WO2011115272A1 - プロテオグリカンを含有するマイクロニードルアレイ - Google Patents
プロテオグリカンを含有するマイクロニードルアレイ Download PDFInfo
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- WO2011115272A1 WO2011115272A1 PCT/JP2011/056643 JP2011056643W WO2011115272A1 WO 2011115272 A1 WO2011115272 A1 WO 2011115272A1 JP 2011056643 W JP2011056643 W JP 2011056643W WO 2011115272 A1 WO2011115272 A1 WO 2011115272A1
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- microneedle
- proteoglycan
- microneedle array
- microneedles
- substrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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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
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
- A61K8/981—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of mammals or bird
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
- A61K8/987—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of species other than mammals or birds
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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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
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/87—Application Devices; Containers; Packaging
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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
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/91—Injection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Definitions
- the present invention relates to a microneedle array used as an external preparation. More particularly, the present invention relates to a cosmetically or pharmaceutically useful microneedle array.
- an external preparation containing the medicinal ingredient has been used.
- external preparations liquid preparations, ointments, cream preparations, tape preparations, patches, poultices, etc. are known, and by applying or applying these locally, the medicinal ingredients are absorbed percutaneously, Desired pharmacological action is exhibited under the skin.
- Patent Documents 1-3 a microneedle array including microneedles to which a medicinal component is added has been actively studied.
- a microneedle array mainly composed of collagen has been proposed as a microneedle material (see Patent Document 1).
- a medicinal component in a microneedle is supplied subcutaneously by inserting the microneedle into the skin surface layer and / or the skin stratum corneum, and the inserted microneedle portion is subcutaneously supplied. Can be dissolved or biodegraded and disappear.
- the microneedle described in Patent Document 1 since the microneedle described in Patent Document 1 has a very thin needle portion, even if it is inserted into the skin surface layer and / or skin stratum corneum, it does not cause pain or bleeding, and the puncture wound is quickly closed. Therefore, it is suitable as a method for supplying a medicinal component under the skin.
- microneedle arrays are required to be optimally designed according to skin diseases and skin symptoms, and it is required to develop and provide various variations of microneedle arrays.
- the microneedle array used as an external preparation the microneedle has (1) strength that can withstand penetration into the skin surface layer and / or skin stratum corneum, and (2) skin surface layer and / or skin stratum corneum.
- proteoglycan is known as a complex carbohydrate composed of a core protein and glycosaminoglycan (acid mucopolysaccharide) that binds to it, and is a major component of the extracellular matrix, skin tissue, cartilage tissue, bone tissue , Present in vascular tissue and the like.
- Proteoglycans have been reported to be involved in subcutaneous cell proliferation and adhesion.
- Proteoglycans have also been reported to be useful for the prevention or treatment of inflammatory diseases and autoimmune diseases, suppression of rejection during organ transplantation, prevention or improvement of allergic symptoms, prevention or improvement of diabetes, and the like (See Patent Document 4).
- proteoglycans for microneedle arrays has not been studied, and there is no idea at present whether or not microneedles can be formed using proteoglycans.
- An object of the present invention is to provide an unprecedented new microneedle array. More specifically, the present invention provides: (1) Strength that can withstand penetration into the skin surface layer and / or skin stratum corneum, (2) Fineness and flexibility so as not to cause pain or bleeding at the site of skin skin and / or stratum corneum, and (3) Solubility or biodegradability in the body of the microneedle part inserted subcutaneously, An object of the present invention is to provide a novel microneedle array having microneedles.
- the present inventors have surprisingly been able to form microneedles based on proteoglycan and to produce a microneedle array provided with the microneedles. I found. Further, the microneedle array was found to be excellent in the properties (1) to (3) and extremely useful as an external preparation. Furthermore, according to the microneedle array, it is considered that a useful pharmacological action based on proteoglycan can be effectively exhibited under the skin.
- the present invention has been completed by further studies based on such knowledge.
- the present invention provides a microneedle array and a method for producing the same according to the following aspects.
- Microneedle array (I-1). A microneedle array, wherein one or more microneedles containing a proteoglycan as a base are formed on the surface of a substrate.
- the root diameter of the microneedle is 120 to 400 ⁇ m
- the tip diameter (diameter) is 5 to 100 ⁇ m
- the length is 100 to 5000 ⁇ m
- the pitch between adjacent microneedles (distance between the tips) is 100 to 1800 ⁇ m.
- the microneedle array according to any one of (I-1) to (I-3).
- microneedles described in the above (I-6) and (I-7) are needles having a length on the order of millimeters, but have a micro-order thinness (base diameter and tip diameter), It can be included in the category of the microneedle of the present invention.
