Triptan micro-poration delivery system

Abstract

A transdermal delivery system for delivering a triptan to a tissue membrane of a subject includes a transdermal microporation device for heating the skin surface and a triptan drug delivery patch. The drug delivery patch includes a top layer containing an adhesive, a middle layer containing the triptan, and a bottom layer. A method for treating a subject includes identifying a subject with migraine headaches, creating multiple micropores in the subject's skin using a transdermal microporation device, and applying the triptan drug delivery patch to the subject's skin over the micropores for a period of time effective to deliver the triptan through the micropores in an amount effective to treat the subject's migraine headache.

Description

Technical Field

[0001] Background Art This application relates to compositions, devices, and methods for transdermal drug delivery, and in particular, to triptan compositions and methods for administering triptans to a subject by a transdermal microporation device.

[0002] Description Migraine is a condition that affects approximately 10% of the adult population worldwide, which amounts to approximately 600 million people, and about 28 million people in the United States alone. Women are more than three times as likely to suffer from migraines as men. Migraine is associated with inflammation and dilation of blood vessels and causes severe one-sided pain that worsens with physical activity. Approximately one-fifth of migraine patients experience sensory or visual symptoms such as light spots, zigzag lines, or grayouts of vision. Migraine typically lasts up to 24 hours, but can range from 4 to 72 hours, and patients often experience migraine attacks twice a month.

[0003] Migraine can be caused by many different factors, including life stressors, certain foods or eating habits, circadian rhythms, changes in schedule or sleep patterns, weather changes such as barometric pressure or altitude, and periodic fluctuations in hormone levels during the menstrual cycle. Pharmacological interventions are central to the treatment of migraine and are available for both acute treatment (abortive) and prevention (prophylaxis).

[0004] Triptans are serotonin receptor agonists that can be used to treat moderate to severe intensity acute migraine headaches. When these agents are used in the early stages of an attack, triptans abort more than 80% of migraines within 2 hours. However, several different triptan products are available, and there is variability in the effectiveness and tolerability of the various drugs in this class. Triptans are also available in a variety of dosage forms. Parenteral formulations are typically used for patients with gastrointestinal symptoms such as nausea or vomiting, and when a more rapid onset of action is desired. Triptans are thought to function by activating serotonin (5-HT) receptors on trigeminovascular nerve terminals and inhibiting the release of neurotransmitters that cause cranial vasodilation associated with pain. Additionally, triptans can cause active vasoconstriction and then relieve migraine symptoms by stimulating 5-HT receptors on cranial blood vessels. Oral tablets containing triptans are generally ineffective and lack sufficient immediate efficacy. Subcutaneous injection shows higher efficacy and immediate efficacy but may cause severe side effects. Oral and nasal routes often cause unwanted taste problems and are difficult to administer for patients with nausea and vomiting associated with migraines.

[0005] Passive transdermal drug delivery is a convenient and effective way to administer various therapeutic drugs. This route of administration is non-invasive and simultaneously provides stable drug delivery over a long period of time. Conventional transdermal systems (such as drug patches) have shown the advantage of delivering drugs through the skin, but these function only in the case of a very limited number of drugs. This is because millions of dead skin cells form a protective barrier (stratum corneum) on the surface of the skin, and this protective barrier prevents most therapeutic molecules from entering the skin.

[0006] The stratum corneum is mainly involved in the barrier properties of the skin. Therefore, this layer represents the greatest barrier to the transdermal flux of drugs or other molecules entering the body and to the transdermal flux of analytes exiting the body. The stratum corneum, which is the outermost layer of the skin, is a complex structure of tightly keratinized cell remnants separated by lipid domains. Compared to oral mucosa or gastric mucosa, the stratum corneum is far less permeable to any molecule, whether from the external or internal environment of the body. The stratum corneum is formed from keratinocytes, which make up the majority of epidermal cells that lose their nuclei and become corneocytes. These dead cells form the stratum corneum, which is only about 10-30 microns thick and protects the body from invasion by external substances as well as the outward movement of internal fluids and dissolved molecules. The stratum corneum is continuously regenerated by shedding corneocytes during desquamination and forming new corneocytes during the keratinization process.

[0007] Historically, most drugs have been delivered orally or by injection. However, neither the oral route nor the injection route is entirely suitable for the continuous delivery of drugs over an extended period. Furthermore, the injection administration method is inconvenient and uncomfortable, and needles continue to pose a danger even after their use. Therefore, transdermal drug delivery to the body is a common and effective method for delivering a limited number of permeants to an organism.

[0008] Passive transdermal patches are typically limited to lipophilic drugs with a molecular weight of less than 500 Daltons. To enhance transdermal drug delivery, there are known methods for increasing the skin permeability of drugs. For example, U.S. Patent No. 8,116,860 describes a transdermal permeant delivery system and method for forming aqueous micropores in the stratum corneum within a few milliseconds without pain. These aqueous channels allow water-soluble drugs to flow from the transdermal patch, enter viable epidermis, and then enter the systemic circulation. The patch can be formulated to achieve bolus or sustained transdermal delivery.

[0009] The transdermal delivery system is developed under the trademark name PASSPORT. The PASSPORT system comprises a reusable handheld applicator and a disposable patcher with a drug patch. When the activation button of the applicator is pressed, an energy pulse is released to the patcher. When this energy is rapidly conducted to the skin surface, the stratum corneum under each filament is excised without pain, and microchannels are formed. Then, a simple transdermal patch is applied to the excised skin, and drug delivery is initiated.

[0010] An iontophoresis system for the transdermal delivery of triptans was approved by the US Food and Drug Administration (FDA) in 2013. This system, sold under the trademark name ZECUITY, used a battery-driven iontophoresis patch to deliver sumatriptan. However, this system was withdrawn from the market in 2016 after the manufacturer received postmarketing reports of application site reactions described as having "burns" and / or "scars" in patients treated with ZECUITY. Explanations of these reactions included severe erythema, skin cracking, blisters or hives, and burns or scars at the location where the patch was worn. Patients reported severe pain, itching, or a burning sensation. Although many cases resolved within hours to weeks, there were reports of unresolved skin reactions, typically with skin discoloration, months later.

[0011] Accordingly, there remains a long-standing need for improved compositions, devices, and methods for the transdermal delivery of triptans.

[0012] SUMMARY OF THE INVENTION In some aspects, patches for delivering a triptan drug to a subject in need thereof are described herein. The patch can include an uppermost layer including an adhesive, an intermediate layer including a triptan, and a lowermost layer including a release liner.

[0013] In some embodiments, the intermediate layer further includes a skin irritation reducing agent.

[0014] In some embodiments, the intermediate layer has a stabilizer in an amount in the range of about 0.01 g / cm 2 to about 0.5 g / cm 2 .

[0015] In some embodiments, the molar ratio of the amount of triptan to the skin irritation reducing agent is in the range of about 1:0.5 to about 1:2.

[0016] In some embodiments, the triptan is selected from sumatriptan, rizatriptan, or zolmitriptan.

[0017] In some embodiments, the skin irritation reducing agent is an organic acid or a salt thereof.

[0018] In some embodiments, the organic acid is selected from ascorbic acid, citric acid, succinic acid, tartaric acid, maleic acid, lactic acid, benzoic acid, and sorbic acid, or a combination thereof.

[0019] In some embodiments, the stabilizer is a saccharide.

[0020] In some embodiments, the saccharide is selected from mannitol, maltose, trehalose, xylitol, xylose, dextrose, lactose, sorbitol, sucrose, fructose, maltitol, erythritol, lactitol, isomalt, and cyclodextrin, or a combination thereof.

[0021] In some embodiments, the intermediate layer further includes a reservoir configured to contain a triptan.

[0022] In some embodiments, the reservoir includes a matrix.

[0023] In some embodiments, the matrix has a water retention capacity in the range of about 0.1 mg / cm 2 to about 10 mg / cm 2 .

[0024] In some embodiments, the matrix comprises a non-woven fabric.

[0025] In some embodiments, the matrix has a thickness in the range of about 10 μm to about 100 μm.

[0026] In some embodiments, the areal weight of the matrix is in the range of about 10 g / m 2 to about 100 g / m 2 .

[0027] In some embodiments, the size of the matrix is in the range of about 0.25 cm 2 to about 5 cm 2 .

[0028] In some embodiments, the patch further comprises an antibacterial agent.

[0029] In some embodiments, the antibacterial agent is selected from at least one of benzoic acid, methylparaben, propylparaben, benzalkonium chloride, chlorhexidine, cresol, salicylic acid, sorbic acid, and benzethonium chloride, or combinations thereof.

[0030] In some embodiments, the skin irritation reducing agent is an inorganic acid or a salt thereof.

