiencing one or more filament failures 302 and 304 Figure 3A 1. A top view of a filament array of FIG. 1. A filament failure occurs when one or more of the filaments 200 of the filament array are damaged and / or destroyed, such that the damaged or destroyed filament 200 is unable to conduct the current generated by the current generator 130 to the skin. For example, if one of the filaments 200 is cut, broken, or fused, such that the filament 200 is not connected to two fingers 301 of the conductive support member, the filament 200 is broken, burned, or otherwise failed. Thus, when in a failed state, the filament 200 effectively serves as an open circuit between the fingers 301 of the conductive support member. Filament failures 302 and 304 correspond to individual failed filaments 200 that no longer provide a conductive path between the individual fingers 301 of the conductive support member to which the failed filament 200 is connected.

[0126] In some embodiments, the failure of a filament 200 in the filament row between two fingers 301 may cause cascading filament failures. For example, when the first filament 200a in filament row 1 fails, the remaining filaments 200 in filament row 1 experience an increase in power flow due to the loss of the path through the failed filament 200a. This increased power flow through the remaining filaments 200 in filament row 1 also increases the risk of one or more failures in the remaining filaments 200. Although the failure of only filament 200a may not cause a cascade (avalanche) effect in the remaining filaments 200 of filament row 1, if a sufficient number of filaments 200 fail in row 1 (for example, approximately 5% of the filaments 200 in row 1), cascading filament failures may occur. Therefore, ultimately, all filaments 200 in row 1 will fail, causing complete cascading failure or open circuit failure. The amount of time that elapses between initial filament failure and the occurrence of a complete cascading failure depends on the amount of current / energy that can be supplied to the filament 200 without being dissipated in one of three ways as described below.

[0127] In some embodiments, the filaments 200 are cooled, thereby dissipating the energy supplied to the filaments 200. Three ways in which this dissipation occurs include: (1) radiating heat into the air, (2) conducting heat into the filament array (e.g., a copper structure), and (3) conducting heat into the skin. Radiating heat from the filaments 200 into the air is a relatively small amount of heat loss compared to conducting heat into the filament array or the skin. Therefore, radiative heat loss can generally be ignored.

[0128] Since the conductive support structure is essentially a metal that generally conducts heat, the amount of heat conducted (back) into the conductive support structure (e.g., made of copper) is relatively large. The amount of heat lost due to conduction into the conductive support structure can be quantified using the physical laws of heat and known material properties and will not be described in detail herein.

[0129] As described above, heat transfer to the skin depends on various properties of the skin, including skin type, morphology, elasticity, hydration, and thermodynamic parameters of the skin layers, as well as at least one or more of the contact / pressure between the filament array and the skin. The relevant properties of the skin can change during perforation because different skin layers have different properties that affect heat transfer. For example, when ablating the dry stratum corneum (which has a layered structure with varying consistency and thickness between different entities of the skin) with the filament array, the epidermis is exposed, which is generally more hydrated and has different properties than the dry stratum corneum.

[0130] As previously described, the resistance of the filament 200 (and thus the temperature) is proportional to the size and / or shape of the filament 200 and the energy delivered to the filament 200 (i.e., the current generated by the current generator 130). To accommodate a variety of sizes, shapes, and energies, the relationship can be normalized using the current density defined by Equation 1 above. Based on the current density defined by Equation 1, the operational constraints that cause the filament 200 to fail, and the operational constraints that cause stratum corneum ablation, a desired current density range is defined. The defined current density range identifies those current densities that, if delivered to the filament 200, produce viable holes without causing pain or damaging the filament array.

[0131] The total energy provided to the filament 200 during a certain time period is defined by Equation 6:

[0132] E = E WU + E M

[0133] (Equation 6)

[0134] in:

[0135] ·E WU is energy delivered as a temperature ramp pulse (e.g., a pulse that brings the temperature of the filament 200 to a desired or operating temperature having desired or operating dynamics);

[0136] ·E M It is energy delivered in a sustaining pulse (eg, a pulse that maintains the filament 200 at a substantially constant temperature level (eg, a desired or operating temperature)) to balance any heat losses experienced by the filament 200.

[0137] E WU can be proportional to:

[0138] · - the specific electrical resistance (temperature dependence) of the material of the filament 200 ;

[0139] T - the operating or desired temperature that the filament 200 should reach during operation;

[0140] ·i Q – Current flux / density (mA / µm 2 ) – Find the square value (E=I 2 R t);

[0141] l – length of the filament 200;

[0142] m or V – the mass or volume of the filament 200 to be heated; and

[0143] t – a time value or period (e.g., WU pulse duration).

[0144] E M The sum of heat losses defined by Equation 7 can be included:

[0145] E M = E S + E CT + E R + E CV

[0146] (Equation 7)

[0147] in:

[0148] ·E S is the energy (e.g., heat) lost (conducted) into the skin (substrate);

[0149] ·E CT is the energy lost to the traces (conductive structures) of the filament array;

[0150] ·E R is the energy lost or radiated;

[0151] ·E CV is the energy lost through convection.

[0152] Because E R and E CV The value is negligible or usually zero, so E M Usually only E needs to be compensated CT and E S Losses, which may be due to the resistance of the filament 200 and / or the energy delivered to the skin to create the path (e.g., distributed between the traces of the filament 200 and losses to evaporate water (living tissue) of the skin). S can be proportional to:

[0153] ΔT – the temperature difference between the filament 200 and the skin (substrate);

[0154] h – heat transfer coefficient between the filament 200 and the skin;

[0155] ·A S - the surface area of ​​contact between the filament 200 and the skin; and

[0156] t – corresponds to the time for which the sustain pulse is “on” or activated.

[0157] Therefore, due to E MThe temperature of the filament 200 is maintained at a substantially constant level, so the energy delivered to the filament 200 during the maintenance period is directly proportional to the amount of water evaporated from the skin. Therefore, E can be determined based on Equation 8 M , this equation governs water evaporation from the skin:

[0158] E M = i 2 R T t = (h A S T t) + E CT

[0159] (Equation 8)

[0160] in:

[0161] i is the current of each filament 200; and

[0162] ·R T is the resistance of the filament 200 at the equilibrium temperature.

[0163] Due to E M and E CT are all time dependent, so Equation 8 can be simplified and expressed as the power delivered to the filament 200 as shown in Equations 9 to 11:

[0164] E M = i 2 R T = (h A S T) + P CT

[0165] (Equation 9)

[0166] E M = (i Q A) 2 ( l / A) = (h A S T) + P CT

[0167] (Equation 10)

[0168] E M = i Q 2 A l = (h A S T) + P CT

[0169] (Equation 11)

[0170] in:

[0171] · is the specific resistance of the filament 200 at the operating temperature;

[0172] A is the average cross-sectional area of ​​the filaments 200; and

[0173] • h is the heat transfer constant between two materials (eg, filament 200 and skin).

