Transdermal drug delivery patch, drug delivery system and drug delivery method

Abstract

A transdermal drug delivery patch is provided that can be adapted for immediate release applications of agents having a relatively low molecular weight. The transdermal drug delivery patch is provided with a matrix and at least one drug disposed within the matrix, wherein the matrix has a water retention capacity of 10 mg / cm<supgt;2< / supgt; or less, and the drug is an agent having a molecular weight of 5000 or less.

Description

BACKGROUND OF THE INVENTION

[0001] FIELD OF THE INVENTION

[0002] The present invention relates to transdermal drug delivery patches, drug delivery systems using such patches, and drug delivery methods. In particular, the present invention relates to transdermal drug delivery patches, drug delivery systems, and drug delivery methods that can be adapted for immediate release applications of agents having a molecular weight of 5000 or less.

[0003] Description of the Related Art

[0004] Over the past 30 years, transdermal drug delivery systems have been marketed for a variety of therapeutic indications. Typically, transdermal drug delivery systems are designed as multilayer polymer laminates in which a drug reservoir or drug-polymer matrix creates a closed environment between two polymer layers: an external backing layer that prevents loss of the drug through the backing surface and an internal polymer layer that serves as an adhesive and / or rate-controlling membrane. In the case of a drug reservoir design, the reservoir is interposed between the backing and the rate-controlling membrane. The drug is released only through the rate-controlling membrane, which can be microporous or non-porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, or gel, or dispersed in a solid polymer matrix. The outer surface of the polymer membrane is drug-compatible, and a thin layer of a low-allergenic adhesive polymer can be applied.

[0005] In the case of a drug matrix design, there are two types: drug-containing adhesive systems and matrix dispersion systems. In drug-containing adhesive systems, the drug is dispersed in an adhesive polymer, a drug-containing polymer adhesive is formed by solvent casting, and the adhesive (in the case of a hot melt adhesive) is melted onto an impermeable backing layer to form a drug reservoir. A non-drug-containing adhesive polymer layer can be applied on top of the reservoir. In matrix dispersion systems, the drug is uniformly dispersed in a hydrophilic or lipophilic polymer matrix and is fixed to an impermeable backing layer by solvent casting or extrusion. Instead of applying an adhesive to the surface of the drug reservoir, an adhesive is applied to form a peripheral adhesion.

[0006] JP 2006-509534 A discloses a transdermal delivery system for an active therapeutic agent from a dry pharmaceutical composition, wherein the system includes means for facilitating transdermal delivery of the active therapeutic agent through the skin of a patient and is capable of producing a patch, wherein the means includes at least one microchannel on a region of the patient's skin and at least one active therapeutic agent in the dry pharmaceutical composition. Further, it is disclosed that the patch further includes a backing layer, an adhesive layer, and a microporous liner layer, the dry pharmaceutical composition is a hydrophilic active therapeutic agent such as a protein, polypeptide, peptide, polynucleotide, oligonucleotide, growth factor, hormone, etc., and also contains a stabilizer such as a disaccharide, etc.

[0007] JP 2013-512865 A discloses a transdermal therapeutic system (TTS) for administering a peptide to a patient on excised skin, wherein the transdermal therapeutic system includes a backing layer provided with a pressure-sensitive adhesive layer containing at least one water-insoluble polymer; an active ingredient layer containing at least one peptide and a carrier substance in the form of a sheet-like textile structure; and a protective sheet.

[0008] JP 2008-543872 A discloses a device for inducing transdermal influx of a permeate into a patient through at least one formed passage through the skin layer of the patient, wherein the device i) has a bottom surface and includes a delivery reservoir including a non-biodegradable matrix defining a plurality of conduits in the matrix, and ii) an insoluble hydrophilic permeate provided in at least a portion of the plurality of conduits of the matrix. Further, it is disclosed that the permeate includes a water-soluble filler such as a humectant or an anti-healing agent. Summary of the Invention

[0009] Problems to be Solved by the Invention

[0010] However, according to the prior art, it is impossible to obtain a transdermal drug delivery patch applicable to immediate release applications of relatively low molecular weight agents, or more specifically, agents having a molecular weight of 5000 or lower.

[0011] Means for Solving the Problems

[0012] The inventors of the present invention have obtained the knowledge that a patch applicable to immediate release applications of agents having a molecular weight of 5000 or lower can be obtained by setting the water retention capacity of a matrix provided with a drug to a predetermined range, the matrix being provided in a patch for transdermal drug delivery.

[0013] While not bound by any theory, it is believed that in the case of a transdermal drug delivery patch where a drug is released from the patch applied to a biological membrane (such as the skin) into the body, when a patch provided with a matrix in which the drug is disposed is applied to microporous skin, biological moisture (such as a small amount of body fluid) exudes from the body through the micropores into the matrix, the biological fluid dissolves the drug disposed in the matrix, and the dissolved drug is transferred into the blood using the concentration gradient as a driving force. It is believed that it is necessary for a predetermined amount or more of biological moisture to exude into the matrix to increase the drug release rate. On the other hand, depending on the composition and dosage of the drug disposed in the matrix, there is a risk that the exuded biological moisture will become excessive, resulting in leakage from the patch, thereby causing a decrease in the drug release rate due to a reduction in the concentration gradient. The present invention enables the production of an article for controlling the drug release rate by adjusting the water retention capacity of the matrix in which the drug is disposed.

[0014] That is, the present invention is a transdermal drug delivery patch provided with a matrix and at least one drug disposed within the matrix, wherein the matrix has a water retention capacity of 10 mg / cm 2 or less, and the drug is a medicament having a molecular weight of 5000 or less.

[0015] In the patch of the present invention, the aforementioned matrix is preferably a nonwoven fabric. Further, the matrix preferably has a thickness of 100 μm or less. Further, the matrix preferably has a weight of 100 g / m 2 or less.

[0016] The aforementioned medicament may have a molecular weight of 2000 or less. Further, the medicament may be a non-peptide medicament. Further, it is desirable that the medicament be administered in an amount of 0.1 to 30 mg.

[0017] The patch of the present invention may also be provided with at least one hygroscopic agent disposed within the matrix. The aforementioned hygroscopic agent is preferably sugar. In the patch of the present invention, the total amount of the drug and the hygroscopic agent disposed within the matrix per unit area of the matrix is 0.1 to 30 mg / m 2 . The total amount of the drug and the hygroscopic agent per unit area of the matrix is more preferably 0.1 to 20 mg / m 2 .

[0018] Desirably, the patch of the present invention can suck out 9.5 to 85 mg / cm 2 of subcutaneous fluid per unit area of the matrix. The patch of the present invention may also be provided with at least one additive disposed within the matrix. Further, the patch of the present invention may also be provided with a backing layer for supporting the matrix. The patch of the present invention can be used for transdermal delivery of a drug through one or more micropores formed by a perforator.

[0019] In addition, the present invention is a system for delivering a drug through an individual's biological membrane, the system being provided with a perforator and a patch, wherein the patch is provided with a matrix and at least one drug disposed within the matrix, wherein at least a portion of the drug is soluble in biological moisture received from the individual through micropores formed by the perforator, and the matrix has a water retention capacity of 10 mg / cm 2 and the drug is an agent having a molecular weight of 5000 or less.

[0020] In the system of the present invention, the aforementioned perforator may be at least one perforator selected from a thermal perforator, a mechanical perforator, a laser perforator, and a water perforator. The perforator may be a heat conducting element configured to be in substantially physical contact with the biological membrane to deliver sufficient energy to thermally ablate the biological membrane. The perforator may also be a thin tissue interface device.