[0031] In some embodiments, the inorganic acid is selected from hydrochloric acid, phosphoric acid, boric acid, and acetic acid.

[0032] In some embodiments, the matrix comprises about 0.1 to about 5.0 mg / cm 2 of sumatriptan.

[0033] In some embodiments, the amounts of sumatriptan and the skin irritation reducing agent are in the range of about 1:0.75 to about 1:1.15.

[0034] In some embodiments, the size of the matrix is about 0.25 cm2 ~about 4 cm 2 is in the range of.

[0035] In some embodiments, the stabilizer is sucrose.

[0036] In some embodiments, the total amount per unit area of the matrix comprising sumatriptan and the stabilizer is 0.05 - 0.5 mg / cm 2 is.

[0037] In some aspects, a method of treating a subject in need thereof is described herein. The method can include identifying a subject having migraine, creating a plurality of micropores in the subject's skin, and applying a patch to the subject's skin over the micropores for a period of time, the patch including a top layer including an adhesive, an intermediate layer including a triptan, and a bottom layer including a release liner, and the period of time is selected to deliver a therapeutically effective amount of the triptan through the plurality of micropores.

[0038] In some embodiments, the intermediate layer further includes a skin irritation reducing agent and a stabilizer.

[0039] In some embodiments, creating a plurality of micropores in the subject's skin includes applying a transdermal micro-poration device to the subject's skin.

[0040] In some embodiments, the transdermal micro-poration is thermal tissue ablation.

[0041] In some embodiments, the transdermal micro-poration forms micropores in the epidermis through the stratum corneum.

[0042] In some embodiments, the transdermal micro-poration device has a perforation energy of about 2 - about 5 mJ / filament.

[0043] In some embodiments, the transdermal micro-poration device has about 200 - about 500 filaments / cm 2has a piercing energy density of

[0044] In some embodiments, the transdermal microporation device has about 400 filaments / cm 2 of piercing energy density.

[0045] In some embodiments, the transdermal microporation piercing energy is about 4 mJ / filament, and the piercing energy density is about 400 filaments / cm 2 of filament.

[0046] In some embodiments, the size of the transdermal microporation filament array is from about 0.5 to about 5 cm 2 in length.

[0047] In some embodiments, the ratio of triptan to skin irritation reducing agent is in the range of about 1:0.5 to about 1:2.

[0048] In some aspects, a transdermal drug delivery patch system for delivering a drug is described herein. The transdermal drug delivery patch system comprises a transdermal microporation device for heating the skin surface and a triptan drug delivery patch.

[0049] In some embodiments, the triptan drug delivery patch system comprises a top layer including an adhesive, an intermediate layer having at least one reservoir configured to contain a triptan, and a bottom layer including a release liner.

[0050] In some embodiments, the intermediate layer further comprises a skin irritation reducing agent and a stabilizer.

[0051] In some embodiments, the microporation device comprises a conductive member configured to generate thermal energy based on an electric current flowing through the conductive member and supply the thermal energy to the skin surface in contact with the conductive member during operation.

[0052] In some embodiments, the transdermal drug delivery patch system further comprises a power source configured to supply current to the conductive member in a plurality of pulses of supply current values.

[0053] These and other embodiments are described in more detail below.

Brief Description of the Drawings

[0054] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below and, together with the specification, serve to explain the principles of the invention. Like numbers represent the same elements throughout the figures.

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[0055] Detailed Description The present invention can be more easily understood by referring to the following detailed description, examples, drawings, and claims, as well as the descriptions before and after them. However, it should be understood that before the present device, system, and / or method are disclosed and described, the present invention is not limited to the specific devices, systems, and / or methods disclosed, unless otherwise specified. It should also be understood that the terms used in this specification are for the purpose of describing specific embodiments only and are not necessarily intended to be limiting.

[0056] This specification is provided to enable the teachings of the present invention. For this purpose, those skilled in the relevant art will recognize and understand that many modifications can be made to the various aspects of the present invention described herein while obtaining beneficial results. It will also be apparent that some of the desired benefits can be obtained by selecting some of the features described herein without using other features. Thus, those skilled in the art will recognize that many modifications and adaptations to this specification are possible and may even be desirable in certain situations, and are part of the present invention. Therefore, this specification is provided to illustrate the specific principles of the present invention and not to limit it.

[0057] Definition As used throughout, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a filament" can include two or more such filaments unless the context indicates otherwise.

[0058] In this specification, ranges may be expressed as from a particular value with "about" and / or to another particular value with "about." When such a range is expressed, another aspect includes from a particular value and / or to another particular value. Similarly, when values are expressed as approximations by use of the preceding "about," the particular value is understood to form another aspect. Further, each endpoint of each range is understood to be significant both in relation to the other endpoint and independently of the other endpoint.

[0059] As used in this specification, the terms "optional" or "optionally" mean that the subsequent described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0060] As used in this specification, the "stratum corneum" refers to the outermost layer of the skin, which consists of about 15 to about 20 layers of cells in various stages of dryness. The stratum corneum forms a barrier against loss of moisture from the body interior to the external environment and against attack from the external environment to the body interior.

[0061] As used in this specification, "tissue" refers to an aggregate of specific types of cells that form a structural material together with their intercellular substances. At least one surface of the tissue needs to be accessible to the device. Preferred tissue is skin. Other tissues suitable for use in the present invention include mucosal tissue and soft organs.

[0062] As used herein, the term "interstitial fluid" is a clear fluid that occupies the spaces between cells in the body. As used herein, the term "biological fluid" is defined as a fluid derived from a living organism, including serum or whole blood as well as interstitial fluid.

[0063] As used herein, "tissue membrane" can be any one or more epidermal layers of a subject. For example, in one aspect, the tissue membrane is a skin layer that includes the outermost layer of the skin, i.e., the stratum corneum. In an alternative aspect, the skin layer can include one or more backing layers of the epidermis, commonly identified as the granular layer, the Malpighian layer, and the basal layer. One of ordinary skill in the art will understand that there is essentially little or no resistance to the transport or absorption of permeates through the backing layers of the epidermis. Thus, in one aspect, at least one formed pathway in the skin layer of the subject is a pathway in the stratum corneum of the subject. Further, as used herein, "stratum corneum" typically refers to the outermost layer of the skin, which includes from about 15 to about 20 layers of cells in various stages of dryness. The stratum corneum forms a barrier against water loss from the body interior to the external environment and against attacks from the external environment to the body interior. Further, as used herein, "tissue membrane" can refer to an aggregate of specific types of cells that form a structural material, together with their intercellular substances. In various embodiments, at least one surface of the tissue membrane is accessible to one or more of the perforated devices and / or permeable compositions described herein. As noted above, a preferred tissue membrane is the skin. Other tissues suitable for use with such devices and compositions include mucosal tissue and soft organs.

[0064] As used herein, the term "subcutaneous fluid" can include, but is not limited to, water, plasma, blood, one or more proteins, interstitial fluid, and any combination thereof. In one aspect, the subcutaneous fluid according to this specification is a water source that includes water.

[0065] As used herein, "perforation", "micro - poration", or any such similar term means forming small holes or gaps (hereinafter also referred to as "micropores") in or through a tissue or biological membrane such as skin or mucosa, or the outer layer of an organism, in order to reduce the barrier properties of the biological membrane so that at least one permeate can pass from one side of the biological membrane to the other for a selected purpose. Preferably, the holes or "micropores" so formed have a diameter of about 1 to 1000 microns and spread sufficiently within the biological membrane to disrupt the barrier properties of the stratum corneum without adversely affecting the underlying tissue. The term "micropore" is used in the singular for simplicity, but it should be understood that the micro - poration devices described herein can form multiple artificial openings. Perforation can reduce the barrier properties of the biological membrane to the body for a selected purpose or for a particular medical or surgical procedure. In this application, "perforation" and "micro - poration" are used interchangeably and mean the same thing.

[0066] A "micro - porator" or "porator" is a component for a micro - poration device capable of micro - poration. Examples of a micro - porator or porator include, but are not limited to, a filament that can conductively deliver thermal energy through direct contact with a biological membrane to cause resection of a portion of the membrane deep enough to form micropores, an optically heated local pigment / absorber layer, an electromechanical actuator, a micro - lancet, an array of micro - needles or lancets, an acoustic energy ablator, a laser ablation system, a high - pressure fluid jet piercer, etc. As used herein, "micro - porator" and "porator" are used interchangeably.

[0067] As used herein, "penetration" means the controlled removal of cells caused by the heat and kinetic energy released when an explosive element detonates, whereby the cells of the biological membrane and perhaps some adjacent cells are "blown out" from the site. As used herein, "fusible" and "fuse" refer to elements that can remove themselves from an electrical circuit when a sufficient amount of energy or heat is applied, i.e., if a resistive electrically activated perforating element is designed to be a fusible element, this means that upon activation, during or after the formation of micropores in the biological membrane, the element breaks down to stop the flow of current therethrough.

