CN108685877B - Patch system for percutaneous absorption with minimized skin irritation - Google Patents
Patch system for percutaneous absorption with minimized skin irritation Download PDFInfo
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- CN108685877B CN108685877B CN201810311417.8A CN201810311417A CN108685877B CN 108685877 B CN108685877 B CN 108685877B CN 201810311417 A CN201810311417 A CN 201810311417A CN 108685877 B CN108685877 B CN 108685877B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0208—Tissues; Wipes; Patches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/10—General cosmetic use
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Abstract
The present invention relates to a patch system for percutaneous absorption, comprising (a) an outer protective layer, (b) a solvent-based adhesive layer, (c) a non-solvent-based adhesive layer, and (d) a release layer which is a film that is removed before use, wherein the solvent-based adhesive layer is adjacent to the outer protective layer, and the non-solvent-based adhesive layer is adjacent to the release layer and is in contact with the skin at the time of use, and wherein the solvent-based adhesive layer and/or the non-solvent-based adhesive layer comprises one or more ingredients selected from the group consisting of a skin active ingredient and a pharmaceutically active ingredient. The patch system is capable of effectively absorbing various active ingredients through the skin and minimizing skin irritation when applied to the skin of a human body.
Description
Technical Field
The present invention relates to a patch system for percutaneous absorption with minimized skin irritation. More particularly, the present invention relates to a patch system capable of effectively absorbing various active ingredients through the skin and minimizing skin irritation when applied to the skin of a human body.
Background
In response to the need to use various active ingredients exhibiting beneficial effects on the human body through the skin for a long time, patches using pressure-sensitive adhesives have been widely used.
Various formulations, such as creams, lotions, ointments, oils, sprays, patches and the like, can be used in methods of delivering active ingredients through the skin that exhibit beneficial effects on the human body. Among them, creams, lotions, ointments, oils, sprays, etc., other than patch-type preparations, generally show short-term effects, and may be washed off or removed in an undesirable manner after application due to external factors such as water or laundry. Furthermore, the application time of the product may be temporary, and therefore, it is troublesome that the product must be applied several times a day.
Conversely, the patch type preparation can be applied to the skin for a long period of time, for example, 3 hours or more, or can last for 24 hours or more if necessary, thereby maintaining the desired effect. Therefore, it can be said that such a formulation is most suitable for effectively delivering an active ingredient to the human body through the skin.
Most conventional patch products use a solvent-type adhesive, and in particular, mainly use a rubber-type adhesive, an acrylate-type adhesive, or a silicone-type adhesive. Products using these solvent-based adhesives may cause skin allergic irritation when they are used daily for a long period of time by contact with the skin.
In addition, conventional solvent-based adhesives are characterized in that they can cause skin irritation when the patch product is applied to the skin and subsequently peeled off. Furthermore, with solvent-based adhesives, it is difficult to control the residual trace amount of residual solvent in the product to the legally permissible range when subjected to the processing.
In particular, when a conventional patch product is applied to a human body, skin irritation may be caused to some extent at the time of use and/or after use, and thus may cause a serious problem to consumers using the patch. If a patch product causes serious problems to the consumer due to such skin irritation, the consumer will avoid such a patch product despite the benefit of being able to apply the active ingredient to the skin for a long period of time in a single application.
Therefore, there is a need for a new patch product that has less skin irritation when applied to the skin and subsequently torn off, and that has fewer problems caused by undesirable residual solvents contained in conventional patches.
Disclosure of Invention
Under these circumstances, the present inventors have conducted extensive studies to overcome the disadvantages of conventional patch products, and found that, when a solvent-type adhesive layer and a non-solvent-type adhesive are laminated as a specific layered structure, not only can an active ingredient be transdermally delivered during application without degradation or reduction in activity of an effective active ingredient, but also a formulation capable of minimizing skin irritation present in conventional patches is obtained, thereby completing the present invention.
Accordingly, the present invention provides a patch system for transdermal absorption, comprising:
(a) An outer protective layer for protecting the outer surface of the substrate,
(b) A solvent-based adhesive layer having at least one layer,
(c) A non-solvent based adhesive layer having at least one layer, an
(d) A release layer, the release layer being a film that is removed prior to use,
wherein the solvent-based adhesive layer is adjacent the outer protective layer and the non-solvent-based adhesive layer is adjacent the release layer and in contact with the skin in use.
According to the present invention, the non-solvent type adhesive layer has a 180 degree peel strength of 0.1N/25mm to 10N/25mm and a tack-back value of 0.1N/25mm to 8N/25 mm.
According to one embodiment, the non-solvent based adhesive layer may comprise a hot melt adhesive.
The hot melt adhesive may include one or more selected from the group consisting of hydrogenated styrene block copolymers and non-hydrogenated styrene block copolymers.
Preferably, the hydrogenated styrene block copolymer may be selected from the group consisting of hydrogenated styrene/butadiene copolymers, hydrogenated styrene/methylstyrene/indene copolymers, hydrogenated ethylene/propylene/styrene copolymers, hydrogenated butylene/ethylene/styrene copolymers; and the non-hydrogenated styrene block copolymer is selected from the group consisting of styrene/isoprene/styrene block copolymers, styrene/butadiene/styrene block copolymers, styrene/isoprene/butadiene/styrene block copolymers.
The solvent-based adhesive layer may include one or more adhesives selected from the group consisting of acrylate-based adhesives, rubber-based adhesives, and silicone-based adhesives.