[0021] In addition, the present invention is a method for delivering a drug through an individual's (however, not including humans) biological membrane, which includes the step of forming one or more micropores in the biological membrane, and the step of placing a patch in physical contact with the one or more micropores, wherein the patch is provided with a matrix and at least one drug disposed within the matrix, and at least a portion of the drug is soluble in biological moisture received from the individual through the one or more micropores, and the matrix has a water retention capacity of 10 mg / cm 2 and the drug is an agent having a molecular weight of 5000 or less. Brief Description of the Drawings

[0023] Figure 1 is a graph illustrating the drug release rate of drug patches produced using matrices having different water retention capacities.

[0024] Figure 2 is a graph illustrating the time course of blood drug concentration obtained in Reference Example 1 and Reference Example 2.

[0025] Figure 3 is a graph illustrating the time course of blood drug concentration obtained in Example 2 and Comparative Example 1.

[0026] Figure 4 is a graph illustrating the time course of blood drug concentration obtained in Example 3 and Comparative Example 2.

[0027] Figure 5 is a graph illustrating the time course of blood drug concentration obtained in Example 4 and Comparative Example 3. Detailed Description

[0028] Modes for Carrying Out the Present Invention

[0029] When used in this specification, the term "patch" can include traditional drug reservoirs or drug matrix patches, or can be suitably used for any other type of patches of transdermal drug delivery technology in non-limiting examples. In an embodiment of drug reservoir design, the reservoir can be inserted between backing and rate control film. Drug is only released by rate control film, and the rate control film can be microporous or non-porous. In the drug reservoir compartment, the drug can be in the form of solution, suspension or gel, or is dispersed in a solid polymer matrix. The outer surface of the polymer film can be applied with a thin layer of a drug-compatible hypoallergenic adhesive polymer. In an embodiment of drug matrix design, it must always include two types of known drug-containing adhesive systems and matrix dispersion systems. In an embodiment of drug-containing adhesive systems, it is also possible to form a drug reservoir by spreading drug-containing polymer adhesives by dispersing the drug in adhesive polymers, then by solvent casting or by melting adhesive (hot melt adhesive) into an impermeable backing layer. Non-drug-containing adhesive polymer layers can be applied to the top of the reservoir. In one embodiment of the matrix dispersion system, the medicine is evenly dispersed on the hydrophilic or lipophilic polymer matrix and is fixed to the impermeable backing layer of the medicine. In another application, instead of adhesive being applied to the surface of the drug reservoir, adhesive is applied to form peripheral adhesion. All embodiments of the patch that can be placed on the skin, including aforesaid traditional drug reservoir and drug matrix type patch, must be included as embodiments of the present invention.

[0030] As used in this specification, "subcutaneous fluid" or "biological moisture" or "exudate" includes, but is not limited to, water, plasma, blood, one or more proteins, interstitial fluid, skin tissue fluid, fluid from any skin layer, sweat, serum, lymph, and / or a combination of two or more thereof. In one aspect, the subcutaneous fluid according to the present invention is an aqueous source comprising water.

[0031] As used in this specification, "subject" refers to any organism having at least one biofilm from which subcutaneous fluid can be obtained. In one aspect, an exemplary biofilm can be at least one skin layer from which subcutaneous fluid can be obtained. For example, in one aspect, the subject is a plant. Alternatively, in another aspect, the subject can be an animal. In one aspect, the animal can be a mammal. In alternative aspects, the animal can be a non-mammal. In addition, the animal can be a cold-blooded animal, such as a fish, a reptile, or an amphibian. Alternatively, the animal can be a warm-blooded animal, such as a human, a domestic animal, a livestock, or even a laboratory animal. Therefore, it should be understood that the present invention is not limited to its use in the context of any particular individual or group of individuals.

[0032] As used in this specification, "biomembrane" includes an inclusive or separating layer that serves as a barrier within a cell or around a cell. In this regard, it can be a lipid bilayer composed of lipid-like molecules and randomly coiled proteins. Additionally, the biomembrane as used in this specification can define an enclosed space or compartment, and the cells therein can maintain a chemical or biochemical environment that is different from the environment outside the space or compartment. In this regard, the biomembrane can be a selectively permeable structure, and the size, charge, and other chemical properties of the atoms and molecules attempting to pass through it determine whether this can be done. In one aspect, the biomembrane can be a mucosa. Exemplary mucosae include, but are not limited to, oral, gingival, gastrointestinal, cervical, vaginal, rectal, intranasal, intraoral, and ocular membranes. In another aspect, the biomembrane can be a skin layer.

[0033] As used in this specification, "skin layer" can be the epithelial layer of any one or more individuals. For example, in one aspect, the skin layer includes the outermost layer of the skin, namely the stratum corneum. In an alternative aspect, the skin layer can include one or more layers of the epidermis beneath the stratum corneum, typically defined as the stratum granulosum, stratum spinosum (stratum germinativum), and stratum basale. Those skilled in the art recognize that there is substantially little or no resistance to the transport or absorption of permeants through the epidermal layers beneath the stratum corneum. Thus, in one aspect of the present invention, the pathway formed by at least one of the individual skin layers is the pathway in the individual's stratum corneum.

[0034] As used in this specification, "additive" is also referred to as "enhancer", "chemical enhancer", "permeability enhancer", or "penetration enhancer", etc.; in other words, it includes all additives that increase the mobility of permeants, analytes, or other molecules through a biomembrane or in tissue fluid. It is intended to include all cell membrane-disrupting compounds and solvents, as well as other chemical enhancers. Additionally, it is intended to include pH regulators, solubility regulators (including ionic strength regulators, salting-out agents, water-soluble polymers), and fillers. Furthermore, all active force enhancers include, but are not limited to, the acoustic energy of tissues, sonophoresis, iontophoresis, or electroporation, mechanical aspiration, pressure, or local deformation. In some cases, hydrophilic permeants can also be used simultaneously as penetration enhancers (with the role of a permeant) or alone as penetration enhancers. One or more enhancer techniques 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 permeant around the capillary bed and into the tissue including the capillary bed.

[0035] As used in this specification, "transdermal" or "transdermally" includes the permeant passing through one or more skin layers and thereby achieving an effective therapeutic blood or local tissue level of the permeant.

[0036] As used in this specification, "formed opening", "artificial opening", or "micropore" refers to any physical pore in a biological membrane that has a size suitable for delivering or expelling fluid therethrough. Thus, "formed opening", "artificial opening", or "micropore" refers to the desired depth in a biological membrane, or a small hole, opening, or crack formed through the biological membrane. In one aspect, the term micropore refers to the result of any technique that penetrates the skin to produce a biological fluid product on the skin surface. In one aspect, the opening can be formed by conduction of thermal energy as taught in U.S. Pat. Nos. 5,885,211 and 7,141,034, or by mechanical treatment, by explosive treatment, or by frequency ablation. These teachings are incorporated herein by reference. In this regard, the size of the hole or pore can have a diameter of, for example, about 1 to 1000, 5 to 700, 10 to 500, 50 to 300, 100 to 250, 50 to 100, or 70 to 90 microns. The hole or pore can be any shape, including, for example, a cylinder, slit, hole, square, groove, pit, etc. For simplicity, the term micropore is used in the singular, but it should be understood that the devices, systems, and methods of the present invention can form an array of multiple openings or holes.