- microneedle array Any of (I-1) to (I-11), wherein the microneedle contains a water-soluble polymer other than proteoglycan, or a medicinal component that can be used cosmetically or pharmaceutically, in addition to proteoglycan A microneedle array according to claim 1.
- Microneedle array production method (II) The microneedle array production method according to (I-1) or (I-11), which comprises the following steps: A step of casting an aqueous solution in which a proteoglycan constituting a microneedle is dissolved in a mold in which the shape of the microneedle array is perforated so that a microneedle portion and a substrate portion can be formed; A step of evaporating and drying moisture at room temperature or by heating, and a step of peeling the formed microneedle array from the mold.
- (II-2) A method for producing a microneedle array according to (I-1), comprising the following steps: Casting an aqueous solution in which the proteoglycan constituting the microneedle is dissolved in a mold having a microneedle shape; A step of evaporating and drying moisture at room temperature or by heating, A step of laminating a substrate on this and bonding or bonding the bottom surface of the microneedle formed in the above step and the substrate, and a step of peeling the microneedle bonded or bonded to the substrate from the mold.
- the aqueous solution in which the proteoglycan constituting the microneedle is dissolved is an aqueous solution containing the proteoglycan at a concentration of about 1 to 30% by weight, preferably about 1 to 25% by weight, (II-1) or ( The production method described in II-2).
- a microneedle array including microneedles formed using a proteoglycan as a base.
- the microneedle array of the present invention comprises the microneedles having excellent (1) strength, (2) fineness and flexibility, and (3) solubility in the body such as subcutaneous, as described above, and are used as external preparations. It is possible to sufficiently supply the proteoglycan subcutaneously or deeper than that with sufficient characteristics.
- microneedle array of the present invention is suitable for application to cosmetic or medical uses utilizing the action of proteoglycan. Furthermore, the microneedle array of the present invention can be expected to have an anti-aging effect such as wrinkle stretching based on the proteoglycan epithelial cell proliferation enhancing effect (Non-patent Document 1).
- FIG. 3 is a cross-sectional view showing a state in which a proteoglycan-containing aqueous solution (reference numeral 2) is cast on a mold (reference numeral 1) in which a microneedle shape (reference numeral 11) is formed.
- the microneedle array has a structure in which a plurality of solid-cone-shaped microneedles (symbol 4) are formed on the surface of a substrate (symbol 3).
- symbol a is the length (height) of the microneedle formed on the substrate; symbol b is the root diameter of the microneedle; symbol c is the diameter of the tip of the microneedle (tip diameter); d is the distance (pitch) between the tips of the microneedles formed on the substrate and the microneedles adjacent to the microneedles; and the symbol e is the thickness of the substrate.
- the “root diameter” of the microneedle means the diameter of the bottom surface of the microneedle attached to the substrate surface. That is, in the cross-sectional view shown in FIG.
- the “root diameter” corresponds to the distance between the contact points (reference numeral 6) of the microneedle when the substrate surface is the baseline (reference numeral 5).
- the perspective view and image of the microneedle array of this invention used in Example 2 are shown.
- (A-1) and (a-2) respectively show a perspective view and an image of the microneedle array before use.
- Reference numeral 3 denotes a substrate
- reference numeral 4 denotes a microneedle.
- the perspective view and image of the microneedle array of this invention used in Example 2 are shown.
- (B-1) and (b-2) respectively show a perspective view and an image of the microneedle array after use.
- Reference numeral 7 denotes a tape used for fixing the microneedle array.
- (A) shows an image obtained by observing the applied site after the microneedle array of the present invention containing a pigment was applied and removed
- (B) shows an image obtained by observing the subcutaneous tissue of the applied site
- the microneedle array of the present invention is characterized in that one or more microneedles containing a proteoglycan as a base are formed on the surface of a substrate.
- the microneedle array of the present invention will be described in detail.
- proteoglycan is a general term for molecules in which one or more glycosaminoglycans are covalently bound to a core protein.
- the type of proteoglycan used in the present invention is not particularly limited, and may be classified into chondroitin sulfate proteoglycan, dermatan sulfate proteoglycan, heparan sulfate proteoglycan, or keratan sulfate proteoglycan.
- Specific examples of the proteoglycan used in the present invention include aggrecan, versican, neurocan, brevican, decorin, biglycan, serglycine, perlecan, syndecan, glypican, lumican, keratocan and the like.