According to one embodiment, the non-solvent based adhesive layer does not contain any active ingredient or contains at least one active ingredient that is stable at temperatures between 120 ℃ and 200 ℃, and the solvent based adhesive layer contains at least one active ingredient, wherein the active ingredient is selected from the group consisting of skin active ingredients and pharmaceutical active ingredients.
In the patch system of the present invention, the weight ratio of the solvent-based adhesive layer to the non-solvent-based adhesive layer may be from 90 to 10, preferably from 80 to 20.
In the patch system of the present invention, the thickness ratio of the solvent-based adhesive layer to the non-solvent-based adhesive layer may be 90 to 10, preferably 80 to 20.
Specifically, the thickness of the solvent-based adhesive layer may be 10 to 200. Mu.m, preferably 20 to 120. Mu.m, and more preferably 30 to 120. Mu.m. The thickness of the non-solvent type adhesive layer may be 10 to 300. Mu.m, preferably 20 to 120. Mu.m, and more preferably 20 to 80 μm.
In particular, the skin active ingredient may be one or more cosmetic ingredients selected from the group consisting of: skin elasticity improving agent, moisturizer, lipolysis promoter, inhibitor of carbohydrate conversion to lipid, burning lipid substance, blood circulation improving agent, exfoliating agent, agent for relieving skin freckle, whitening agent, agent for relieving atopic dermatitis, anti-wrinkle agent, anti-aging agent, light aging inhibitor, heat aging inhibitor, collagen production promoter, elastin activator, hyaluronic acid production enhancer, radical scavenger, cell proliferation agent, keratinocyte proliferation inhibitor, inhibitor of harmful active oxygen production, cell regeneration substance, skin regeneration promoter, anti-acne agent, and antioxidant.
Preferably, the skin active ingredient may be one or more selected from the group consisting of: collagen, retinoids, vitamin a, vitamin C, vitamin E, alpha-hydroxy acids, beta-hydroxy acids, curcuminoids, resveratrol, hyaluronic acid, arbutin, niacinamide, vitamin B5, coenzyme Q10, adenosine, elastin, chitosan, albumin, egg yolk, milk protein, capsaicin, conjugated linolenic acid, caffeine, garcinia cambogia (HCA), pyruvic acid and inulin propionate, phosphatidylcholine, L-carnitine, L-arginine, modified capsaicin, catechin, chromium, lipase, extracts of: aloe vera, green tea, korean ginseng, red ginseng, pyroligneous liquor, pine leaves, ginkgo leaves, propolis, mulberry leaves, silkworms, snail mucilage, kakadu plum, camu fruit, acai palm, squalane, caviar, broccoli, blueberry, hamamelis virginiana, phlogopite, chlorella vulgaris, mangosteen, guava, dogwood, carrot, coffee beans, murraya paniculata, spirulina, salmon roe, ecklonia cava, kelp, common purslane, green laver, gelidium amabilis, mulberry roots, raspberry, strawberries, hizikia fusiforme, gulfweed, chamomile, lavender, mint, eucalyptus, lemon balm, oregano, tea tree, scutellaria, houttuynia, sea buckthorn, lemon, and soybean, and their free base forms, pharmaceutically acceptable salt forms, and their derivatives.
Specifically, the pharmaceutically active ingredient may be one or more ingredients selected from the group consisting of: hormonal agents, contraceptives, anti-inflammatory agents, dermatitis therapeutic agents, smoking cessation aids, angina therapeutic agents, bronchial asthma therapeutic agents, attention deficit/hyperactivity disorder therapeutic agents, hypertension therapeutic agents, analgesics, narcotic analgesics, anti-emetics, nausea relieving agents, dementia therapeutic agents, therapeutic agents in alzheimer's disease, parkinson's disease therapeutic agents, allergic cystitis therapeutic agents, vaccines and antidepressants.
Preferably, the pharmaceutically active ingredient is one or more ingredients selected from the group consisting of: estradiol, testosterone, estradiol/progesterone complex, estradiol/norethindrone, ethinyl estradiol/norethindrone, estradiol/levonorgestrel, ketoprofen, piroxicam, triamcinolone acetonide, flurbiprofen, naproxen, meloxicam, flusufamide, oxybutynin, indomethacin, buprenorphine, capsaicin, diclofenac, nicotine, nitroglycerin, tulobuterol, methylphenidate, clonidine, lidocaine, fentanyl, sufentanil, granisetron, ramosetron, scopolamine, rivastigmine, carbapenem, donepezil, rotigotine, oxybutynin and selegiline, as well as their free base forms, their pharmaceutically acceptable salts and their derivatives.
In the solvent-based adhesive layer, the amount of the active ingredient is 0.001 to 30wt%, preferably 0.01 to 20wt%, relative to the weight of the solvent-based adhesive. In the non-solvent type adhesive layer, the amount of the active ingredient (if any) is 0.001 to 30wt%, preferably 0.01 to 20wt%, relative to the weight of the non-solvent type adhesive.
It is therefore an object of the present invention to provide a patch system for percutaneous absorption which can minimize skin problems occurring at the time of use and/or before and after use of the patch product due to skin irritation, while enhancing the benefit of the patch product in providing an active ingredient to the skin for a long period of time.
Drawings
Fig. 1 is a view showing the structure of a patch system for percutaneous absorption according to the present invention.
Detailed Description
Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings.