[0037] As used in this specification, "perforation", "microperforation", and any similar terms refer to shaping the outer layer of an organism that is used to reduce a small hole or notch (hereinafter referred to as "micropore") in or through a tissue or biological membrane (such as skin or mucosa, etc.), or to reduce the wall properties of the biological membrane for a selected purpose to allow at least one permeate to pass from one side of the biological membrane to the other side. Preferably, the hole or "micropore" formed in this way has a diameter of about 1 to 1000 microns and is sufficiently dispersed on the biological membrane to disrupt the wall properties of the stratum corneum without adversely affecting the underlying tissue. In another embodiment, the hole or micropore formed in this way has a diameter of about 1 to 1000, 5 to 700, 10 to 500, 50 to 300, 100 to 250, 50 to 100, or 70 to 90 microns. For simplicity, the term "micropore" is used in the singular, but it should be understood that the device of the present invention can form multiple artificial openings. For a selected purpose or for certain medical or surgical purposes, perforation reduces the wall properties of the biological membrane in the body, and the main difference between the microperforation techniques mentioned in this specification and the openings formed by electroporation is that the typical minimum size of the micropore is usually at least about 1 micron or a larger diameter and is usually at least about 1 micron in depth, while any diameter of the openings formed by electroporation is usually only a few nanometers. Nevertheless, after the permeate has passed through the micropores in these deeper tissue layers, electroporation can be used to facilitate the absorption of the selected permeate by the target tissue under the outer layer of the organism. For the purposes of this application, "perforation" and "microperforation" are used interchangeably.

[0038] A "micropuncher" or "puncher" is a component of a micropore manufacturing device capable of micropore manufacturing. Examples of micropunchers or punchers include, but are not limited to, thermal punching devices, which include devices having one or more filaments capable of conductively delivering thermal energy by direct contact with a biological membrane to ablate the membrane to a depth sufficient to form micropores; heat transfer elements arranged to be in substantially physical contact with the biological membrane to transfer sufficient energy to the biological membrane to thermally ablate the biological membrane; and any heated local dye / absorbing layer; mechanical ablation devices, including electromechanical actuators, micro lancets, and arrays of solid or hollow micro needles or lancets; radiofrequency ablation, acoustic energy ablation; laser ablation systems; hydrostatic punching devices including high-pressure fluid jet punctures; techniques for physically piercing the skin surface; or skin ballistic delivery devices, etc. The thin tissue interface described in U.S. Patent No. 7,141,034 is another example of a punch, which is incorporated herein by reference in its entirety. When used in this specification, "micropuncher" and "puncher" may be used interchangeably.

[0039] A "thin film layer interface" or "TFTI" is used to describe devices that generate micropores using thermal energy generated by an electric current passing through a resistive element, as well as methods for manufacturing TFTI devices and functionally operating TFTI devices. TFTI devices generate one or more micropores in a wide range of biological membranes. TFTI has applications including analyte monitoring and thermal micropunching of human skin for increasing the delivery of permeants, which include therapeutic agents or tattoo pigments, etc. TFTI is characterized by their ability to rapidly and effectively generate patterns or arrays of micropores on the surface of a biological membrane. The pattern can be any geometric space of micropores with various possible pore densities. In one aspect, the pore density is up to every 0.2 mm 2A pore, with a pore density covering the entire perforated area in the range from a few square millimeters to several hundred square centimeters, and including 0.005 to 800, 0.01 to 500, 0.1 to 500, 1 to 300, 10 to 200, 25 to 100, and 50 to 75 square centimeters. The TFTI device is designed as a thin, flexible compliant structure that can form an interface between the biofilm and the controller. Alternatively, the TFTI can be integrated with the controller itself, and the integrated device can be in contact with the biofilm. The controller part is not limited to other active components such as each perforating element or electrode or piezoelectric transducer, etc., and provides the electrical signals required to affect other functions (such as the perforation of the TFTI, or iontophoresis, sonophoresis, electroporation, or impedance measurement of the tissue in contact) to the TFTI. The TFTI can be flexible and adapted to the shape of the target biofilm. The TFTI is very thin and can be processed for weighing, used separately from the patch, or used in an integrated form, and is also connected to the controller or power supply via an umbilical cable, which is a form familiar to many users. When one or more controllable active additional flux enhancement features are incorporated into the TFTI, such as but not limited to pressure regulation, mechanical operation, iontophoresis, electroosmosis, sonophoresis, or electroporation, the activation of this additional flux enhancement feature can be controlled by a remote controller module in a pre-programmed manner, in a user-controlled manner via input to the controller, or in an automatic closed-loop manner. Here, the infusion rate of the permeate is adjusted as the measured level of the selected analyte in the body or other measurable properties of the organism change. Other recognizable properties can include heart rate, blood pressure, temperature, respiration, and skin surface conductivity. For example, in one embodiment, it is useful to control the insulin infusion rate based on real-time measurement of the glucose concentration in the interstitial fluid or serum of the organism. In another embodiment, it is desirable to use several therapeutic compounds, and more specifically, it is desirable to determine when the effective drug level of a compound with a narrow therapeutic window deteriorates to such an extent that the negative side effects on something are extremely unbearable, so as to extremely precisely adjust the infusion rate based on the measurable level of the compound in the body, thereby achieving a very precise, self-adapting method to bring the drug concentration to and maintain within the desired therapeutic window, regardless of the patient's weight or metabolism. In the design and manufacture of the TFTI, many conductive traces including the TFTI can be used to achieve multiple functions. For example, the trace used to deliver a short pulse current to the resistive perforating element that induces thermal cycling can also be used for the closed-loop feedback control of microporation, or combined with the enhancer as an electrode for iontophoresis or electroporation treatment, and this is achieved after the micropores have been formed.

[0040] As used in this specification, "iontophoresis" refers to the delivery of ionized or non-ionized forms of a drug by applying an external electric field to the tissue surface using two or more electrodes, as well as the delivery of a water flow associated with ion transport (electroosmosis) to the tissue or a similar extract of a biological fluid or analyte.

[0041] As used in this specification, "electroporation" refers to the creation of openings in cell walls by an electric current, the openings being much smaller than micropores. The openings formed by electroporation are typically only a few nanometers in any dimension, for example 1 to 10 nanometers. In one embodiment, electroporation can be used to facilitate the cellular uptake of a selected permeate according to the target tissue underlying the biological outer layer after the permeate has entered deeper tissue through the micropores.

[0042] As used in this specification, "sonophoresis" or "sonication" refers to piezoelectric crystals or acoustic energy, which can include vibrations commonly described as ultrasound, which are caused by oscillating other electrochemical elements by passing an alternating current through a material. The use of acoustic energy to enhance the permeability of the skin to drug molecules is called sonophoresis or sonopermation.

[0043] As used in this specification, "bioavailability" refers to both absolute bioavailability and relative bioavailability. Absolute bioavailability determines the proportion of the active drug in the systemic circulation after non-intravenous administration (oral, rectal, transdermal, subcutaneous, etc.). In pharmacokinetics, it is necessary to obtain the change in plasma drug concentration per unit time in both intravenous administration (IV) and non-intravenous administration to determine the absolute bioavailability of a drug. Absolute bioavailability is determined by dividing the area under the concentration curve (AUC) calculated when a fixed amount of the drug is administered non-intravenously by the AUC calculated when the same amount of the drug is administered intravenously (IV). In addition, relative bioavailability is used to evaluate the differences in its absorbability among different administration routes, so if the control administration route is intravenous administration, its value is the absolute bioavailability. In addition, relative bioavailability is used when comparing the absorbability of a certain drug with that of a control drug. For example, in generic drugs, the relative bioavailability with the target generic drug as the control drug is used to evaluate bioequivalence.