- the origin of the proteoglycan used in the present invention is not particularly limited, and mammals such as humans, cows and pigs; birds such as chickens; fishes such as sharks, cormorants and jellyfish; crustaceans such as crabs and shrimps; It may be derived from any animal. Among these origins, they are preferably derived from fish, more preferably from salmon, and particularly preferably from vomeronasal cartilage.
- shark cartilage-derived proteoglycans are highly transparent and effective as a raw material for topical skin preparations, and this shark cartilage-derived proteoglycan is intended to improve stains, wrinkles and tarmi. It is known to combine a melanin production inhibitor and a herbal extract having an active oxygen scavenging action (see Patent Document 5).
- the molecular weight of the proteoglycan used in the present invention is not particularly limited, and is appropriately set.
- the proteoglycan having a molecular weight in the range of 80,000 to 3,000,000 can be used without particular limitation, but the proteoglycan having a molecular weight of preferably 200,000 to 2,500,000, more preferably 300,000 to 800,000 is preferable. It is.
- the microneedle contains a proteoglycan as a base, and so long as the proportion of the proteoglycan is not particularly limited.
- the proportion of proteoglycan contained in the microneedle is usually 20 to 100% by weight, preferably 50 to 100% by weight, more preferably 70 to 100% by weight, particularly preferably 80 to 100% by weight, more preferably 90 to 90% by weight. 100% by weight.
- the microneedle of the present invention containing proteoglycan as a base may be composed only of proteoglycan, or 80% by weight unless the following characteristics of the microneedle composed of proteoglycan are impaired. It may contain other components than proteoglycan, preferably up to 50% by weight: (1) Strength that can withstand penetration into the skin surface layer and / or skin stratum corneum, (2) Fineness and flexibility so as not to cause pain or bleeding at the site of skin skin and / or stratum corneum, and (3) The solubility or biodegradability of the microneedle part inserted subcutaneously in the skin.
- components other than proteoglycans that can be blended in microneedles include water-soluble polymers other than proteoglycans.
- a water-soluble polymer may be any one that can be dissolved or decomposed in vivo.
- hyaluronic acid, chondroitin sulfate, glycogen, dextrin, dextran, dextran sulfate, hydroxypropylmethylcellulose, alginic acid examples include polysaccharides such as chitin, chitosan, and pullulan; proteins such as collagen, gelatin, and hydrolysates thereof; synthetic polymer compounds such as polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, and carboxyvinyl polymer.
- the proportion of the water-soluble polymer contained in the microneedle is usually 1 to 30% by weight, preferably 1 to 25% by weight, more preferably 1 -20% by weight, more preferably 1-10% by weight.
- the microneedle may contain a medicinal component that can be used cosmetically or pharmaceutically as the other component.
- those that can be used cosmetically include, for example, ascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, ascorbyl palmitate, kojic acid, lucinol, tranexamic acid, licorice extract, vitamin Whitening agents such as A derivatives; anti-wrinkle agents such as retinol, retinoic acid, retinol acetate, retinol palmitate; blood circulation promoters such as tocopherol acetate, capsaicin, nonyl acid vanillamide; dieting agents such as raspberry ketone, evening primrose extract, seaweed extract; Antibacterial agents such as isopropylmethylphenol, photosensitizer and zinc oxide; anti-inflammatory agents such as salicylic acid; vitamins such as vitamin D 2 , vitamin D 3 and vitamin K, and the like.
- vitamin Whitening agents such as A derivatives
- anti-wrinkle agents such as retinol, retinoic acid, retinol
- those that can be used pharmaceutically include drugs that are used in the field of medicine, in addition to those that can be used cosmetically.
- drugs other than those that can be used cosmetically include antipyretic analgesics and anti-inflammatory agents such as ibuprofen, flurpiprofen, and ketoprofen; steroidal anti-inflammatory agents such as hydrocortisone, triamcinolone, and prednisolone; Vasodilators such as diltiazem hydrochloride and isosorbide nitrate; antiarrhythmic agents such as procainamide hydrochloride and mexiletine hydrochloride; antihypertensive agents such as clonidine hydrochloride, bunitrolol hydrochloride and captopril; local anesthetics such as tetracaine hydrochloride and propitocaine hydrochloride; Hormonal agents such as uracil, estradiol,
- the drug added to the microneedle may be, other than those exemplified above, bioactive peptides and derivatives thereof, nucleic acids, oligonucleotides, antigen proteins, bacteria, virus fragments, and the like. .
