Triptans Microporation Delivery System

Abstract

A transdermal delivery system for delivering a triptan into a tissue membrane of an individual. The system includes a transdermal microporation device for heating a skin surface and a triptan drug delivery patch. The drug delivery patch includes a top layer comprising an adhesive, an intermediate layer comprising a triptan, and a bottom layer. A method for treating an individual includes identifying an individual suffering from migraine, opening a plurality of micropores in the skin of the individual using a transdermal microporation device, and applying the triptan drug delivery patch to the skin of the individual for a period of time on the micropores to effectively deliver an effective amount of a triptan through the micropores to treat the migraine of the individual.

Description

[0001] background

[0002] field

[0003] The present application relates to compositions, devices and methods for transdermal drug delivery, and in particular to triptan compositions and methods of administering a triptan to an individual via a transdermal microporation device.

[0004] describe

[0005] Migraine is a condition that affects approximately 10% of the adult population worldwide, affecting approximately 600 million people, including approximately 28 million in the United States alone. Women experience migraine headaches three times more often than men. Migraine headaches are associated with inflamed and dilated blood vessels, resulting in severe, unilateral pain that worsens with physical activity. About one in five people with migraines experience aura or visual symptoms, such as bright spots, jagged lines, or gray vision. Migraines typically last up to 24 hours, but can be anywhere from four to 72 hours, and patients often experience migraine attacks once or twice a month.

[0006] Migraines can be triggered by many different factors, including stressors in life, certain foods or eating habits, changes in circadian rhythms, schedules or sleep patterns, and climate changes such as air pressure or altitude, and cyclical changes in hormone levels during the menstrual cycle. Pharmacological interventions constitute the mainstay of treatment for migraines, and are used for both acute treatment (ablation) and prevention (prophylaxis).

[0007] Triptans are serotonin receptor agonists that can be used to treat moderate to severe acute migraines. When these agents are used early in the course of an attack, triptans stop more than 80% of migraines within two hours. However, there are several different triptan products available, and there are differences in the efficacy and tolerability of different drugs in this class. Triptans are also available in various preparations. Non-oral preparations are usually used for patients with gastrointestinal symptoms of nausea or vomiting and when a faster onset is required. Triptans are believed to work by activating serotonin (5-HT) receptors on trigeminovascular nerve endings, inhibiting the release of neurotransmitters that cause painful cranial vasodilation. In addition, triptans produce active vasoconstriction and can relieve the symptoms of migraine by stimulating 5-HT receptors on cranial blood vessels. Oral tablets containing triptans generally have insufficient efficacy and lack a sufficiently fast onset. Subcutaneous injections show higher efficacy and rapid onset, but sometimes cause serious side effects. Oral and nasal routes often cause undesirable taste problems and are difficult to administer to migraine patients with nausea and vomiting.

[0008] Passive transdermal drug delivery is a convenient and effective way to administer various therapeutic agents. This route of administration is non-invasive and produces stable drug delivery over an extended period of time. Although conventional transdermal systems (e.g., drug patches) have demonstrated the benefits of delivering drugs via the skin, they are only applicable to extremely limited quantities of drugs. This is because millions of dead skin cells form a protective barrier (stratum corneum) on the surface of the skin, preventing most therapeutic molecules from entering the skin.

[0009] The stratum corneum is mainly responsible for the barrier properties of the skin. Therefore, it is this layer that provides the maximum barrier to the transdermal flux of drugs or other molecules entering the body and analytes being discharged from the body. The stratum corneum (external keratinized layer of the skin) is a complex structure of dense cornified cell residues separated by lipid domains. Compared with the oral or gastric mucosa, the permeability of the stratum corneum to molecules outside or inside the body is much smaller. The stratum corneum is formed by keratinocytes, which include epidermal cells that mostly lose their nuclei and become keratinocytes. These dead cells constitute the stratum corneum, which has a thickness of only about 10 to 30 microns, and protects the body from the invasion of exogenous substances and the outward migration of endogenous fluids and dissolved molecules. The stratum corneum is constantly renewed by the shedding of stratum corneum cells and the keratinization process during the peeling to form new stratum corneum cells.

[0010] Historically, most drugs have been delivered orally or by injection. However, neither the oral or injection routes are well suited for continuous delivery of drugs over extended periods of time. In addition, injection methods of administration are neither convenient nor comfortable; in addition, needles continue to pose a hazard after their use. Therefore, transdermal drug delivery to the body has been a popular and effective method for delivering limited amounts of permeant to an organism.

[0011] Passive transdermal patches are generally limited to lipid-soluble drugs with a molecular weight of less than 500 Daltons. In order to enhance transdermal drug delivery, there are known methods for increasing the permeability of the skin to drugs. For example, U.S. Patent No. 8,116,860 describes a transdermal permeate delivery system and method that painlessly produces aqueous micropores in the stratum corneum within a few milliseconds. These aqueous channels enable water-soluble drugs to flow out of the transdermal patch, enter the active epidermis, and then enter the systemic circulation. The patch can be formulated to provide a bolus or continuous transdermal delivery.

[0012] A transdermal permeant delivery system is being developed under the PASSPORT trade name. The PASSPORT system consists of a reusable handheld applicator and a disposable perforator with a drug patch. Pressing the activation button of the applicator releases a pulse of energy to the perforator. This energy is rapidly conducted to the skin surface, painlessly ablating the stratum corneum beneath each filament to create microchannels. A simple transdermal patch is then applied to the ablated skin and drug delivery begins.

[0013] In 2013, the U.S. Food and Drug Administration (FDA) approved an iontophoresis system for transdermal delivery of triptan. The system is sold under the trade name ZECUITY and uses a battery-powered iontophoresis patch to deliver sumatriptan. However, in 2016, it was recalled from the market after the manufacturer received post-marketing reports of application site reactions described as "burns" and / or "scars" in patients treated with ZECUITY. Descriptions of these reactions include severe redness, skin lacerations, blisters or welds, and burns or scars where the patch is worn. Patients have described severe pain, itching, or burning. Although many cases subside within hours to weeks, there are reports of cases where skin reactions (usually skin discoloration) have not subsided after several months.

[0014] Thus, there remains a long felt need for improved compositions, devices, and methods for the transdermal delivery of triptans. Summary of the invention

[0015] In some aspects, described herein are patches for delivering a triptan drug to an individual in need thereof. The patch can include: a top layer comprising an adhesive; a middle layer comprising a triptan; and a bottom layer, wherein the bottom layer comprises a release liner.

[0016] In some embodiments, the intermediate layer further comprises a skin irritation reducing agent.

[0017] In some embodiments, the middle layer further comprises about 0.01 g / cm 2 To about 0.5g / cm 2 The amount of stabilizer.

[0018] In some embodiments, the amount of the triptan and the skin irritation reducing agent are in a molar ratio of about 1:0.5 to about 1:2.

[0019] In some embodiments, the triptan is selected from sumatriptan, rizatriptan, or zolmitriptan.

[0020] In some embodiments, the skin irritation reducing agent is an organic acid or a salt thereof.

[0021] 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.

[0022] In some embodiments, the stabilizer is a sugar.

[0023] In some embodiments, the sugar is selected from mannitol, maltose, trehalose, xylitol, xylose, dextrose, lactose, sorbitol, sucrose, fructose, maltitol, erythritol, lactitol, isomalt, and cyclodextrin, or a combination thereof.