[0044] The transdermal drug delivery patch according to the present invention is provided with a matrix and at least one drug disposed within the matrix, wherein the matrix has a water retention capacity of 10 mg / cm 2 or less, and the drug is a pharmaceutical agent having a molecular weight of 5000 or less.

[0045] The matrix for use in the present invention has a water retention capacity of 10 mg / cm 2 or less. The water retention capacity of the matrix means that for every 1 cm of the matrix 2The amount of water that can be retained. Specifically, a 1 cm 2 substrate is prepared and immersed in a solution (phosphate buffered saline (Tween 80) containing 0.1% surfactant) for a sufficient length of time. Then, the substrate is slowly pulled out of the solution for about 5 seconds, the weight of the sample before immersion, which has been previously measured, is subtracted from the weight of the sample holding the liquid, and then the water retention capacity of the substrate per unit area (1 cm 2 ) can be determined. The substrate used in the present invention preferably has a water retention capacity of 10 mg / cm 2 or lower, more preferably having a water retention capacity of 1 mg / cm 2 to 10 mg / cm 2 .

[0046] Although the structure of the substrate used in the present invention is not particularly limited, a nonwoven fabric is preferred. Nonwoven fabrics made of hydrophobic materials (such as polyester, polypropylene, polysulfone, EVAL, polyacrylonitrile, cellulose, nylon, etc.) and nonwoven fabrics made of hydrophilic materials (such as cellulose, wool, silk, rayon, cuprammonium fiber, pulp, etc.) are given as examples of preferred nonwoven fabrics. In addition to nonwoven fabrics, the substrate used in the present invention can be in the form of a net, a woven fabric, paper, etc. In addition, the substrate used in the present invention can also be in the form of a film. In this case, it is preferable to roughen the surface of the film to make it uneven because it is difficult to carry drugs when the surface of the film is too smooth. In addition, the substrate used in the present invention can also be in the form of a membrane. If a hydrophobic membrane is used, there is no penetration of pores, thus providing a usage feeling similar to that of a film. On the other hand, if a hydrophilic membrane is used, it is easy to penetrate into the interior, thus providing a usage feeling similar to that of a nonwoven fabric. From the viewpoint of the amount of drug and water that can be carried inside, it is desirable to use a membrane with a low density. The water retention capacity of the substrate can be controlled by adjusting the thickness and weight of the substrate. The substrate preferably has a thickness of 100 μm or less. In addition, the substrate preferably has a weight of 100 g / m 2 or lower.

[0047] The surface of the matrix used in the present invention is adapted to contact with the biofilm, and in addition, is adapted to absorb or otherwise receive bio - moisture from at least one passage formed by the biofilm. In this case, the patch is arranged to be in fluid communication with at least one formed passage. The matrix can comprise at least one polymer and can comprise two or more polymers. The polymer(s) can be a water - soluble polymer or a water - insoluble polymer. A single matrix can comprise both a water - soluble polymer and a water - insoluble polymer. Non - limiting examples of water - soluble polymers are given as polyethylene glycol (PEG, PEO or POE), polyvinyl alcohol (PVA or PVOH), and polyvinylpyrrolidone (PVP). Non - limiting examples of water - insoluble polymers are given as ethylene - vinyl acetate (EVA) and ethyl cellulose (EC). By way of non - limiting examples, the matrix material accounts for from about 1 wt% to about 99 wt% of the patch. In addition, it also accounts for amounts of about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt% and about 80 wt% of the patch. In addition, the matrix material can also account for any weight percentage within any range derived from these values. For example, by way of non - limiting examples, the matrix material can be from about 1 wt% to about 60 wt% of the patch, from about 20 wt% to about 60 wt% of the patch, from about 20 wt% to about 40 wt% of the patch, and further from about 1 wt% to about 40 wt% of the patch.

[0048] The matrix material can include a water - insoluble polymer material or a combination of polymer materials. For example, although not limited, in one aspect, the matrix comprises ethylene - vinyl acetate (EVA) copolymer, ethyl cellulose (EC), polyethylene, polyethyl acrylate, a copolymer of ethylene and ethyl acrylate, and any combination thereof. In one aspect, the matrix can comprise an ethylene - vinyl acetate copolymer having a relative percentage of vinyl acetate from 0% to about 60%, and can comprise a certain percentage of other vinyl acetates, such as about 0%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% and 60% etc., and any percentage within the range derived from these values. Note that in another aspect, the ethylene - vinyl acetate copolymer contains about 40% vinyl acetate.

[0049] The medicaments used in the present invention are medicaments having a molecular weight of 5000 or less. Examples of medicaments generally include, but are not limited to, anti-infective agents such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorectics; anthelmintics; anti-arthritis agents; anti-asthma agents; anticonvulsants; antidepressants; anti-diabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine preparations; antiemetics; anti-tumor agents; anti-angiogenesis agents; Parkinson's disease treatment; antipruritics; antipsychotics; antipyretics; anticonvulsants; anticholinergics; sympathomimetics; and xanthine derivatives; cardiovascular drugs such as potassium and calcium channel blockers; beta blockers, alpha blockers and anti-arrhythmic agents; antihypertensive agents; and diuretics and anti-diuretics; vasodilators, commonly used for coronary, peripheral and cerebral; central nervous system stimulants; and vasoconstrictors; cough and cold preparations such as decongestants; hormones such as estradiol and other steroids such as corticosteroids; sleep drugs; immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; sedatives; tranquilizers; anti-fibromyalgia drugs; xerostomia drugs; bone resorption inhibitors; agents for enhancing bone strength; agents for reducing bone fragility; anti-incontinence agents; anti-anxiety drugs; anti-myocardial hypertrophy agents; anti-edema agents; anti-obesity drugs; bone resorption inhibitors; anesthetics; anti-anxiety drugs; sedatives; muscle relaxants; acetylcholinesterase inhibitors; ACE inhibitors; anticoagulants; sleep drugs; anti-obsessive-compulsive disorder agents; anti-bulimia drugs; antiemetics; anti-anxiety drugs; NSAIDs; anti-rheumatic agents; hypothyroidism drug treatment; hypothyroidism drug treatment NMDA receptor antagonists; NMDA receptor agonists; partial NMDA receptor agonists; ADHD treatment drugs, antispasmodics, antispasmodics, migraine prophylaxis drugs; benign prostatic hyperplasia drugs; sedatives; anesthetics; pulmonary artery blood pressure reducing agents; sleep drugs; osteoporosis drugs; anti-inflammatory agents; diabetes blood glucose control agents; multiple sclerosis drugs; thrombocytopenia drugs; and bone marrow reconstruction drugs.