[0174] The combination of variables (h A S ΔT) corresponds to the energy delivered to the filament 200 to evaporate water from the skin. T can be relatively constant, and the cross-sectional area (A S ) can highly determine the amount of water evaporated from the skin and / or the volume of the path generated. In addition, as the volume of the filament 200 increases, the energy delivered through the filament 200 and transmitted to the skin increases. However, in some embodiments, the volume of the filament 200 can be increased by increasing the length of the filament 200 rather than the cross-section to remain within the range of functional current density achievable via the microporous drug delivery system. In addition, an increase in the cross-section of the filament 200 may increase the P CT In some embodiments, a more complex and larger cross-sectional area of ​​the filaments 200 can increase energy transfer to the skin while reducing or maintaining small energy losses. For example, using Figure 3A and Figure 3B The filament is 200, A = w d (width times thickness), A S =w l (contacts the skin only at the bottom surface of the filament 200), and P CT is proportional to A. Therefore, Equation 11 simplifies to the following Equation 12:

[0175] E M = i Q 2 w d l = (h w l ) + (constant w d )

[0176] (Equation 12)

[0177] In some embodiments, heat transfer from the filament 200 to the skin is independent of the thickness of the filament 200, and the energy delivered to the skin (and the volume of the resulting path) will increase with the length of the filament 200. For example, based on the current density i Q = 2.67 mA / μm2, where 400 filaments 200 have a length of 400 microns, a width of 50 microns, and a thickness of 15 microns, using approximately 3 mJ per filament 200 to create a minimum viable path. In some embodiments, a viable path is formed using filaments 200 with an applied energy of 2 mJ / filament to 12 mJ / filament, 2 mJ / filament to 8 mJ / filament, or 3 mJ / filament to 6 mJ / filament (as demonstrated in TEWL studies). Such filaments 200 can be formed of stainless steel and have a thickness of 30,000 μm. 3 , yielding 0.0067 µJ / µm for 2 mJ / filament to 12 mJ / filament 3 Up to 0.0400 mJ / µm 3 In some embodiments, the relationship between the energy applied to the filament 200 and the TEWL is linear. In addition, comparing filaments 200 of different sizes with the same volume of filament 200 shows that the drug delivery of the filament 200 remains the same when the volume of the filament 200 is the same. Based on the analysis herein, the ideal energy for heating the filament 200 in the microporation device to create the path can be 0.0067 µJ / µm 3 Up to 0.0400 µJ / µm 3 , where V is the volume of the filament 200.

[0178] For example, the filament array includes 200 filaments, the filament length is 500 micrometers (μm), the filament width is 50 μm, the filament thickness is 15 μm, and i Q The value is 2.67 mA / μm2 , and the time required for the filament array to reach the desired temperature or operating temperature is about 700 to 800 ms, and about 2 mJ of energy is used per filament 200 to reach the desired temperature or operating temperature.

[0179] Alternatively or additionally, when the filament array comprises 400 filaments, the filament length is 400 micrometers (μm), the filament width is 50 μm, the filament thickness is 15 μm, and i Q The value is 2.67 mA / μm 2 When the filament array is heated to a desired temperature or operating temperature, the time taken is about 700 to 800 ms, and each filament 200 can use about 1.5 mJ of energy to reach the desired temperature or operating temperature.

[0180] Figure 4 4 is a graph showing a pulse distribution, which shows the relationship between TEWL and the energy delivered to the filament array of the microporous drug delivery system via the pulse; and a graph 450 showing the relationship between the energy delivered and the TEWL of a high power applicator (HPA) that produces about 400 paths. In various embodiments, the HPA can produce more paths, and it can depend at least in part on the size of the filaments. For example, under certain parameters, it can produce up to about 1,600 paths. Using prior art manufacturing techniques, it can be about 2,000 paths. If the design and / or geometry of the filaments (and / or materials) are changed, the number of paths can be higher.

[0181] Graph 400 shows that, in an average filament 200 with a volume of 300,000 µm 3 In the case of a filament 200 formed of stainless steel having a width of 50 μm, a length of 400 μm, and a depth of 15 μm, about 400 paths are formed in the skin in 10% of the skin area exposed to the filament 200. The graph 400 shows that for different levels of pulse intervals (normal pulse interval, shorter pulse interval, no pulse interval), different energies result in different TEWLs. For example, for a normal pulse interval of about 6 mJ / filament, the TEWL is about 75 g / m 2 For a shorter pulse interval of about 7 mJ / filament, the TEWL is about 75 g / m 2 hr, and for a pulse-free interval of about 6 mJ / filament, the TEWL is about 73 g / m 2 hr.

[0182] Graph 450 shows the general relationship between TEWL and the energy applied to filament 200. As described above, the energy range applied to the filament is 2 mJ / filament to 12 mJ / filament. Line 452 shows that as energy / filament increases (for energy levels exceeding 2 mJ / filament), the resulting TEWL increases, although increasing at a smaller or decreasing rate. For example, the ΔTEWL of 2 mJ / filament to 3 mJ / filament is greater than the ΔTEWL of 5 mJ / filament to 6 mJ / filament. Therefore, graph 450 shows that as energy / filament increases, TEWL appears to be generally saturated, so that energy greater than 12 mJ / filament can provide minimal TEWL increase. In addition, higher energy / filament may not be needed to avoid pain and / or discomfort in patients. Therefore, graphs 400 and 450 represent that the energy applied to the filament can be maintained at 3 mJ / filament to 10 mJ / filament to maximize TEWL while maintaining patient comfort without wasting energy.

[0183] Figure 5 5 is a graph 500 showing pulse TEWL as a function of pulse length for a given energy / filament. Graph 500 includes pulse length (time) along the x-axis and TEWL along the y-axis. Each point or marker shows which pulse length results in which TEWL.

[0184] Graph 500 shows that, in an average filament 200 with a volume of 300,000 µm 3 In the case of a filament 200 formed of stainless steel with a width of 50 μm, a length of 400 μm, and a depth of 15 μm, approximately 400 paths were formed in 10% of the skin area exposed to the filament 200 when an energy of approximately 5 mJ / filament was applied. Graph 500 shows that different levels of TEWL were achieved for different pulse lengths ranging from approximately 3 ms to 18 ms. Graph 500 also shows that TEWL did not begin to significantly decay until the pulse length exceeded 12 ms, thus, energy delivery was inefficient for long pulses. Therefore, as described above, the pulse length of the microporation device can be maintained at less than 12 ms.

[0185] Figure 66 is a graph showing TEWL as a function of total path depth, a graph showing TEWL as a function of total path area, and a graph showing TEWL as a function of total path volume. The data for graph 600 were measured using an artificial membrane (polyurethane). The figure shows the relationship between TEWL (in vivo hairless guinea pig model) and the measured total PU area (top), the measured total PU depth (middle), and the measured total PU depth (bottom). Graph 600 shows TEWL along the y-axis and the total path depth of polyurethane in µm along the x-axis (e.g., the sum of the depths of all paths created by the microporation device). Graph 640 shows TEWL along the y-axis and the total path depth of polyurethane in mm along the x-axis. 2 The total path area in the polyurethane measured in mm is plotted against the TEWL along the y-axis (e.g., the sum of the areas of all paths created by the microperforation device). 3 The total path volume in the polyurethane calculated (e.g., the sum of the volumes of all paths created by the microperforation device).

[0186] Graphs 600, 640, and 680 show that, when the average filament 200 volume is 300,000 µm 3 In the case of a filament 200 formed of stainless steel having a width of 50 μm, a length of 400 μm, and a depth of 15 μm, when an energy of approximately 5 mJ / filament is applied, approximately 100 to 400 paths are formed in approximately 2.5% to 10% of the skin area exposed to the filament 200. Coordinate graph 600 shows that different levels of TEWL are obtained for different path depths. Coordinate graph 600 shows that TEWL increases with increasing depth. Coordinate graph 640 shows that different levels of TEWL are obtained for different path areas. Coordinate graph 640 shows that TEWL increases with increasing total area. Coordinate graph 680 shows that different levels of TEWL are obtained for different path volumes. Coordinate graph 680 shows that TEWL increases with increasing total volume.

[0187] Therefore, TEWL is related to total path depth, total path area, and total path volume. Total path volume may be most correlated with TEWL. An optimal total path volume may be approximately 0.05 to 0.35 mm per square centimeter of skin opposite the filament 200. 3 In some embodiments, the total path depth can be about 2500 to 30000 μm.

[0188] Figure 7A top perspective view 700 of a transdermal patch 102 is shown. The patch 102 can include multiple layers, such as a backing material layer 702, a retention material layer 704, and an exudate layer 706. The backing material layer 702 can form a "pocket" in which the retention material layer 704 and the exudate layer 706 are located, while the backing material layer 702 adheres or couples the patch 102 to the skin.