As shown in fig. 1, a patch system for percutaneous absorption according to the present invention includes: an outer protective layer 1; a solvent-based adhesive layer 2; a non-solvent type adhesive layer 3 in contact with the skin; and a release layer 4 which is a film removed before use; wherein the solvent-based adhesive layer is adjacent to the outer protective layer and the non-solvent-based adhesive layer is in contact with the skin in use. That is, in the present invention, the solvent-based adhesive layer and the non-solvent-based adhesive layer are included in the form of separate layers, and they have the following unique structures: they are in adjacent contact at specific locations, for example for the solvent-type layer, which is in contact with the outer protective layer, and for the non-solvent-type layer, which is in adjacent contact with the release layer and, in use, is in direct contact with the skin.
Further, the solvent-based adhesive layer and the non-solvent-based adhesive layer employed in the present invention may include a plurality of layers, i.e., 2 or more layers, respectively. According to a specific embodiment, the solvent-based adhesive layer and the non-solvent-based adhesive layer may have 1 to 7 layers, respectively.
In the layered structure of such a patch system for percutaneous absorption, the outer protective layer 1 functions to impart mechanical properties to the preparation and support the preparation, and protects the active ingredient-containing adhesive layer from the outside. The outer protective layer may use a material capable of adhering to the solvent-based adhesive layer, preventing loss of active ingredients during storage, and having the property of maintaining its own shape without being reactive to the skin without causing allergic reaction to the skin. Also, the material is not particularly limited.
The material that can be used as the outer protective layer is not particularly limited. By way of example, such materials may include, but are not limited to, one or more materials selected from the group consisting of: polyester, polyolefin film, polyurethane, polyvinyl acetate, polyvinylidene chloride, polyethylene, ethylene vinyl acetate, polyethylene terephthalate, polyacrylonitrile, polybutylene terephthalate, nylon, rayon, non-woven fabric, acryl (acryl), silk, cotton, aluminum sheet, polyamide, and the like. The outer protective layer may be in the form of a sheet, film, fiber, fabric, knitted fabric, nonwoven fabric, or the like. The outer protective layer may be a permeable or impermeable material, such as a porous film formed from a material including a laminate composed of a combination of two or more of the above polymers.
In the present invention, the non-solvent type adhesive layer 3 is adjacent to the release layer 4, and is a layer that is directly in contact with the skin after the release layer is removed at the time of use.
The non-solvent adhesive layer comprises a hot melt adhesive. Hot melt adhesives are adhesives which: exists in a solid state at room temperature and is used in a molten state by melting 100% of the solid content only by heating without being dissolved or dispersed in a solvent. The hot melt adhesive is a pressure-sensitive synthetic rubber-based adhesive which does not require a drying process, and is an environmentally friendly material since a solvent is not used, compared to a solvent-based adhesive and the like.
The hot melt adhesive used for the non-solvent type adhesive layer may be a base resin commonly used in the art. Examples of these hot melt adhesives include polyolefin types such as polybutadiene type, polyisoprene type, polyethylene type, polypropylene type; styrene block copolymer type; polyindene type; a polyamide type; non-hydrogenated styrenic block copolymers; polyester type such as ethylene vinyl acetate type; polyurethane type (reactive hot melt); hydrogenated styrene block copolymers, and the like, but are not limited thereto.
Specific examples of such a hot melt adhesive include, but are not limited to, hydrogenated styrene block copolymers.
Further, the hydrogenated styrene block copolymer includes, but is not limited to, hydrogenated styrene/butadiene copolymer, hydrogenated styrene-methylstyrene/indene copolymer, hydrogenated ethylene/propylene/styrene copolymer, hydrogenated butylene/ethylene/styrene copolymer, and the like. The non-hydrogenated styrene block copolymer includes, but is not limited to, a styrene/isoprene/styrene block copolymer, a styrene/butadiene/styrene block copolymer, a styrene/isoprene/butadiene/styrene block copolymer, and the like. In a particular embodiment of the present invention, PSM154A DERMA-TAK (available from Henkel) is used as a non-solvent hot melt adhesive to construct a patch system for transdermal absorption.
In the present invention, the hot melt adhesive used in the non-solvent type adhesive layer preferably has a weight average molecular weight of 50,000 to 3,000,000 and a polymerization degree distribution of 100 to 1,000,000, but is not limited thereto.
The hot melt adhesive used for the non-solvent type adhesive layer generally has processability at a temperature of 150 to 180 ℃, which is relatively higher than the processing temperature of the adhesive used for the solvent type adhesive layer, which will be described in detail later.
The non-solvent type hot melt adhesive is used to significantly reduce skin irritation when the patch system for percutaneous absorption of the present invention is applied to and removed from the skin.
In particular, the hot melt adhesive can be smoothly released with a smaller force than that required to remove a conventional patch product from the skin during the process of attaching and detaching the patch product, compared to a solvent-type acrylate adhesive, and thus exhibits excellent physical properties in terms of reducing skin irritation. Preferably, the non-solvent type hot melt adhesive layer has a 180 degree peel strength of 0.1N/25mm to 10N/25mm and a tack back value of 0.1N/25mm to 8N/25 mm.