[0024] In some embodiments, the intermediate layer further comprises a reservoir configured to contain a triptan.

[0025] In some embodiments, the reservoir comprises a matrix.

[0026] In some embodiments, the matrix has a density of about 0.1 mg / cm 2 To about 10mg / cm 2 water retention capacity.

[0027] In some embodiments, the substrate comprises a nonwoven fabric.

[0028] In some embodiments, the matrix has a thickness of about 10 μm to about 100 μm.

[0029] In some embodiments, the substrate area weight is about 10 g / m 2 About 100g / m 2 .

[0030] In some embodiments, the size of the matrix is ​​about 0.25 cm 2 To about 5cm 2 .

[0031] In some embodiments, the patch further comprises an antimicrobial agent.

[0032] In some embodiments, the antimicrobial agent is selected from at least one of benzoic acid, methylparaben, propylparaben, benzalkonium chloride, chlorhexidine, cresol, salicylic acid, sorbic acid, and benzethonium chloride, or a combination thereof.

[0033] In some embodiments, the skin irritation reducing agent is a non-organic acid or a salt thereof.

[0034] In some embodiments, the non-organic acid is selected from hydrochloric acid, phosphoric acid, boric acid, and acetic acid.

[0035] In some embodiments, the matrix comprises from about 0.1 to about 5.0 mg / cm 2 of zolmitriptan.

[0036] In some embodiments, the amount of zolmitriptan and the skin irritation reducing agent is from about 1:0.75 to about 1:1.15.

[0037] In some embodiments, the size of the matrix is ​​about 0.25 cm 2 To about 4cm 2 .

[0038] In some embodiments, the stabilizer is sucrose.

[0039] In some embodiments, the total amount of zolmitriptan and stabilizer per unit area of ​​the matrix is ​​0.05 to 0.5 mg / cm 2 .

[0040] In some aspects, described herein are methods of treating an individual in need thereof. The methods may include identifying an individual suffering from migraine, opening a plurality of micropores in the skin of the individual, applying a patch to the skin of the individual for a period of time over the micropores, wherein the patch comprises: a top layer comprising an adhesive; a middle layer comprising a triptan; and a bottom layer, wherein the bottom layer comprises a release liner, wherein the period of time is selected to deliver a therapeutically effective amount of the triptan through the plurality of micropores.

[0041] In some embodiments, the intermediate layer further comprises a skin irritation reducing agent and a stabilizer.

[0042] In some embodiments, opening the plurality of micropores in the skin of the individual comprises applying a transdermal microporation device to the skin of the individual.

[0043] In some embodiments, transdermal microporation is thermal tissue ablation.

[0044] In some embodiments, transdermal microporation creates micropores through the stratum corneum to the epidermis.

[0045] In some embodiments, the transdermal microporation device has a poration energy of about 2 to about 5 mJ / filament.

[0046] In some embodiments, the transdermal microporation device has about 200 to about 500 filaments / cm 2 The perforation energy density.

[0047] In some embodiments, the transdermal microporation device has about 400 filaments / cm 2 The perforation energy density.

[0048] In some embodiments, the transdermal microporation perforation energy is about 4 mJ / filament and the perforation energy density is about 400 filaments / cm 2 .

[0049] In some embodiments, the transdermal microporation filament array has a size of about 0.5 to about 5 cm 2 .

[0050] In some embodiments, the triptan and skin irritation reducing agent are in an amount of about 1:0.5 to about 1:2.

[0051] In some aspects, described herein are transdermal drug delivery patch systems for delivering drugs. The transdermal drug delivery patch system includes a transdermal microporation device for heating the skin surface; and a triptan drug delivery patch.

[0052] In some embodiments, a triptan drug delivery patch system comprises: a top layer comprising an adhesive; a middle layer having at least one reservoir configured to hold a triptan; and a bottom layer, wherein the bottom layer comprises a release liner.

[0053] In some embodiments, the intermediate layer further comprises a skin irritation reducing agent and a stabilizer.

[0054] In some embodiments, the microporation device includes a conductive member configured to generate thermal energy based on an electric current flowing through the conductive member during operation, and to supply the thermal energy to a skin surface in contact with the conductive member.

[0055] In some embodiments, the transdermal drug delivery patch system further comprises a power source configured to provide current to the conductive member in a plurality of pulses at a power source current value.

[0056] These and other embodiments are described in greater detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects of the following description and, together with the description, serve to explain the principles of the invention. In all drawings, like numerals represent like elements.

[0059] Figure 1 The results of a comparative study of routes of administration on hairless rats are illustrated.

[0060] Figure 2 The results of a comparative study of routes of administration in guinea pigs are illustrated.

[0061] Figure 3 Comparison of human and hairless guinea pig data is illustrated.

[0062] Figure 4 Pharmacokinetic (PK) curves of different filament densities are illustrated.

[0063] Figure 5 PK curves for different filament densities are illustrated.

[0064] Figure 6 The relationship between filament density and PK outcomes is illustrated.

[0065] Figure 7 Skin irritation results for different filament densities are illustrated.

[0066] Figure 8 Skin irritation results for different filament densities are illustrated.

[0067] Fig. 9 The relationship between filament density and side effects is illustrated.

[0068] Fig.10 PK curves for different pore energies are illustrated.

[0069] Fig.11 The relationship between pore energy and PK outcomes is illustrated.

[0070] Fig.12 Skin irritation results for different perforation energies are illustrated.

[0071] Fig.13 The relationship between perforation energy and side effects is illustrated.

[0072] Fig.14 PK curves for different filament array sizes are illustrated.

[0073] Fig.15 Dose responses for different filament array sizes are illustrated.

[0074] Fig.16 Skin irritation results for different filament array sizes are illustrated.

[0075] Fig.17 The relationship between dose and side effects is illustrated.

[0076] Fig.18 Comparative results of the subcutaneous injection route and the transdermal microporation system are exemplified. DETAILED DESCRIPTION

[0077] The present invention may be more readily understood by reference to the following detailed description, examples, drawings and claims and their preceding and subsequent descriptions. However, before disclosing and describing the present application apparatus, system and / or method, it should be understood that, unless otherwise stated, the present invention is not limited to the specific apparatus, system and / or method disclosed. It should also be understood that the terms used herein are only used for the purpose of describing specific aspects and are not necessarily intended to be limiting.

[0078] This description is provided as an effective teaching of the present invention. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the present invention described herein while still obtaining beneficial results. It will also be apparent that some desired benefits can be obtained by selecting some of the features described herein without utilizing other features. Therefore, those skilled in the art will recognize that many modifications and adjustments to this specification are possible, and even desirable in some cases, and are part of the present invention. Therefore, this description is provided to illustrate certain principles of the present invention, rather than to limit the present invention.

[0079] definition

[0080] 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" may include two or more such filaments unless the context dictates otherwise.

[0081] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another aspect includes from a particular value and / or to another particular value. Similarly, when a value is expressed as an approximation by using the antecedent "about," it is understood that the particular value constitutes another aspect. It is also understood that the endpoints of each range are both relevant to the other endpoint and are meaningful independently of the other endpoint.

[0082] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not occur.

[0083] As used herein, "stratum corneum" refers to the outermost layer of the skin, which is composed of about 15 to about 20 layers of cells in various stages of dryness. The stratum corneum provides a barrier that prevents water from being lost from the interior of the body to the external environment and prevents damage to the interior of the body from the external environment.