[0189] The patch 102 can provide controlled drug release and diffusion for delivering macromolecules into a patient's body. The polymer matrix can be optimized to achieve effective and controlled release and delivery of the drug. Such optimization can include creating a polymer matrix that includes or contains fibers. In some embodiments, the fibers can be non-woven. Additionally, the optimized polymer matrix can include a matrix formed from a laminate of a film and fibers. In some embodiments, the fibers in the polymer matrix have a thickness of less than 300 μm or a thickness of less than 200 μm. In some embodiments, the fibers in the polymer matrix have a density of less than 100 g / m 2 Fiber or less than 20 g / m 2 In some embodiments, the permeate in the polymer matrix is ​​about 0.01 to 20 milligrams (mg) per square centimeter of skin (mg / cm 2 ), wherein the patch is exposed to the skin. In addition, the polymer matrix may have a polymer matrix that has a water retention capacity of less than 10 mg / cm2 of skin.

[0190] The patch 102 provides immediate release of small molecule drugs to large molecule drugs through at least one path formed by the microporation device. The patch 102 releases a predetermined amount of drug from the exudate layer 706. In some embodiments, the relative predetermined amount of exudate entering the exudate layer 706 accounts for about 0 mg / cm 2 Up to 85 mg / cm 2 In some embodiments, the predetermined amount of exudate released accounts for about 9.5 mg / cm 2 Up to 85 mg / cm 2 When the exudate is delivered into the body via the pathway formed by the microporation device, the exudate dissolves the permeant and immediately releases the drug into the body, for example, into the bloodstream.

[0191] The exudate layer 706 may contain a predetermined amount of an exudate-soluble component (eg, about 0.1 to 20 mg / cm 2 The amount of exudate delivered by the patch 102 can be adjusted using a predetermined amount of exudate-soluble components.

[0192] The retention material layer 704 may include a retention material having an optimal water retention capacity ("WHC"). In some embodiments, the optimal WHC is selected to maximize permeate delivery from the patch 102. In some embodiments, the optimal WHC is less than 10 mg / cm 2 The weight of the retention material in the retention material layer 704 may be less than 100 g / m 2 , less than 30 g / m 2 , or less than 20 g / m 2 The thickness of the retention material layer 704 may be less than 100 μm or less than 60 μm.

[0193] In some embodiments, when used in conjunction with a microporation device, various factors or aspects of the patch 102 can be optimized and / or controlled to maintain controlled, effective, and efficient drug delivery to the body through the skin. For example, as described above, the exudate layer 706 can accommodate approximately 10 to 85 mg / cm 2 In some embodiments, the total amount of exudate soluble components loaded on patch 102 is about 0.1 to 20 mg / cm 2 In some embodiments, the retention material in the retention material layer 704 has a density of about 0 to 10 mg / cm 2 WHC and less than 100 g / m 2 or less than 20 g / m 2 In some embodiments, the retaining material has a nonwoven thickness of less than 300 μm or 200 μm. In some embodiments, the backing material of the backing material layer 702 has an adhesive on one side to prevent exudate from leaking from the patch 102.

[0194] Figure 8 is a graph 800 showing sucrose content relative to the amount of exudate extracted from patch 102, and a graph 840 showing the amount of exudate extracted from two sucrose patch formulations compared under different applicator conditions.

[0195] Coordinate diagram 800 shows the amount (mg) of the exudate extracted on the y-axis for multiple patches 102 with different sucrose levels shown along the x-axis. Each patch 102 shown in the coordinate diagram 800 has different amounts of sucrose and is applied to the skin with 200 paths produced via microperforation under 2 ms pulse conditions. The patches 102 are placed 6 hours after application. Coordinate diagram 800 shows the amount of the exudate extracted from each patch 102. Coordinate diagram 800 shows that, generally, as the amount of sucrose on the patch increases (from about 0.1 mg to 25 mg), the amount of the exudate extracted also increases (from about 15 mg to about 70 mg). Therefore, when maintaining microperforation parameters (forming 200 paths in the same way for all patches 102), the concentration of the drug on the patch 102 limits the amount of the exudate extracted from the body.

[0196] Graph 840 illustrates how variations in microperforation can alter the amount of exudate extracted from the body. Graph 840 shows the amount of exudate extracted (mg) on ​​the y-axis. Graph 840 includes paired patch 102 formulations with 0.1 mg and 20 mg of sucrose compared under different applicator conditions, where the applicator conditions correspond to variations in microperforation along the x-axis. For example, the different microperforation variations include: 1) 100 paths formed with a 4 ms energy pulse; 2) 200 paths formed with a 1.5 ms energy pulse; 3) 200 paths formed with a 2 ms energy pulse; 4) 200 paths formed with a 4 ms energy pulse; 5) 400 paths formed with a 2 ms energy pulse; 6) 400 paths formed with a 4 ms energy pulse; and 7) 400 paths formed with an 8 ms energy pulse. As shown in graph 840, for the 0.1 mg sucrose patch 102 formulation, the amount of exudate extracted from the body generally increased with increasing number of pathways or increasing duration of energy pulses. However, graph 840 shows that the amount of exudate extracted from the 20 mg patch 102 varied more significantly with increasing number of pathways or increasing duration of energy pulses.

[0197] Different materials have different water holding capacities and / or abilities. The water holding capacity (WHC) of a substrate is the amount of water per 1 cm 2 The amount of water that the substrate can hold. For example, to prepare a 1 cm 2 The matrix is ​​immersed in a solution (phosphate buffered saline containing 0.1% surfactant (Tween 80)) for a sufficient amount of time. The matrix is ​​then slowly pulled out of the solution for about 5 seconds. The weight of the sample before immersion, which was previously measured, is subtracted from the weight of the sample remaining in the liquid. The mass per unit area (1 cm) can then be determined. 2) of the matrix. In some embodiments, the matrix has a water retention capacity of 10 mg / cm 2 In some embodiments, the matrix has a water retention capacity of 1 mg / cm 2 Up to 10 mg / cm 2 Water retention capacity. In an example, Tween 80 (Spectrum Chemical Mfg. Corp. or Croda) that has been weighed is dissolved in phosphate buffered saline (Sigma-Aldrich) to prepare PBS (hereinafter referred to as test solution) containing 0.1 w / v% Tween 80. The thickness of the matrix material is measured according to a digital indicator (U30A, manufactured by Sony). The matrix materials 1 to 3 shown in Table 1A (all manufactured by Japan Vilene Company, Inc.) are formed into 10 mm × 10 mm squares to prepare samples. The prepared samples are weighed to obtain their dry weights (hereinafter referred to as weight A). Then, the above samples are immersed in the test solution and fully impregnated with the test solution. The sample impregnated with the solution is slowly taken out from the test solution (about 5 seconds / cm) and weighed to obtain their weight after immersion in the test solution (hereinafter referred to as weight B). Note that, when the host material has a film surface, after pulling it out, the test solution adhering to the film surface is wiped off and then weighed to obtain weight B. Note that the thickness of the host material, weight A and weight B are each measured three times, and average value is adopted as final value. The results are shown in Table 1A (below).

[0198] Table 1A

[0199]

[0200] Thus, different materials can be used for the retention material layer 704 of the patch 102. 2 Compared with water-retaining materials, the WHC has less than 10 mg / cm 2 The water-retaining material with a WHC can release the permeate more quickly under controlled optimal exudate extraction. In some embodiments, pharmacokinetic (PK) results of a microporous drug delivery system for delivering small-molecule compounds to macromolecular compounds show that, for the WHC of the water-retaining material, the weight and thickness of the water-retaining material, and the weight of the soluble components of the exudate are parameters that can optimize the PK profile of a specific drug and / or patch 102. By maintaining these parameters within the above ranges, the patch 102 can be used in a microporous drug delivery system to effectively and efficiently release the drug into the body in a controlled manner.