[0050] Specific examples of drugs may include acitretin (Soriatane), amitriptyline (Elavil), alendronate sodium, aripiprazole (Abilify), bethanechol chloride (Urecholine), bromocriptine (Parlodel), bumetanide (Bumex), bupivacaine (Marcaine), buprenorphine (Buprenex), buspirone (Buspar), cetirizine hydrochloride, citalopram (Celexa), chlordiazepoxide (Tranxene), clomipramine hydrochloride, cyclobenzaprine (Flexeril), donepezil (Aricept), doxazosin (Cardura), enalapril (Vasotec), enoxaparin (Lovenox), escitalopram (Lexapro), felodipine (Plendil), fentanyl (Sublimaze, Duragesic), fosinopril, galantamine HBr (Reminyl, Razadyne ER), glibenclamide (Glucotrol), granisetron (Kytril), haloperidol (Haldol), hydrocodone bitartrate, hydrocortisone acetate, hydroxyzine hydrochloride, isradipine (Dynacirc), ketorolac (Acura, Toradol), leflunomide (Arava), levothyroxine (Levoxyl, Levothroid), Synthroid, lisinopril (Prinivil, Zestril), lorazepam (Achiban), loxapine (Loxitane), meloxicam (Mobic), memantine (Namenda), methylphenidate (Ritalin, Concerta), methimazole (Tapazole), metoclopramide (Reglan), metolazone (Mykrox,Zaroxolyn, Mirtazapine (Remeron), Montelukast, Nalbuphine (Nubain), Neostigmine (Prostigmin), Nortriptyline Hydrochloride, Olanzapine (Zyprexa), Ondansetron (Zofran), Oxybutynin Chloride (Ditropan Chorinated Oxybutynin) (Ditropane XL), Oxycodone Hydrochloride, Oxymorphone (Numorphan), Palonosetron (Aloxi), Paliperidone, Paliperidone Palmitate, Paroxetine (Paxil), Pergolide (Permax), Perphenazine (trilafon), Phenytoin Sodium, Pramipexole (Mirapex), Prochlorperazine (Compazine), Procyclidine (Kemadrin), Promethazine Hydrochloride, Propranolol Hydrochloride, Protriptyline (Vivactil), Ramipril, Risperidone (Risperdal), Ropinirole (Requip), Rosiglitazone (Avandia), Selegiline (Eldepryl) (R-(-)1-Propargylphenylisopropylamine Hydrochloride), Tamsulosin (Flomax), Temazepam (Restoril), Thiethylperazine (Torecan), Tiagabine (Gabitril), Timolol, Tramadol, Treprostinil Sodium (Remodulin), Tropisetron (Navoban), Warfarin Sodium, ATI5923, Zolpidem Tartrate, and DPP-4 inhibitors (Sitagliptin (Januvia), Vildagliptin (Galvus), Saxagliptin (BMS477118), Alogliptin (SYR-322), Denagliptin (Redona), PHX1149, TA-6666, GRC8200 / EMD675992, MP513, PSN9301, R1579, BI1356, PF-734200, ALS2-0426, TS-021, AMG221, ABT-279, SK-0403, KRP-104, SSR162369, ARI2243, S40010, PT-630, SYR-619, E3024, and A-899301).

[0051] The drugs used in the present invention can be conventional known therapeutic agents for parenteral administration. Specific examples of such therapeutic agents include adenosine, fluorouracil, alprostadil, amikacin sulfate, amiodarone, azithromycin, bleomycin, carboplatin, ceftriaxone, ciprofloxacin, cisplatin, dacarbazine, daunorubicin hydrochloride, deferoxamine mesylate, desmopressin acetate, dexamethasone sodium phosphate, dipyridamole, doxorubicin hydrochloride, enalaprilat, epirubicin hydrochloride, fluconazole, fludarabine phosphate, flumazenil, fosphenytoin sodium, granisetron hydrochloride, haloperidol decanoate, haloperidol, idarubicin hydrochloride, ifosfamide, irinotecan hydrochloride, L-cysteine, leucovorin calcium, leuprorelin acetate, medroxyprogesterone acetate, mesna, methylprednisolone acetate, metoclopramide, mitoxantrone, norepinephrine tartrate, octreotide acetate, ondansetron, ONXOL (registered trademark) (paclitaxel), oxytocin, pamidronate disodium, pancuronium bromide, promethazine hydrochloride, propofol, sulfamethoxazole and trimethoprim, terbutaline sulfate, testosterone cypionate, tobramycin, TOPOSAR (registered trademark) (etoposide), vecuronium bromide, VINCASAR PFS (registered trademark) (vincristine sulfate), vinorelbine tartrate, ZANOSAR (registered trademark) (streptozocin), Abraxin, Actrel, Adensocan, Elidel, Amevive, amikacin, dolasetron, Arimidex, fondaparinux sodium, Arimidex, Avastin, Aponex, Betaseron, carmustine, Botox, Campus, Camptosar, Casodex, Ceenu, imiglucerase, Cetrozide, Ciprobay, Copegas, cyclophosphamide, testosterone enanthate, dobutamine, Doxil, leuprorelin acetate, Oxaliplatin, Elspar, Enbrel, Erbitux, Ettilol, galactosidase, fulvestrant, Follistim, Fuzeon, Ganirex (Antagon), Gemzar, Genotropin, Genotropin Miniquick, Gleevec, gonadorelin-f, Herceptin, Hexarene, HumatroPen, Humira, Hycamtin, Infergen, Infumorph, Interferon alfa-2b, Kineret, sapropterin, Triol-Intra, ranibizumab, RubronPediatric, pegaptanib (Macugen), Matsuran, Menogon, Mastergen, botulinum toxin (Myobloc), Nabi-HB, Neumega, filgrastim, Nexavar, Norditropin, Nutropin, Nutropin AQ, Oryzanol, Ovidrel, Pegasys, Pegintron, Pantam, Prograf, aldesleukin (Proleukin), dornase alfa, ribavirin, Rebif, zoledronic acid (Reclast), Refludan, Remicade, Repronex, lenalidomide, RibaPak, ribavirin, risperidone (Rispadal Consta), Rituxan, Roferon-A, Saizen, Sandostatin LAR, Therostim, dasatinib (Sprycel), Sapprelin LA, Sutent, palivizumab, Synthroid, Desuccinyl, Tace, tamoxifen, Taxotere, temozolomide, Tev-Tropin, thalidomide, Thyrogen, Tobi, Tubersol, natalizumab, lapatinib (Tykerb), Velcade, tretinoin, Vidaza, vinblastine, vincristine, Viread, cidofovir, vitamin K, naltrexone, Xeloda, zoledronic acid, Advate, AlphaNight, AlphaNin, Aranesp, Bebulin, Benefix, Epogen, Patate, Fragmin, Helixate, Hemofil, humate, Hyate, Koate, Kogenate, sargramostim, enoxaparin, Monoclate, Mononine, Myocristin, filgrastim, Neumega, Novarel, NovoSeven, Procrit, fibrinogen, Raptiva, Revetron, Recombinate, Refacto, Caverject, D.H.E.45, ondansetron (Zofran), BayRho D, Protropin, testosterone enanthate, Plenaxis, Hemofil-M, Monarch-M, ProplexT, Hyalgan, Schwarz, Synvisc, Excellence, Zoladex, Pregnyl, Carimune, Gamimune N, Gammagard, Gammar, Iveegam, Panglobulin, Polygam and Venoglobulin.

[0052] The aforementioned medicament may have a molecular weight of 2000 or less, so as to include so-called medium molecular weight drugs and low molecular weight drugs, may further have a molecular weight of 700 or less, so as to include so-called low molecular weight drugs, and desirably may have a molecular weight of 500 or less. In addition, the medicament may be a non-peptide drug. Further, it is desirable that the medicament be administered in an amount of 0.1 to 30 mg per 1 cm 2 of the matrix.