[0084] As used herein, "tissue" refers to an aggregate of cells of a particular type and their intercellular material that constitutes the structural material. At least one surface of the tissue must be accessible to the device. The preferred tissue is skin. Other tissues suitable for use in the present invention include mucosal tissues and soft organs.

[0085] 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 biological organism, including serum or whole blood, and interstitial fluid.

[0086] As used herein, "tissue membrane" can be any one or more epidermal layers of an individual. For example, in one aspect, the tissue membrane is a skin layer, which 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, generally identified as the stratum granulosum, the stratum spinosum, and the stratum germinativum. It will be understood by those of ordinary skill in the art that there is substantially no resistance or no resistance to transporting or absorbing permeates through the backing layer of the epidermis. Therefore, in one aspect, at least one path formed in the skin layer of an individual is a path in the stratum corneum of an individual. In addition, as used herein, "stratum corneum" refers to the outermost layer of the skin, generally composed of about 15 to about 20 layers of cells in different stages of drying. The stratum corneum provides a barrier to prevent water from being lost from the inside of the body to the external environment and to prevent the external environment from causing damage to the inside of the body. In addition, as used herein, "tissue membrane" can refer to an aggregate of structural materials formed by cells of a specific type and their intercellular substances. In various embodiments, at least one surface of the tissue membrane is accessible to one or more perforating devices and / or permeate compositions described herein. As described above, a preferred tissue membrane is skin. Other tissues suitable for use with such devices and compositions include mucosal tissues and soft organs.

[0087] As used herein, the term "subcutaneous fluid" may 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 the present specification is a moisture source comprising water.

[0088] As used herein, "perforation", "microperforation" or any such similar terms means the formation of small holes or gaps (hereinafter also referred to as "micropores") in or through a tissue or biological membrane (such as skin or mucous membrane) or the outer layer of an organism to reduce the barrier properties of the biological membrane for the purpose of selection to allow at least one permeate to pass from one side of the biological membrane to the other side. Preferably, the diameter of the hole or "micropore" so formed is about 1 to 1000 microns and extends into the biological membrane sufficient to disrupt the barrier properties of the stratum corneum without adversely affecting the underlying tissue. It should be understood that for simplicity, the term "micropore" is used in the singular, but the microperforation device described herein can form a plurality of artificial openings. For the purpose of selection or for certain medical or surgical purposes, perforation can reduce the barrier properties of the biological membrane to the body. For the purposes of this application, "perforation" and "microperforation" are used interchangeably and mean the same thing.

[0089] A "microporator" or "perforator" is a component of a microporation device capable of performing microporation. Examples of microporators or perforators include, but are not limited to, filaments capable of conductively delivering thermal energy via direct contact with a biological membrane to ablate a portion of the membrane to a depth sufficient to form a micropore, optically heated local dye / absorbent layer, electromechanical actuator, micro-lancet, array of micro-needles or lancets, sonic ablators, laser ablation systems, high pressure fluid jet puncture devices, etc. As used herein, "microporator" and "perforator" are used interchangeably.

[0090] As used herein, "penetration" means the controlled removal of cells caused by the heat and kinetic energy released when the pyrotechnic element explodes, which causes the cells of the biofilm and possibly some neighboring cells to be "blown away" from the site. As used herein, "fusible" and "fuse" refer to an element that can remove itself from an electrical circuit when a sufficient amount of energy or heat is applied to the circuit. That is, when the resistive, electrically activated perforating element is designed as a fusible element, this means that during or after the formation of micropores in the biofilm, upon activation, the element opens, thereby preventing current from flowing through the element.

[0091] As used herein, "penetration enhancement" or "permeation enhancement" means an increase in the permeability of a biological membrane to a drug, biologically active composition, or other chemical molecule, compound, particle, or substance (also referred to as a "permeate"), thereby increasing the rate at which the drug, biologically active composition, or other chemical molecule, compound, or particle penetrates the biological membrane.

[0092] As used herein, "enhancer", "chemical enhancer", "penetration enhancer", "permeation enhancer" and the like include all enhancers that increase the flux of permeates, analytes or other molecules across biological membranes, and are limited only by function. In other words, all cell envelope disordering compounds and solvents and any other chemical enhancers are intended to be included. In addition, all active force enhancer technologies are included, such as the application of acoustic energy, mechanical suction, pressure or local deformation of tissue, iontophoresis or electroporation. One or more enhancer technologies can be combined sequentially or simultaneously. For example, a chemical enhancer can be applied first to make the capillary wall permeable, and then iontophoresis or an acoustic energy field can be applied to actively drive the permeate into those tissues surrounding and including the capillary bed.

[0093] As used herein, "transdermal" or "percutaneous" refers to the passage of a permeant into and through a biological membrane to achieve therapeutically effective blood levels or local tissue levels of the permeant, or the passage of molecules or fluids ("analytes") present in the body through a biological membrane so that the analyte molecules can be collected outside the body.

[0094] As used herein, the terms "permeant," "drug," "permeant composition," or "pharmacologically active agent," or any other similar term, are used interchangeably and 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 in this specification that induces a desired biological or pharmacological effect, which may include, but is not limited to (1) having a prophylactic effect on an organism and preventing an undesirable biological effect, such as infection, (2) alleviating a condition caused by a disease, such as relieving pain or inflammation, and / or (3) alleviating, reducing, or completely eliminating a disease in an organism. The effect may be local, such as providing a local anesthetic effect, or may be systemic. Such substances include a variety of compounds that are typically delivered into the body (including through body surfaces and membranes, including the skin). Typically, by way of example and not limitation, such substances may include any biologically active agent, such as a drug, chemical, or biological material, that induces a desired biological or pharmacological effect. To this end, in one aspect, the permeant may be a small molecule agent. In another aspect, the permeant may be a macromolecular agent. In various embodiments, the permeant is a triptan. Examples of triptans include sumatriptan, zolmitriptan, rizatriptan, naratriptan, eletriptan, donetriptan, almotriptan, frovatriptan, avitriptan, LY-334370, L0703,664, and GR 46611.

[0095] In various embodiments, transdermal permeate delivery systems and methods that can be used with and / or are suitable for use with compositions and methods as described herein are described in one or more of the 6022316th, 6142939th, 6173202nd, 6183434th, 6508785th, 6527716th, 6692456th, 6730028th, 7141034th, 7392080th, 7758561st, 8016811th, 8116860th and / or 9498609th U.S. Patents, all of which are hereby incorporated by reference as a whole, and particularly for the purpose of describing such systems and methods. In various embodiments, a transdermal permeate delivery system commercially available from NittoDenko Corporation under the trade name PASSPORT can be used for or adapted to deliver a permeate composition as described herein.

[0096] 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 effect and performance at a reasonable benefit / risk ratio when participating in any medical treatment. An "effective" amount of a penetration enhancer or chemical enhancer as used herein means an amount selected to provide the desired increase in biomembrane permeability, desired penetration depth, rate of administration, and amount of drug delivered.

[0097] As used herein, "animal" or "organism" refers to humans and other living organisms, including plants, to which the present invention may be applied.

