JP4521492B2 - Microneedle array and manufacturing method thereof - Google Patents

Description

  The present invention relates to a microneedle array for providing a modification effect and / or functional effect to the skin surface layer and / or the skin stratum corneum, and a method for producing the same.

  Conventionally, liquid substances containing medicinal ingredients, ointments, cream preparations, tape preparations, batch preparations, pup preparations, and the like have been used to give a modification effect and / or functional effect to the skin surface layer and / or skin stratum corneum. The drug is administered through the skin or mucous membrane by applying or sticking it to the local area.

  However, since these preparations are used by being applied or pasted onto the skin, there is a drawback that they disappear or fall off due to sweating, washing, external pressure, etc. during use. In addition, these preparations exhibit medicinal effects by penetrating medicinal ingredients into the skin and diffusing into the body, but the skin surface layer and / or skin stratum corneum has a barrier function to prevent the invasion of foreign substances into the body. Therefore, it is difficult to absorb a sufficient amount of a medicinal component to exert a pharmacological effect, and it is difficult to reliably supply a medicinal component to a specific location on the skin surface layer and / or the skin stratum corneum. It was difficult.

  Recently, research on microneedles has been actively conducted as a method for solving these problems and reliably supplying a medicinal component to a specific location on the skin surface layer and / or the skin stratum corneum. For example, it is composed of a carbohydrate that dissolves and disappears in a living body such as maltose, and has a square or circular cross-sectional shape with a side or diameter of 0.1 to 100 μm and a length of 0.5 to 500 μm. A functional micropile provided with a pile on a substrate (Patent Document 1) and a skin needle provided with a plurality of needles containing biodegradable materials such as polylactic acid and maltose as components around a central member (Patent Document 2) Has been proposed. Recently, a microneedle made of a resin polymer such as gelatin has also been proposed (Patent Documents 3 and 4).

  In order to improve the penetration performance and pull-out performance of injection needles and suture needles, it has also been proposed to impart lubricity to the surface with an aqueous silicone coating composition (Patent Document 5).

JP 2003-238347 A JP 2006-346126 A JP 2008-6178 A JP 2008-142183 A Japanese Unexamined Patent Publication No. 7-070517

  When the microneedle is used, when the micropile (needle) is stabbed into the skin surface and / or skin stratum corneum, the micropile (needle) breaks and remains on the skin surface and / or skin stratum corneum and dissolves and disappears. . Therefore, a medicinal component can be reliably supplied to a specific place on the skin surface layer and / or the skin stratum corneum. In addition, since the micropile (needle) is very thin, there is little pain and no bleeding even when puncturing the skin surface layer and / or skin stratum corneum, and the puncture wound is quickly closed, so the skin surface layer and / or skin stratum corneum It is suitable as a method for reliably supplying a medicinal component to a specific place.

  When using the above microneedle, it is necessary to make the microneedle thin so that the patient does not bleed and feel pain. However, if the microneedle is made thin, the mechanical strength of the microneedle is insufficient, and the microneedle is placed on the skin. When stabbed, there was a defect that it would break without being uniformly stabbed. On the other hand, in order to allow the microneedle to puncture the skin uniformly and without breaking, it is necessary to make the microneedle thick to some extent.

  In view of the above-described drawbacks, an object of the present invention is a microneedle array that can be easily and uniformly inserted into the skin surface layer and / or skin stratum corneum and dissolves in the skin surface layer and / or skin stratum corneum, and a method for producing the same Is to provide.

The microneedle array of the present invention has a frustum shape or a conical shape formed of a water-soluble or water-swellable resin that can be dissolved in a living body, and one side or a diameter of the tip thereof is 0.01 to 0.00. A plurality of fine needle-like microneedles having a length of 08 mm, one side or a diameter of the base of 0.15 to 1.0 mm, and a height of 0.1 to 3.0 mm are formed on the surface of the substrate. The surface of the needle is coated with a lubricating component composed of one or more hydrocarbons selected from liquid paraffin, squalene, and squalane .