- bioactive peptides and derivatives thereof include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1 ⁇ 34), insulin, secretin, oxytocin, angiotensin, ⁇ -endorphin, glucagon, vasopressin, Somatostatin, gastrin, luteinizing hormone releasing hormone, enkephalin, neurotensin, atrial natriuretic peptide, growth hormone, growth hormone releasing hormone, bradykinin, substance P, dynorphin, thyroid stimulating hormone, prolactin, interferon, interleukin, G- Examples include CSF, glutathione peroxidase, superoxide dismutase, desmopressin, somatomedin, endothelin, and salts thereof.
- antigen protein include HBs surface antigen and HBe antigen.
- the microneedle array of the present invention has a structure in which one or two or more microneedles are formed on the surface of the substrate.
- the desired pharmacological action can be enhanced. Therefore, it is desirable that a plurality of microneedles be provided on the substrate.
- the shape of the microneedle should be set appropriately so that it can be easily inserted into the skin, can be dissolved in the inserted body (in the skin or deeper), and does not cause pain or bleeding.
- a cone shape, a truncated cone shape and the like are exemplified.
- the conical shape is a so-called volcanic shape, and is a shape in which the side surface of the truncated cone shape is curved inward as shown in FIG.
- the microneedle is preferably not a hollow needle having a hollow inside but a solid needle having a uniform composition.
- the microneedle When the microneedle is shaped like a cone or frustoconical, its root diameter decreases as the amount of proteoglycan that penetrates into the skin decreases. Therefore, it is desirable that the thickness is about 120 to 400 ⁇ m, preferably about 150 to 300 ⁇ m.
- the “root diameter” of the microneedle means the diameter of the bottom surface of the microneedle in contact with the substrate surface.
- tip diameter of a conical or frustoconical microneedle When the tip diameter of a conical or frustoconical microneedle is thin (if it is sharp), it tends to break when it penetrates the skin, and when it becomes thick, it is difficult to penetrate the skin and is painful, and it is 5 to 100 ⁇ m. About 10 to 80 ⁇ m is desirable.
- the length of the conical or frustoconical microneedles is short, the depth of penetration into the skin becomes shallow and it becomes difficult to supply proteoglycan, so about 100 ⁇ m or more, preferably about 150 ⁇ m or more, more preferably 200 ⁇ m. It is desirable that the degree is more than about.
- the upper limit of the length of the microneedle is not particularly limited as long as it does not break when the microneedle is inserted into the skin, but is usually about 5000 ⁇ m or less, preferably about 3000 ⁇ m or less, more preferably about 1600 ⁇ m. It is as follows. Specific lengths of the microneedles include, for example, about 100 to 5000 ⁇ m or about 100 to 3000 ⁇ m.
- microneedles having a length of about 100 to 1600 ⁇ m, preferably about 150 to 1200 ⁇ m, more preferably about 150 to 1000 ⁇ m, and longer than 1000 ⁇ m to about 5000 ⁇ m, preferably longer than 1600 ⁇ m to about 5000 ⁇ m, More preferably, a needle having a length longer than 1600 ⁇ m and not longer than about 3000 ⁇ m can be mentioned.
- the distance between one microneedle and the microneedle adjacent to it becomes difficult to insert into the skin, and if the distance is longer, the number of microneedles per unit area decreases, and proteoglycan is sufficient. Can not be supplied subcutaneously.
- the arrangement interval of the microneedles in the microneedle array is such that the distance between the tip portion of the microneedle and the tip portion of the microneedle adjacent thereto (referred to as “pitch” in the present invention) is about 100 to 1800 ⁇ m, The thickness is preferably set to about 150 to 1200 ⁇ m.
- the number of microneedles per unit area of the substrate surface of the microneedle array is appropriately set according to the pitch and the like, but usually about 50 to 300 per 1 cm 2 of the substrate surface of the microneedle array, preferably Is about 100 to 200, more preferably about 120 to 160.
- the arrangement of the plurality of microneedles is not particularly limited, but is preferably arranged in a lattice pattern.
- the substrate is not particularly limited as long as it is a film or sheet on which the microneedle can be placed, held, or formed.
- the substrate may be a film or sheet having the same composition as the microneedles, or may be a film or sheet having a composition different from that of the microneedles.
- Specific examples of films or sheets having a composition different from that of microneedles include polymethyl methacrylate, cellulose acetate, ethyl cellulose, polyethylene resin, polypropylene resin, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, vinyl chloride.
- the substrate is preferably composed of a film or sheet having the same composition as the microneedles. In this case, the substrate can be integrally formed with the microneedles.