Peel strength, measured herein according to the method of ASTM D903, is one of the methods for measuring adhesion, and represents the force required to peel a test piece at an angle of 180 ° after adhering the test piece to a glass plate having a uniform and smooth surface. Higher values mean higher adhesion, indicating a higher force is required to remove the test strip. Further, tack (tack) refers to instantaneous tack, and loop tack (loop tack), measured herein according to the method of ASTM D6195, refers to a value representing the force required to peel a test piece at a constant speed after a particular area (typically, an area of 1 square inch) of the test piece is contacted with a metal surface at a constant speed under a constant force, and a higher value indicates a higher adhesion force. In the patch system of the present invention, the non-solvent type hot melt adhesive layer has peel strength and tack-back within the above-mentioned ranges, and therefore, the product can be easily removed from the skin with only about 6% of force compared to solvent type products.
Therefore, in the patch system of the present invention, when the non-solvent type adhesive layer formed of the hot melt adhesive is placed on the side capable of being in direct contact with the skin, the product can be easily peeled without skin irritation when the product is applied to the skin for a long time or when the product is removed from the skin.
The thickness of the non-solvent type adhesive layer is 10 to 300. Mu.m, preferably 20 to 120. Mu.m, and more preferably 20 to 80 μm.
Further, referring again to fig. 1, the solvent-based adhesive layer 2 of the patch system of the present invention is adjacent to the outer protective layer 1 and the non-solvent-based adhesive layer 3. The solvent-based adhesive layer 2 includes a solvent-based adhesive. A solvent-based adhesive refers to an adhesive used by dissolving or dispersing in a solvent to be in a liquid state, unlike a non-solvent-based adhesive.
Examples of the solvent-based adhesive include acryl-based adhesives, rubber-based adhesives, silicone-based adhesives, and the like, but any adhesive may be used without limitation as long as it can be used as a solvent-based adhesive.
Specifically, the monomer for the acryl-based adhesive may have no substituent, and may have at least one substituent such as a hydroxyl group, an epoxy group, a carboxyl group, and the like. The monomer of the acryl-based adhesive includes (meth) acrylic acid, alkyl (meth) acrylate, wherein the alkyl group may have 1 to 12 carbon atoms.
Further, the rubber-based adhesive may be a natural rubber, a synthetic rubber, or a graft rubber-based adhesive. Preferably, the rubber-based adhesive may be selected from the group consisting of polyisobutylene, polyisobutylene blends, neoprene, polybutadiene, polyisoprene, polysiloxanes, acryl-based adhesives, vinyl acetate adhesives, polyacrylates, ethylene vinyl acetate copolymers, styrene-isoprene copolymers, and polyurethanes.
As the silicone-based adhesive, silicone rubber (such as polysiloxane) or a silicone resin adhesive may be used. These solvent-based adhesives exhibit various adhesion and physical properties depending on the degree of polymerization, and they may be used alone or in combination. The adhesive used in the solvent-based adhesive layer of the present invention has a weight average molecular weight of 50,000 to 3,000,000, preferably 100,000 to 1,000,000, but is not limited thereto.
The thickness of the solvent-based adhesive layer is 10 to 200. Mu.m, preferably 20 to 120. Mu.m, and more preferably 30 to 120. Mu.m.
Solvent-based adhesives, such as acryl-based adhesives, rubber-based adhesives, and silicone-based adhesives, have slightly different processing temperatures depending on the solvent used, but processing at 80 ℃ to 120 ℃ is a typical condition of the manufacturing process.
However, as described above, since the non-solvent type hot melt adhesive exists in a solid block at room temperature, and in order to perform its processing, it is necessary to perform a treatment at a high temperature of about 150 ℃ to 200 ℃. Therefore, when a heat-sensitive or unstable active ingredient and/or additive is contained, there may occur a problem that degradation occurs or stability is deteriorated.
In the patch system for percutaneous absorption according to the present invention, when the active ingredient or additive to be supported is supported on a solvent-type adhesive layer or a non-solvent-type adhesive layer, it is characterized in that they are supported (included) in consideration of these processing characteristics.
Specifically, in the patch system according to the present invention, the active ingredient and the additive that are stable to heat even at a temperature of 120 to 200 ℃ can be all supported on the solvent-type adhesive layer or the non-solvent-type adhesive layer. However, the thermally unstable active ingredient and the additive are separately supported on the solvent-type adhesive layer having a lower processing temperature.
That is, although a hot melt adhesive can be easily peeled without skin irritation when peeled from the skin, an active ingredient or additive which is unstable at a high processing temperature of 120 to 200 ℃ does not have a method capable of being applied to a hot melt adhesive having a high processing temperature. However, in the patch system according to the present invention, these problems can be avoided by using a solvent-based adhesive layer having a relatively low processing temperature and a non-solvent-based adhesive layer having a higher processing temperature at the same time.
In the patch system according to the present invention, an active ingredient stable at a high processing temperature of 120 to 200 ℃ is contained in a non-solvent type adhesive layer in contact with the skin, and thus is absorbed by direct contact with the skin. In addition, since an active ingredient that is unstable at a high processing temperature of 120 to 200 ℃ is contained in the solvent-type adhesive layer that is in contact with the skin, the active ingredient supported on the solvent-type adhesive layer diffuses in a concentration gradient and migrates into the adjacent non-solvent-type adhesive layer. Thus, the active ingredient diffused into the non-solvent type adhesive layer is eventually brought into contact with the skin.
Thus, the solvent-based adhesive layer and the non-solvent-based adhesive layer are formed as separate layers, and active ingredients that are unstable at high temperature processing are not absorbed by direct contact with the skin, but are in contact with the skin through one or more non-solvent-based adhesive layers. Therefore, due to the problems of the solvent-based adhesive layer itself, there is a disadvantage in that it is difficult to move to the non-solvent-based adhesive layer, or the non-solvent-based adhesive layer may become a barrier layer, and thus the amount of active ingredient eventually contacting the skin and its release rate may be inconstant or insufficient.