  The water-soluble or water-swellable resin used in the present invention may be any resin that can be dissolved or swelled in a living body. For example, glycogen, dextrin, dextran, dextran sulfate, sodium chondroitin sulfate, hydroxypropylcellulose, chitosan, Synthesis of polysaccharides such as alginic acid, agarose, chicken, chitosan, pullulan, amylopectin, starch, hyaluronic acid, proteins such as collagen, gelatin, albumin, polyvinyl alcohol, carboxyvinyl polymer, sodium polyacrylate, polyvinylpyrrolidone, polyethylene glycol, etc. Examples thereof include polymers, and a polymer substance selected from hyaluronic acid, collagen, gelatin, polyvinyl pyrrolidone and polyethylene glycol is preferable. These water-soluble or water-swellable resins may be used alone or in combination of two or more.

  Hyaluronic acid is a kind of glycosaminoglycan (mucopolysaccharide) and has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are linked. Examples of hyaluronic acid include hyaluronic acid derived from organisms isolated from chicken crowns, umbilical cords, and the like, hyaluronic acid derived from culture mass-produced by lactic acid bacteria, streptococci, and the like. Biologically-derived hyaluronic acid cannot completely remove the collagen of the organism from which it is derived, and the remaining collagen may adversely affect it, so culture-derived hyaluronic acid that does not contain collagen is preferred. Therefore, the hyaluronic acid preferably contains 50% by weight or more of culture-derived hyaluronic acid.

  Collagen is obtained by hydrolysis of gelatin. Gelatin is obtained by purifying from tissue proteins such as chicken and pig. Polyvinyl pyrrolidone and polyethylene glycol are obtained by a polymerization reaction.

  When making a microneedle using a polymer substance selected from hyaluronic acid, collagen, gelatin, polyvinyl pyrrolidone and polyethylene glycol as a component, it becomes harder when the weight average molecular weight becomes smaller, and mechanical strength improves and becomes tenacious when it becomes larger. Become. That is, microneedles formed from these polymer substances become harder and easier to pierce the skin when the weight average molecular weight becomes smaller, but the mechanical strength decreases, and the microneedles easily break when stored or inserted into the skin. Conversely, when the weight average molecular weight is increased, the mechanical strength is improved and the tenacity is increased, so that it is difficult to break during storage or penetration into the skin, but the hardness is reduced and the skin is less likely to penetrate, so the weight average molecular weight is 5,000. ~ 2 million is preferred.

  In addition, when the microneedle is inserted into the skin, it is easy to puncture and does not break, and in order to be easily dissolved in the body, a high molecular weight polymer substance having a weight average molecular weight of 100,000 or more and a weight average molecular weight of 50,000 or less. A microneedle may be formed from a mixture of the low molecular weight polymer substances.

  The high molecular weight polymer substance may have a weight average molecular weight of 100,000 or more, preferably 2 million or less. The weight average molecular weight of the low molecular weight polymer substance may be 50,000 or less, preferably 1000 or more. In the present invention, the weight average molecular weight is a value measured by gel permeation chromatography (GPC).

  In addition, the mixing ratio of the high molecular weight polymer substance and the low molecular weight polymer substance varies depending on the type and weight average molecular weight of each polymer substance, so that it is appropriately determined so as to obtain a preferable mechanical strength and hardness. In general, however, it preferably comprises 60 to 95% by weight of a high molecular weight polymer substance and 40 to 5% by weight of a low molecular weight polymer substance.

  Furthermore, a medicinal component may be added to the water-soluble or water-swellable resin. The medicinal component is not particularly limited as long as it is a drug and a cosmetic raw material conventionally used as a percutaneous absorption preparation. For example, antipyretic analgesic / antiinflammatory agent, steroidal anti-inflammatory agent, vasodilator, arrhythmia agent, Antihypertensive agent, local anesthetic agent, hormonal agent, antihistamine agent, general anesthetic agent, sleep analgesic agent, antiepileptic agent, neuropsychiatric agent, skeletal muscle relaxant agent, independent nerve agent, antiparkinsonian agent, diuretic agent, vasoconstrictor agent , Respiratory stimulants, narcotics and the like.