[0201] Figure 9is a graph 900 showing how the weight density of a water retaining material affects the WHC of the water retaining material and a graph 940 showing how the thickness of a water retaining material affects the WHC of the water retaining material.

[0202] Graph 900 shows WHC along the y-axis, which is weight density (g / m2) shown along the x-axis. 2 ). Graph 900 shows that, in general, the WHC of a water-retaining material increases linearly with increasing weight density of the water-retaining material. Graph 900 includes a shaded portion representing water-retaining materials having low WHC and low weight density.

[0203] Graph 940 shows WHC along the y-axis as a function of thickness (μm) shown along the x-axis. Graph 940 shows that, generally, the WHC of a water-retaining material increases linearly with increasing thickness of the water-retaining material. Graph 940 includes shaded portions representing water-retaining materials having low WHC and small thicknesses.

[0204] As mentioned above, the water-retaining material used in patch 102 should have a water-retaining capacity of about 0 to 10 mg / cm 2 WCH, less than 100 g / m 2 or less than 20 g / m 2 The invention relates to a nonwoven fabric having a weight density of less than 100 μm and a nonwoven thickness of less than 300 μm or less than 200 μm to achieve effective, efficient and controlled administration of drugs to the body via a pathway in the skin.

[0205] As mentioned above, the selection of effectiveness and / or microperforation parameters of drug delivery system delivery can depend on the medicine used by patch 102.The various aspects of medicine and / or microperforation drug delivery system can affect the effectiveness of medicine, and wherein effectiveness corresponds to the bioavailability of medicine in vivo.As mentioned above, the combination of microperforation factor or parameter (for example, the energy, filament material, the path quantity produced using microperforation device of filament 200, the skin area of ​​generation path and treatment area (percentage of the path in the skin for treatment of per square centimeter)) can affect the bioavailability of rear medicine after using.In addition, the combination of patch 102 parameters (thickness, matrix parameter, weight, WHC, active pharmaceutical ingredient (" API ") weight in patch 102, patch area) can affect the bioavailability of rear medicine after using.

[0206] Table 1 below provides data on three sets of microporation values ​​used to create pathways in the skin of hairless guinea pigs prior to weekly application of a patch 102 containing a long-acting peptide (e.g., semaglutide). Table 2 below provides data on six drug administration groups: three groups that used the patch 102, one group that administered the long-acting peptide orally, and two groups that administered the long-acting peptide by injection.

[0207] Table 1

[0208]

[0209] Table 2

[0210]

[0211] Groups 1 through 3 in Tables 1 and 2 correspond to combinations of patches 102 and microperforation parameters for a particular application. For example, Group 1 of microperforation parameters in Table 1 is used in conjunction with applying the patch 102 according to the parameters in Group 1 of Table 2. Thus, Group 1 patches 102 have a nonwoven matrix, a water-retaining material thickness of 38 μm, and a 12 g / m 2 The weight of water-retaining material and 4 mg / cm 3 Patches 102 of Group 1 contained 1 mg of drug and 3.25 mg of total solid weight and had an area of ​​0.5 cm 2 The patch 102 was applied to a skin area having 200 paths generated according to the first set of microporation parameters, wherein the energy applied to the microporation device was 5.2 mJ / filament, the filaments 200 were made of stainless steel and had a treatment area of ​​10% per square centimeter of skin, wherein the filaments 200 treated an area of ​​0.5 cm 2 Similarly, the patch 102 parameters for Group 2 apply to the microporation parameters for Group 2, and the patch 102 parameters for Group 3 apply to the microporation parameters for Group 3. Groups 4 and 5 represent injections of 0.5 mg and 1.0 mg of the drug, respectively, and Group 6 represents oral administration of 2.0 mg of the drug.

[0212] Figure 10Graph 1000 in FIG. 1 shows a comparison of the long-acting peptide concentration for each of Groups 1 through 3 of Tables 1 and 2 for microporation parameters and patch 102 parameters. Graph 1000 includes the concentration of the long-acting peptide in nanograms per milliliter (ng / mL) along the y-axis and time in hours (hr) along the x-axis. Graph 1000 shows three lines 1002, 1004, and 1006. Line 1002 represents Group 1 microporation parameters and Group 1 patch 102 parameters. Line 1004 represents Group 2 microporation parameters and Group 2 patch 102 parameters. Line 1006 represents Group 3 microporation parameters and Group 3 patch 102 parameters. Each of the three lines 1002, 1004, and 1006 follows the same general trend. For each of Groups 1 through 3, the concentration of the long-acting peptide generally increases relatively quickly to a maximum concentration, then gradually decreases, ultimately reaching a concentration of zero. The parameters of Group 3, shown by line 1006, have the highest peak concentration level and higher concentration values ​​over the duration of in vivo bioavailability of the long-acting peptide, compared to the parameters of Group 1 and Group 2, represented by lines 1002 and 1004. Although the parameters of Group 2, shown by line 1004, have a higher peak concentration level than the parameters of Group 2, shown by line 1002, for the parameters of Group 1, the concentration level of bioavailability of the long-acting peptide is actually higher after about 70 hours (shown by line 1002, indicating higher concentration values ​​at greater than about 70 hours).

[0213] Figure 10 Graph 1020 in Figure 1 shows a comparison of the in vivo concentration of the long-acting peptide for each of Groups 4 through 6 over time. Graph 1020 includes the concentration of the long-acting peptide in nanograms per milliliter (ng / mL) along the y-axis and time in hours (hr) along the x-axis. Graph 1020 shows three lines 1022, 1024, and 1026. Line 1022 represents the drug injected into Group 4. Line 1024 represents the drug injected into Group 5. Line 1026 represents the drug orally administered into Group 6. Each of lines 1022 and 1024 follows the same general trend, rising to a peak concentration level and then gradually decreasing to approach a concentration level of zero. Line 1026 demonstrates that oral administration of the long-acting peptide does not provide any measurable concentration in vivo. Compared to the parameters for Group 14, shown by line 1022, the parameters for Group 5, shown by line 1024, have higher peak concentration levels over the duration of the long-acting peptide's in vivo bioavailability.

[0214] Graph 1040 is a zoomed-out view of graph 1000, giving a higher level view of the relationship of lines 1002, 1004, and 1006. Similarly, graph 1060 is a zoomed-out view of graph 1020, showing that line 1026 (oral administration of the long-acting peptide) hovers near a concentration of 10 ng / mL rather than 0, as indicated by graph 1020.

[0215] Based on the graphs 1000 , 1020 , 1040 , and 1060 , the area under the curve for each of Groups 1 to 6 is shown in Table 3 below:

[0216]

[0217] Table 3 shows the changes in bioavailability of the long-acting peptide for various administrations. Although the injection administration of Groups 4 and 5 showed the highest percentage of bioavailability, the administration of the patch 102 of Groups 1 to 3 via the microporous drug delivery system was able to provide a concentration level similar to that of the injection administration of Groups 4 and 5.

[0218] Table 4 below provides data for one group (Group 1) of patches 102 containing a long-acting protein (e.g., etanercept) that were applied without any microperforation; three groups (Groups 2 through 4) of microperforation values ​​for patches 102, and one group (Group 5) of long-acting proteins administered by injection. Table 5 below provides details of the patches 102 for the five groups of Table 4. Table 6 below provides details of the components of the patches or drug formulations applied according to Groups 1 through 5.

[0219] Table 4

[0220]

[0221] Table 5

[0222]

[0223] Table 6

[0224]

[0225] Data for six groups of drug administration: three groups of patch 102, one group of oral administration of long-acting peptide, and two groups of injection administration of long-acting peptide.