In order to release these active ingredients in an effective amount and rate sufficient to contact the skin, as a method for allowing the active ingredients supported on the solvent-based adhesive layer to easily migrate into the adjacent non-solvent-based adhesive layer, different concentrations may be used in the adjacent layers, or a component capable of completely dissolving the active ingredients in the solvent-based adhesive layer may be supported into the non-solvent-based adhesive layer, thereby inducing the active ingredients supported on the solvent-based adhesive layer to migrate into the non-solvent-based adhesive layer.
Further, in the patch system for percutaneous absorption according to the present invention, the weight ratio of the solvent-based adhesive layer to the non-solvent-based adhesive layer (solvent-based adhesive layer: non-solvent-based adhesive layer) may be 90 to 10. Further, the thickness ratio of the solvent-based adhesive layer to the non-solvent-based adhesive layer (solvent-based adhesive layer: non-solvent-based adhesive layer) may be from 90 to 10, preferably from 80 to 20. When the solvent-based adhesive layer and the non-solvent-based adhesive layer have the weight ratio and/or the thickness ratio as described above, in particular, the active ingredient carried in the solvent-based adhesive layer can be suitably eluted and easily and efficiently absorbed by the skin through the non-solvent-based adhesive layer.
Further, when various additives are mixed and loaded to only one adhesive layer to cause various problems in stability, it may be particularly useful to load an active ingredient or an additive to be loaded to a patch onto two different adhesive layers having different processing temperatures. In addition, even other problems in stability due to mixing of various active ingredients or additives together, or the occurrence of chemical reactions such as acid-base reactions, can be similarly avoided, thereby providing advantageous advantages.
The active ingredient that may be contained in the patch system of the present invention may include one or more ingredients selected from the group consisting of pharmaceutically active ingredients exhibiting a beneficial effect on the human body and cosmetic ingredients exhibiting a beneficial effect on the skin, but is not limited thereto. However, as described above, they may be selectively supported to a solvent-type or non-solvent-type adhesive layer in consideration of their denaturation or stability at high temperature, interaction with an active ingredient used together, and the like.
In particular, cosmetic ingredients that may be included in the patch system of the present invention that exhibit a beneficial effect on the skin include one or more of the following: skin elasticity improving agents, moisturizers, lipolysis accelerators, inhibitors of carbohydrate conversion to lipid, burning lipid substances, blood circulation improving agents, exfoliating agents, agents for relieving skin freckles, whitening agents, agents for relieving atopic dermatitis, anti-wrinkle agents, anti-aging agents, light aging inhibitors, heat aging inhibitors, collagen production promoters, elastin activators, hyaluronic acid production enhancers, radical scavengers, cell proliferating agents, keratinocyte proliferation inhibitors, inhibitors of harmful reactive oxygen species production, cell regenerating substances, skin regeneration promoters, anti-acne agents, antioxidants and the like, but are not particularly limited as long as they exhibit a beneficial effect when applied to the skin.
Examples of useful active ingredients for cosmetic ingredients are selected from one or more of the group consisting of: collagen, retinoids (retinoids), vitamin a, vitamin C, vitamin E, alpha-hydroxy acids, beta-hydroxy acids, curcuminoids, resveratrol, hyaluronic acid, arbutin (arbutin), niacinamide, vitamin B5, coenzyme Q10, adenosine, elastin, chitosan, albumin, egg yolk, milk proteins, capsaicin, conjugated linolenic acid, caffeine, garcinia cambogia (HCA), pyruvic acid and inulin propionate, phosphatidylcholine, L-carnitine, L-arginine, modified capsaicin, catechin, chromium, lipase, extracts of: aloe, green tea, korean ginseng, red ginseng, pyroligneous liquor (pyroligneous liquor), pine leaves, ginkgo leaves, propolis, mulberry leaves, silkworms, snail mucus, kakakadu plum (kakakakadu plum), camu fruit (camu camu), assai palm (acai palm), squalane, caviar, broccoli, blueberry, witch hazel (witch hazel), tiger (acola), chlorella (chlorella), mangosteen (mangosteen), guava, dogwood (Cornus officinalis), carrot, coffee bean, murraya (hamamelis), spirulina, salmon seeds, cavity Ecklonia (klonia cava), macroalgae (giant kelp), kelp (Laminaria japonica areschuchi), common purslane (common purslane), kelp (kelp), gelidium (kelp), raspberry (agar), mulberry root, mulberry leaf, strawberries, sargassum fusiforme (hijiki), gulfweed (gulfweed), edelweiss (edelweiss), chamomile, lavender, peppermint, eucalyptus, lemon balm (lemon balm), oregano, tea tree, scutellaria (skullcaps), houttuynia cordata (Houttuynia cordia), sea buckthorn (sea buckthorn), citrus citrin (citronon), and soybean, as well as their free base forms, pharmaceutically acceptable salt forms, and their derivatives, but are not limited thereto.
Examples of therapeutic agents that may be included in the patch system of the present invention that exhibit a pharmaceutically beneficial effect may include one or more pharmaceutically active ingredients from the group consisting of: hormonal agents, contraceptives, anti-inflammatory agents, dermatitis therapeutic agents, smoking cessation aids, angina pectoris therapeutic agents, bronchial asthma therapeutic agents, attention deficit/hyperactivity disorder therapeutic agents, hypertension therapeutic agents, analgesics, narcotic analgesics, anti-emetics, nausea relieving agents, dementia therapeutic agents, therapeutic agents in alzheimer's disease, parkinson's disease therapeutic agents, allergic cystitis therapeutic agents, vaccines and antidepressants, but are not particularly limited as long as they exhibit pharmaceutically beneficial effects when applied to the skin.