  Examples of the antipyretic analgesic and anti-inflammatory agent include ibuprofen, flurpiprofen, ketoprofen and the like, and examples of the steroidal anti-inflammatory agent include hydrocortisone, triamcinolone and prednisolone. Examples of the vasodilator include diltiazem hydrochloride and isosorbide nitrate. Examples of the arrhythmia agent include procainamide hydrochloride, mexiletine hydrochloride and the like.

  Examples of the antihypertensive agent include clonidine hydrochloride, bunitrolol hydrochloride, captopril and the like. Examples of the local anesthetic include tetracaine hydrochloride and propitocaine hydrochloride. Examples of the hormone agent include propylthiouracil, estradiol, estriol, progesterone and the like. Examples of the antihistamine include diphenhydramine hydrochloride and chlorpheniramine maleate.

  Examples of the general anesthetic include pentobarbital sodium. Examples of the sleep / analgesic agent include amobarbital and phenobarbital. Examples of the anti-epileptic agent include phenytoin sodium. Examples of the neuropsychiatric agent include chlorpromazine hydrochloride, imipramine hydrochloride, chlordiazepoxide, diazepam and the like. Examples of the skeletal muscle relaxant include sisamethonium hydrochloride, eperisone hydrochloride, and the like.

  Examples of the above-mentioned autonomic nerve agent include neostigmine bromide and betanecol chloride. Examples of the anti-Parkinson agent include amantadine hydrochloride and the like. Examples of the diuretic include hydroflumethiazide, isosorbide, furosemide and the like. Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the respiratory accelerator include lobeline hydrochloride, dimorphoamine, naloxone hydrochloride and the like. Examples of the narcotic include morphine hydrochloride, cocaine hydrochloride, pethidine hydrochloride and the like.

Examples of the cosmetic material include whitening ingredients such as ascorbyl palmitate, kojic acid, lucinol, tranexamic acid, oily licorice extract, vitamin A derivatives; anti-wrinkles such as retinol, retinoic acid, retinol acetate, retinol palmitate, etc. Ingredients; blood circulation promoting ingredients such as tocopherol acetate, capsine, and vanillylamide; diet ingredients such as raspberry ketone, evening primrose extract and seaweed extract: antibacterial ingredients such as isopropylmethylphenol, photosensitizer and zinc oxide; vitamin D ₂ , vitamin D ₃ , Vitamins such as vitamin K are listed.

  The above-mentioned medicinal ingredients are all low molecular compounds having a molecular weight of 600 or less, but may be polymeric medicinal ingredients. Preferred polymer medicinal ingredients include, for example, physiologically active peptides and derivatives thereof, nucleic acids, oligonucleotides And various antigen proteins, bacteria, virus fragments and the like.

  Examples of the physiologically active peptides and derivatives thereof include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1 → 34), insulin, secretin, oxytocin, angiotensin, β-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.Examples of the antigen protein include diphtheria toxoid, tetanus toxoid, HBs surface antigen, HBe antigen and the like.

  The shape of the microneedle of the microneedle array of the present invention is a pyramid shape, a frustum shape, or a cone shape, one side or diameter of the root is 0.15 to 1.0 mm, and the height is 0.1 to 3.0 mm. It is.

  Examples of the spindle-shaped microneedle include a microneedle having a conical shape, an elliptical cone shape, a triangular pyramid shape, a quadrangular pyramid shape, a hexagonal pyramid shape, and one side or a diameter of the root is 0.15 to 1. 0 mm, height is 0.1 to 3.0 mm, and the pitch between microneedles and microneedles is less likely to pierce the skin, and when longer, the number of microneedles per area decreases, and a predetermined narrow area is formed. Since a large amount of microneedles cannot be supplied, 0.4 to 1.0 mm is preferable.

  Examples of the frustum-shaped microneedles include a triangular frustum shape, a quadrangular frustum shape, a hexagonal frustum shape, and other microneedles such as a truncated cone shape, a truncated cone shape, and an elliptic frustum shape. When the pitch of the microneedles becomes shorter, it becomes difficult to pierce the skin, and when the pitch becomes longer, the number of microneedles per area decreases, and a large amount of microneedles cannot be supplied to a predetermined narrow portion. preferable.