[0068] As used herein, "enhanced penetration" or "enhanced permeation" means increasing the permeability of a biological membrane to a drug, bioactive composition, or other chemical molecule, compound, particle, or substance (also referred to as a "permeate") in order to increase the rate at which the drug, bioactive composition, or other chemical molecule, compound, particle, or substance permeates the biological membrane.

[0069] As used herein, "enhancer", "chemical enhancer", "penetration enhancer", "permeation enhancer", etc. include all enhancers that increase the flux of a permeate, analyte, or other molecule across a biological membrane and are limited only by their function. In other words, it is intended to include all cell envelope disordered compounds and solvents, as well as other chemical enhancers. Furthermore, all active force enhancer technologies such as the application of acoustic energy, mechanical suction, pressure, or local deformation of tissue, iontophoresis, or electroporation are included. One or more enhancer technologies may be combined sequentially or simultaneously. For example, a chemical enhancer can be applied first to make the capillary wall permeable, and then an iontophoresis or acoustic energy field can be applied to actively propel the permeate into the tissue surrounding and including the capillary bed.

[0070] As used herein, "transdermal" or "percutaneous" means that the permeant enters and passes through a biological membrane to achieve an effective therapeutic blood level or local tissue level of the permeant, or that a molecule or fluid ("analyte") present in the body passes through the biological membrane so that the analyte molecule can be collected outside the body.

[0071] As used herein, the terms "permeant", "drug", "permeable composition" or "pharmacologically active agent", or any other similar terms, are used interchangeably to refer to any chemical or biological material or compound suitable for transdermal administration by methods previously known in the art and / or by methods taught herein, and this material or compound induces a desired biological or pharmacological effect, and such effects include: (1) having a preventive effect on an organism and preventing undesirable biological actions such as infection; (2) reducing symptoms caused by a disease, for example, reducing pain or inflammation, and / or (3) reducing, alleviating or completely eliminating a disease from an organism, but are not limited thereto. Such an effect may be local, such as providing a local anesthetic effect, or systemic. Such substances include a wide class of compounds that are usually delivered to the body, including passage through the surfaces and membranes of the body including the skin. Generally, by way of example and not limitation, such substances may include any bioactive agent such as a drug, chemical or biological material that induces a desired biological or pharmacological effect. For this purpose, in one aspect, the permeant can be a small molecule drug. In another aspect, the permeant can be a macromolecular drug. In various embodiments, the permeant is a triptan. Examples of triptans include sumatriptan, zolmitriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, avitriptan, LY-334370, L0703,664, and GR46611.

[0072] In various embodiments, transdermal delivery systems and methods that can be used and / or adapted for use of the compositions and methods described herein can be found in U.S. Patent Nos. 6,022,316; 6,142,939; 6,173,202; 6,183,434; 6,508,785; 6,527,716; 6,692,456; 6,730,028; 7,141,034; 7,392,080; 7,758,561; 8,016,811; 8,116,860; and / or 9,498,609, all of which are hereby incorporated by reference in their entirety for the purpose of particularly describing such systems and methods. In various embodiments, transdermal delivery systems commercially available from Nitto Denko Corporation under the trademark PASSPORT can be used or adapted for use in delivering the permeable compositions described herein.

[0073] As used herein, an "effective" amount of a pharmacologically active agent means an amount of the compound sufficient to provide the desired local or systemic effects and performance with a reasonable benefit / risk ratio attendant to any medical treatment. An "effective" amount of a permeation or chemical enhancer as used herein means an amount selected to provide the desired increase in biological membrane permeability, desired depth of permeation, rate of administration, and amount of drug delivered.

[0074] As used herein, "animal" or "organism" refers to humans and other living organisms, including plants, to which the present invention can be applied.

[0075] As used herein, "analyte" means any chemical or biological material or compound suitable for passage through a biological membrane by the techniques taught in the present invention or by techniques previously known in the art, and those skilled in the art would desire to know its concentration or activity in the body. Glucose is a specific example of an analyte as it is a sugar suitable for passage through the skin. For example, a person suffering from diabetes would desire to know their blood glucose level. Other examples of analytes include, but are not limited to, compounds such as sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylate, etc.

[0076] As used herein, "transdermal flux rate" means the rate of passage of any analyte through the skin of an individual, human, or animal, or the rate of passage of any permeant, drug, pharmacological agent, dye, or pigment within and through the skin of an organism.

[0077] As used herein, "non-invasive" means that there is no need to insert a needle, catheter, or other invasive medical device into a part of the body.

[0078] As used herein, "minimally invasive" refers to the use of mechanical, hydraulic, or electrical means to penetrate the stratum corneum to form small holes or micropores without causing substantial damage to the underlying tissue.

[0079] As used herein, "pharmaceutically acceptable carrier" refers to a carrier into which a pharmaceutically acceptable substance such as a drug can be provided for delivery. Pharmaceutically acceptable carriers are described in the art, for example, in "Remington: The Science and Practice of Pharmacy," Mack Publishing Company, Pennsylvania, 1995, the disclosure of which is incorporated herein by reference. Examples of carriers include water and other aqueous solutions, sugars, polysaccharides, buffers, excipients, and biodegradable polymers such as polyesters, polyanhydrides, polyamino acids, liposomes, and mixtures thereof.

[0080] As used herein, "reservoir" refers to a designated area or chamber within a device that is designed to contain a permeate for delivery to an organism through an artificial opening in a biological membrane or to contain a biological fluid sample that has been extracted from an organism through an artificial opening in a biological membrane. The reservoir may also contain excipient compounds that enhance the effect of a separately contained bioactive permeate. Additionally, the reservoir may contain or be treated with reactive enzymes or reagents designed to enable the measurement or detection of selected analytes in the extracted biological fluid. The reservoir may be composed of an open volume space, a gel, a flat planar space coated or treated with selected compounds for later release or reaction, or a permeable solid structure such as a pellet, tablet, or porous polymer.

[0081] The devices and methods of the present disclosure can be used to transdermally deliver triptans across the skin. In some embodiments, the patch can include a top layer that includes an adhesive, an intermediate layer that includes a triptan, and a bottom layer. In some embodiments, the bottom layer includes a release liner. In some embodiments, the intermediate layer further includes a skin irritation reducing agent. In some embodiments, the intermediate layer further includes a stabilizer. In some embodiments, the patch includes a tissue interface layer.

[0082] Examples of suitable tissue interface layers are described in U.S. Patent No. 7,392,080, which is hereby incorporated by reference in its entirety for the purpose of particularly describing transdermal drug delivery patch systems. In some embodiments, the tissue interface layer can include some or all of the following: elements for effecting tissue perforation, adhesives for attaching the device to the tissue, reservoirs containing permeants for delivery, reservoirs for holding extracted biological fluids, and reagents for evaluating analytes. The tissue interface layer can also include hydrophilic and hydrophobic surface treatments that act as fluid flow modifiers to control the movement of collected liquid permeants or biological fluids. The tissue interface layer can also incorporate antibacterial agents for preventing sepsis, or anticoagulants or anti-coagulants for controlling the aggregation of extracted permeants or biological fluids. The tissue interface layer can also be treated with permeation enhancers or buffers used for pH stabilization. The tissue interface layer can include a stimulus-responsive polymer gel section saturated with a beneficial permeant, which can be induced to release the beneficial permeant through thermal, chemical, or electrical stimuli. The tissue interface layer can, for example, release a beneficial permeant as needed when heated by a perforation element or other similar element on the tissue interface layer. The tissue interface layer can include piezoelectric elements for the delivery of acoustic energy to the tissue, or for the delivery of permeants being delivered, or for the extraction of biological fluids.

[0083] In some embodiments, the tissue interface layer may include one or more reservoirs. In the case of multiple reservoirs, these reservoirs can be used to separate different, perhaps incompatible, permeates. Delivery of the permeate from the reservoir can be simultaneous or sequential. In some embodiments, the reservoir wall can be perforated to break the reservoir membrane and allow delivery of the permeate to the tissue. This perforation of the reservoir is accomplished using the same type of perforating element used to perforate the tissue. Prior to the reservoir being breached, the reservoir maintains a stable, sealed, sterile environment for the permeate, thereby allowing the disposable portion of the integrated device to be manufactured and packaged efficiently and economically. The breaching of the reservoir can be done before, simultaneously with, or after the perforation of the tissue, as needed. Further, when all other factors such as pore density or iontophoresis current are the same, the flux rate of the permeate from a particular reservoir to the tissue is proportional to the area of the pores that couple the reservoir to the biological membrane. The reservoir may initially be empty or may contain an absorbent material in order to function as a storage place for the extracted biological fluid. Reagents for assessing analytes in the biological fluid will typically be placed at the inlet of the storage reservoir for the extracted biological fluid.