Examples of pharmaceutically active ingredients exhibiting pharmaceutically beneficial effects that can be used in the present invention include one or more pharmaceutically active ingredients selected from the group consisting of: estradiol, testosterone, estradiol/progesterone complex, estradiol/norethindrone, ethinyl estradiol/norethindrone, estradiol/levonorgestrel, ketoprofen, piroxicam, triamcinolone acetonide, flurbiprofen, naproxen, meloxicam, flusufamide, oxybutynin, indomethacin, buprenorphine, capsaicin, diclofenac, nicotine, nitroglycerin, tulobuterol, methylphenidate, clonidine, lidocaine, fentanyl, sufentanil, granisetron, ramosetron, scopolamine, rivastigmine, donepezil, rotigotigold, oxybutynin and selegiline, as well as their free base forms, their pharmaceutically acceptable salts and their derivatives, but are not particularly limited as long as they exhibit a pharmaceutically beneficial effect when applied to the skin.
The total amount of active ingredient that may be included in the patch system according to the present invention may be 0.001 to 30wt%, preferably 0.01 to 20wt%, based on the weight of the solvent-based or non-solvent-based adhesive, under the conditions of the drug and additives determined by the concentration at which these active ingredients may exhibit beneficial effects and the area of the appropriate formulation. When the amount of the active ingredient is more than 30wt%, the concentration of the active ingredient in the adhesive layer is high, and the active ingredient may precipitate out of crystals after formulation. When the amount of the active ingredient is less than 0.001wt%, the concentration of the active ingredient in the adhesive layer is low, which reduces the permeability of the skin, thereby reducing the therapeutic effect of the active ingredient exhibiting effective effects.
In addition, various additives may be used in the solvent-based adhesive layer and/or the non-solvent-based adhesive layer of the present invention, as needed. Examples of the additives include percutaneous absorption promoters, tackifiers, plasticizers, antioxidants, fillers, and the like.
In the present invention, the adhesive layer may contain a percutaneous absorption enhancer to increase the rate of penetration of the active ingredient into the skin. Examples of the percutaneous absorption enhancer include pyrrolidone derivatives, compounds having C 8-18 Fatty acid derivatives or fatty acid alcohol derivatives, myristic acid derivatives, tocopherol derivatives, polyhydric alcohols, alkylamines, surfactants, triacetin, or the like, and they may be used alone or in combinationAnd (4) mixing and using.
Examples of the tackifier include rosin and derivatives thereof having 3 to 12 carbon atoms, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, maleic acid resins, and the like, and the rosin derivatives may include glycerol esters of rosin, hydrogenated rosin, glycerol esters of hydrogenated rosin, pentaerythritol esters of rosin, and the like.
Examples of the plasticizer include petroleum oils (paraffin processing oil, naphthalene processing oil, aromatic processing oil), squalene, vegetable oils (olive oil, camellia oil, castor oil, tall oil, peanut oil), silicone oils, dibasic acid esters (dibutyl phthalate, dioctyl phthalate), liquid rubber components (polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, diethylene glycol, polyethylene glycol, salicylic acid, ethylene glycol, propylene glycol, dipropylene glycol, and glyceryl triacetate, and the like.
The release layer 4 of the present invention is a layer which is laminated under the non-solvent type adhesive layer 3 and protects the adhesive layer before/until the use of the transdermal patch system. There is no particular limitation in the material or shape thereof as long as these functions can be achieved.
Examples of suitable materials for the release layer include materials such as polyester, polyvinyl acetate, polyvinylidene chloride, polypropylene, polystyrene, polycarbonate, ethylene vinyl acetate, polyethylene terephthalate, polybutylene terephthalate, aluminum sheet, paper, and combinations thereof. The release layer may be formed from one or more of the above materials in the form of films and silicone coated on one side of these films. In a preferred embodiment, the thickness of the release layer may be 20 μm to 300 μm, preferably 30 μm to 150 μm.
The present invention provides a preparation for percutaneous absorption, which includes an outer protective layer, a solvent-based adhesive layer, a non-solvent-based adhesive layer, and a release layer, wherein the solvent-based adhesive layer is in contact with the outer protective layer, and the non-solvent-based adhesive layer is in direct contact with the skin when applied to the skin. The preparation has the advantages that: the formulation of the present invention, when applied to and/or removed from the skin, can not only significantly reduce skin irritation while stably supporting an active ingredient or additive that is unstable at high processing temperatures, but also can use the active ingredient in a sufficient amount and rate, as compared to conventional transdermal formulations, and thus can be very usefully used as a patch.
Hereinafter, the constitution and effect of the present invention will be described in more detail by way of examples. However, these examples are given for illustrative purposes only, and the scope of the present invention is not limited to these examples.
Example 1: preparation of Patch for percutaneous absorption according to the present invention
To prepare a patch system for percutaneous absorption according to the present invention, patches were prepared according to the compositions shown in table 1 below.