[0098] As used herein, "analyte" means any chemical or biological material or compound suitable for passing through a biological membrane by the techniques taught herein or by techniques previously known in the art, of which an individual may wish to know the concentration or activity in vivo. Glucose is a specific example of an analyte because it is a sugar suitable for passing through the skin, and an individual, such as an individual with diabetes, may wish to know their blood sugar level. Other examples of analytes include, but are not limited to, compounds such as sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylates, and the like.

[0099] As used herein, "transdermal flux rate" refers to the rate of passage of any analyte out through the skin of an individual, human or animal, or the rate of passage of any permeant, drug, pharmacologically active agent, dye or pigment into and through the skin of an organism.

[0100] As used herein, "non-invasive" means not requiring a needle, catheter, or other invasive medical device to enter a part of the body.

[0101] As used herein, "minimally invasive" refers to the use of mechanical, hydraulic, or electrical mechanisms that penetrate the stratum corneum to create small holes or micropores without causing substantial damage to the underlying tissue.

[0102] As used herein, "pharmaceutically acceptable carrier" refers to a carrier in which a substance for delivery (e.g., a pharmaceutically acceptable drug) can be provided. 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. Carriers can include, for example, water and other aqueous solutions, sugars, polysaccharides, buffers, excipients, and biodegradable polymers, such as polyesters, polyanhydrides, polyamino acids, liposomes, and mixtures thereof.

[0103] As used herein, "reservoir" refers to a designated area or chamber in a device, which is designed to hold a permeate for delivery to an organism through an artificial opening in a biofilm, or can be designed to receive a biofluid sample extracted from an organism through an artificial opening in a biofilm. The reservoir can also contain an excipient compound that enhances the effect of the bioactive permeate held alone. In addition, the reservoir can include a reactive enzyme or reagent designed to allow measurement or detection of a selected analyte in the extracted biofluid or process it. The reservoir can be composed of an open volume space, a gel, a planar space or a permeable solid structure (e.g., a pill, a tablet, or a porous polymer) that has been coated or processed with a selected compound for subsequent release or reaction.

[0104] The devices and methods of the present disclosure can be used to deliver triptans transdermally across the skin. In some aspects, the patch can include: 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 intermediate layer also includes a skin irritation reducing agent. In some embodiments, the intermediate layer also includes a stabilizer. In some embodiments, the patch includes a tissue interface layer.

[0105] The example of suitable tissue interface layer is described in U.S. Patent No. 7,392,080, which is hereby incorporated by reference as a whole, particularly for the purpose of describing transdermal drug delivery patch system. In some aspects, the tissue interface layer may include some or all of the following: an element for realizing tissue perforation, an adhesive for attaching the device to the tissue, a reservoir for accommodating the permeate for delivery, a reservoir for accommodating the extracted biological fluid, and a reagent for determining the analyte. The tissue interface layer may also include hydrophilic and hydrophobic surface treatments to act as fluid flow modifiers for controlling the movement of the collected liquid permeate or biological fluid. The tissue interface layer may also incorporate antimicrobial agents to prevent sepsis, or incorporate anticoagulants or anticoagulants to control the aggregation of permeates or extracted biological fluids. The tissue interface layer may also be treated with a permeation enhancer or a buffer for pH stability. The tissue interface layer may include a stimulus-responsive polymer gel segment filled with a beneficial permeate, which may be triggered by heat, chemical or electrical stimulation to release the beneficial permeate. When heated by, for example, perforating elements or other similar elements on the tissue interface layer, the tissue interface layer can release beneficial permeates as desired. The tissue interface layer can include piezoelectric elements for transmitting acoustic energy into the tissue or delivered permeate or extracted biological fluid.

[0106] In some respects, the tissue interface layer may include one or more reservoirs. In the case of multiple reservoirs, these reservoirs may be used to keep different and possibly incompatible permeates apart. Delivery of permeates from the reservoir may be performed simultaneously or sequentially. In some embodiments, the reservoir wall may be perforated to open a breach on the reservoir film and allow the permeate to be delivered to the tissue. This perforation of the reservoir is completed with the same perforating element as the type used to perforate the tissue. Before opening a breach on the reservoir, the reservoir may maintain a stable, sealed and sterile environment of the permeate, thereby allowing the entire disposable part of the integrated device to be manufactured and packaged effectively and economically. Opening a breach on the reservoir may occur before, simultaneously or afterwards as required for the perforation of tissue. In addition, if all other factors such as micropore density or ion introduction current are identical, the flux rate of the permeate entering the tissue from a specific reservoir is proportional to the area of ​​the micropores of the biofilm to which the reservoir is connected. The reservoir may be empty or contain an absorbent material initially, so as to be used as the storage location of the biological fluid extracted. Reagents for determining analytes in biological fluids are typically located at the inlet of a storage reservoir from which the biological fluid is extracted.

[0107] Additionally, as used herein, "triptan" means a class or family of tryptamine-based drugs used as stopgap drugs in the treatment of migraine and cluster headaches. Examples of triptans include, but are not limited to, sumatriptan, rizatriptan, naratriptan, eletriptan, donetriptan, almotriptan, frovatriptan, avitriptan, and zolmitriptan. In some embodiments, triptans include zolmitriptan, sumatriptan, or rizatriptan. In some embodiments, triptans include zolmitriptan.

[0108] In some aspects, the skin irritation reducing agent is an organic acid. In some embodiments, the skin irritation reducing agent is a salt form 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 a combination thereof. In some embodiments, the skin irritation reducing agent is selected from non-organic acids. In some embodiments, the skin irritation reducing agent is a salt form of a non-organic acid. In some embodiments, the non-organic acid is hydrochloric acid, phosphoric acid, boric acid, acetic acid or a combination thereof. In some embodiments, the non-organic acid evaporates during the manufacturing process.

[0109] In some aspects, the stabilizer is sugar. In some embodiments, the sugar is selected from mannitol, maltose, trehalose, xylitol, xylose, dextrose, lactose, sorbitol, sucrose, fructose, maltitol, erythritol, lactitol, isomalt and cyclodextrin or a combination thereof. In some embodiments, the stabilizer is sucrose.

[0110] In some embodiments, the amount of triptan and skin irritation reducing agent in the patch is in a molar ratio of about 1:0.5 to about 1:2. In some embodiments, the molar ratio of triptan and skin irritation reducing agent is in a molar ratio of about 1:0.75 to about 1:1.5.

[0111] In some aspects, the middle layer of the patch includes a reservoir. In some embodiments, the reservoir comprises about 0.1 wt % to about 90 wt % of the triptan. In some embodiments, the triptan accounts for about 20 wt % to about 80 wt % of the middle layer, including, for example, 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 including any weight percentage range derived from these values.

[0112] In some embodiments, the intermediate layer comprises about 0.1 wt % to about 90 wt % of the stabilizer. In some embodiments, the stabilizer comprises about 20 wt % to about 80 wt % of the intermediate layer, including, for example, 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 including any weight percentage range derived from these values.

[0113] In some embodiments, the middle layer comprises from about 0.1 wt % to about 90 wt % of the skin irritation reducing agent. In some embodiments, the skin irritation reducing agent accounts for from about 20 wt % to about 80 wt % of the middle layer, including, for example, 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 including any weight percentage range derived from these values.

[0114] In some aspects, the intermediate layer comprises a substrate. In some embodiments, the substrate is a nonwoven fabric.