  When the side or diameter of the base of the frustum-shaped microneedle is thin, it breaks when it is stabbed into the skin, and the amount of microneedles remaining in the skin decreases, and it becomes easy to break when stabbed into the skin. It is 0.15 to 1.0 mm because it causes pain when stabbed, and preferably 0.2 to 0.5 mm. One side or the diameter of the tip is preferably 0.01 to 0.08 mm because it is easy to break when it is stabbed into the skin when it is thin (pointed), and it is difficult to stab into the skin when it becomes thick and painful.

  When the height of the frustum-shaped microneedle is low, it becomes difficult to supply the microneedle to a predetermined position of the skin surface layer and / or the skin stratum corneum, and when the height is high, the microneedle is easily broken when piercing the skin. 0 mm, preferably 0.2 to 1.2 mm.

  The coneide shape is a so-called volcano shape, and the shape of the truncated cone-shaped side surface is curved inward as shown in FIG. 5. When the tip diameter of a coneide microneedle becomes thin ( When the skin is pierced, it becomes easier to bend and break, and when it gets thicker, it is difficult to pierce the skin and causes pain.

  When the height of the conical microneedle is low, it is difficult to pierce the skin, and it is difficult to supply the microneedle to a predetermined position of the skin surface layer and / or the horny layer of the skin. The thickness is 0.1 to 3.0 mm, preferably 0.15 to 1.2 mm, because it becomes stabbed and painful.

  If the root diameter of a cone needle-shaped microneedle becomes thinner, the degree of side curvature of the microneedle frustoconical shape will become smaller, and it will be necessary to make it thinner overall. In this case, the number of microneedles standing in a certain area is reduced, so that it is 0.15 to 1.0 mm, preferably 0.5 to 1.2 times the height of the microneedle.

  In addition, if the pitch between the conical microneedles and the microneedles is shortened, it becomes difficult to pierce the skin, and if the pitch is increased, the number of microneedles per area decreases, and a large amount of microneedles cannot be supplied to a predetermined narrow portion. 0.4 to 1.0 mm is preferable.

  The microneedle array of the present invention has the fine needle-like microneedles formed on the surface of the substrate, but the substrate is not particularly limited as long as it can form microneedles on the surface. It is necessary that the substance has an affinity for. For example, a film or sheet of ethyl cellulose, urethane resin, aluminum, or the like can be given. The substrate may be a film or sheet made of a water-soluble or water-swellable resin that constitutes the microneedle.

In the microneedle array of the present invention, the surface of the microneedle is coated with a lubricating component in order to improve the penetration performance of the microneedle into the skin. The lubricating component improves the slipperiness of the microneedles and makes the microneedles easily pierce the skin without causing pain. The lubricating component is preferably a hydrocarbon or ester that has a boiling point of 200 ° C. or higher at normal pressure, is liquid or semi-solid at room temperature, and is not compatible with water-soluble or water-swellable resins. The water-soluble or water-swellable resin that constitutes the microneedle dissolves in the skin and disappears due to metabolism involving the enzyme, but these lubricating components also dissolve in the skin and are thought to disappear due to metabolism involving the enzyme. .
The lubricating component may also cover the substrate.

  If the boiling point at normal pressure of the lubricating component is less than 200 ° C., it will easily evaporate during processing or storage, and if it is compatible with the water-soluble or water-swellable resin, it will be compatible with the water-soluble or water-swellable resin. It becomes soluble and the lubricating component layer disappears, and the slipperiness is not improved.

  Examples of the lubricating component include liquid paraffin, silicone oil, squalene, squalane, lanolin, jojoba oil, isopropyl myristate, ethyl palmitate, isopropyl palmitate, vitamin C palmitate, vitamin A oil, vitamin E oil, safflower oil. Etc.