[ Table 1]
| Components | Amount (wt%) |
| DuroTak 87-2196 | 60％ |
| PSM 154A DERMA-TAK | 30％ |
| Alpha- |
4％ |
| Caffeine | 5％ |
| Myristic acid isopropyl ester | 1％ |
Specifically, in the solvent-based adhesive Duro _ TAK 87-2196, caffeine/α -tocopheryl acetate/isopropyl myristate were uniformly mixed to prepare a solution. The thus prepared solution is coated on a polyester film or an equivalent protective film, and then the solvent is volatilized at 80 to 120 ℃, thereby preparing a primary coating roll (roll).
A hot melt adhesive (PSM 154A DERMA-TAK) was placed in a melting tank and sufficiently melted at 180 ℃, and then coated on a silicone-coated polyester film or an equivalent film to prepare a secondary coating roll. The secondary coating roll is laminated to the primary coating roll and subsequently molded into a pre-prepared shape.
Example 2: analysis of physical Properties and skin irritation Effect of non-solvent adhesive layer (Hot melt)
In order to compare the physical properties of the non-solvent type adhesive of the present invention and a typical solvent type acrylate adhesive DURO-TAK8027 (acrylic copolymer, manufactured by Henkel), the following experiment was performed.
Specifically, the above DURO-TAK8027 (solvent-based adhesive) was prepared as a solution using ethyl acetate (76.5 v/v%), isopropyl alcohol (20.5 v/v%) and toluene (3 v/v%) as solvents, and then coated on a polyether film, dried to prepare a test piece having a size of 25mm × 110 mm. In addition, PSM154A DERMA-TAK (hydrogenated ethylene propylene styrene copolymer) as a non-solvent type adhesive was melted at 180 ℃ to form a solution, which was then coated on a polyether film, dried to prepare a test piece having a size of 25mm × 110 mm.
Since the 180 degree peel strength is affected by temperature and humidity, the temperature and humidity were maintained at a standard temperature of 23 ± 2 ℃ and a standard relative humidity of 50% at the time of measurement. The adhesive tape to be tested is cut to a length of 25mm and a width of 110mm and the test strip to be measured is washed with a standard solvent. Subsequently, after the release layer was peeled off from the surface to be measured, it was adhered to the surface to be measured using a rectangular adhesive sponge. At this point, the minimum force is applied. After peeling the release layer from the opposite surface of the surface to be measured, a 0.023mm thick polyester film was laminated thereon. The bonding was performed by moving back and forth at a rate of 300mm/min using a 2kg automatic press roll, followed by standing at 23 ℃/50% for 24 hours.
The Test piece left standing at room temperature was fixed on a tensile strength tester (Instron Corporation) and an adhesive force tester (Test Machines inc.), and 180-degree peel strength was measured while peeling the Test piece at a tensile angle of 180 ° and a tensile rate of 300 mm/min.
In addition, the force when the test strip prepared as above was contacted with a metal surface at a constant force in an area of 24mm × 24mm and then peeled at a constant angle of 90 °, was measured for tack back, and the results are shown in table 2 below.
[ Table 2] Properties of adhesive
As can be seen from Table 2, the non-solvent (hot melt) adhesive 154A DERMA-TAK has a 180 degree peel strength of only 9% and a tack back of 6% respectively, compared to the typical solvent adhesive, acrylate adhesive DURO-TAK 8027. This shows that the force required for peeling a patch-type product made of a non-solvent type after application to the skin is significantly reduced to a level of only 1/17 (-6%) of a patch-type product made of a solvent-type adhesive. Thus, it was confirmed that, in the case of a non-solvent type adhesive (hot melt), even after the product was applied to the skin for a long period of time, the force required to peel the product was only about 6% of that in the case of a solvent type acrylate adhesive, and the product could be easily removed from the skin without causing skin irritation.
Claims (12)
1. A patch system for percutaneous absorption comprises
(a) An outer protective layer, which is formed on the outer surface of the substrate,
(b) A solvent-based adhesive layer, a pressure-sensitive adhesive layer,
(c) A non-solvent type adhesive layer, and
(d) A release layer, the release layer being a film that is removed prior to use,
wherein the solvent-based adhesive layer is adjacent to the outer protective layer and the non-solvent-based adhesive layer is adjacent to the release layer and in contact with the skin at the time of use, and
wherein the solvent-based adhesive layer and/or the non-solvent-based adhesive layer comprises one or more ingredients selected from the group consisting of skin active ingredients and pharmaceutical active ingredients,
wherein the solvent-based adhesive layer comprises an acrylate-based adhesive;
the non-solvent based adhesive layer comprises a hydrogenated ethylene/propylene/styrene copolymer;
the non-solvent type adhesive layer has 180-degree peel strength of 0.1N/25 mm-10N/25 mm and a tack-back value of 0.1N/25 mm-8N/25 mm;
the weight ratio of the solvent-based adhesive layer to the non-solvent-based adhesive layer is as follows, the solvent-based adhesive layer is 80; and
the amount of the skin active ingredient is 0.001wt% to 30wt% based on the total weight of the solvent-based adhesive or the non-solvent based adhesive.
2. The patch system of claim 1, wherein said solvent-based adhesive layer or said non-solvent-based adhesive layer comprises two or more layers.
3. The patch system of claim 1, wherein the skin active ingredient of the non-solvent adhesive is thermally stable even at temperatures of 120 ℃ to 200 ℃.
4. The patch system according to claim 1, wherein the thickness ratio of the solvent-based adhesive layer to the non-solvent-based adhesive layer is from 90.