[0084] Further, as used herein, "triptan" means a class or family of triptamine-based drugs used as abortive agents in the treatment of migraine and cluster headache. Examples of triptans include, but are not limited to, sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, avitriptan, and zolmitriptan. In some embodiments, the triptan includes zolmitriptan, sumatriptan, or rizatriptan. In some embodiments, the triptan includes zolmitriptan.

[0085] In some embodiments, the skin irritation reducing agent is an organic acid. In some embodiments, the skin irritation reducing agent is in the form of a salt of an organic acid. In some embodiments, the organic acid is selected from ascorbic acid, citric acid, succinic acid, tartaric acid, maleic acid, lactic acid, benzoic acid, and sorbic acid, or combinations thereof. In some embodiments, the skin irritation reducing agent is an inorganic acid. In some embodiments, the skin irritation reducing agent is in the form of a salt of an inorganic acid. In some embodiments, the inorganic acid is hydrochloric acid, phosphoric acid, boric acid, acetic acid, or combinations thereof. In some embodiments, the inorganic acid evaporates during the manufacturing process.

[0086] In some embodiments, the stabilizer is a saccharide. In some embodiments, the saccharide is selected from mannitol, maltose, trehalose, xylitol, xylose, dextrose, lactose, sorbitol, sucrose, fructose, maltitol, erythritol, lactitol, isomalt, and cyclodextrin, or combinations thereof. In some embodiments, the stabilizer is sucrose.

[0087] In some embodiments, the molar ratio of the amount of triptan and the skin irritation reducing agent in the patch is in the range of about 1:0.5 to about 1:2. In some embodiments, the triptan and the skin irritation reducing agent are in a molar ratio in the range of about 1:0.75 to about 1:1.5.

[0088] In some embodiments, the middle layer of the patch contains a reservoir. In some embodiments, the reservoir contains about 0.1 wt% to about 90 wt% of the triptan. In some embodiments, the triptan occupies about 20 wt% to about 80 wt% of the middle layer, including amounts such as 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, and 75 wt% of the middle layer, and any range of weight percentages derived from these values.

[0089] In some embodiments, the intermediate layer comprises from about 0.1 wt% to about 90 wt% stabilizer. In some embodiments, the stabilizer occupies from about 20 wt% to about 80 wt% of the intermediate layer, including amounts such as 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, and 75 wt% of the intermediate layer, and any range of weight percentages derivable from these values.

[0090] In some embodiments, the intermediate layer comprises from about 0.1 to about 90 wt% skin irritation reducing agent. In some embodiments, the skin irritation reducing agent occupies from about 20 wt% to about 80 wt% of the intermediate layer, including further amounts such as 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, and 75 wt% of the intermediate layer, and any range of weight percentages derivable from these values.

[0091] In some aspects, the intermediate layer comprises a matrix. In some embodiments, the matrix is a non-woven fabric.

[0092] In some embodiments, the matrix has a matrix water holding capacity (WHC) of from about 0.1 mg / cm 2 to about 10 mg / cm 2 . The water holding capacity of the matrix means the amount of water that the matrix can hold per 1 cm 2 . Specifically, a 1 cm 2 matrix is prepared and immersed in a solution (phosphate buffered saline containing 0.1% surfactant (Tween 80)) for a sufficiently long time. Then, the matrix is slowly withdrawn from the solution for about 5 seconds, and the weight of the sample before immersion, which was previously measured, is subtracted from the weight of the sample holding the liquid, and then the water holding capacity of the matrix per unit area (1 cm 2 ) can be determined. In some embodiments, the matrix water holding capacity is from about 0.5 mg / cm 2 to about 8 mg / cm 2It is. In some embodiments, the matrix water retention capacity is about 1 mg / cm 2 ~ about 6 mg / cm 2 It is. In some embodiments, the matrix water retention capacity is about 2 mg / cm 2 ~ about 5 mg / cm 2 It is.

[0093] The water retention capacity of the matrix can be controlled by adjusting the thickness and weight of the matrix. The matrix preferably has a thickness of 100 μm or less. In some embodiments, the matrix has a thickness in the range of about 10 μm to about 100 μm. In some embodiments, the thickness of the matrix is about 20 μm to about 90 μm. In some embodiments, the thickness of the matrix is about 30 μm to about 80 μm. In some embodiments, the thickness of the matrix is about 40 μm to about 60 μm.

[0094] In some embodiments, the areal weight of the matrix is about 10 g / m 2 ~ about 100 g / m 2 It is. In some embodiments, the areal weight of the matrix is about 20 g / m 2 ~ about 80 g / m 2 It is. In some embodiments, the areal weight of the matrix is about 30 g / m 2 ~ about 70 g / m 2 It is. In some embodiments, the areal weight of the matrix is about 40 g / m 2 ~ about 60 g / m 2 It is.

[0095] In some embodiments, the areal weight of the matrix is about 0.1 mg / cm 2 ~ about 30 mg / cm 2 It is. In some embodiments, the areal weight of the matrix is about 5 mg / cm 2 ~ about 30 mg / cm 2 It is. In some embodiments, the areal weight of the matrix is about 10 mg / cm 2 ~ about 30 mg / cm 2It is. In some embodiments, the areal weight of the matrix is about 20 mg / cm 2 ~ about 30 mg / cm 2 It is. In some embodiments, the areal weight of the matrix is about 0.5 mg / cm 2 ~ about 5 mg / cm 2 It is. In some embodiments, the areal weight of the matrix is about 0.5 mg / cm 2 ~ about 10 mg / cm 2 It is.

[0096] In some embodiments, the size of the matrix is about 0.25 cm 2 ~ about 4 cm 2 It is. In some embodiments, the size of the matrix is about 0.5 cm 2 ~ about 3 cm 2 It is. In some embodiments, the size of the matrix is about 1 cm 2 ~ about 2 cm 2 It is. In some embodiments, the size of the matrix is about 1 cm 2 It is. In some embodiments, the size of the matrix is about 2 cm 2 It is. In some embodiments, the size of the matrix is about 3 cm 2 It is.

[0097] In some embodiments, the total amount of triptan and stabilizer per unit area of the matrix is 0.05 mg / cm 2 ~ 0.5 mg / cm 2 It is. In some embodiments, the total amount of triptan and stabilizer per unit area of the matrix is 0.1 mg / cm 2 ~ 0.5 mg / cm 2 It is. In some embodiments, the total amount of triptan and stabilizer per unit area of the matrix is 0.2 mg / cm 2 ~ 0.5 mg / cm 2 It is. In some embodiments, the total amount of triptan and stabilizer per unit area of the matrix is 0.3 mg / cm 2 ~ 0.5 mg / cm 2It is. In some embodiments, the total amount of triptan and stabilizer per unit area of the matrix is 0.05 mg / cm 2 ~0.5 mg / cm 2 .

[0098] In some embodiments, the pH of the matrix component is from about 3 to about 6. In some embodiments, the pH of the matrix is from about 4 to about 6. In some embodiments, the pH of the matrix is from about 5 to about 6. In some embodiments, the pH of the matrix is about 3. In some embodiments, the pH of the matrix is about 4. In some embodiments, the pH of the matrix is about 5. In some embodiments, the pH of the matrix is about 6.

[0099] In some aspects, the matrix contains about 0.1 mg / cm 2 ~about 5.0 mg / cm 2 of triptan. In some embodiments, the matrix contains about 0.1 mg / cm 2 ~about 3.0 mg / cm 2 of triptan. In some embodiments, the matrix contains about 0.5 mg / cm 2 ~about 5.0 mg / cm 2 of triptan. In some embodiments, the matrix contains about 0.5 mg / cm 2 ~about 3.0 mg / cm 2 of triptan. In some embodiments, the matrix contains about 0.5 mg / cm 2 ~about 2.0 mg / cm 2 of triptan. In some embodiments, the matrix contains about 0.5 mg / cm 2 of triptan. In some embodiments, the matrix contains about 1 mg / cm 2 of triptan. In some embodiments, the matrix contains about 2 mg / cm 2 of triptan. In a preferred embodiment, the triptan is sumatriptan.

[0100] In some embodiments, the matrix comprises a stabilizer of about 0.1 mg / cm 2 to about 5.0 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 0.1 mg / cm 2 to about 3.0 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 0.5 mg / cm 2 to about 5.0 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 0.5 mg / cm 2 to about 3.0 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 0.5 mg / cm 2 to about 2.0 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 0.5 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 1 mg / cm 2 In some embodiments, the matrix comprises a stabilizer of about 2 mg / cm 2 In a preferred embodiment, the stabilizer is sucrose.