[0226] Figure 11Graph 1100 in FIG. 4 shows a comparison of the concentration of the long-acting protein for each of Groups 1 through 5 of Tables 4 through 6. Graph 1100 includes the concentration of the long-acting protein in nanograms per milliliter (ng / mL) along the y-axis and time in hours (hr) along the x-axis. Graph 1100 shows five lines 1102, 1104, 1106, 1108, and 1110. Line 1102 represents Group 1 patches 102 without microperforations. Line 1104 represents Group 2 microperforation parameters and Group 2 patch 102 parameters. Line 1106 represents Group 3 microperforation parameters and Group 3 patch 102 parameters. Line 1108 represents Group 4 microperforation parameters and Group 4 patch 102 parameters. Line 1110 represents the injected long-acting protein. Each of the three lines 1104, 1106, and 1108 follows the same general trend. For each of the parameters in Groups 2 to 4, the concentration of the long-acting protein generally increased relatively quickly to a maximum concentration, then gradually decreased, ultimately reaching a concentration of 0. The parameters for Groups 3 and 4 are shown by lines 1106 and 1108 as having the highest concentration level peaks, while the parameters for Group 4 produced higher long-term concentrations. Compared to the parameters for Groups 3 and 4, the parameters for Group 2 are represented by line 1104 as generally having lower concentration levels throughout the entire process. The administration of Groups 1 and 5 was lower than that of all Groups 2 to 4. Therefore, for the long-acting protein, patch administration at a skin site treated with microporation produced better bioavailability than even injection administration of the drug, as detailed in Table 7 below. Graphs 1100 and 1120 also show the effects of other components in the drug formulation (e.g., sucrose, urea, etc.) on the bioavailability and blood concentration of the long-acting protein in rats.

[0227] Graph 1120 is a zoomed-out view of graph 1100 , giving a higher level view of the relationship of lines 1102 , 1104 , 1106 , 1108 , and 1110 .

[0228] Table 7

[0229]

[0230] The area under the curve for each of Groups 1 to 5 based on graphs 1100 and 1120 is shown in Table 7 above. Table 7 shows the change in bioavailability of the long-acting protein for various administrations. Administration using patch 102 under different microporation parameters resulted in the highest concentration levels of the drug available for the longest duration.

[0231] Table 8 below provides data on microporation values ​​for two groups (Group 1 and Group 2) of patches 102 containing a long-acting protein (e.g., etanercept). Table 9 below provides details of the two groups of patches 102 from Table 8. Table 10 below provides details of the components of the patches or drug formulations administered according to Groups 1 and 2. As shown, both groups had the same drug formulation with the same amount of long-acting protein and sucrose.

[0232] Table 8

[0233]

[0234] Table 9

[0235]

[0236] Table 10

[0237]

[0238] Figure 12 Graph 1200 in Figure 1 shows a comparison of the concentration of the long-acting protein in each of Groups 1 and 2 of Tables 8 to 10. Graph 1200 shows the average curve between the long-acting protein concentrations in rats. Graph 1200 includes the concentration of the long-acting protein in nanograms per milliliter (ng / mL) along the y-axis and time in hours (hr) along the x-axis. Graph 1200 shows two lines 1202 and 1204. Line 1202 represents Group 1 patches 102 having microporation parameters according to Table 8 and patch 102 parameters according to Table 9. Line 1204 represents Group 2 patches 102 having microporation parameters according to Table 8 and patch 102 parameters according to Table 9. Lines 1202 and 1204 follow different trends. Line 1202 quickly peaks above 800 ng / mL and then generally remains between 500 and 700 ng / mL for at least about 70 hours. Line 1204 gradually increases to a peak of approximately 275 ng / mL at approximately 32 hours, then drops below 100 ng / mL at approximately 70 hours. This highlights the impact that patch 102 parameters can have on drug formulation administration.

[0239] Table 11 below provides molecular weights of exemplary permeant materials that may be used in the patch 102 of the microporous drug delivery system.

[0240] Table 11

[0241]

[0242] Details regarding the use of these permeant materials (eg, the amounts to be applied to the patch 102 when used with a microporous drug delivery system) are provided below.

[0243] Figure 13 Graph 1300 in FIG. 1 shows a comparison of concentration levels in hairless guinea pigs when polysaccharide is the type of drug formulation applied to patch 102. Figure 13 The patch 102 of the coordinate graphs 1300 and 1320 has a nonwoven matrix, a thickness of 180 μm, and a weight of 18 g / m 2 weight, 17 mg / cm 2 WHC, 0.01 mg / cm 2 of drugs and 6.1 mg / cm 2 Energy pulses of 6.3 mJ and 5.2 mJ per filament generate approximately 200 to 400 paths through the microperforations, which have a 1 cm 2 The treatment area is approximately 5% to 10% of each square centimeter of skin.

[0244] Graph 1300 shows the average curve of the polysaccharide for 200 paths generated under a 4 ms pulse as described above. Graph 1300 includes the concentration of the polysaccharide (e.g., fondaparinux) in micrograms / milliliter (μg / mL) along the y-axis and the time in hours (hr) along the x-axis. Graph 1300 shows three lines 1302, 1304, and 1306. Line 1302 represents patch 102, which has a 2.5 mg polysaccharide formulation applied with patch 102 and the above-mentioned microporation parameters. Line 1304 represents patch 102, which has a 5.0 mg polysaccharide formulation applied with patch 102 and the above-mentioned microporation parameters. Line 1306 represents patch 102, which has a 7.5 mg polysaccharide formulation applied with patch 102 and the above-mentioned microporation parameters. Each of the three lines 1302, 1304, and 1306 follows the same general trend: increasing to a peak concentration value, then gradually decreasing in concentration. Line 1306 has the highest concentration value, followed by line 1304, and then line 1302. Line 1302 has a concentration of 72.8 μg / mL. h area under the curve (AUC), 170.9% bioavailability, and a maximum concentration of 5.1 μg / mL. Line 1304 has a bioavailability of 100.9 μg / mL. h AUC, 118.4% bioavailability, and a maximum concentration of 6.7 μg / mL. Line 1306 has 152.3 μg / mL h, a bioavailability of 119.2%, and a maximum concentration of 9.1 µg / mL.

[0245] Graph 1320 shows the average curve of the polysaccharide for 400 paths generated under a 4 ms pulse as described above. Graph 1320 includes the concentration of the polysaccharide (e.g., fondaparinux) in micrograms / milliliter (μg / mL) along the y-axis and the time in hours (hr) along the x-axis. Graph 1320 shows three lines 1322, 1324, and 1326. Line 1322 represents patch 102, which has a 2.5 mg polysaccharide formulation applied with patch 102 and the above-mentioned microperforation parameters. Line 1324 represents patch 102, which has a 5.0 mg polysaccharide formulation applied with patch 102 and the above-mentioned microperforation parameters. Line 1326 represents patch 102, which has a 7.5 mg polysaccharide formulation applied with patch 102 and the above-mentioned microperforation parameters. Each of the three lines 1322, 1324, and 1326 follows the same general trend: increasing to a peak concentration value, then gradually decreasing in concentration. Line 1326 has the highest concentration value, followed by line 1324, and then line 1322. Line 1322 has a concentration of 97.3 µg / mL. h AUC, 228.5% bioavailability, and a maximum concentration of 8.0 µg / mL. Line 1324 has 125.2 µg / mL h AUC, 146.9% bioavailability, and a maximum concentration of 10.5 µg / mL. Line 1326 has 145.8 µg / mL h, a bioavailability of 114.1%, and a maximum concentration of 11.5 µg / mL.

[0246] Comparison of graph 1300 and graph 1320 illustrates how increasing the number of pathways can improve the concentration of polysaccharides in hairless guinea pigs.

[0247] Figure 14 Graph 1400 in FIG. 1 shows a comparison of blood drug concentration levels in hairless guinea pigs when a peptide is the type of drug formulation applied to the patch 102, for four groups of patches 102 having different patch parameters. The patch 102 parameters are provided in Table 12 below.

[0248] Table 12

[0249]

[0250] The 6.3 mJ energy pulse per filament creates approximately 200 paths through the microperforations with a treatment area of ​​approximately 5% per square centimeter of skin.