[0053] The patch of the present invention may also be provided with at least one hygroscopic agent disposed in the matrix. The hygroscopic agent may be a water-soluble substance, a mixture in a water-soluble state, etc., and is preferably a substance having high water solubility. The aforementioned hygroscopic agent is preferably sugar. Note that if the drug is a substance soluble in the exudate or in a soluble state, the drug may also be regarded as a hygroscopic component. In the patch of the present invention, the total amount of the drug and the hygroscopic agent disposed in the matrix per unit area of the matrix is preferably 0.1 to 30 mg / m 2 . The total amount of the drug and the hygroscopic agent per unit area of the matrix is more preferably 0.1 to 20 mg / m 2 . In addition to the drug and the hygroscopic agent, the patch of the present invention may also be provided with any components disposed in the matrix and dissolved in the exudate, such as excipients, stabilizers, pH regulators, buffers, preservatives, antibacterial agents, solubilizers, thickeners, antioxidants, transdermal absorption enhancers, irritation regulators, chelating agents, etc. The patch of the present invention may also be provided together with water, alcohols, organic solvents, and mixtures of these solvents, etc.

[0054] It is desirable that the patch of the present invention can absorb 9.5 to 85 mg / cm per unit area of the matrix 2An amount of subcutaneous fluid. The patch of the present invention may also be provided with at least one additive disposed within the matrix. In addition, the patch of the present invention may also be provided with a backing layer for supporting the matrix. A support coated with an acrylic, rubber or silicone adhesive may be used as a preferred backing layer. The support in this case is not particularly limited as long as it is suitable for supporting the matrix provided with the drug, and a stretchable or non-stretchable support may be used. Specifically, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester and nylon. Films or sheets (such as polyurethanes, etc.), laminates thereof, porous bodies, foams, fabrics and non-woven fabrics, and laminated products thereof, etc. may be used. The patch of the present invention may be provided with a release coating that peels off before application to the skin on the surface of the patch or on the surface of the adhesive provided on the backing layer support. Polyethylene, polypropylene, polyester, polyethylene terephthalate and those obtained by subjecting them to release treatment with silicone, or release paper, etc. may be used as such a release coating. The patch of the present invention may be used to transdermally deliver a drug through one or more micropores formed by a perforator. The perforator and the patch may be independent of each other, or they may be combined. In the case where the perforator and the patch are used in combination, the patch is adhered while being aligned with the skin area where hot piercing is performed using the perforator. During this period, it may be aligned visually, or a system for aligning it may also be used for alignment.

[0055] In a system for delivering a drug through a target biological membrane, the patch of the present invention may be used together with a perforator, thereby ensuring that at least a portion of the drug is soluble in the biological moisture received from the target through the micropores generated by the perforator.

[0056] The patch of the present invention may also be used in a method for delivering a drug through a target biological membrane, wherein the method includes the step of forming one or more micropores on the biological membrane, and the step of placing the patch in physical contact with the one or more micropores, thereby ensuring that at least a portion of the drug is soluble in the biological moisture received from the target through the one or more micropores.

[0057] The patch of the present invention may be prepared according to the following method. First, a backing layer material is formed into a predetermined size (e.g., 25×25 mm 2 ) using a die. Second, a matrix material (e.g., non-woven fabric) is formed into a predetermined size (e.g., 10×10 mm 2)。The formed matrix material is fixed to the central part of the backing layer material (hereinafter referred to as the blank patch). The additives (ascorbic acid, sucrose, citric acid monohydrate, etc.) and the drug are weighed, and then a solution (deionized water, PBS, ethanol, etc.) is added and stirred until completely dissolved to prepare the drug solution. The required drug solution is dropped onto the matrix material area of the blank patch using a mechanical pipette. It is dried in an oven at 60 °C for 20 to 50 minutes, and then the patch structure is obtained. A release coating (release liner) is applied to the patch structure. The completed patch is made into a sachet together with a desiccant by sealing with a heat sealer.

[0058] The patch of the present invention can be used according to the following method. The patch of the present invention is particularly expected to be suitable for diseases where immediate onset is desired, as well as diseases that require a PK curve comparable to subcutaneous injection. Drugs administered orally are generally mainly absorbed from the intestine, and it takes time for the drug to reach the intestine. On the other hand, when the patch of the present invention is used for transdermal drug delivery through one or more micropores formed by a perforator, by piercing the outermost stratum corneum of the epidermis and applying the patch there, the drug passes through the epidermis, diffuses into the dermal capillaries and enters the systemic circulation. Therefore, the patch of the present invention can provide a drug administration method instead of injection, which can be applicable to immediate release applications of drugs and is much faster than oral drug administration.

[0059] Examples

[0060] Examples will be described in detail below according to the present invention, but the present invention is not limited to such examples.

[0061] Method for measuring water retention capacity

[0062] The already weighed Tween 80 (Spectrum Chemical Mfg. Corp. or Croda) was dissolved in phosphate buffered saline (Sigma - Aldrich) to prepare PBS containing 0.1 w / v% Tween 80 (hereinafter referred to as the test solution). The thickness of the matrix material was measured using a digital indicator (U30A, manufactured by Sony Corporation). The matrix materials 1 to 3 (all manufactured by Japan Vilene Company, Inc.) shown in Table 1 were formed into squares of 10 mm × 10 mm to prepare samples. The prepared samples were weighed to obtain their dry weights (hereinafter referred to as weight A). Then, the above - mentioned samples were immersed in the test solution and completely impregnated with the test solution. The samples impregnated with the solution were slowly taken out from the test solution (about 5 seconds / cm) and weighed to obtain their weights after impregnation with the test solution (hereinafter referred to as weight B). Note that in the case where the matrix material has a film surface, it was weighed after wiping off the test solution adhering to the film surface after pulling out to obtain weight B. Note that the thickness, weight A, and weight B of the matrix material were each measured three times, and the average value was taken as the final value. The results are shown in Table 1.

[0063] Table 1

[0064]

[0065]

[0066] In vitro flux test

[0067] An in vitro flux test was performed using human skin with epidermis and stratum corneum to investigate the possibility of controlling the drug release rate when matrix materials 1 to 3 were used in the patches.

[0068] Drug patch preparation

[0069] The backing layer material was formed into a square of 25 mm × 25 mm using a die. Then, matrix materials 1 to 3 were each formed into squares of 10 mm × 10 mm using a die. The formed matrix materials 1 to 3 were fixed to the central part of the backing layer material (hereinafter referred to as blank patches 1 to 3). Water containing 0.1 w / v% Tween 80 was added to a tube containing weighed methylnaltrexone bromide to prepare a drug solution. The required drug solution was dropped onto the matrix material areas of blank patches 1 to 3 using a mechanical pipette. They were dried in an oven at 50 °C for 15 minutes to obtain patch structures 1 to 3. A release liner was coated on patch structures 1 to 3, and then drug patches 1 to 3 were obtained. The completed patches were made into sachets together with desiccants by sealing with a heat sealer.

[0070] Application of Human Skin Perforation and Patch

[0071] Human skin stored at -80 °C was placed at room temperature for 1 hour and, after thawing, cut into a size of 3 cm × 3 cm and then used. PBS was used as the receiving solution. Untreated human skin or perforated human skin as required was placed on the cell. The perforated area of the perforated human skin was 1 cm 2 . Drug patches 1 to 3 were applied to the human skin. The fluid was continuously stirred and the cell was maintained at 32 °C. At the desired observation time, 500 μl of the receiving solution was collected for analysis. In the collected receiving solution, 200 μl was analyzed by HPLC. The results are shown in Figure 1 . According to Figure 1 It is understood that, compared with drug patch 2 provided with matrix material 2 and drug patch 3 provided with matrix material 3, drug patch 1 provided with matrix material 1 is expected to be more suitable for immediate release applications of drugs.