  Among these, liquid paraffin is particularly preferable. This is because paraffin is chemically inactive because it does not have an active substituent, and it hardly reacts with the medicinal component in the microneedle to decompose or alter the medicinal component.

  The lubricating component preferred for microneedles is different from the preferred lubricating component for injection needles. In the microneedle, the lubricating component needs to be eliminated by metabolism in the body. However, in the injection needle, a component that does not remain in the body is preferable because it is taken out together with the needle. Accordingly, silicone-based coating compositions often used for injection needles are not easily metabolized by enzymes in the body and are not suitable for microneedles.

  The lubricating component only needs to be coated on at least the surface of the microneedle, but may also be coated on the surface of the substrate. The thickness of the coating layer of the lubricating component is not particularly limited, and is generally 0.1 μm to 10 μm.

  The manufacturing method of the microneedle array of the present invention is not particularly limited, and may be manufactured by any conventionally known method. For example, the above-described water-soluble or water-swelling type is formed in a mold having a microneedle shape. A method of casting a water-soluble resin and, if necessary, an aqueous solution of a medicinal component, drying and then peeling off is exemplified. As a method of coating the lubricating component, for example, after peeling, a lubricating component is applied on the microneedle, The method of spraying etc. is mentioned. As another manufacturing method, after applying a lubricating component to a mold having a microneedle shape, the water-soluble or water-swellable resin and, if necessary, an aqueous solution of a medicinal component are cast and dried. The method of exfoliating is mentioned. Furthermore, as a different production method, it may be utilized that a lubricating component is bleed on the surface of the microneedle by dispersing a small amount of the lubricating component in the aqueous microneedle forming composition solution and volatilizing water. This manufacturing method is a manufacturing method that utilizes the fact that all the components constituting the microneedle in the present invention are water-soluble polymers or water-swellable and are extremely incompatible with the lubricating component.

  The configuration of the microneedle array of the present invention is as described above, and is a weight, frustum, or coneide shape formed of a water-soluble or water-swellable resin, and one side or diameter of the root is 0.15 to 0.15. Since a plurality of fine needle-like microneedles having a thickness of 1.0 mm and a height of 0.1 to 3.0 mm are formed on the surface of the substrate, and at least the surface of the microneedles is coated with a lubricating component, the skin It can be easily stabbed into the surface layer and / or the skin stratum corneum without breaking, and microneedles dissolved or swollen in the skin can be reliably supplied to a specific location on the skin surface layer and / or the skin stratum corneum. Further, when a medicinal component is added to the microneedle, the medicinal component can be reliably supplied to a specific location on the skin surface layer and / or the skin stratum corneum.

  Next, the present invention will be described in detail with reference to the drawings, but the present invention is not limited to the examples.

Example 1
FIG. 1 is a cross-sectional view showing an example of a method for producing a microneedle array of the present invention. In FIG. 1, a microneedle forming recess 11 is formed by forming a microneedle pattern having a predetermined shape by a lithography method in which a photosensitive resin is irradiated with light, and then transferring the microneedle pattern having a predetermined shape by electroforming. Mold.

Microneedle forming recess 11 is 0.2mm is the root diameter, the tip diameter 0.04 mm, a frustoconical depth 0.8 m, are arranged in a lattice pattern on 0.8mm interval, per 1 cm ² 144 are formed. The microneedle forming recess 11 is formed in a square having a side of 1.0 cm.

  In the figure, 2 is a hyaluronic acid aqueous solution layer, high molecular weight hyaluronic acid having a weight average molecular weight of 100,000 (manufactured by Kibun Food Chemical Co., Ltd., trade name “FUH-SU”), 13.5 parts by weight and weight average molecular weight 1 Formed by casting on a mold 1 an aqueous solution of hyaluronic acid obtained by dissolving 1.5 parts by weight of 10,000 low molecular weight hyaluronic acid (trade name “Hyal-oligo”, culture origin) by 85 parts by weight of water. did.