[0251] Graph 1400 shows a backing material study of the above-mentioned peptide (e.g., exenatide) for 200 paths generated under 4 ms pulses, as described above. Graph 1400 includes the concentration of the peptide in ng / mL along the y-axis and the time in hours (hr) along the x-axis. Graph 1400 shows four lines 1402, 1404, 1406, and 1408. Line 1402 represents a patch 102 having the patch 102 parameters of group G1 of Table 12 and the above-mentioned microperforation parameters. Line 1404 represents a patch 102 having the patch 102 parameters of group G2 of Table 12 and the above-mentioned microperforation parameters. Line 1406 represents a patch 102 having the patch 102 parameters of group G3 of Table 12 and the above-mentioned microperforation parameters. Line 1408 represents a patch 102 having the patch 102 parameters of group G4 of Table 12 and the above-mentioned microperforation parameters. Each of the four lines 1402, 1404, 1406, and 1408 follows the same general trend: increasing to a peak concentration value and then gradually decreasing in concentration. Line 1402 has the highest concentration value, followed by line 1404, then line 1406, and finally line 1408.

[0252] Graph 1400 shows that with lower WHC (e.g., below 20 mg / cm 2 ) compared to those with larger WHC (e.g., greater than 30 mg / cm 2 The weight density of the patch 102 actually reduces the drug delivery efficiency of the patch 102. Line 1402 has 86.275 ng / mL h AUC, 75.284% bioavailability, and a maximum concentration of 14.317 ng / mL. Line 1404 has 51.583 µg / mL h AUC, 45.011% bioavailability, and a maximum concentration of 8.996 ng / mL. Line 1406 has 1.714 ng / mL h AUC, 1.496% bioavailability, and a maximum concentration of 0.438 ng / mL. Line 1408 has 15.643 ng / mL h, a bioavailability of 13.650%, and a maximum concentration of 2.849 ng / mL.

[0253] Figure 15 Graph 1500 in FIG. 1 shows a comparison of blood drug concentration levels in hairless guinea pigs when a peptide is the type of drug formulation applied to patch 102 .

[0254] Microporation was performed using stainless steel filaments 200, with energy pulses of 6.3 mJ / filament and 5.2 mJ / filament applied to the stainless steel filaments 200 to generate approximately 200 to 400 paths, with a treatment area of ​​approximately 5% to 10% per square centimeter of skin. The patch 102 for administering peptides shown in the graph 1500 has a thickness of 38 μm, a mass of 12 g / m², and a mass of 100 g / m². 2 weight, 4 mg / cm 2 WHC, 0.4mg / cm 2 API and 10.4 mg / cm 2 Groups 2 and 4 should be applied to 10% / cm 2 For the treatment area, Group 1 and Group 3 were applied at 5% / cm 2 treatment area.

[0255] Graph 1500 shows the 5% / cm2 curves for 200 or 400 paths and for 4 ms pulses as described above. 2 or 10% / cm 2 The average curve of a peptide (e.g., exenatide) in a treated area. Graph 1500 includes the concentration of the peptide in ng / mL along the y-axis and the time in hours (hr) along the x-axis. Graph 1500 shows four lines 1502, 1504, 1506, and 1508. Line 1502 represents the concentration of the peptide at 5% / cm 2 Patch 102 with microperforation parameters of 200 paths in the treated area. Line 1504 represents the microperforation parameters at 10% / cm 2 Patch 102 with microperforation parameters of 400 paths in the treated area. Line 1506 represents the microperforation parameters at 5% / cm 2 Patch 102 with microperforation parameters of 200 paths in the treated area (Note: a density of 100 wide filaments is equivalent to a density of 200). Line 1508 represents the microperforation parameters at 10% / cm 2 Patch 102 with microperforation parameters of 500 paths in the treatment area (Note: a wide filament with a density of 200 is equivalent to a density of 200). Each of the four lines 1502, 1504, 1506, and 1508 follows the same general trend: increasing to a peak concentration value, then gradually decreasing in concentration. Line 1508 generally has the highest concentration value, followed by line 1504, then line 1502, and finally line 1506.

[0256] The area under the curve for each of Groups 1 to 4 based on the graph 1500 is shown in Table 13 below. Table 13 shows the changes in bioavailability for various administered peptides. Administration of Group 1 produced 509.247 ng / mL The administration of Group 2 produced 1416.218 ng / mL of AUC and a bioavailability of 20.282%. The administration of Group 3 produced 407.298 ng / mL of AUC and a bioavailability of 56.404%. The administration of Group 4 resulted in 1757.651 ng / mL of AUC and a bioavailability of 16.221%. hr AUC and 70.002% bioavailability. Thus, graph 1500 shows that peptide delivery may be related to pathway density and that pharmacokinetics (PK) is also related to total pathway area, which may be related to the shape of filament 200.

[0257] Table 13

[0258]

[0259] Figure 16 Graph 1600 in FIG. 1 shows blood drug concentration levels in hairless guinea pigs when a peptide (eg, lixisenatide) is the type of drug formulation applied to patch 102 .

[0260] Microporation was performed using a stainless steel filament 200, to which an energy pulse of 6.3 mJ / filament was applied to produce approximately 200 paths, treating an area of ​​approximately 5% / cm2 of skin. The patch 102 for applying the peptide shown in the graph 1600 has a thickness of 38 μm, a mass of 12 g / m 2 weight, 4 mg / cm 2 WHC, 0.2 mg / cm 2 of API and about 10.2 mg / cm 2 of the total solid weight.

[0261] Graph 1600 shows that when combined with 2.0 mg sucrose and 8.0 mg urea to form approximately 10.2 mg / cm 2 102 and 104. The average curve of the above-mentioned peptide (e.g., lixisenatide) is shown when the total solid weight of the patch is 102. The coordinate graph 1600 includes the concentration of the peptide in ng / mL along the y-axis and the time in hours (hr) along the x-axis. The coordinate graph 1600 shows a line 1602. Line 1602 represents the patch 102 and the above-mentioned microperforation parameters. Line 1602 shows a trend that increases to a peak concentration value and then the concentration value decreases.

[0262] Based on the graph 1600, the AUC, bioavailability, and maximum concentration values ​​for line 1602 are shown below in Table 14. AUC was 264.1 ng / mL hr, bioavailability was 46.8%, and maximum concentration was 27.1 ng / mL.

[0263] Table 14

[0264]

[0265] Figure 17 Graph 1700 in FIG. 1 shows concentration levels in hairless guinea pigs when a peptide (eg, teriparatide) is the type of drug formulation applied to patch 102 .

[0266] Microperforation was performed based on the parameters provided in Table 15 below.

[0267] Table 15

[0268]

[0269] Table 15 identifies two groups (Group 4 and Group 6) that used stainless steel filaments 200 and generated 200 and 400 paths, respectively, applying energy pulses of 9.3 mJ / filament, and treating areas of 0.5 cm and 1.5 cm, respectively. 2 and 1.0 cm 2 The patch 102 for applying the peptide shown in the coordinate graph 1700 has a thickness of 38 μm, a pressure of 12 g / m 2 weight, 4 mg / cm 2 WHC, 0.2 mg / cm 2 of API and about 0.7 mg / cm 2 of the total solid weight.

[0270] Graph 1700 shows that when combined with 0.5 mg sucrose to form approximately 0.7 mg / cm 2 102 and 104. The average curve of the above-mentioned peptide (e.g., hPTH) is shown when the total solid weight is 100%. Coordinate graph 1700 includes the concentration of the peptide in ng / mL along the y-axis and the time in hours (hr) along the x-axis. Coordinate graph 1700 shows two lines 1702 and 1704. Line 1702 represents the microperforation parameters of patch 102 and the above-mentioned Group 4. Line 1704 represents the microperforation parameters of patch 102 and the above-mentioned Group 6. Both lines 1702 and 1704 show a general trend: an increase to a peak concentration value, and then a decrease in concentration value, wherein line 1702 of Group 4 shows a higher concentration than line 1704 at all displayed times.