[0072] Example 1

[0073] Drug Patch Preparation

[0074] The backing layer material (medical polyethylene tape, 1774W, manufactured by 3M Company) was formed into 25 mm × 25 mm using a die. Then, matrix material 1 was formed into 10 mm × 10 mm using a die. The formed matrix material 1 was fixed to the central part of the backing layer material (hereinafter referred to as the blank patch). 2 mg of zolmitriptan (molecular weight 287.36 (g / mol)) measured as the API, 0.5 mg of sucrose measured as the additive, and 4.0 mg of ascorbic acid were placed in a tube and dissolved in water to prepare a drug solution. The required drug solution was dropped onto the matrix material area of the blank patch using a mechanical pipette. They were dried in an oven at 60 °C for 20 minutes and then a patch structure was obtained. A release liner (silicone-coated release liner, manufactured by Fujimori Kogyo Co., Ltd.) was coated on the patch structure to obtain a drug patch. The completed patch was made into a sachet together with a desiccant.

[0075] Animal Experiment: Transdermal Delivery through Microperforation

[0076] Hairless rats 77 to 84 days old were used as experimental animals. The drug patch was fixed to the side of the skin of the experimental animal that had been perforated under the required conditions. During the period of fixing the patch and after the patch adhered, blood was collected at the required 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).

[0077] Reference Example 1

[0078] Animal experiment: intravenous administration

[0079] Hairless rats aged 77 to 84 days were used as experimental animals. After intravenous administration of a drug solution (200 μl) containing 1 mg of zolmitriptan and 1 mg of ascorbic acid, 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).

[0080] Reference Example 2

[0081] Animal experiment: oral administration

[0082] Hairless rats aged 77 to 84 days were used as experimental animals. After oral administration of a drug solution (2.0 ml) containing 10 mg of zolmitriptan, 7.3 mg of citric acid, and 4.9 mg of disodium hydrogen phosphate, 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 results obtained in Example 1, Reference Example 1, and Reference Example 2 are shown in Figure 2 as follows. From the results shown in Figure 2 it can be understood that the patch of Example 1 can be used for immediate release applications of drugs, and such immediate release applications of drugs can be an alternative means to intravenous administration (Reference Example 1) and are much faster than the patch of Reference Example 2 (oral administration).

[0083] Example 2 and Comparative Example 1

[0084] Drug patches were prepared using the same method as in Example 1, but using 5 mg of methylnaltrexone bromide (molecular weight 436.36 (g / mol)) as the drug, and transdermal delivery through microperforations (Example 2) was evaluated using hairless guinea pigs as experimental animals. Similarly, drug patches were prepared in the same manner as in Example 2, but using Matrix Material 2 instead of Matrix Material 1, and transdermal delivery through microperforations was evaluated (Comparative Example 1). The results obtained in Example 2 and Comparative Example 1 are shown in Figure 3 as follows. From the results shown in Figure 3 it can be understood that the patch of Example 2 is different from the patch of Comparative Example 1 and that it can be applied to immediate release applications of drugs.

[0085] Example 3 and Comparative Example 2

[0086] The drug patch was prepared using the same method as in Example 1, but 6 mg of fondaparinux sodium (molecular weight 1728 (g / mol)) was used as the drug, and hairless guinea pigs were used as experimental animals to evaluate transdermal delivery through microperforations (Example 3). Similarly, a drug patch was prepared in the same manner as in Example 3, but matrix material 2 was used instead of matrix material 1, and hairless guinea pigs were used as experimental animals to evaluate transdermal delivery through microperforations (Comparative Example 2). The results obtained in Example 3 and Comparative Example 2 are shown in Figure 4 In accordance with the results shown in Figure 4 it can be understood that the patch of Example 3 is different from the patch of Comparative Example 2 and that it can be applied to immediate release applications of drugs.

[0087] Example 4 and Comparative Example 3

[0088] The drug patch was prepared using the same method as in Example 1, but 0.1 mg of exenatide (molecular weight 4186.6 (g / mol)) was used as the drug, and hairless guinea pigs were used as experimental animals to evaluate transdermal delivery through microperforations (Example 4). Similarly, a drug patch was prepared in the same manner as in Example 4, but matrix material 3 was used instead of matrix material 1, and hairless guinea pigs were used as experimental animals to evaluate transdermal delivery through microperforations (Comparative Example 3). The results obtained in Example 4 and Comparative Example 3 are shown in Figure 5 In accordance with the results shown in Figure 5 it has been determined that the patch of Example 4 is different from the patch of Comparative Example 3, that the drug concentration reached a maximum at approximately 2.2 hours after the start of measurement in Example 4, that the drug concentration reached a maximum after approximately 3.2 hours in Comparative Example 3, and that the patch of Example 4 can be applied to immediate release applications of drugs.

[0089] Table 2

[0090]

[0091] The patch of the present invention includes a patch preparation for maintaining various drugs at a predetermined concentration or higher concentration, and a patch having the same bioavailability in a bioequivalence test. Here, the bioequivalence test refers to a test for determining bioequivalence, that is, whether the bioavailability (the rate and amount of the unchanged substance or active metabolite entering the systemic circulation, or the rate and amount reaching the site of action) is equivalent. Specifically, it can be determined whether the bioavailability is equivalent according to, for example, the bioequivalence test described in "Guidelines for Bioequivalence Testing of Generic Drugs" and "Bioequivalence Testing Guidelines for Generic Medicines of Topical Dermatological Preparations", as measured by PFSB / ELD Notification No. 1124005 (Heisei 18) issued by the Ministry of Health, Labour and Welfare of Japan on November 24, 2006.

[0092] For example, in "Guidelines for Bioequivalence Testing of Generic Drugs", in principle, when the cross-over method is used to collect blood as the body fluid, in a single-dose study, AUCt (the AUC (area under the blood concentration-time curve) until the final sampling time t) and Cmax (the maximum blood concentration) are used as bioequivalence determination parameters. If F (the relative absorption of the test preparation relative to the reference preparation (aqueous solution or intravenous administration)) can be calculated by deconvolution, F can be used instead of AUC. In addition, AUC∞ (the AUC until infinite time), tmax (the time to reach the maximum blood concentration or the time to reach the maximum urinary excretion rate), MRT (the mean residence time), and kel (the elimination rate constant), etc. are used as reference parameters. When urine is taken as the body fluid, Aet (the cumulative urinary excretion until the final sampling time t), Aeτ (the cumulative urinary excretion within one dosing interval (τ) after reaching steady state), Ae∞ (the cumulative urinary excretion until infinite time), Umax (the maximum urinary excretion rate), and Uτ (the urinary excretion rate at time τ after dosing at steady state) are used as parameters instead of AUCt, AUCτ (the AUC within one dosing interval (τ) after reaching steady state), AUC∞, Cmax, and Cτ (the blood concentration at time τ after dosing at steady state).

[0093] In addition, in the "Bioequivalence Testing Guidelines for Generic Medicines of Topical Dermatological Preparations", during the process of evaluating the bioequivalence of topical skin preparations, the most suitable test methods can be selected according to the characteristics of the drug and the preparation, such as 1. Skin pharmacokinetic studies (equivalence evaluation parameters: drug recovery at steady state, average stratum corneum drug concentration or stratum corneum drug concentration), 2. Pharmacological studies (equivalence evaluation parameter: AUEC (area under the intensity-time curve of the change to blue after removal of the preparation)), 3. Residue testing (equivalence evaluation parameter: amount of drug distributed from the preparation to the skin), 4. Pharmacokinetic studies (equivalence evaluation parameters: AUC or steady-state blood drug concentration), 5. Clinical trials (using clinical effects as indicators), 6. In vitro efficacy testing (using in vitro efficacy as indicators), and 7. Animal testing (using the pharmacological reactions occurring on the skin surface of animals by applying the preparation as indicators).