5. The patch system of claim 1, wherein said skin active ingredient is one or more cosmetic ingredients selected from the group consisting of: skin elasticity improving agent, moisturizing agent, lipolysis promoter, inhibitor of carbohydrate conversion to lipid, burning lipid substance, blood circulation improving agent, exfoliating agent, agent for relieving skin freckle, whitening agent, agent for relieving atopic dermatitis, anti-wrinkle agent, anti-aging agent, collagen production promoter, elastin activator, hyaluronic acid production enhancer, cell proliferation agent, keratinocyte proliferation inhibitor, inhibitor of harmful active oxygen production, cell regeneration substance, skin regeneration promoter, anti-acne agent, and antioxidant.
6. The patch system of claim 5, wherein said anti-aging agent is selected from the group consisting of light aging inhibitors and heat aging inhibitors.
7. The patch system of claim 5, wherein said antioxidant is selected from free radical scavengers.
8. The patch system of claim 1, wherein said skin active ingredient is one or more selected from the group consisting of: collagen, retinoid, vitamin A, vitamin C, vitamin E, alpha-hydroxy acid, beta-hydroxy acid, curcuminoid, resveratrol, hyaluronic acid, arbutin, nicotinamide, vitamin B5, retinol, coenzyme Q10, adenosine, elastin, chitosan, aloe, green tea, korean ginseng, red ginseng, pyroligneous liquor, pine leaf, ginkgo leaf, propolis, mulberry leaf, silkworm, snail mucus, kakadu plum, camu fruit, arisaema, squalane, caviar, broccoli, blueberry, hamamelis virginiana, chrysopharia cunea, chlorella, mangosteen, guava, dogwood, mangosteen, guava, and the likeCornus officinalisCarrot, caffeine and MulixianghamamelisSpirulina, IIISea tangle and roeEcklonia cavaKelp, kelp and kelpLaminaria japonica areschoungCommon purslane, green sea sedge and agarGelidium amansiiMulberry root, raspberry, wild strawberry, sargassum fusiforme, gulfweed, edelweiss, chamomile, lavender, mint and eucalyptusEucalyptusLemon balm, origanum vulgaris, tea tree, scutellaria, houttuyniaHouttuynia cordataSea buckthorn, lime, albumin, egg yolk, milk protein, capsaicin, conjugated linolenic acid, caffeine, garcinia cambogia, pyruvic acid and inulin propionate, phosphatidylcholine, L-carnitine, L-arginine, modified capsaicin, catechin, chromium, lipase, soy, as well as in the form of their free bases, in the form of their pharmaceutically acceptable salts and in their extracts.
9. The patch system of claim 1, wherein said pharmaceutically active ingredient is one or more ingredients selected from the group consisting of: hormonal agents, contraceptives, anti-inflammatory agents, dermatitis therapeutics, smoking cessation aids, angina therapeutics, bronchial asthma therapeutics, attention deficit/hyperactivity disorder therapeutics, hypertension therapeutics, analgesics, anti-emetics, nausea-relieving agents, dementia therapeutics, parkinson's disease therapeutics, allergic cystitis therapeutics, vaccines and antidepressants.
10. The patch system of claim 9, wherein said analgesic is selected from the group consisting of narcotic analgesics.
11. The patch system of claim 9, wherein said dementia therapeutic is selected from therapeutic in alzheimer's disease.
12. The patch system of claim 1, wherein said pharmaceutically active ingredient is one or more ingredients selected from the group consisting of: estradiol, testosterone, estradiol/progesterone complex, estradiol/norethindrone, ethinyl estradiol/norethindrone, estradiol/levonorgestrel, ketoprofen, piroxicam, triamcinolone acetonide, flurbiprofen, naproxen, meloxicam, flusufamide, oxybutynin, indomethacin, buprenorphine, capsaicin, diclofenac, nicotine, nitroglycerin, tulobuterol, methylphenidate, clonidine, lidocaine, fentanyl, sufentanil, granisetron, ramosetron, scopolamine, rivastigmine, donepezil, rotigotine, oxybutynin and selegiline, as well as their free base forms and their pharmaceutically acceptable salts.
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|---|---|---|---|
| KR1020170045510A KR101892270B1 (en) | 2017-04-07 | 2017-04-07 | Patch system for transdermal absorption with minimized skin irritation |
| KR10-2017-0045510 | 2017-04-07 |
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| CN108685877A CN108685877A (en) | 2018-10-23 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5662926A (en) * | 1992-04-01 | 1997-09-02 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
| CN103313705A (en) * | 2010-12-24 | 2013-09-18 | 株式会社三养生物制药 | Percutaneous absorption preparation containing rivastigmine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3910543A1 (en) * | 1989-04-01 | 1990-10-11 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM WITH INCREASED ACTIVE FLUID AND METHOD FOR THE PRODUCTION THEREOF |
| DE10042412B4 (en) * | 2000-08-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | Transceiver for bus subscriber of bus system of building system engineering, has two wires, where microcontroller is connected with receiver unit over connection on one hand, which is connected to two wires of bus system |
| US8906413B2 (en) * | 2003-05-12 | 2014-12-09 | Supernus Pharmaceuticals, Inc. | Drug formulations having reduced abuse potential |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5662926A (en) * | 1992-04-01 | 1997-09-02 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
| CN103313705A (en) * | 2010-12-24 | 2013-09-18 | 株式会社三养生物制药 | Percutaneous absorption preparation containing rivastigmine |
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| CN108685877A (en) | 2018-10-23 |
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