[0101] In some embodiments, the patch further comprises an antibacterial agent. In some embodiments, the antibacterial agent is selected from benzoic acid, methylparaben, propylparaben, benzalkonium chloride, chlorhexidine, cresol, salicylic acid, sorbic acid, benzethonium chloride, and combinations thereof.

[0102] In some embodiments, the present application also includes a method for using a patch as described herein for administering a triptan to a subject in need thereof. In some embodiments, the method of treating a subject includes identifying a subject having migraine, creating a plurality of micropores in the subject's skin, and applying a patch to the subject's skin over the micropores for a period of time. In some embodiments, the patch includes a top layer comprising an adhesive, an intermediate layer comprising a triptan, and a bottom layer. In some embodiments, the bottom layer includes a release liner. In some embodiments, the period of time is selected to deliver a therapeutically effective amount of the triptan through the plurality of micropores.

[0103] In some embodiments, creating a plurality of micropores in the subject's skin includes applying a transdermal micro-poration device to the subject's skin. In some embodiments, the transdermal micro-poration device includes a conductive member including an array of conductive filaments. In some embodiments, the transdermal micro-poration creates micropores by thermal tissue ablation. In some embodiments, the transdermal micro-poration forms micropores in the epidermis through the stratum corneum.

[0104] In some embodiments, the transdermal micro-poration device has a piercing energy in the range of about 2 mJ / filament to about 8 mJ / filament. In some embodiments, the transdermal micro-poration device has a filament density in the range of about 200 filaments / cm 2 to about 500 filaments / cm 2 In some embodiments, the transdermal micro-poration device has a filament density of about 400 filaments / cm 2 In some embodiments, the transdermal micro-poration piercing energy is about 4 mJ / filament to about 5 mJ / filament, and the filament density is about 400 filaments / cm 2 In some embodiments, the size of the transdermal micro-poration filament array is in the range of about 0.5 cm 2 to about 3 cm 2 ​

[0105] In some embodiments, the patch does not substantially irritate the skin of the subject. As used herein, the term "does not substantially irritate the skin of the subject" includes obtaining a skin erythema score of about 3.0 or less, preferably about 2.0 or less, more preferably about 1.0 or less after patch removal. In another embodiment, the state of "not substantially irritating the skin of the subject" may refer to a skin irritation relief days of about 4.0 days or less, preferably about 3.0 days or less, more preferably about 2.5 days or less. In another embodiment, the state of "not substantially irritating the skin of the subject" is that the obtained skin erythema score is about 3.0 or less, preferably about 2.0 or less, more preferably about 1.0 or less after patch removal, and the skin irritation relief days is about 4.0 days or less, preferably about 3.0 days or less, more preferably about 2.5 days or less.

[0106] In some aspects, the present application also includes a system for administering a triptan to a subject in need thereof using a patch. In some embodiments, the transdermal drug delivery patch system includes a transdermal microporation device for heating the skin surface and a triptan drug delivery patch, including but not limited to, a triptan drug delivery patch as described herein. In some embodiments, the drug delivery patch includes a top layer including an adhesive, an intermediate layer having at least one reservoir for containing a triptan, and a bottom layer including a release liner. In some embodiments, the microporation device comprises a conductive member configured to generate thermal energy based on an electric current flowing through the conductive member and supply the thermal energy to the skin surface in contact with the conductive member during operation. In some embodiments, the transdermal drug delivery patch system further comprises a power source configured to supply an electric current to the conductive member in a plurality of pulses of a supply current value effective to create micropores in the skin surface.

[0107] Examples Various embodiments and alternative forms are disclosed in more detail in the following examples, which are in no way intended to limit the scope of the claims. In the following, Zol = zolmitriptan; CA = citric acid monohydrate; Suc = sucrose; AA = ascorbic acid; SB = sodium benzoate; TA = tartaric acid. The PASSPORT micro - poration system was utilized. The administration site was formed on the skin of the animal subject by electro - poration using a device having an array of 100 - 400 electro - poration filaments, such as the PassPort (trademark) electro - poration system of Nitto Denko Corporation.

[0108] Zolmitriptan and rizatriptan benzoate were purchased from INKE S.A. (Spain). Sumatriptan succinate was purchased from LGM Pharma (USA). The matrix of the drug patches used in Examples 1 - 10 was EH - 1212 as a non - woven material (Japan Vilene Company, LTD, Japan, WHC = 4mg / cm 2 ) It was manufactured by thermally bonding two materials, a white polyester fiber aggregate and a transparent polyester film (12 micrometers), to produce a connected sheet.

[0109] Example 1 Preparation of Drug Patch The drug patches of Examples 1 - 3 below were prepared by the following method.

[0110] This patch was prepared by the following method. First, a backing layer material of a predetermined size was formed using a punching die. For example, it was a 25×25 mm square. Next, a matrix material, such as a non-woven fabric, was formed into a predetermined size, such as a 10×10 mm square, using a punching die. The formed matrix material was attached to the central portion of the backing layer material (hereinafter referred to as a blank patch). Next, additives such as CA, AA, Suc, and a drug were weighed. Then, a solution was added to this additive and the drug. The solution used was deionized water or alcohol. Next, the solution was stirred until the additive and the drug were completely dissolved, thereby preparing a drug solution. Using a mechanical pipette, the desired drug solution was dropped onto the matrix material area of the blank patch. The matrix material was dried in an oven, for example, at 60 °C for 20 to 50 minutes to form a patch structure. A release coating such as a release liner was coated on the patch structure. By sealing with a heat sealer, the completed patch was made into a pouch with or without a desiccant.

[0111] Animal Experiment: Transdermal Delivery by Micro-poration Hairless guinea pigs aged 77 to 84 days were used as experimental animals. A drug patch was attached to the flanks of the skin of the experimental animals that had undergone a punching process under the desired punching conditions. The filament density mainly affects the area to be utilized for the movement of body fluids and components between the skin and the patch. The filament density was 200 or 400 filaments / cm 2 and the punching energy was about 4 and about 5 mJ / filament. Each drug patch was tested for each test subject by applying it to a 1 cm 2 micro-porated administration site. Blood was collected at the desired time during the time the patch was attached and after the patch was adhered, and each active ingredient was extracted by a conventional method. Next, the blood concentration was quantified by high performance liquid chromatography (LC-MS / MS). The given bioavailability in Tables 1 to 3 is the relative bioavailability with respect to subcutaneous injection.

[0112] Skin Irritation Score Criteria Following the removal of the patch, a skin irritation test was conducted. The scale of the skin irritation test was the evaluation of the skin directly under the matrix. The scale of the skin irritation test is shown in Table 1.

[0113]

Table 1

[0114] This example describes the effects of a skin irritation reducing agent and micro-poration conditions on tryptan-induced skin irritation. These results are summarized in Table 2.

[0115]

Table 2

[0116] Example 2 This example describes the effects of a skin irritation reducing agent and micro-poration conditions on tryptan-induced skin irritation. These results are summarized in Table 3.

[0117]

Table 3

[0118] Example 3 This example describes the effects of a skin irritation reducing agent and micro-poration conditions on tryptan-induced skin irritation. These results are summarized in Table 4.

[0119]

Table 4

[0120] Example 4 This example describes a study on the administration routes in hairless rats. In this study, four groups of hairless rats were tested under the following conditions: (1) Group 1 (2 mg of sumatriptan, oral administration); (2) Group 2 (2 mg of sumatriptan, intranasal administration); (3) Group 3 (2 mg of sumatriptan, intravenous injection); and (4) Group 4 (2 mg of sumatriptan, transdermal micro-poration). These results are summarized in Figure 1 and Table 5.

[0121] Animal Experiment: Oral Administration, Group 1 Hairless rats were used as experimental animals. After orally administering a chemical solution (2.0 ml) containing 2.0 mg of sumatriptan, blood was collected at the desired time, each active ingredient was extracted by a conventional method, and then the blood concentration was quantified by high performance liquid chromatography (LC-MS / MS).

[0122] Animal Experiment: Intranasal Administration, Group 2 Hairless rats were used as experimental animals. After intranasally administering a chemical solution (10 μl) containing 2 mg of sumatriptan, blood was collected at the desired time, each active ingredient was extracted by a conventional method, and then the blood concentration was quantified by high performance liquid chromatography (LC-MS / MS).

[0123] Animal Experiment: Intravenous Administration, Group 3 Hairless rats were used as experimental animals. After intravenously administering a chemical solution (200 μl) containing 2 mg of sumatriptan, blood was collected at the desired time, each active ingredient was extracted by a conventional method, and then the blood concentration was quantified by high performance liquid chromatography (LC-MS / MS).