[0115] In some embodiments, the matrix has a density of about 0.1 mg / cm 2 To about 10mg / cm 2 The water holding capacity of the substrate (WHC). The water holding capacity of the substrate refers to the amount of water per 1 cm 2 The amount of water that can be retained. Specifically, prepare 1cm 2 The matrix was immersed in a solution (phosphate buffered saline containing 0.1% surfactant (Tween 80)) for a sufficient time. Then, the matrix was slowly pulled out of the solution for about 5 seconds, and the weight of the sample before immersion, which was measured in advance, was subtracted from the weight of the sample remaining in the liquid. Then, the weight per unit area (1 cm 2) of the matrix. In some embodiments, the matrix water retention capacity is about 0.5 mg / cm 2 About 8mg / cm 2 In some embodiments, the matrix has a water retention capacity of about 1 mg / cm 2 About 6 mg / cm 2 In some embodiments, the matrix has a water retention capacity of about 2 mg / cm 2 To about 5mg / cm 2 .

[0116] The water retention capacity of the substrate can be controlled by adjusting the thickness and weight of the substrate. Preferably, the substrate has a thickness of 100 μm or less. In some embodiments, the substrate has a thickness of about 10 μm to about 100 μm. In some embodiments, the substrate thickness is about 20 μm to about 90 μm. In some embodiments, the substrate thickness is about 30 μm to about 80 μm. In some embodiments, the substrate thickness is about 40 μm to about 60 μm.

[0117] In some embodiments, the substrate area weight is about 10 g / m 2 About 100g / m 2 In some embodiments, the substrate area weight is about 20 g / m 2 About 80g / m 2 In some embodiments, the substrate area weight is about 30 g / m 2 About 70g / m 2 In some embodiments, the substrate area weight is about 40 g / m 2 About 60g / m 2 .

[0118] In some embodiments, the matrix area weight is about 0.1 mg / cm 2 To about 30mg / cm 2 In some embodiments, the matrix area weight is about 5 mg / cm 2 To about 30mg / cm 2 In some embodiments, the matrix area weight is about 10 mg / cm 2 To about 30mg / cm 2 In some embodiments, the matrix area weight is about 20 mg / cm 2 To about 30mg / cm 2 In some embodiments, the matrix area weight is about 0.5 mg / cm 2 To about 5mg / cm 2 In some embodiments, the matrix area weight is about 0.5 mg / cm 2 To about 10mg / cm 2 .

[0119] In some embodiments, the size of the matrix is ​​about 0.25 cm 2 To about 4cm 2 In some embodiments, the size of the matrix is ​​about 0.5 cm 2 About 3cm 2 In some embodiments, the size of the matrix is ​​about 1 cm 2 About 2cm 2 In some embodiments, the size of the matrix is ​​about 1 cm 2 In some embodiments, the size of the matrix is ​​about 2 cm 2 In some embodiments, the size of the matrix is ​​about 3 cm 2 .

[0120] In some embodiments, the total amount of triptan and stabilizer per unit area of ​​the matrix is ​​0.05 mg / cm 2 Up to 0.5mg / cm 2 In some embodiments, the total amount of triptan and stabilizer per unit area of ​​the matrix is ​​0.1 mg / cm 2 Up to 0.5mg / cm 2 In some embodiments, the total amount of triptan and stabilizer per unit area of ​​the matrix is ​​0.2 mg / cm 2 Up to 0.5mg / cm 2 In some embodiments, the total amount of triptan and stabilizer per unit area of ​​the matrix is ​​0.3 mg / cm 2 Up to 0.5mg / cm 2 In some embodiments, the total amount of triptan and stabilizer per unit area of ​​the matrix is ​​0.05 mg / cm 2 Up to 0.5mg / cm 2 .

[0121] In some embodiments, the pH of the matrix component is about 3 to about 6. In some embodiments, the pH of the matrix is ​​about 4 to about 6. In some embodiments, the pH of the matrix is ​​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.

[0122] In some aspects, the matrix comprises about 0.1 mg / cm 2 To about 5.0mg / cm 2 In some embodiments, the matrix comprises about 0.1 mg / cm 2 To about 3.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm2 To about 5.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm 2 To about 3.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm 2 To about 2.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm 2 In some embodiments, the matrix comprises about 1 mg / cm 2 In some embodiments, the matrix comprises about 2 mg / cm 2 In a preferred embodiment, the triptan is zolmitriptan.

[0123] In some aspects, the matrix comprises about 0.1 mg / cm 2 To about 5.0mg / cm 2 In some embodiments, the matrix comprises about 0.1 mg / cm2 to about 3.0 mg / cm2 of a stabilizer. In some embodiments, the matrix comprises about 0.5 mg / cm2 of a stabilizer. 2 To about 5.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm 2 To about 3.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm 2 To about 2.0mg / cm 2 In some embodiments, the matrix comprises about 0.5 mg / cm 2 In some embodiments, the matrix comprises about 1 mg / cm 2 In some embodiments, the matrix comprises about 2 mg / cm 2 In a preferred embodiment, the stabilizer is sucrose.

[0124] In some aspects, the patch further comprises an antimicrobial agent. In some embodiments, the antimicrobial agent is selected from benzoic acid, methylparaben, propylparaben, benzalkonium chloride, chlorhexidine, cresol, salicylic acid, sorbic acid, and benzethonium chloride, and combinations thereof.

[0125] In some aspects, the present application also includes a method of administering a triptan to an individual in need using a patch as described herein. In some embodiments, the method of treating an individual comprises: identifying an individual suffering from migraine; opening a plurality of micropores in the skin of the individual; and applying the patch to the skin of the individual for a certain period of time on the micropores. In some embodiments, the patch comprises: a top layer comprising an adhesive, an intermediate layer comprising a triptan, and a bottom layer. In some embodiments, the bottom layer comprises a release liner. In some embodiments, a time period is selected to deliver a therapeutic amount of a triptan through a plurality of micropores.

[0126] In some embodiments, opening a plurality of micropores in the skin of an individual comprises applying a transdermal microporation device to the skin of the individual. In some embodiments, the transdermal microporation device comprises a conductive member comprising an array of conductive filaments. In some embodiments, the transdermal microporation device comprises a conductive member comprising an array of conductive filaments. In some embodiments, the transdermal microporation opens micropores by thermal tissue ablation. In some embodiments, the transdermal microporation creates micropores through the stratum corneum to the epidermis.

[0127] In some embodiments, the transdermal microporation device has a perforation energy of about 2 mJ / filament to about 8 mJ / filament. In some embodiments, the transdermal microporation device has a perforation energy of about 200 filaments / cm 2 To about 500 filaments / cm 2 In some embodiments, the transdermal microporation device has a filament density of about 400 filaments / cm 2 In some embodiments, the transdermal microporation perforation 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 transdermal microporation filament array has a size of about 0.5 cm 2 About 3cm 2 .

[0128] In some embodiments, the patch does not substantially irritate the skin of the individual. As used herein, the term "substantially does not irritate the skin of the individual" includes a skin erythema score of about 3.0 or less, preferably about 2.0 or less, more preferably about 1.0 or less, produced when the patch is removed. In another embodiment, the condition "substantially does not irritate the skin of the individual" may refer to a skin irritation relief number of days of about 4.0 or less, preferably about 3.0 or less, more preferably about 2.5 or less. In another embodiment, the condition "substantially does not irritate the skin of the individual" refers to a skin erythema score of about 3.0 or less, preferably about 2.0 or less, more preferably about 1.0 or less, and a skin irritation relief number of days of about 4.0 or less, preferably about 3.0 or less, more preferably about 2.5 or less.