  Next, after heating to evaporate the moisture in the hyaluronic acid aqueous solution layer 2, it was peeled off from the mold 1. Next, a 1% liquid paraffin / ethyl alcohol solution was sprayed on the microneedles, and then the ethyl alcohol was evaporated to obtain the microneedle array of the present invention shown in FIG. FIG. 3 is an enlarged view of a portion A in FIG. In the microneedle array, a large number of fine conical microneedles 4 in which the shape of the concave portions 11 for forming microneedles is transferred are formed on the surface of the substrate 3, and both the substrate 3 and the microneedles 4 have the above high molecular weight hyaluron. It was formed from acid and low molecular weight hyaluronic acid.

The microneedle 4 has a truncated cone shape having a height a of 0.8 mm, a root diameter b of 0.2 mm, and a tip diameter c of 0.04 mm. The distance d between the microneedle 4 and the microneedle 4 is 0.8 mm. And 144 pieces were formed per 1 cm ² . The surface of the microneedle 4 was coated with a liquid paraffin layer 5 having a thickness of about 1 μm. Further, the thickness e of the substrate 3 was 0.2 mm, and it was a square having one side of 1.0 cm.

  When the obtained microneedle array was lightly pressed against the subject's forehead, the microneedles 4 were easily pierced into the skin, and after 60 minutes, the puncture site in the skin dissolved in the skin and did not retain its shape. At this time, the subject felt no pain. Further, when the peeled substrate 2 was observed with a microscope, the microneedle 4 was 100% dissolved and did not remain at all.

(Example 2)
High molecular weight gelatin with a weight average molecular weight of 500,000 (Nippi, trade name “Nippi Gelatin”, derived from pork skin) 13.5 parts by weight and low molecular weight hyaluronic acid with a weight average molecular weight of 10,000 (trade name “Hyaluoligo”, produced by Kewpie) ", Derived from culture) 1.5 parts by weight was dissolved in 85 parts by weight of water to obtain a mixed aqueous solution.

  A 1% liquid paraffin / ethyl alcohol solution is sprayed on the recess 11 for forming the microneedle of the mold used in Example 1, and then the ethyl alcohol is evaporated. Then, the obtained aqueous mixture is cast on the mold 1 and heated. A microneedle is formed, and a 10% by weight aqueous solution of polyvinyl alcohol (trade name “PVA203”, manufactured by Kuraray Co., Ltd.) is cast on the microneedle and heated to evaporate moisture to form a substrate. Thus, a microneedle array was prepared. The surface of the microneedle 4 was covered with a liquid paraffin layer having a thickness of about 1 μm. In the obtained microneedle array, the microneedle was formed from the high molecular weight gelatin and the low molecular weight hyaluronic acid, and the substrate was composed of polyvinyl alcohol.

  When the obtained microneedle array was lightly pressed against the subject's forehead, the microneedles 4 were easily inserted into the skin. At this time, the subject felt no pain. When the peeled substrate 2 was observed with a microscope after 180 minutes, all of the microneedles 4 remained in the skin of the tip portion and did not remain at all on the substrate.

(Example 3)
FIG. 4 is a cross-sectional view showing a different example of the manufacturing method of the microneedle array of the present invention. In the figure, 1 ′ represents a concave portion for forming a coneide type microneedle, in which a coneide type microneedle pattern is formed by electroforming after forming a coneide type microneedle pattern by a lithography method in which a photosensitive resin is irradiated with light. 11 ′ is a template formed.

Microneedle forming recess 11 'is 0.6mm is the root diameter, the tip diameter 0.02 mm, a volcano-type depth 0.4 m, are arranged in a lattice pattern on 0.8mm interval, per 1 cm ² 144 are formed. In addition, the microneedle forming recess 11 was formed in a square having a side of 1.0 cm.

  In the figure, 2 ′ represents 24 parts by weight of an aqueous solution obtained by dissolving 20 parts by weight of collagen (trade name “Rias Shark”, weight average molecular weight 5,000, manufactured by Nippi Corporation) in 100 parts by weight of water at room temperature and 1 part by weight of water-soluble collagen. It is an aqueous solution layer formed by casting an aqueous solution mixed with 100 parts by weight of a 100% aqueous solution (trade name “Butaate Collagen”, manufactured by Koken Co., Ltd.) on the mold 1 ′.