- the substrate is not particularly limited, but has a thickness that can support or hold the microneedles on its surface and can serve as a support for inserting the microneedles into the skin surface layer and / or the skin stratum corneum. It is preferable. As this thickness, the thickness of about 50 micrometers or more can be mentioned normally. An example is preferably about 50 to 500 ⁇ m, more preferably about 80 to 300 ⁇ m, and particularly preferably about 100 to 200 ⁇ m.
- the method for producing the microneedle array of the present invention is not particularly limited, and can be produced by a conventionally known method.
- Specific examples of the manufacturing method of the microneedle array of the present invention include the following manufacturing methods (i) and (ii).
- aqueous solution in which the components constituting the microneedle are dissolved is cast on a mold in which the shape of the microneedle is perforated, and dried by evaporating moisture at room temperature or by heating, and then the substrate. After laminating and bonding or bonding the bottom surface of the microneedle formed above and the substrate, the microneedle is peeled from the mold together with the substrate. In this method, a microneedle array in which the microneedle and the substrate have different compositions can be manufactured.
- the aqueous solution in which the components constituting the microneedles are dissolved is not particularly limited as long as the proteoglycan can be dissolved.
- the proteoglycan is about 1 to 30% by weight, preferably An aqueous solution containing a concentration of about 1 to 25% by weight can be used.
- the microneedle array of the present invention is used by being applied to the skin so that the microneedle is inserted into the skin surface layer and / or the skin stratum corneum.
- the microneedle array of the present invention is attached to the skin so that the microneedle penetrates into the skin surface layer and / or the skin stratum corneum, and is left in that state.
- the proteoglycan in the microneedle is dissolved by the body temperature and moisture such as subcutaneously and eluted subcutaneously, and a useful pharmacological action based on the proteoglycan is exerted in the subcutaneous or deeper tissue.
- the microneedle contains the above-mentioned water-soluble polymer, or a medicinal component that can be used cosmetically or pharmaceutically, these components contained in the microneedle elute subcutaneously together with the proteoglycan.
- useful pharmacological action based on proteoglycan and these components is exerted in the tissue under the skin or deeper than that.
- the microneedle inserted into the skin surface layer and / or the skin stratum corneum is in that state for about 30 minutes or more, preferably about 30 to 300 minutes. More preferably, it is preferably kept for about 60 to 180 minutes. By doing so, the proteoglycan constituting the microneedle can be sufficiently dissolved and eluted under the skin.
- the microneedle array of the present invention can supply at least proteoglycan to a tissue subcutaneously or deeper than that, it is used for cosmetic or medical applications utilizing the action of proteoglycan.
- the microneedle array of the present invention is based on the action of such proteoglycan.
- it can be used in cosmetic applications for the purpose of preventing aging.
- the microneedle array of the present invention is an immune enhancer for skin tissue, skin tissue It is also effective for medicinal uses such as anti-inflammatory agents against inflammation occurring in
- the proteoglycan used was chondroitin sulfate proteoglycan derived from salmon nasal cartilage (eluted from salmon nasal cartilage using acetic acid) (manufactured by Kakuhiro, Japan).
- FIG. 1 is a cross-sectional view showing a state in which an aqueous solution (2) containing 20% by weight of proteoglycan is cast on a mold (1) having a microneedle array shape.
- the mold indicated by reference numeral 1 in FIG. 1 is formed by forming a microneedle pattern having a predetermined shape on the surface of the photosensitive resin by a light irradiation lithography method, and then performing electroforming to form the microneedle having a predetermined shape.
- the microneedle forming recess (11) shown in FIG. 1 has an opening diameter of 200 ⁇ m corresponding to the root diameter of the microneedle, a bottom diameter of the recess corresponding to the tip diameter (diameter) of the microneedle of 40 ⁇ m, It has a conical depression with a recess depth corresponding to the length of 800 ⁇ m.
- the concave portions are arranged in a lattice pattern in the photosensitive resin at intervals of 800 ⁇ m, and 144 are formed per 1 cm 2 .
- FIG. 1 means an aqueous solution layer formed by casting an aqueous solution containing 20% by weight of proteoglycan onto the mold (1).
- the aqueous solution containing 20% by weight of proteoglycan cast on the mold (1) is dried as it is for 5 hours in a drier at 35 ° C. to evaporate the water, and then the dried formed on the mold (1).
- the product was peeled from the mold (1) to obtain the microneedle array of the present invention shown in FIG.
- the microneedle array is a fine solid conical microneedle (4) formed by casting and drying an aqueous solution containing 20% by weight of proteoglycan on a microneedle forming recess (11) on the surface of a substrate (3). There are many standing cones. Both the substrate (3) and the microneedle (4) are composed of proteoglycans.