[0124] Animal Experiment: Transdermal Delivery by Micro-poration, Group 4 Hairless rats were used as experimental animals. A drug patch was attached to the flanks of the skin of the experimental animals that had received micro-poration treatment under the desired conditions. In this study, the micro-poration conditions for transdermal micro-poration were 400 pores / cm 2 , 5.2 mJ / filament. The administration side was 1 cm2 It was. During the time the patch was being applied and after the patch was attached, blood was collected at the desired time, each active ingredient was extracted by a conventional method, and then the blood concentration was quantified by high performance liquid chromatography (LC-MS / MS). The patch formulation in this study contained 2 mg of zolmitriptan, 0.5 mg of sucrose, 4 mg of AA, and a 1 cm 2 nonwoven matrix (EH-1212, WHC = 4 mg / cm 2 ).

[0125] The given bioavailability in Table 5 is the absolute bioavailability relative to an IV injection.

[0126]

Table 5

[0127] Example 5 This example describes a study of the route of administration in guinea pigs using the same method as described in Example 4. In this study, the base refers to zolmitriptan. The perforation conditions of the transdermal micro-poration and the matrix of the drug patch were the same as those in Group 4 of Example 4.

[0128] In this study, five groups of guinea pigs were tested under the following conditions: (1) Group 1 (10 mg / 4 ml of base, oral route); (2) Group 2 (5 mg / 2 ml of base, oral route); (3) Group 3 (2 mg / 4 mL of base, oral route); (4) Group 4 (2.0 mg / cm 2 of base, transdermal micro-poration); and (5) Group 5 (2 mg / 200 μL, SubQ). These results are summarized in Figure 2 and Table 6. The given bioavailability in Table 6 is the relative bioavailability relative to a subcutaneous injection.

[0129] In further research, PK studies were conducted comparing humans with hairless guinea pigs (HGP). These results are summarized in Figure 3 (Headache 2006, 46, 138 - 149).

[0130]

Table 6

[0131] Example 6 This example describes various stabilizers and skin irritation reducers in micro - poration. The matrix is the same as above. Briefly, the micro - poration conditions for transdermal micro - poration are as follows: the pore density is 400 pores / cm 2 and the perforation energy is 4 mJ / filament, and the filament density is 400 filaments / cm 2 The administration site was 1 cm 2 These results are summarized in Tables 7 - 11. Table 7 describes a study on the amount of citric acid in micro - poration using guinea pigs. The given bioavailability in Tables 7 - 10 is the relative bioavailability to subcutaneous injection.

[0132]

Table 7

[0133] Table 8 summarizes the results of a study using organic acids as skin irritation reducers in micro - poration for guinea pigs.

[0134]

Table 8

[0135] Table 9 summarizes the results of a study using stabilizers, sucrose, and micro - poration on guinea pigs.

[0136]

Table 9

[0137] Table 10 summarizes the results of studies using sumatriptan by micro - poration in guinea pigs.

[0138]

Table 10

[0139] Table 11 summarizes the results of a dose - comparison study using hairless rats.

[0140]

Table 11

[0141] The given bioavailability in Table 11 is the absolute bioavailability relative to IV injection.

[0142] Example 7 This example describes various effects of filament density. These studies were conducted to investigate the effects of filament density on the PK profile and side effects (pain due to perforation and skin irritation). Filament density mainly affects the area available for the movement of body fluids and components between the skin and the patch. The range of filament density is from 100 filaments / cm 2 ~ 400 filaments / cm 2 and the perforation energy was 3 - 4 mJ / filament. The detailed conditions are summarized in Table 12.

[0143]

Table 12

[0144] Regarding the results of the PK profile, 100 filaments / cm2 The density showed a lower Cmax and a slower Tmax, which means that the profile is of a certain sustained-release form (see Figures 4 and 5). This is because the density of 100 filaments / cm 2 showed that the density of the filaments was slower in delivering the drug to the systemic circulation. On the other hand, the higher the density, the higher the Cmax and the faster the Tmax. In particular, at an energy of 4 mJ and a density of 400 filaments / cm 2 showed the highest Cmax and the fastest Tmax among the tested groups. Furthermore, the relative BA under this condition was approximately 100%. Under the tested conditions, a density of 400 filaments / cm 2 seems to be an excellent candidate for forming an area sufficient to obtain body fluid for dissolving the components and delivering the triptan drug. The PK data are summarized in Figure 6 and Table 13.

[0145]

Table 13

[0146] From the perspective of side effects, the density of 100 filaments / cm 2 is the mildest condition in both pain due to perforation and skin irritation, and is reasonable (Figures 7, 8, 9). When comparing the density of 200 filaments / cm 2 and the density of 400 filaments / cm 2 no significant difference was observed, and no severe side effects occurred under either condition.

[0147] The given bioavailability in Table 13 is the relative bioavailability with respect to SC injection.

[0148] Example 8 This example describes various effects regarding heating energy. The perforation energy is related to the pore shape such as depth and width. In these animal experiments, as shown in Table 14, at a density of 400 filaments / cm 2In the case of the density, a piercing energy of 2 to 5 mJ / filament was used.

[0149] [Table 14]

[0150] As a result of the PK study, all evaluated data (AUC, BA, Cmax, and Tmax) showed a nearly proportional trend in the range of 2 to 4 mJ / filament, and 4 mJ / filament was the most desirable condition for any evaluation item (see Figures 10 and 11). However, when comparing 4 and 5 mJ / filament, the PK results of 5 mJ / filament were almost the same as or slightly inferior to those of 4 mJ / filament. This means that 5 mJ / filament forms pores that are larger than necessary and induces more body fluid than is required for a 2 mg dose formulation. In other words, the drug concentration in the body fluid induced by the energy of 5 mJ / filament can be lower than the drug concentration by 4 mJ / filament in the case of a 2 mg dose formulation. Therefore, the osmotic pressure and diffusion of the drug at 5 mJ / filament are also lower than those at 4 mJ / filament. For this reason, a filament density of 400 filaments / cm with a piercing energy of 4 mJ / filament 2 is an excellent condition for a 2 mg dosage form.

[0151] Regarding side effects, as shown in Figures 12 and 13, there is no significant difference among the tested piercing energies. Although higher energy may cause somewhat more severe adverse effects, their scores seem to be within the acceptable range.

[0152] Briefly speaking, appropriate piercing conditions have been specified according to the dose. However, for now, the filament density is 400 filaments / cm 2It should be up to this point, and if not necessary, it is better to set a lower filament heating energy. For a formulation with a dose of 2 mg, a filament density of 400 filaments / cm at 4 mJ / filament 2 is the most effective among the tested conditions. This data is summarized in Table 15.

[0153]

Table 15

[0154] The given bioavailability in Table 15 is the relative bioavailability with respect to SC injection.

[0155] Example 9 This example describes the selection of a desirable filament array size. Assuming a filament density of 400 filaments / cm 2 and an energy of 4 or 5 mJ / filament for a dose higher than 2 mg, it may be necessary to make the filament array size larger. The dose range is 0.5 - 4 mg, and the filament array size range is 1.0 - 2.0 cm 2 was. These results are summarized in Table 16.

[0156]

Table 16

[0157] As described in Figures 14 and 15, from the PK data, it was found that a filament array size of 2 cm 2 showed a good dose response up to a dose of 4 mg when using an energy of 4 mJ / filament. 1.5 cm 2 was less effective at a dose of 4 mg. This is the case for a density of 400 filaments / cm at an energy of 4 mJ / filament 2 and a size of 1 cm 2A dose of 2 mg per perforation area means the best condition in this study. For an energy of 5 mJ / filament, it may be sufficient for a dose of 4 mg with a filament array size of 1.5 cm 2 However, for a dose of 4 mg, the former condition (filament density of 400 filaments / cm 2 , 4 mJ / filament, 2 cm 2 ) may be better than the latter condition (filament density of 400 filaments / cm 2 , 5 mJ / filament, 1.5 cm 2 ).

[0158] Regarding side effects, a larger perforation area and higher energy seem to cause slightly more severe adverse effects, as seen in Figures 16 and 17. In particular, the pain due to perforations of 1.5 cm 2 and 2.0 cm 2 was greater.

[0159] In summary, when a filament density of 400 filaments / cm 2 and an energy of 4 mJ / filament are used, a dose of 2 mg per 1 cm 2 perforation area is the best condition in this study. If a wider perforation area than 1 cm 2 is required at a dose higher than 2 mg, the pain caused by the perforation should be taken into account. This data is summarized in Table 17.