[0129] In some aspects, the present application also includes a system for administering triptans to individuals in need 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 system includes: a top layer comprising an adhesive; an intermediate layer having at least one reservoir for containing triptans; and a bottom layer, wherein the bottom layer includes a release liner. In some embodiments, the microporation device includes a conductive member, the conductive member being configured to generate heat energy based on the current flowing through the conductive member during operation and supplying heat energy to the skin surface in contact with the conductive member. In some embodiments, the transdermal drug delivery patch system also includes a power supply, the power supply being configured to provide current to the conductive member in multiple pulses at a power supply current value, and the conductive member effectively opens micropores on the skin surface.

[0130] Example

[0131] Various embodiments and alternatives are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way. In the following, Zol = zolmitriptan; CA = citric acid monohydrate; Suc = sucrose; AA = ascorbic acid; SB = sodium benzoate; TA = tartaric acid. A PASSPORT microporation system is used. A device having an array of 100 to 400 heat perforating filaments (e.g., PassPort from Nitto Denko Corporation) is used. TM Thermoporation systems) provide an application site on the skin of an animal subject by thermoporation.

[0132] Zolmitriptan and rizatriptan benzoate were purchased from INKE SA (Spain). Sumatriptan succinate was purchased from LGMPharma (USA). The matrix of the drug patch used in Examples 1 to 10 was EH-1212 (Japan Vilene Company, LTD, Japan, WHC=4 mg / cm 2 ), which is a nonwoven fabric material. This material is made by thermally bonding two materials (white polyester fiber aggregate and transparent polyester film) (12 microns) to produce a consolidated sheet.

[0133] Example 1

[0134] Drug patch preparations

[0135] The drug patches of Examples 1 to 3 were prepared according to the following method.

[0136] The patch was prepared according to the following method. First, a die was used to form a backing layer material of a predetermined size. For example, 25×25 mm 2 Then, a die is used to form the matrix material (eg, nonwoven fabric) into a predetermined size, such as 10×10 mm. 2 . The formed matrix material is fixed to the central part of the backing layer material (hereinafter referred to as a blank patch). Then, the additives (e.g., CA, AA, Suc) and the drug are weighed. The solution is then added to the additives and the drug. The solution used is deionized water or alcohol. Then, the solution is stirred until the additives and the drug are completely dissolved, thereby preparing a drug solution. A mechanical pipette is used to drop the desired drug solution onto the matrix material area of ​​the blank patch. The matrix material is dried in an oven at, for example, 60° C. for 20 to 50 minutes to form a patch structure. A release coating, such as a release liner, is applied to the patch structure. By sealing with a heat sealer, the completed patch is made into a pouch with a desiccant or is not made into a pouch with a desiccant.

[0137] Animal Experimentation: Transdermal Delivery via Microporation

[0138] Hairless guinea pigs aged 77 to 84 days were used as experimental animals. The drug patch was fixed on the side of the skin of the experimental animal that had been perforated under the desired perforation conditions. The filament density mainly affects the area for transferring body fluids and components between the skin and the patch. The filament density was 200 or 400 filaments / cm 2 , and the perforation energy is about 4 mJ / filament and about 5 mJ / filament. By applying the patch to 1 cm 2 Microperforated application site, each drug patch is tested on each test individual. During the period of fixing the patch, and after the patch is adhered, blood is collected at the required time, and each drug component is extracted according to a conventional method. Then, the blood concentration is quantitatively measured by high performance liquid chromatography (LC-MS / MS). The bioavailability given in Table 1 to Table 3 is the relative bioavailability for subcutaneous injection.

[0139] Skin irritation score standard

[0140] After removing the patch, a skin irritation test was performed. The skin irritation test scale is an assessment of the skin directly below the matrix. The skin irritation test scale is shown in Table 1.

[0141] Table 1

[0142]

[0143]

[0144] This example describes the effects of skin irritation reducing agents and microporation conditions on triptan-induced skin irritation. Table 2 summarizes the results.

[0145] Table 2

[0146]

[0147] Example 2

[0148] This example describes the effects of skin irritation reducing agents and microporation conditions on triptan-induced skin irritation. Table 3 summarizes the results.

[0149] Table 3

[0150]

[0151]

[0152] Example 3

[0153] This example describes the effects of skin irritation reducing agents and microporation conditions on triptan-induced skin irritation. Table 4 summarizes the results.

[0154] Table 4

[0155]

[0156] Example 4

[0157] This example describes a route of administration study in hairless rats. In this study, four groups of hairless rats were tested under the following conditions: (1) Group 1 (2 mg zolmitriptan, oral administration); (2) Group 2 (2 mg zolmitriptan, intranasal administration; (3) Group 3 (2 mg zolmitriptan, intravenous injection); and (4) Group 4 (2 mg zolmitriptan, transdermal microporation). Figure 1 and Table 5 summarize the results.

[0158] Animal experiment: Oral administration, Group 1

[0159] Hairless rats were used as experimental animals. After oral administration of a drug solution (2.0 ml) containing 2.0 mg of zolmitriptan, blood was collected at desired times, each drug component was extracted according to a conventional method, and then blood concentration was quantified by high performance liquid chromatography (LC-MS / MS).

[0160] Animal experiment: intranasal administration, group 2

[0161] Hairless rats were used as experimental animals. After intravenous administration of a drug solution (10 μl) containing 2.0 mg of zolmitriptan, blood was collected at desired times, each drug component was extracted according to a conventional method, and then blood concentration was quantified by high performance liquid chromatography (LC-MS / MS).

[0162] Animal experiment: intravenous administration, group 3

[0163] Hairless rats were used as experimental animals. After intravenous administration of a drug solution (200 μl) containing 2 mg of zolmitriptan, blood was collected at desired times, each drug component was extracted according to a conventional method, and then blood concentration was quantified by high performance liquid chromatography (LC-MS / MS).

[0164] Animal Experimentation: Transdermal Delivery via Microporation, Group 4

[0165] Hairless rats were used as experimental animals. The drug patch was fixed on the side of the skin of the experimental animal that had been microporated under the desired conditions. In this study, the microporation conditions for transdermal microporation were 400 holes / cm 2 , 5.2mJ / filament. Application site is 1cm 2 During the patch fixation period and after the patch was attached, blood was collected at the desired time, each drug component was extracted according to a conventional method, and then the blood concentration was quantified by high performance liquid chromatography (LC-MS / MS). The patch formulation of this study was 2 mg zolmitriptan, 0.5 mg sucrose, 4 mg AA, 1 cm 2 Nonwoven matrix (EH-1212, WHC = 4 mg / cm 2 ).

[0166] The bioavailabilities given in Table 5 are absolute bioavailabilities for IV injection.

[0167] Table 5

[0168]

[0169] Example 5

[0170] This example describes a route of administration study conducted 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 microporation and the matrix of the drug patch were the same as those of Group 4 of Example 4.