[0271] Based on the graph 1700, the AUC, bioavailability, and maximum concentration values ​​for lines 1702 and 1704 are shown below in Table 16. For Group 4, the AUC was 3261.325 ng / mL hr, bioavailability was 37.427%, and the maximum concentration was 9.156 ng / mL. For group 6, AUC was 2208.956 ng / mL hr, the bioavailability was 25.350%, and the maximum concentration was 11.236 ng / mL.

[0272] Table 16

[0273]

[0274] Figure 18 Graph 1800 in FIG shows a comparison of blood drug concentration levels in hairless guinea pigs when a peptide (e.g., somatropin) is the type of drug formulation applied to patch 102. Microporation was performed according to the parameters in Table 17. Table 17 shows four groups, each representing a stainless steel filament 200 to which energy pulses of 5.2 mJ / filament and 9.3 mJ / filament were applied to produce approximately 200 to 400 paths, treating an area of ​​approximately 10% / square centimeter of skin. The 200-wide filament is twice the width of a standard filament (2 × 50 microns), so the energy pulses were 5.2 mJ / filament and 9.3 mJ / filament, thereby providing the same current density / flux and similar power used.

[0275] Table 17

[0276]

[0277] The parameters of the patches 102 used for the four groups are provided below in Table 18. Table 18 shows that the patches 102 used for each of Groups 1 to 4 of Table 17 and shown in the graph 1800 have a thickness of 38 μm, a weight of 12 g / m², and a viscosity of 100 μm. 2 weight, 4 mg / cm 2 WHC, 1.0 mg / cm 2 of drug and 1.0 mg / cm 2 The total solid weight and 1.0 cm 2 area.

[0278] Table 18

[0279]

[0280] Graph 1800 shows the average curves for the peptides (e.g., growth hormone) described above for 200 or 400 paths and at 4 ms or 8 ms pulses. Graph 1800 includes the concentration of the peptide in ng / mL along the y-axis and the time in hours (hr) along the x-axis. Graph 1800 shows four lines 1802, 1804, 1806, and 1808. Line 1802 represents the first set of parameters from Tables 17 and 18. Line 1804 represents the second set of parameters from Tables 17 and 18. Line 1806 represents the third set of parameters from Tables 17 and 18. Line 1808 represents the fourth set of parameters from Tables 17 and 18. Each of the four lines 1802, 1804, 1806, and 1808 follows the same general trend: increasing to a peak concentration value, and then the concentration gradually decreases. Line 1808 has the highest concentration value, followed by line 1802, then line 1804 and finally line 1806. Note that line 1804 exceeds line 1806 between about 2 hours and about 3 hours.

[0281] Based on the coordinate graph 1800, AUC, bioavailability, maximum concentration, and time to maximum concentration are shown in Table 19 below. Table 19 shows the changes in each of these values ​​in each group. Administration of Group 1 resulted in an AUC of 87.1 ng / mL hr, bioavailability was 35.8%, and the maximum concentration was 20.4 ng / mL, which occurred 1.3 hours after drug administration (after patch 102 was applied to the skin). Administration of Group 2 resulted in an AUC of 90.1 ng / mL hr, bioavailability was 37.0%, and the maximum concentration was 16.1 ng / mL, which occurred 1.8 hours after administration. Administration of Group 3 resulted in an AUC of 78.1 ng / mL hr, bioavailability was 32.1%, and the maximum concentration was 16.4 ng / mL, which occurred 1.5 hours after administration. Administration of Group 4 resulted in an AUC of 94.9 ng / mL hr, bioavailability was 32.1%, and maximum concentration was 16.4 ng / mL, which occurred 1.5 hours after drug administration. Thus, graph 1800 illustrates the effect of the amount of power and pulse length on peptide delivery.

[0282] Table 19

[0283]

[0284] Figure 19 A bar graph 1900 and a graph 1920 are shown, indicating serum titer values ​​for seven groups of vaccines administered in rats according to the parameters in Table 20.

[0285] According to Table 20 below, Groups 1 to 5 are vaccines (e.g., antigen ovalbumin) administered using a microporation drug delivery system with different microporation parameters. Group 6 corresponds to intradermal administration of the vaccine, and Group 7 corresponds to intramuscular administration of the vaccine. Table 21 provides the parameters of the patch 102 used for each of Groups 1 to 5.

[0286] Table 20

[0287]

[0288] Table 21

[0289]

[0290] Figure 20 A bar graph 2000 showing the total amount of antibody titers in mice for Groups 1 to 10 of vaccines administered according to the parameters in Table 22 and a bar graph 2020 showing the in vivo Th1 cell antibody titers for Groups 1 to 10 are shown. According to Table 22 below, Groups 1 to 8 are vaccines administered using a microporation drug delivery system with different microporation parameters (e.g., ovalbumin antigen with or without adjuvant containing CpG). Groups 9 and 10 correspond to intradermal administration of vaccines. Table 23 provides the parameters of the patch 102 used for each of Groups 1 to 8 and the solution values ​​for Groups 9 and 10. Table 24 shows the dose variables provided by Tables 22 and 23 for Groups 1 to 10.

[0291] Table 22

[0292]

[0293] Table 23

[0294]

[0295] Table 24

[0296]

[0297] Figure 21 A bar graph 2100 showing the total antibody titers of mice in groups 1 to 6 of vaccines administered according to the parameters in Table 22 and a bar graph 2120 showing the in vivo Th1 humoral antibody titers of groups 1 to 6 are shown. Groups 1 to 5 are vaccines administered using a microporation drug delivery system with different microporation parameters (e.g., the antigen ovalbumin without an adjuvant). Group 6 corresponds to intradermal administration of the vaccine. The immune response is illustrated under several conditions: CpG (adjuvant), sucrose content, applicator conditions, and different retaining materials.

[0298] Those skilled in the art will recognize that the various exemplary logic blocks, modules, circuits and algorithm steps described below and the combination with the embodiments disclosed herein can be implemented as electronic hardware, stored on a computer-readable medium and software that can be executed by a hardware processor, or a combination of the two. In order to clearly illustrate this interchangeability of hardware and software, various exemplary components, blocks, modules, circuits and steps have been generally described above according to their functions. Whether this function is implemented as hardware or software depends on the specific application and the design constraints assigned to the entire system. Those skilled in the art can implement the functions in different ways for each specific application, but such implementation decisions should not be interpreted as causing deviations from the scope of the present invention.

[0299] The various exemplary logic blocks, modules, and circuits described in conjunction with the embodiments disclosed herein may be implemented or executed with a general-purpose processor, a digital signal processor (DSP), an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor may be a microprocessor, but in the alternative, the processor may be any conventional processor, controller, microcontroller, or state machine. A processor may also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0300] The steps of the methods or algorithms described in conjunction with the embodiments disclosed herein can be implemented directly in hardware, software modules executed by a processor, or a combination of the two. The software modules can be stored in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, removable disk, CD-ROM, or any other form of storage medium known in the art. An exemplary storage medium is coupled to the processor so that the processor reads information from the storage medium and writes information to the storage medium. In an alternative, the storage medium can be integrated into the processor. The processor and storage medium can be stored in an ASIC.

[0301] While the above detailed description has shown, described, and pointed out the novel features of the developments as applied to the various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the illustrated devices or processes may be made by those skilled in the art without departing from the spirit of the invention. As will be appreciated, the developments of the present invention may be embodied in a form that does not provide all of the features and benefits set forth herein, as some features may be used or practiced separately from others. All changes that come within the meaning and range of equivalents of the claims are intended to be included within their scope.

[0302] Those skilled in the art will recognize that each of these subsystems may be interconnected and controllably connected using a variety of techniques and hardware, and that the present disclosure is not limited to any particular method of connection or connecting hardware.