[0160]

Table 17

[0161] The given bioavailability in Table 17 is the relative bioavailability with respect to SC injection.

[0162] Example 10 This example describes a study on the administration route in hairless rats using sumatriptan succinate. In this study, four groups of hairless rats were tested under the following conditions: (1) Group 1 (3 mg of free base API, Suc: 0.5 mg, AA: 1 mg); (2) Group 2 (6 mg of free base API, Suc: 0.5 mg, AA: 1 mg); (3) Group 3 (9 mg of free base API, Suc: 0.5 mg, AA: 1 mg); (4) Group 4 (6 mg of free base API per head of 100 μL of physiological saline). In the context of these investigations, the term "free base" refers to the weight of the sumatriptan free base present (for example, referring to Example 1, 4.2 mg of sumatriptan succinate containing 3.0 mg of sumatriptan free base was used). Further, for example, referring to Figure 18, "4.2SS" indicates the presence of 4.2 mg of sumatriptan succinate. The perforation conditions of transdermal micro-poration and the matrix of the drug patch were the same as those in Group 4 of Example 4. These results are summarized in Figure 18 and Table 18.

[0163]

Table 18

[0164] The given bioavailability in Table 18 is the relative bioavailability with respect to SC injection. Item 1 A patch for delivering a triptan drug to a subject in need thereof, comprising a top layer containing an adhesive, an intermediate layer containing a triptan, and a bottom layer containing a release liner The patch. Item 2 The patch according to Item 1, wherein the intermediate layer further contains a skin irritation reducing agent. Item 3 The patch according to Item 1 or 2, wherein the intermediate layer further contains a stabilizer in an amount in the range of about 0.01 g / cm 2 to about 0.5 g / cm 2 . Item 4 The patch according to Item 2 or 3, wherein the molar ratio of the amounts of the triptan and the skin irritation reducing agent is in the range of about 1:0.5 to about 1:2. Item 5 The patch according to any one of Items 1 to 4, wherein the triptan is selected from sumatriptan, rizatriptan, or zolmitriptan. Item 6 The patch according to any one of Items 1 to 5, wherein the skin irritation reducing agent is an organic acid or a salt thereof. Item 7 The patch according to Item 6, wherein the organic acid is selected from ascorbic acid, citric acid, succinic acid, tartaric acid, maleic acid, lactic acid, benzoic acid, and sorbic acid, or a combination thereof. Item 8 The patch according to any one of Items 3 to 7, wherein the stabilizer is a saccharide. Item 9 The patch according to Item 8, wherein the saccharide is selected from mannitol, maltose, trehalose, xylitol, xylose, dextrose, lactose, sorbitol, sucrose, fructose, maltitol, erythritol, lactitol, isomalt, and cyclodextrin, or a combination thereof. Item 10 The patch according to any one of Items 1 to 9, wherein the intermediate layer further contains a reservoir configured to contain a triptan. Item 11 The patch according to Item 10, wherein the reservoir contains a matrix. Item 12 The patch according to Item 10, wherein the matrix is in the range of about 0.1 mg / cm 2 to about 10 mg / cm 2 The patch according to item 11, having a water retention capacity within the range of Item 13 The patch according to item 11 or 12, wherein the matrix includes a non-woven fabric. Item 14 The patch according to any one of items 11 to 13, wherein the matrix has a thickness in the range of about 10 μm to about 100 μm. Item 15 The basis weight of the matrix is about 10 g / m 2 ~about 100 g / m 2 The patch according to any one of items 11 to 14, which is in the range of. Item 16 The size of the matrix is about 0.25 cm 2 ~about 5 cm 2 The patch according to any one of items 11 to 15, which is in the range of. Item 17 The patch according to any one of items 1 to 16, further comprising an antibacterial agent. Item 18 The patch according to item 17, wherein the antibacterial agent is selected from at least one of benzoic acid, methyl paraben, propyl paraben, benzalkonium chloride, chlorhexidine, cresol, salicylic acid, sorbic acid, and benzethonium chloride, or a combination thereof. Item 19 The patch according to any one of items 2 to 18, wherein the skin irritation reducing agent is an inorganic acid or a salt thereof. Item 20 The patch according to item 19, wherein the inorganic acid is selected from hydrochloric acid, phosphoric acid, boric acid, and acetic acid. Item 21 The matrix contains about 0.1 to about 5.0 mg / cm 2 of sumatriptan, and the patch according to any one of items 11 to 20. Item 22 The matrix contains about 0.5 to 3.0 mg / cm 2 of sumatriptan, and the patch according to any one of items 11 to 21. Item 23 The patch according to any one of items 4 to 22, wherein the amounts of the sumatriptan and the skin irritation reducing agent are in the range of about 1:0.75 to about 1:1.5. Item 24 The size of the matrix is about 0.25 cm 2 ~about 4 cm 2 The patch according to any one of items 16 to 23, which is in the range of. Item 25 The patch according to any one of items 8 to 24, wherein the stabilizer is sucrose. Item 26 The total amount per unit area of the matrix containing sumatriptan and the stabilizer is 0.05 to 0.5 mg / cm 2 The patch according to any one of items 11 to 25. Item 27 Identifying a subject having migraine, Creating a plurality of micropores on the skin of the subject, Applying a patch to the skin of the subject over a certain period of time on the micropores including, wherein the patch is an uppermost layer containing an adhesive, An intermediate layer containing a triptan, and A bottom layer containing a release liner A method of treating a subject in need thereof, wherein the predetermined period is selected to deliver a therapeutically effective amount of the triptan through the plurality of micropores. Item 28 The method according to item 27, wherein the intermediate layer further comprises a skin irritation reducing agent and a stabilizer. Item 29 The method according to item 27 or 28, wherein creating a plurality of micropores in the skin of the subject comprises applying a transdermal microporation device to the skin of the subject. Item 30 The transdermal microporation is thermal tissue ablation by using a filament array having a plurality of filaments disposed on the skin of the subject, and each filament conductively delivers thermal energy through direct contact with the tissue membrane to form the plurality of micropores in the micropore region of the tissue membrane. The method according to any one of items 27 to 29. Item 31 The method according to any one of items 27 to 30, wherein the transdermal microporation forms the micropores in the epidermis through the stratum corneum. Item 32 The method according to any one of items 27 to 31, wherein the transdermal microporation device has a piercing energy of about 2 to about 5 mJ / filament. Item 33 The transdermal microporation device has a piercing energy density of about 200 to about 500 filaments / cm 2 The method according to any one of items 27 to 32. Item 34 The transdermal microporation device has a piercing energy density of about 400 filaments / cm 2 The method according to any one of items 27 to 33. Item 35 The transdermal microporation piercing energy is about 4 mJ / filament, and the piercing energy density is about 400 filaments / cm 2 The method according to any one of items 27 to 34. Item 36 The size of the micropore region of the tissue membrane is about 0.5 to about 5 cm 2 The method according to any one of items 27 to 35. Item 37 The method according to any one of items 27 to 36, wherein the triptan and the skin irritation reducing agent are in the range of about 1:0.5 to about 1:2. Item 38 A transdermal drug delivery patch system for delivering a drug, comprising A transdermal microporation device for heating the skin surface, and A triptan drug delivery patch A transdermal drug delivery patch system. Item 39 The transdermal drug delivery patch system according to item 38, comprising an uppermost layer containing an adhesive, an intermediate layer having at least one reservoir configured to contain a triptan, and a lowermost layer containing a release liner. Item 40 The transdermal drug delivery patch system according to item 38 or 39, wherein the intermediate layer further contains a skin irritation reducing agent and a stabilizer. Item 41 The transdermal drug delivery patch system according to any one of items 38 to 40, wherein the micro-poration device includes a conductive member configured to generate thermal energy based on an electric current flowing through the conductive member and supply the thermal energy to a skin surface in contact with the conductive member during operation. Item 42 The transdermal drug delivery patch system according to any one of items 38 to 41, further comprising a power source configured to supply an electric current to the conductive member in a plurality of pulses of supply current values. Item 43 The transdermal drug delivery system according to any one of items 39 to 42, wherein the intermediate layer further contains a skin irritation reducing agent and a stabilizer. Item 44 The transdermal drug delivery system according to any one of items 38 to 43, wherein the transdermal micro-poration device is configured to form a plurality of micropores in the skin of the subject. Item 45 The transdermal drug delivery system according to any one of items 38 to 44, wherein the transdermal micro-poration device is configured to effect thermal tissue ablation by using a filament array having a plurality of filaments disposed on the skin of the subject, and each filament is configured to conductively deliver thermal energy through direct contact with the tissue membrane to form the plurality of micropores in the micropore region of the tissue membrane. Item 46 The transdermal drug delivery system according to item 44 or 45, wherein the transdermal micro-poration forms the micropores in the epidermis through the stratum corneum. Item 47 The transdermal drug delivery system according to any one of items 38 to 46, wherein the transdermal micro-poration device is configured to provide a perforation energy of about 2 to about 5 mJ / filament. Item 48 The transdermal micro-poration device has about 200 to about 500 filaments / cm 2 The transdermal drug delivery system according to any one of items 38 to 47, configured to provide a perforation energy density of. Item 49 The transdermal micro-poration device has about 400 filaments / cm 2 The transdermal drug delivery system according to any one of items 38 to 48, which is configured to provide a perforation energy density of Item 50 wherein the transdermal micro-poration provides a perforation energy of about 4 mJ / filament and about 400 filaments / cm 2 The transdermal drug delivery system according to any one of items 38 to 49, which is configured to provide a perforation energy density of Item 51 wherein the size of the micropore region of the tissue membrane is about 0.5 to about 5 cm 2 The transdermal drug delivery system according to any one of items 38 to 50. Item 52 The transdermal drug delivery system according to any one of items 38 to 51, wherein the triptan and the skin irritation reducing agent are in a ratio of about 1:0.5 to about 1:2. Item 53 Use of a therapeutically effective amount of a triptan for treating migraine by applying a patch according to any one of items 1 to 26 to the skin of a subject, wherein the patch is applied to the skin of the subject for a certain period, and the certain period is selected to deliver the therapeutically effective amount of the triptan through a plurality of micropores opened in the skin of the subject. Item 54 The use according to item 53, wherein opening the plurality of micropores in the skin of the subject includes applying a transdermal micro-poration device to the skin of the subject. Item 55 The use according to item 54, wherein the transdermal micro-poration is configured to cause thermal tissue ablation by using a filament array having a plurality of filaments disposed on the skin of the subject, and each filament conducts thermal energy through direct contact with the tissue membrane to form the plurality of micropores in the micropore region of the tissue membrane. Item 56 The use according to item 54 or 55, wherein the transdermal micro-poration forms the micropores in the epidermis through the stratum corneum. Item 57 The use according to any one of items 54 to 56, wherein the transdermal micro-poration device provides a perforation energy of about 2 to about 5 mJ / filament. Item 58 wherein the transdermal micro-poration device provides a perforation energy density of about 200 to about 500 filaments / cm 2 The use according to any one of items 55 to 57. Item 59 wherein the transdermal micro-poration device provides a perforation energy density of about 400 filaments / cm 2 The use according to any one of items 55 to 58. Item 60 The percutaneous microporation perforation energy is about 4 mJ / filament, and the perforation energy density is about 400 filaments / cm 2 The use according to any one of items 55 to 59, wherein the use is as described above. Item 61 The size of the micropore region of the tissue membrane is about 0.5 to about 5 cm 2 The use according to any one of items 55 to 60, wherein the use is as described above. Item 62 The use according to any one of items 55 to 61, wherein the triptan and the skin irritation reducing agent are in a ratio of about 1:0.5 to about 1:2.