[0171] In this study, five groups of guinea pigs were tested under the following conditions: (1) Group 1 (10 mg base / 4 ml, oral route); (2) Group 2 (5 mg base / 2 ml, oral route); (3) Group 3 (2 mg base / 4 mL, oral route); (4) Group 4 (2.0 mg base / cm 2 , transdermal microporation); and (5) Group 5 (2 mg / 200 μL, SubQ). Figure 2 The results are summarized in Table 6. The bioavailabilities given in Table 6 are relative bioavailabilities for subcutaneous injection.

[0172] In a further study, a PK study comparing humans and hairless guinea pigs (HGP) was performed. Figure 3 The results are summarized (Headache 2006, 46, 138-149).

[0173] Table 6

[0174] Group AUC (ng / ml*hr) BA(%) Cmax(ng / mL) Tmax(hours) 1 1387 16.2 910 0.44 2 353 8.3 259 0.56 3 77 4.5 25 0.33 4 1439 84.2 864 0.50 5 1709 100.0 3878 0.09

[0175] Example 6

[0176] This example describes various stabilizers and skin irritation reducing agents with microporation. The matrix is ​​the same as above. In brief, the microporation conditions for transdermal microporation are as follows; the pore density is 400 pores / cm 2 , perforation energy is 4mJ / filament, filament density is 400 filaments / cm 2 The application area is 1cm 2 The results are summarized in Tables 7 to 11. Table 7 describes the citric acid dosing study using microporation in guinea pigs. The bioavailabilities given in Tables 7 to 10 are relative bioavailabilities for subcutaneous injection.

[0177] Table 7

[0178]

[0179]

[0180] Table 8 summarizes the results of a microporation study in guinea pigs using organic acids as skin irritation reducers.

[0181] Table 8

[0182]

[0183] Table 9 describes the summary results of studies conducted in guinea pigs using stabilizers, sucrose, and microporation.

[0184] Table 9

[0185]

[0186]

[0187] Table 10 summarizes the results of the microporation studies in guinea pigs using zolmitriptan.

[0188] Table 10

[0189]

[0190] Table 11 summarizes the results of the dose comparison study using hairless rats

[0191] Table 11

[0192]

[0193]

[0194] The bioavailabilities given in Table 11 are absolute bioavailabilities for IV injection.

[0195] Example 7

[0196] This example describes the various effects of filament density. These studies were performed to investigate the effects of filament density on the PK profile and side effects (pain and skin irritation caused by puncture). Filament density primarily affects the area available for transfer of fluids and ingredients between the skin and the patch. The range of filament density was 100 filaments / cm 2 Up to 400 filaments / cm 2 , and the perforation energy is 3mJ / filament to 4mJ / filament. The detailed conditions are summarized in Table 12.

[0197] Table 12

[0198]

[0199] As for the results of the PK curve, 100 filaments / cm 2 The density of 100 mg / ml showed a lower Cmax and a slower Tmax, which means that the curve is a sustained release shape (see Figure 4 and Figure 5 ). This indicates that 100 filaments / cm 2 The density of 400 filaments / cm2 with 4 mJ energy delivered the drug to the systemic circulation more slowly. On the other hand, higher density resulted in higher Cmax and faster Tmax. In particular, in the test group, 400 filaments / cm2 with 4 mJ energy delivered the drug to the systemic circulation more slowly. 2 The density of 100% showed the highest Cmax and the fastest Tmax. In addition, the relative BA of the condition was about 100%. Under the test conditions, it seems that 400 filaments / cm 2 The density of is an excellent candidate to create sufficient area to obtain body fluid for dissolving the ingredients and then delivering the triptan drug. The PK data are summarized in Figure 6 and Table 13.

[0200] Table 13

[0201]

[0202]

[0203] From the perspective of side effects, 100 filaments / cm 2The density is the mildest condition for pain and skin irritation caused by piercing, which is reasonable ( Figure 7 , Figure 8 , Fig. 9 ). Compare 200 filaments / cm 2 density and 400 filaments / cm 2 No significant differences were observed in the density of the samples, and neither condition caused serious side effects.

[0204] The bioavailabilities given in Table 13 are relative bioavailabilities for SC injection.

[0205] Example 8

[0206] This example describes the various effects of heating energy. The perforation energy is related to the hole shape, such as depth and width. In these animal studies, as shown in Table 14, for 400 filaments / cm 2 A density of 2 to 5 mJ / filament was used for the perforation energy.

[0207] Table 14

[0208]

[0209] As a result of the PK study, all evaluation data (AUC, BA, Cmax, and Tmax) showed an almost proportional trend in the range of 2 to 4 mJ / filament, and 4 mJ / filament was the most desirable condition in any evaluation item (see Fig.10 and Fig.11 ). However, comparing 4mJ / filament and 5mJ / filament, the PK results of 5mJ / filament are almost the same as or even slightly worse than those of 4mJ / filament. This means that 5mJ / filament produces larger pores than required and induces more body fluid than required for a 2mg dose formulation. In other words, in the case of a 2mg dose formulation, the drug concentration in the body fluid induced by 5mJ / filament energy may be lower than the drug concentration in the body fluid induced by 4mJ / filament energy. Therefore, the osmotic pressure and diffusion of the drug in the case of 5mJ / filament are also lower than those in the case of 4mJ / filament. This is why 400 filaments / cm 2 The filament density of 100 μg and the perforation energy of 4 mJ / filament are excellent conditions for a 2 mg dosage form.

[0210] In terms of side effects, there were no significant differences between the perforation energies tested, such as Fig.12 and Fig.13 Although higher energies may lead to slightly more severe adverse effects, it seems that their scores are within the acceptable range.

[0211] In short, the appropriate perforation conditions have been determined based on the dose. However, the filament density should be as high as 400 filaments / cm 2 , and if it is not necessary, it is better to set the filament heating energy lower. For the 2mg dose formulation, under the test conditions, 400 filaments / cm 2 The filament density of 100 μL and 4 mJ / filament were the most effective. The data are summarized in Table 15.

[0212] Table 15

[0213]

[0214]

[0215] The bioavailabilities given in Table 15 are relative bioavailabilities for SC injection.

[0216] Example 9

[0217] This example describes the selection of the desired filament array size. Assuming 400 filaments / cm 2 For doses above 2 mg, it may be necessary to make the filament array larger, with a filament density of 0.5 to 4 mg and an energy of 4 or 5 mJ / filament. The dose range is 0.5 to 4 mg, and the filament array size range is 1.0 to 2.0 cm 2 Table 16 summarizes the results.

[0218] Table 16

[0219]

[0220] like Fig.14 and Fig.15 As described in the literature, PK data showed that when an energy of 4 mJ / filament was used, the 2 cm 2 The filament array size showed a good dose response. For the 4 mg dose, 1.5 cm 2 This means that for 400 filaments / cm 2 density and 4mJ / filament energy, per 1cm 2 The perforation area of ​​2 mg dose was the best condition in this study. 2 The filament array size of 400 filaments / cm may be sufficient for a 4 mg dose. 2 Density, 4mJ / filament, 2cm 2 ) is better than the latter condition (400 filaments / cm 2 Density, 5mJ / filament, 1.5cm 2 ).

[0221] Regarding side effects, wider perforation areas and higher energies appear to cause slightly more severe side effects, e.g. Fig.16 and Fig.17 In particular, by 1.5cm 2 and 2.0cm 2 The pain caused by the piercing is greater.