  Next, the mixture was heated to evaporate moisture from the mixed aqueous solution layer 2 ′, and then peeled off from the mold 1 ′. Next, after spraying a 1% by weight liquid paraffin / ethyl alcohol solution onto the microneedles, the ethyl alcohol was evaporated to obtain the microneedle array of the present invention shown in FIG. The microneedle array has a large number of fine coneide type microneedles 4 ′ formed by transferring the shape of the concave portion 11 ′ for forming microneedles on the surface of the substrate 3 ′, and both the substrate 3 ′ and the microneedles 4 ′. Both were formed from the collagen.

The microneedle 4 ′ is a coneide type having a height a ′ of 0.4 mm, a root diameter b ′ of 0.6 mm, and a tip diameter c ′ of 0.02 mm, and the distance between the microneedle 4 ′ and the microneedle 4 ′. d ′ was 0.8 mm and arranged in a lattice pattern, and 144 pieces were formed per 1 cm ² . The surface of the microneedle 4 ′ was covered with a liquid paraffin layer having a thickness of about 1 μm. Further, the thickness e ′ of the substrate 3 ′ was 0.2 mm, and it was a square having one side of 1.0 cm.

  When the obtained microneedle array was lightly pressed against the subject's forehead, the microneedle 4 'was easily inserted into the skin, and after 60 minutes, the intradermal insertion portion dissolved in the skin and did not retain its shape. . At this time, the subject felt no pain. Further, when the peeled substrate 2 'was observed with a microscope, the upper part 30% (0.12mm) of the microneedle 4' was melted, and the lower part 70% (0.28mm) remained.

Example 4
15 parts by weight of gelatin (manufactured by Nippi Corporation, trade name “Nippi High Great Gelatin APAT”, weight average molecular weight 60,000) was dissolved in 100 parts by weight of water at room temperature to obtain a gelatin aqueous solution. In the same manner as in Example 3 using the obtained aqueous solution, a microneedle array having a Conide type microneedle having a surface coated with a liquid paraffin layer having a thickness of about 1 μm was obtained. The obtained microneedle array was placed on a circular protective bandage having a diameter of 2 cm, and inserted into the skin of the subject's forehead together with the protective bandage, and removed after 1 hour. Immediately after administration, the wrinkles swelled and the wrinkles became inconspicuous, and the effect persisted for about 1 month after administration.

(Example 5)
0.15 g of gelatin (Nippi, trade name “Nippi Gelatin”, weight average molecular weight 100,000) and sodium hyaluronate (trade name “FCH-SU”, trade name “FCH-SU”, manufactured by Kibun Food Chemical Co., Ltd.) An average molecular weight of 100,000) 0.05 g was dissolved to obtain a gelatin-sodium hyaluronate mixed aqueous solution. Separately, bovine insulin (manufactured by Nacalai Tesque) was dissolved in a hydrochloric acid aqueous solution having a pH of 2.5 to obtain a 0.003 g / ml aqueous solution. 1 ml of the obtained aqueous solution was added to the above mixture to obtain an insulin-gelatin-sodium hyaluronate aqueous solution. Further, a solution obtained by dissolving 1 mg of methyl stearate in 0.1 ml of ethanol was added to the obtained insulin-gelatin-sodium hyaluronate aqueous solution, and stirred well to obtain an insulin aqueous solution. A microneedle array having a coneide type microneedle was obtained in the same manner as in Example 3 using the obtained aqueous insulin solution. In addition, the 1 wt% liquid paraffin / ethyl alcohol solution was not sprayed on the microneedle.
On the surface of the microneedle of the obtained microneedle array, methyl stearate was bleeded to form a methyl stearate layer having a thickness of about 1 μm. The obtained microneedle array was placed on a circular protective bandage having a diameter of 2 cm, and subjected to the following blood glucose lowering test together with the protective bandage.