[0303] The technology can be operated with a variety of other general-purpose or special-purpose computing system environments or configurations. Examples of well-known computing systems, environments, and / or configurations suitable for use with the present invention include, but are not limited to, personal computers, server computers, handheld or laptop devices, multiprocessor systems, microprocessor-based systems, microcontrollers or microcontroller-based systems, programmable consumer electronics, network PCs, minicomputers, mainframe computers, distributed computing environments including any of the above systems or devices, and the like.

[0304] As used herein, instructions refer to computer-implemented steps for processing information in a system. Instructions can be implemented in software, firmware, or hardware, and include any type of programming steps taken by components of the system.

[0305] The microprocessor can be any conventional general-purpose single-chip or multi-chip microprocessor, such as a Pentium® processor, a Pentium® Pro processor, an 8051 processor, a MIPS® processor, a Power PC® processor, or an Alpha® processor. In addition, the microprocessor can be any conventional special-purpose microprocessor, such as a digital signal processor or a graphics processor. The microprocessor typically has conventional address lines, conventional data lines, and one or more conventional control lines.

[0306] The system can be used in conjunction with various operating systems (such as Linux®, UNIX®, MacOS® or Microsoft Windows®), or a customized one can be created.

[0307] System controls can be written in any conventional programming language, such as C, C++, BASIC, Pascal, .NET (e.g., C#), or Java, and run under a conventional operating system. C, C++, BASIC, Pascal, Java, and FORTRAN are industry-standard programming languages, and many commercial compilers are available for creating executable code for them. System controls can also be written in interpreted languages, such as Perl, Python, or Ruby. Other languages, such as PHP and JavaScript, can also be used.

[0308] The foregoing description describes in detail certain embodiments of the systems, devices, and methods disclosed herein. However, it should be understood that no matter how the foregoing detailed description appears in text, the systems, devices, and methods can be practiced in a variety of ways. As also mentioned above, it should be noted that the use of a particular term when describing certain features or aspects of the present invention should not be taken to mean that the term is redefined herein to be limited to include any specific characteristics of the features or aspects of the technology associated with the term.

[0309] It will be understood by those skilled in the art that various modifications and changes may be made without departing from the scope of the technology described. Such modifications and changes are intended to fall within the scope of the embodiments. It will also be understood by those skilled in the art that components included in one embodiment may be interchangeable with other embodiments; one or more components from a depicted embodiment may be included in any combination with other depicted embodiments. For example, any of the various components described herein and / or in the accompanying drawings may be combined, interchanged, or excluded from other embodiments.

[0310] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can translate the plural to the singular and / or the singular to the plural, as appropriate to the context and / or application. For purposes of clarity, various singular / plural permutations are expressly set forth herein.

[0311] All numerical values ​​expressing quantities of ingredients, reaction conditions, and the like used in the specification and claims should be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximate and may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not attempting to apply the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

[0312] The above description discloses several methods and materials of the present development. The present development is susceptible to modifications in the methods and materials, as well as changes in the manufacturing methods and apparatus. Such modifications will become apparent to those skilled in the art from consideration of this disclosure or practice of the development disclosed herein. Therefore, this development is not intended to be limited to the specific embodiments disclosed herein, but is intended to cover all modifications and alternatives coming within the true scope and spirit of the development as reflected in the appended claims.

[0313] As will be appreciated by those skilled in the art, in some embodiments, the processes described in the following materials may be performed on a computer network having a central server with a processor, data storage (e.g., a database and memory), and communication features that allow wired or wireless communication with various components of the network, including terminals and any other required network access points or mechanisms.

Claims

1. A transdermal permeant delivery system for delivering at least one permeant into a tissue membrane of a subject, comprising: a) a substrate having an upper substrate surface and defining a perforated area, the substrate comprising a filament array having a plurality of filaments disposed in the perforated area, wherein each filament is capable of conductively transferring thermal energy via direct contact with the tissue membrane to form a plurality of micropores in the microporous area of ​​the tissue membrane, the microporous area being 1% to 20% of the perforated area; b) an applicator electrically connected to the filament array and configured to supply a controlled amount of electrical energy to the filaments so as to generate the plurality of micropores in the micropore region of the tissue membrane by heating the filaments; as well as c) a patch configured to be applied over the microporous area and releasably containing at least one permeant, the patch comprising a 2 Up to 10 mg / cm 2 a matrix having a water-retaining capacity and at least one penetrant dispersed in the matrix, wherein the matrix comprises at least one fiber having a thickness of less than 300 μm and the areal weight of the fibers in the matrix is ​​less than 100 g / m 2 , The permeate was 0.01 mg / cm 2 Up to 20 mg / cm 2 The amount of is dispersed in the matrix, The method for measuring the water retention capacity of the substrate comprises: Prepare 1 cm 2 the matrix; Immersing the prepared matrix in a phosphate-buffered saline solution containing 0.1 w / v% Tween 80 for a sufficient amount of time; slowly pulling the matrix out of the solution for 5 seconds; and measuring the weight of the solution held by the matrix, In the case where the substrate has a membrane surface, the test solution adhering to the membrane surface is wiped off after it is pulled out, and then weighed.

2. The system of claim 1 , wherein the controlled amount of electrical energy to generate the plurality of micropores by heating the filament is 0.0067 µJ / µm 3 Up to 0.0400 µJ / µm 3 .

3. The system of claim 1 , wherein the microporous area is 1.25% to 10% of the perforated area.

4. The system according to any one of claims 1 to 3, wherein the cumulative volume of the plurality of micropores is 0.05 mm 3 / cm 2 Up to 0.35 mm 3 / cm 2 .

5. The system according to any one of claims 1 to 3, wherein the permeate is a long-acting drug.

6. The system of claim 5, wherein the long-acting drug is selected from the group consisting of: a GLP-1 antagonist, a derivative of a GLP-1 antagonist with an extended half-life, an Fc protein, a derivative of an Fc protein with an extended half-life, and an antibody.

7. The system of claim 5, wherein the long-acting drug acts for more than 24 hours.

8. The system of claim 5, wherein the long-acting drug acts for 1 to 7 days.

9. The system of claim 5, wherein the long-acting drug acts for more than 7 days.

10. The system of claim 1, wherein the patch is configured to release the permeate for more than 24 hours.

11. The system of any one of claims 1 to 3, wherein the system further comprises a backing layer having at least a partial adhesive.

12. The system of any one of claims 1 to 3, wherein the filament comprises a conductive layer of copper and an underlying resistive layer of stainless steel.

13. The system of any one of claims 1 to 3, wherein the applicator is configured to supply the controlled amount of electrical energy of 2 mJ / filament to 12 mJ / filament to the filament.

14. The system of any one of claims 1 to 3, wherein the applicator is configured to supply the controlled amount of electrical energy to the filament for a time period of 2 ms to 12 ms.

15. The system according to any one of claims 1 to 3, wherein the plurality of micropores in the micropore area is 50 micropores / cm 2 Up to 400 micropores / cm 2 exist.

16. The system according to any one of claims 1 to 3, wherein the cumulative depth of the plurality of micropores is 2500 μm / cm 2 Up to 30,000 µm / cm 2 .

17. The system of any one of claims 1 to 3, wherein the substrate comprises a laminate material, and the laminate material comprises the fibers and a membrane.

18. The system of any one of claims 1 to 3, wherein the fibers have a thickness of less than 200 μm.

19. The system of any one of claims 1 to 3, wherein the fibers in the matrix have an areal weight of less than 20 g / m 2 .

20. The system of claim 19, wherein the fibers in the matrix have an areal weight of less than 12 g / m 2 And the water holding capacity of the matrix is ​​4 mg / cm 2 .

21. The system of any one of claims 1 to 3, wherein the fibers are nonwoven fibers.

22. The system of any one of claims 1 to 3, wherein the permeant is a small molecule, a peptide, a protein, an oligonucleotide, or a combination thereof.

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