- the size and shape of the microneedle array manufactured here is an ellipse of 6 mm (minor axis) ⁇ 10 mm (major axis) depending on the size of the substrate (3).
- the microneedle (4) has a solid conical shape with a length (symbol a) of 800 ⁇ m, a root diameter (symbol b) of 200 ⁇ m, and a tip diameter (symbol c) of 40 ⁇ m.
- the tip of the microneedle (4) And a distance (symbol d) between the tip of another microneedle (4) adjacent thereto and the other microneedle (4) is 800 ⁇ m.
- Microneedles (4) are arranged in a grid above the intervals on the substrate (3), are formed 144 or so per 1 cm 2.
- the thickness of the substrate (3) (symbol e) is 200 ⁇ m.
- the microneedle array thus prepared has a microneedle that is fine as described above, excellent in strength and flexibility, and hardly breaks against the skin surface layer and / or the skin stratum corneum. It was possible to insert without pain. In addition, since this microneedle is composed of only proteoglycan except for residual moisture, the microneedle showed excellent solubility in the skin by being inserted and held subcutaneously for about 90 minutes.
- the obtained microneedle array is composed of 100% proteoglycan (excluding residual water) as described above, the obtained microneedle array is effective for cosmetic use and pharmaceutical use based on the action of proteoglycan. It is believed that there is. The obtained microneedle array is also considered effective for cosmetic use for wrinkle stretching based on the action of proteoglycan.
- Example 1 a microneedle array provided with a conical microneedle was manufactured.
- the shape of the concave portion for forming the microneedle (11) to be used is a truncated cone shape. Can be manufactured.
- Example 2 Evaluation of Usability of Microneedle Array Using an aqueous solution containing 20% by weight of proteoglycan and 10% by weight of Evans Blue dye, an ellipse of 8 mm (minor axis) ⁇ 10 mm (major axis) was prepared in the same manner as in Example 1. A microneedle array (microneedle length: 800 ⁇ m) was produced. The microneedle array thus prepared was cut into a square of about 7 mm and then applied to the knee joint of a rat to examine how the Evans blue dye penetrated into the periphery of the knee joint.
- Test animal SD rat (Crl: CD strain, male, 5 weeks old, 164 to 183 g) (Nippon Charles River Co., Ltd.) overnight at a temperature of 23 ⁇ 2 ° C and humidity of 60 ⁇ 10% (Illumination time 12 hours, extinguishing time 12 hours) After rearing, the animals were subjected to the following experiment. The test animals were handled according to the animal experiment guidelines of Otsuka Pharmaceutical Co., Ltd., and food (MF: Oriental Yeast Co., Ltd.) and water (tap water) were freely consumed.
- the microneedle array (about 7 mm ⁇ 7 mm) produced above was affixed to the skin of the knee joint where hair was removed. Specifically, the microneedle array was pressed and applied to the skin of the knee joint so that the microneedle was inserted into the skin, and was fixed by pressure bonding with taping. Thus, the test animal to which the microneedle array was attached was placed in a Ballman cage and fixed so as not to move.
- the test animals were removed from the Ballman cage and euthanized under ether anesthesia. Thereafter, the microneedle array is peeled off from the skin, the shape of the microneedle, the skin surface and the subcutaneous tissue of the application site (the knee joint) are observed, the solubility of the microneedle in the skin, the skin surface by the Evans Blue dye, The presence or absence of staining of the subcutaneous tissue was evaluated.
- Test results (3-1) Microneedle shape All the microneedle portions with a length of 800 ⁇ m of the attached microneedle array were lost. From this, it was confirmed that the microneedle inserted into the skin was dissolved subcutaneously by body temperature and surrounding water.