[0222] In short, when using 400 filaments / cm 2 density and 4mJ / filament energy, per 1cm 2 The 2 mg dose per perforation area was the optimal condition in this study. 2 For wider perforation areas and higher doses than 2 mg, pain due to perforation should be considered. The data are summarized in Table 17.

[0223] Table 17

[0224]

[0225]

[0226] *: The average value could not be calculated. Individual results were 2.0, 5.0, >7.0, >7.0 (n=4).

[0227] The bioavailabilities given in Table 17 are relative bioavailabilities for SC injection.

[0228] Example 10

[0229] This example describes a route of administration study of hairless rats using sumatriptan succinate. In this study, four groups of hairless rats were tested under the following conditions: (1) Group 1 (3 mg free base API, Suc: 0.5 mg, AA: 1 mg); (2) Group 2 (6 mg free base API, Suc: 0.5 mg, AA: 1 mg); (3) Group 3 (9 mg free base API, Suc: 0.5 mg, AA: 1 mg); and (4) Group 4 (6 mg free base API / 100 μL saline). In the context of these studies, the term "free base" refers to the weight of sumatriptan free base present (e.g., referring to Example 1, 4.2 mg sumatriptan succinate was used, which contained 3.0 mg sumatriptan free base). In addition, for example, referring to Fig.18 "4.2SS" means that there is 4.2 mg of sumatriptan succinate. The perforation conditions of transdermal microporation and the matrix of the drug patch are the same as those of Group 4 of Example 4. Fig.18 and Table 18 summarize the results.

[0230] Table 18

[0231]

[0232] The bioavailabilities given in Table 18 are relative bioavailabilities for SC injection.

Claims

1. A patch for delivering a triptan drug to an individual in need thereof, comprising: a top layer comprising an adhesive; An intermediate layer comprising a triptan, a skin irritation reducing agent, an antimicrobial agent and a stabilizer, wherein the stabilizer comprises 0.1 mg / cm 2 Up to 5.0mg / cm 2 an amount of sucrose; and a bottom layer, wherein the bottom layer comprises a release liner, The molar ratio of the amount of the triptan to the skin irritation reducing agent is 1:0.5 to 1:2, and the skin irritation reducing agent is an organic acid or a salt thereof, and 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.

2. The patch as claimed in claim 1, wherein the amount of sucrose is 0.1 mg / cm 2 Up to 3.0mg / cm 2 .

3. The patch of claim 1, wherein the triptan is selected from sumatriptan, rizatriptan or zolmitriptan.

4. The patch of any one of claims 1 to 3, wherein the intermediate layer further comprises a reservoir configured to contain the triptan.

5. The patch of claim 4, wherein the reservoir comprises a matrix.

6. The patch of claim 5, wherein the matrix has a 2 Up to 10mg / cm 2 water retention capacity.

7. The patch of claim 5, wherein the substrate comprises a nonwoven fabric.

8. The patch of claim 5, wherein the matrix has a thickness of 10 μm to 100 μm.

9. The patch of claim 5, wherein the matrix area weight is 10 g / m 2 Up to 100g / m 2 .

10. The patch of claim 5, wherein the size of the matrix is ​​0.25 cm 2 Up to 5cm 2 .

11. The patch of any one of claims 1 to 3, wherein the antimicrobial agent is selected from at least one of benzoic acid, methylparaben, propylparaben, benzalkonium chloride, chlorhexidine, cresol, salicylic acid, sorbic acid and benzethonium chloride, or a combination thereof.

12. The patch of claim 5, wherein the matrix comprises 0.1 to 5.0 mg / cm 2 of zolmitriptan.

13. The patch of claim 5, wherein the matrix comprises 0.5 to 3.0 mg / cm 2 of zolmitriptan.

14. The patch of claim 12, wherein the molar ratio of the amount of the zolmitriptan and the skin irritation reducing agent is 1:0.75 to 1:1.

5.

15. The patch of claim 10, wherein the size of the matrix is ​​0.25 cm 2 Up to 4cm 2 .

16. The patch of claim 12, wherein the matrix has a total amount of zolmitriptan and the stabilizer per unit area of ​​0.2 mg / cm 2 Up to 0.5mg / cm 2 .

17. The patch of claim 5, wherein: The matrix contains 0.5 mg / cm 2 Up to 3.0mg / cm 2 zolmitriptan; The skin irritation reducing agent comprises citric acid; and The molar ratio of zolmitriptan to citric acid is 1:0.5 to 1:

2.

18. A transdermal drug delivery patch system for delivering a drug, comprising: transdermal microporation devices for heating the skin surface; as well as The patch according to any one of claims 1 to 17.

19. A transdermal drug delivery patch system as described in claim 18, wherein the transdermal microporation device includes a conductive member, which is configured to generate thermal energy based on current flowing through the conductive member during operation and supply the thermal energy to the skin surface in contact with the conductive member.

20. The transdermal drug delivery patch system of claim 18, further comprising a power source configured to provide current to the conductive member at a power source current value in a plurality of pulses.

21. The transdermal drug delivery patch system of claim 18, wherein the transdermal microporation device is configured to open a plurality of micropores in the skin of the individual.

22. A transdermal drug delivery patch system as described in claim 18, wherein the transdermal microporation device is configured to provide thermal tissue ablation by using a filament array having a plurality of filaments disposed in the skin of the individual, wherein each filament is capable of conductively delivering thermal energy via direct contact with a tissue membrane to form a plurality of micropores in a microporous region of the tissue membrane.

23. The transdermal drug delivery patch system of claim 21, wherein the transdermal microporation device creates the micropores through the stratum corneum to the epidermis.

24. The transdermal drug delivery patch system of claim 18, wherein the transdermal microporation device is configured to provide a perforation energy of 2 to 5 mJ / filament.

25. The transdermal drug delivery patch system of claim 24, wherein the transdermal microporation device is configured to provide 200 to 500 filaments / cm 2 filament density.

26. The transdermal drug delivery patch system of claim 24, wherein the transdermal microporation device has 400 filaments / cm 2 filament density.

27. The transdermal drug delivery patch system of claim 24, wherein the transdermal microporation device is configured to provide a perforation energy of 4 mJ / filament and a filament density of 400 filaments / cm 2 filament density.

28. The transdermal drug delivery patch system of claim 22, wherein the size of the microporous region of the tissue membrane is 0.5 cm 2 Up to 5cm 2 .

29. Use of a patch as claimed in any one of claims 1 to 17 for the preparation of a medicament for treating migraine via a transdermal microporation device.

30. The use of claim 29, wherein the transdermal microporation device is configured to provide thermal tissue ablation using a filament array having a plurality of filaments disposed in the skin of the individual, wherein each filament is capable of conductively delivering thermal energy via direct contact with a tissue membrane to form a plurality of micropores in a microporous region of the tissue membrane.

31. The use of claim 30, wherein the transdermal microporation device creates the micropores through the stratum corneum to the epidermis.

32. The use of claim 29, wherein the transdermal microporation device provides a perforation energy of 2 to 5 mJ / filament.

33. The use of claim 32, wherein the transdermal microporation device has 200 to 500 filaments / cm 2 filament density.

34. The use of claim 32, wherein the transdermal microporation device has 400 filaments / cm 2 filament density.

35. The use of claim 30, wherein the transdermal microporation device provides a perforation energy of 4 mJ / filament and has 400 filaments / cm 2 filament density.

Images