[0094] Each of the above-mentioned test methods is selected as needed, and statistical processing is performed on the bioequivalence determination parameters of the obtained test preparation and the reference preparation, and it can be determined whether the test preparation and the reference preparation are bioequivalent within a predetermined range. For example, in the "Guidelines for Bioequivalence Testing of Generic Drugs", when AUC and Cmax are log-normally distributed, when expressed as the ratio of the mean values of the parameters of the test preparation and the reference preparation, the bioequivalence tolerance range is 0.80 to 1.25, and when the 90% confidence interval of the log-mean values of the bioequivalence determination parameters of the test preparation and the reference preparation is log(0.80) to log(1.25), it is determined that the test preparation and the reference preparation are bioequivalent. In addition, in the "Bioequivalence Testing Guidelines for Generic Medicines of Topical Dermatological Preparations", when the equivalence evaluation parameter can be regarded as log-normally distributed, the bioequivalence tolerance range is expressed as the ratio of the mean values of the parameters of the test preparation and the reference preparation, and is 0.80 to 1.25 for highly potent drugs and 0.70 to 1.43 for drugs other than highly potent drugs. And when the equivalence evaluation parameter is considered to be normally distributed, when the difference between the population means of the test preparation and the reference preparation is expressed as the ratio to the population mean of the reference preparation, it is -0.20 to +0.20 for highly potent drugs and -0.30 to +0.30 for drugs other than highly potent drugs. When evaluating in a potency test or a clinical test, an appropriate tolerance band can be set according to the characteristics of the drug. Note that the bioequivalence tests described in these guidelines are well-known to those of ordinary skill in the art.

Claims

1. A transdermal drug delivery patch, comprising: a substrate, the substrate comprising a hydrophilic nonwoven fabric or film and having a water retention capacity of 1 mg / cm 2 to 10 mg / cm 2 , a thickness of 100 μm or less, and a weight of 100 g / m 2 or less, and At least one drug disposed within the matrix, wherein the drug is an agent having a molecular weight of 5000 or less, and the amount of the at least one drug is 0.1 mg / 1 cm 2 of the matrix to 30 mg / 1 cm 2 the matrix.

2. The patch according to claim 1, wherein the matrix comprises polyethylene terephthalate, and the matrix has a water retention capacity of 1 mg / cm 2 to 4 mg / cm 2 , a thickness of 38 μm or less, and a weight of 12 g / m 2 or less.

3. The patch according to claim 1, wherein the matrix comprises polyethylene terephthalate, and the matrix has a water retention capacity of 4 mg / cm 2 , a thickness of 38 μm, and a weight of 12 g / m 2 .

4. The patch according to claim 1, wherein the agent has a molecular weight of 2000 or less.

5. The patch according to claim 1, wherein the agent is a non-peptide agent.

6. The patch according to any one of claims 1 to 5, further comprising at least one humectant disposed within the matrix.

7. The patch according to claim 6, wherein the humectant is sugar.

8. The patch according to claim 6, wherein the total amount of the drug and the hygroscopic agent provided in the matrix per unit area is 0.1 to 30 mg / m 2 .

9. The patch according to claim 8, wherein the total amount of the drug and the hygroscopic agent per unit area of the matrix is 0.1 to 20 mg / m 2 .

10. The patch according to any one of claims 1 to 5, wherein the matrix per unit area can aspirate a subcutaneous fluid in an amount of 9.5 to 85 mg / cm 2 2.

11. The patch according to any one of claims 1 to 5, further comprising at least one additive disposed within the matrix.

12. The patch according to any one of claims 1 to 5, further comprising a backing layer for supporting the matrix.

13. The patch according to any one of claims 1 to 5, for transdermal delivery of a drug through one or more microholes formed by a perforator.

14. A system for delivering a drug through a target biological membrane, comprising: a perforator, and a patch, wherein the patch comprises: A substrate, said substrate comprising a hydrophilic nonwoven fabric or film, and having a water retention capacity of 1 mg / cm 2 to 10 mg / cm 2 , a thickness of 100 μm or less, and a weight of 100 g / m 2 or less, and At least one drug disposed within the matrix, wherein at least a portion of the drug is soluble in the biological moisture received by the target biofilm through one or more micropores formed by the perforator, the drug is an agent having a molecular weight of 5000 or less, and the amount of the at least one drug is 0.1 mg / 1 cm 2 of the matrix to 30 mg / 1 cm 2 of the matrix.

15. The system according to claim 14, wherein the substrate comprises polyethylene terephthalate, and the substrate has a water retention capacity of 1 mg / cm 2 to 4 mg / cm 2 , a thickness of 38 μm or less, and a weight of 12 g / m 2 or less.

16. The system according to claim 14, wherein the substrate comprises polyethylene terephthalate, and the substrate has a water retention capacity of 4 mg / cm 2 , a thickness of 38 μm, and a weight of 12 g / m 2 .

17. The system according to claim 14, wherein the perforator is at least one perforator selected from a thermal perforator, a mechanical perforator, a laser perforator, and a water perforator.

18. The system according to claim 14, wherein the perforator is a heat conducting element configured to be in substantially physical contact with the biological membrane to deliver sufficient energy to thermally ablate the biological membrane.

19. The system according to any one of claims 14 to 18, wherein the perforator is a thin tissue interface device.

20. The system according to any one of claims 14 to 18, wherein the agent has a molecular weight of 2000 or less.

21. The system according to any one of claims 14 to 18, wherein the agent is a non-peptide agent.

22. The system according to any one of claims 14 to 18, wherein the patch further comprises at least one humectant disposed within the matrix.

23. The system according to claim 22, wherein the humectant is sugar.

24. The system according to claim 22, wherein the total amount of the drug and the hygroscopic agent provided in the matrix per unit area is 0.1 to 30 mg / cm 2 .

25. The system according to claim 24, wherein the total amount of the drug and the hygroscopic agent per unit area of the substrate is 0.1 to 20 mg / cm 2 .

26. The system according to any one of claims 14 to 18, wherein the substrate per unit area can aspirate subcutaneous fluid in an amount of 9.5 to 85 mg / cm 2 .

27. The system according to any one of claims 14 to 18, wherein the patch further comprises at least one additive disposed within the matrix.

28. The system according to any one of claims 14 to 18, wherein the patch further comprises a backing layer for supporting the matrix.

29. Use of the patch according to any one of claims 1 to 13 in the preparation of a drug for delivering an agent through a target biological membrane, wherein the patch is in physical contact with one or more microholes on the target biological membrane, and wherein the agent is a non-peptide agent.

30. The use according to claim 29, wherein a device selected from a thermal perforator, a mechanical perforator, a laser perforator, and a water perforator is used to form the one or more microholes.

31. The use according to claim 29, wherein a heat conducting element configured to be in substantially physical contact with the biological membrane to deliver sufficient energy to thermally ablate the biological membrane is used to form one or more microholes.

32. The use according to any one of claims 29 to 31, wherein a thin tissue interface device is used to form the one or more microholes.

33. Use of the system according to any one of claims 14 to 28 in the preparation of a device for delivering a drug across a target biological membrane.

34. Use according to claim 33, wherein the drug is a non-peptide drug.

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