Claims

Patch for transdermal delivery of triptan drugs through a plurality of micropores formed in a target skin layer, An uppermost layer containing an adhesive, An intermediate layer containing a triptan, a skin irritation reducing agent, an antibacterial agent, and a stabilizer, wherein the stabilizer contains saccharides in an amount in the range of 0.1 mg / cm2 to 5.0 mg / cm2, the intermediate layer, A lowermost layer containing a release liner And a patch. The patch according to claim 1, wherein the stabilizer is present in an amount in the range of 0.1 g / cm2 to 3.0 g / cm2. The patch according to claim 1 or 2, wherein the molar ratio of the amount of the triptan and the skin irritation reducing agent is in the range of 1:0.5 to 1:

2. The patch according to any one of claims 1 to 3, wherein the triptan is selected from sumatriptan, rizatriptan, or zolmitriptan. The patch according to any one of claims 1 to 4, wherein the skin irritation reducing agent is an organic acid or its salt, or an inorganic acid or its salt. The patch according to any one of claims 1 to 5, wherein the intermediate layer further includes a reservoir, and wherein the reservoir is a designated area or chamber within the patch configured to contain a triptan for delivery through the micropores formed in the target skin layer. The patch according to claim 6, wherein the reservoir contains a matrix. The patch according to claim 10, wherein the molar ratio of the amount of the zolmitriptan and the skin irritation reducing agent is in the range of 1:0.75 to 1:1.

5. A transdermal drug delivery patch system for delivering a drug, A transdermal microporation device for heating the skin surface, And a triptan drug delivery patch Including, The transdermal drug delivery patch system, wherein the triptan drug delivery patch includes an uppermost layer containing an adhesive, an intermediate layer containing a triptan, and a lowermost layer containing a release liner. The transdermal drug delivery patch system according to claim 13, wherein the transdermal microporation device includes a conductive member configured to generate thermal energy based on a current flowing through the conductive member and supply the thermal energy to the skin surface in contact with the conductive member during operation. The matrix has a water retention capacity in the range of 0.1 mg / cm ２ to 10 mg / cm ２ The patch according to claim 7, which has a water retention capacity in the range of 0.1 mg / cm to 10 mg / cm. ​ The matrix includes a non-woven fabric, has a thickness in the range of 10 μm to 100 μm, has an area weight in the range of 10 g / m ２ to 100 g / m ２ , or has a size in the range of 0.25 cm ２ to 5 cm ２ The patch according to claim 7 or 8. ​ The matrix contains 0.1 to 5.0 mg / cm ２ of zolmitriptan, and the patch according to any one of claims 7 to 9. ​ ​ ​ The total amount per unit area of the matrix containing zolmitriptan and the stabilizer is in the range of 0.05 to 0.5 mg / cm ２ The patch according to claim 10 or 11, wherein the range is as described. ​ ​ ​ ​ ​ ​ ​ ​ ​ The transdermal drug delivery patch system according to claim 13 or 14, further comprising a power supply configured to supply current to the conductive member with a plurality of pulses of supply current values.

16. The transdermal drug delivery patch system according to any one of claims 13 to 15, wherein the intermediate layer further comprises a skin irritation reducing agent and a stabilizer.

17. The transdermal drug delivery patch system according to any one of claims 13 to 16, wherein the transdermal microporation device is configured to form a plurality of micropores in a target skin layer.

18. The transdermal drug delivery patch system according to any one of claims 13 to 17, wherein the transdermal microporation device is configured to effect thermal tissue ablation by using a filament array having a plurality of filaments disposed on the target skin, and each filament is capable of conductively delivering thermal energy through direct contact with the tissue membrane to form the plurality of micropores in the micropore region of the tissue membrane.

19. The transdermal drug delivery patch system according to claim 17 or 18, wherein the transdermal microporation device forms the plurality of micropores in the epidermis through the stratum corneum.

20. The transdermal microporation device is configured to provide a perforation energy in the range of 2 to 5 mJ / filament, or a filament density in the range of 200 to 500 filaments / cm ２ The transdermal drug delivery patch system according to any one of claims 13 to 19, wherein the transdermal microporation device is configured to provide a filament density in the range of 200 to 500 filaments / cm.

21. The transdermal microporation device is configured to provide a piercing energy of 4 mJ / filament and a filament density of 400 filaments / cm ２ The transdermal drug delivery patch system according to any one of claims 13 to 20, which is configured to provide such filament density.

22. The size of the micropore region of the tissue membrane is in the range of 0.5 to 5 cm ２ The transdermal drug delivery patch system according to any one of claims 13 to 21, wherein the size is in the range of 0.5 to 5 cm

23. A patch for delivering a triptan drug according to any one of claims 1 to 12 for treating migraine, wherein the patch is applied to the skin of the subject for a certain period of time, and the certain period of time is selected to deliver the therapeutically effective amount of triptan through a plurality of micropores opened in the skin layer of the subject.

24. The patch according to claim 23, wherein opening the plurality of micropores in the skin layer of the subject includes applying a transdermal microporation device to the skin of the subject.

25. The patch according to claim 24, wherein the transdermal microporation device is configured to effect thermal tissue ablation by using a filament array having a plurality of filaments, and each filament is capable of conductively delivering thermal energy through direct contact with the tissue membrane to form the plurality of micropores in the micropore region of the tissue membrane.

26. The patch according to claim 24 or 25, wherein the transdermal microporation device provides a perforation energy of 2 to 5 mJ / filament.

27. The transdermal microporation device has a filament density of 200 to 500 filaments / cm ２ The patch according to claim 25 or 26, having a filament density of

28. The size of the micropore region of the tissue membrane is 0.5 to 5 cm ２ The patch according to any one of claims 25 to 27, which is such.

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