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Abstract
Description
(1) 皮膚表層及び/又は皮膚角質層に刺入するのに耐え得る強度、
(2) 皮膚表層及び/又は皮膚角質層に刺入された局所において痛みや出血を引き起こさないための微細さと柔軟性、並びに
(3) 皮下に刺入されたマイクロニードル部分の体内での溶解性又は生分解性、
を兼ね備えたマイクロニードルを有する新規なマイクロニードルアレイを提供することを目的とする。
(I-1).プロテオグリカンを基剤として含む1以上のマイクロニードルが、基板の表面に形成されていることを特徴とする、マイクロニードルアレイ。
(II-1)下記の工程を有する、(I-1)または(I-11)に記載するマイクロニードルアレイの製造方法:
マイクロニードルアレイの形状が穿設された鋳型に、マイクロニードルを構成するプロテオグリカンを溶解した水溶液を、マイクロニードル部分と基板部分が形成できるように流延する工程、
室温下又は加熱して水分を蒸発して乾燥する工程、及び
形成されたマイクロニードルアレイを鋳型から剥離する工程。
マイクロニードルの形状が穿設された鋳型に、マイクロニードルを構成するプロテオグリカンを溶解した水溶液を流延する工程、
室温下又は加熱して水分を蒸発して乾燥する工程、
これに基板を積層して、上記工程で形成されたマイクロニードルの底面部と基板とを結合または接着する工程、及び
基板に結合または接着されたマイクロニードルを鋳型から剥離する工程。
(1) 皮膚表層及び/又は皮膚角質層に刺入するのに耐え得る強度、
(2) 皮膚表層及び/又は皮膚角質層に刺入された局所において痛みや出血を引き起こさないための微細さと柔軟性、並びに
(3) 皮下に刺入されたマイクロニードル部分の皮下内での溶解性又は生分解性。
プロテオグリカン20重量%を含有する水溶液をマイクロニードルアレイの形状が穿設された鋳型に流延した。図1は、マイクロニードルアレイの形状が穿設された鋳型(1)に、プロテオグリカン20重量%含有水溶液(2)を流延した状態を示す断面図である。図1中の符号1で示す鋳型は、詳細には、感光性樹脂の表面に、光照射するリソグラフィ法により所定形状のマイクロニードルパターンを形成した後、電鋳加工することにより所定形状のマイクロニードルパターンを転写したマイクロニードル形成用凹部(11)が形成された鋳型である。図1に示すマイクロニードル形成用凹部(11)は、マイクロニードルの根元直径に相当する凹部の開口直径が200μm、マイクロニードルの先端径(直径)に相当する凹部の底面直径が40μm、マイクロニードルの長さに相当する凹部深さが800μmの、コニーデ状の凹部を有している。当該凹部は感光性樹脂に800μm間隔に格子状に配列されており、1cm2当たり144個形成されている。
プロテオグリカン20重量%及びエバンスブルー色素10重量%を含有する水溶液を用いて、実施例1と同様の方法で、8mm(短径)×10mm(長径)の楕円状のマイクロニードルアレイ(マイクロニードルの長さ:800μm)を製造した。斯くして調製したマイクロニードルアレイを、約7mm角に裁断した後、ラットの膝関節部に貼付し、膝関節部周辺部にエバンスブルー色素がどのように浸透するかを調べた。
SDラット(Crl:CD系統、雄、5週齢、164~183g)(日本チャールス・リバー(株))を、温度23±2℃、湿度60±10%の条件で一晩(照明時間12時間、消灯時間12時間)飼育した後、下記の実験に供した。なお、被験動物は、大塚製薬(株)の動物実験指針に従って取り扱い、餌(MF:オリエンタル酵母(株))及び水(水道水)は自由に摂取させた。
被験動物(n=5)の左右の膝関節部分の毛を、バリカンで剃った後、除毛クリームで除毛した。除毛した膝関節部分の皮膚に、上記で製造したマイクロニードルアレイ(約7mm×7mm)を貼付した。具体的には、マイクロニードルアレイを、皮膚にマイクロニードルが刺入するように膝関節部分の皮膚に押し付け貼付し、テーピングで圧着固定した。斯くしてマイクロニードルアレイを貼付した被験動物をボールマンケージに入れて、動かないように固定した。
(3-1)マイクロニードルの形状
貼付したマイクロニードルアレイの長さ800μmのマイクロニードル部分はすべて消失していた。このことから皮膚に刺入されたマイクロニードルは皮下内で、体温と周囲の水分により溶解することが確認された。
いずれの被験動物(n=5)も、貼付部位の表皮と皮下組織にエバンスブルー色素による染色が認められたが、筋層には染色は認められなかった。このことから、マイクロニードルの溶解によって溶出した成分(プロテオグリカン及びエバンスブルー色素)は皮下に達することが確認された。また、いずれの個体の貼付部位(皮膚、皮下組織、筋層)にも、出血等の異常な所見は認められなかった。
Claims (12)
- プロテオグリカンを基剤として含む1以上のマイクロニードルが、基板の表面に形成されていることを特徴とする、マイクロニードルアレイ。
- マイクロニードルがコニーデ状又は円錐台状である、請求項1に記載のマイクロニードルアレイ。
- マイクロニードルが中実針である、請求項1または2に記載のマイクロニードルアレイ。
- マイクロニードルの根元直径が120~400μm、先端径(直径)が5~100μm、長さが100~5000μmであり、近接するマイクロニードルの先端部間の距離が100~1800μmである、請求項2または3に記載のマイクロニードルアレイ。
- マイクロニードル中のプロテオグリカン含量が20~100重量%である、請求項1乃至4のいずれかに記載のマイクロニードルアレイ。
- プロテオグリカンが、コンドロイチン硫酸プロテオグリカンである、請求項1乃至5のいずれかに記載のマイクロニードルアレイ。
- プロテオグリカンが、魚類由来である、請求項1乃至6のいずれかに記載のマイクロニードルアレイ。
- 上記魚類がサケ、サメまたはクラゲである、請求項7記載のマイクロニードルアレイ。
- マイクロニードルが、プロテオグリカンに加えて、プロテオグリカン以外の水溶性高分子、または香粧的若しくは薬学的に利用可能な薬効成分を含有するものである、請求項1乃至8のいずれかに記載のマイクロニードルアレイ。
- 基板がマイクロニードルと同一組成からなるものである、請求項1乃至8のいずれかに記載のマイクロニードルアレイ。
- 下記の(1)~(3)の工程を有するか、または(1’)~(4’)の工程を有する、請求項1または10に記載するマイクロニードルアレイの製造方法:
(1) マイクロニードルアレイの形状が穿設された鋳型に、マイクロニードルを構成するプロテオグリカンを溶解した水溶液を、マイクロニードル部分と基板部分が形成できるように流延する工程、
(2) 室温下又は加熱して水分を蒸発して乾燥する工程、及び
(3) 形成されたマイクロニードルアレイを鋳型から剥離する工程;
(1’) マイクロニードルの形状が穿設された鋳型に、マイクロニードルを構成するプロテオグリカンを溶解した水溶液を流延する工程、
(2’) 室温下又は加熱して水分を蒸発して乾燥する工程、
(3’) これに基板を積層して、上記工程で形成されたマイクロニードルの底面部と基板とを結合または接着する工程、及び
(4’) 基板に結合または接着されたマイクロニードルを鋳型から剥離する工程。 - マイクロニードルを構成するプロテオグリカンを溶解した水溶液が、プロテオグリカンを1~30重量%程度の濃度で含有する水溶液である、請求項11に記載する製造方法。
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CA2792927A CA2792927A1 (en) | 2010-03-19 | 2011-03-18 | Proteoglycan-containing microneedle array |
CN201180014657.8A CN102811763B (zh) | 2010-03-19 | 2011-03-18 | 含有蛋白聚糖的微针阵列 |
NZ602692A NZ602692A (en) | 2010-03-19 | 2011-03-18 | Proteoglycan-containing microneedle array |
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JP2017145226A (ja) * | 2016-02-19 | 2017-08-24 | 日本写真印刷株式会社 | マイクロニードルシート |
US11065428B2 (en) | 2017-02-17 | 2021-07-20 | Allergan, Inc. | Microneedle array with active ingredient |
WO2019135717A1 (en) * | 2018-01-03 | 2019-07-11 | Micropoint Technologies Pte Ltd | Dissolving microneedle patches comprising corticosteroid |
US11590331B2 (en) | 2018-01-03 | 2023-02-28 | Micropoint Technologies Pte Ltd | Dissolving microneedle patches comprising corticosteroid |
Also Published As
Publication number | Publication date |
---|---|
CN105107083B (zh) | 2018-04-24 |
AU2011228020A1 (en) | 2012-09-27 |
JPWO2011115272A1 (ja) | 2013-07-04 |
AR080778A1 (es) | 2012-05-09 |
CN105107083A (zh) | 2015-12-02 |
CN102811763A (zh) | 2012-12-05 |
TW201138881A (en) | 2011-11-16 |
KR20130007615A (ko) | 2013-01-18 |
JP5800799B2 (ja) | 2015-10-28 |
BR112012023693A2 (pt) | 2017-10-03 |
SG183913A1 (en) | 2012-10-30 |
EP2548608A4 (en) | 2013-10-09 |
CO6620002A2 (es) | 2013-02-15 |
US20130012882A1 (en) | 2013-01-10 |
EP2548608B1 (en) | 2018-01-31 |
CA2792927A1 (en) | 2011-09-22 |
EA201290928A1 (ru) | 2013-04-30 |
MX2012010681A (es) | 2012-10-09 |
NZ602692A (en) | 2013-12-20 |
KR101813735B1 (ko) | 2017-12-29 |
EP2548608A1 (en) | 2013-01-23 |
CN102811763B (zh) | 2015-11-25 |
ES2663095T3 (es) | 2018-04-11 |
US9539418B2 (en) | 2017-01-10 |
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