Preparation of diabetic rat model Streptozotocin (STZ) was dissolved in citrate buffer (pH 4.4) to prepare an STZ solution. A 50 mg / 1 kg STZ solution was administered from the rat tail vein, blood glucose levels were measured at 2 and 3 weeks, and rats with fasting blood glucose of 250 mg / dl or more were diabetic model rats and used in the following hypoglycemic test. did.

Diabetic model rats were fasted for 14 hours from the day before the hypoglycemic test . The rat was anesthetized with Nembutal (30 mg / kg), the abdominal skin was shaved, and the insulin microneedle was lined with one protective bandage and administered. The administration time was 1 hour. Blood was collected after 3 hours, 5 hours, 7 hours and 9 hours, and blood glucose was measured. The results are shown in Table 1.

(Comparative Example 1)
A microneedle array was obtained in the same manner as in Example 1 except that the microneedles 4 were not coated with liquid paraffin. When the obtained microneedle array was pressed against the subject's forehead, it was difficult to pierce into the skin, and when pressed with force, the subject felt strong pain and bleeding was also observed.

(Comparative Example 2)
A microneedle array was obtained in the same manner as in Example 1 except that the height a of the microneedles 4 was set to 3.5 mm. When the obtained microneedle array was pressed against the subject's forehead, it was stabbed into the skin, but the subject felt intense pain and bleeding was also observed. When the substrate 2 after peeling was observed with a microscope, about 15% of the microneedles 4 were bent and remained.

(Comparative Example 3)
A microneedle array was obtained in the same manner as in Example 1 except that the root diameter b of the microneedle 4 was 1.5 mm. When the obtained microneedle array was pressed firmly against the back of the subject's hand and pierced, the subject felt pain. One hour later, the needle was taken out and the substrate 2 was observed with a microscope. As a result, 0.2 mm of the tip of the microneedle 4 was melted.

  It is sectional drawing which shows an example of the manufacturing method of the microneedle array of this invention.   It is sectional drawing which shows an example of the microneedle array of this invention.   It is an enlarged view of the A section in FIG.   It is sectional drawing which shows the example from which the manufacturing method of the microneedle array of this invention differs.   It is sectional drawing which shows the example from which the microneedle array of this invention differs.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Mold 11 Microneedle formation recessed part 2 Hyaluronic acid aqueous solution layer 3 Substrate 4 Microneedle 5 Liquid paraffin layer

Claims (9)

It is in the shape of a frustum or coneyde formed of a water-soluble or water-swellable resin that can be dissolved in a living body, and one side or diameter of its tip is 0.01 to 0.08 mm , and one side of its root or A plurality of fine needle-like microneedles having a diameter of 0.15 to 1.0 mm and a height of 0.1 to 3.0 mm are formed on the surface of the substrate, and at least the surface of the microneedles has liquid paraffin and squalene. And a microneedle array, which is coated with a lubricating component composed of one or more hydrocarbons selected from squalane .   2. The microneedle array according to claim 1, wherein the water-soluble or water-swellable resin is at least one polymer selected from hyaluronic acid, collagen, gelatin, polyvinyl pyrrolidone and polyethylene glycol.   3. The high molecular weight material comprises 60 to 95% by weight of a high molecular weight high molecular weight material having a weight average molecular weight of 100,000 or more and 40 to 5% by weight of a low molecular weight high molecular weight material having a weight average molecular weight of 50,000 or less. The microneedle array as described. The frustum-shaped microneedle has a frustum shape or a truncated pyramid shape, one side or a diameter of the root is 0.15 to 1.0 mm , and a height is 0.2 to 1.2 mm. The microneedle array according to any one of claims 1 to 3, wherein the pitch of the microneedles is 0.4 to 1.0 mm.   The tip diameter of the conical microneedle is 0.01 to 0.05 mm, the height is 0.15 to 1.2 mm, and the root diameter is 0.5 to 1.2 times the height. The microneedle array according to any one of claims 1 to 3.   The microneedle array according to any one of claims 1 to 5, further comprising a medicinal component added to the microneedles.   It is characterized by casting an aqueous solution of a water-soluble or water-swellable resin on a mold in which the shape of the microneedle is perforated, drying and peeling, and then applying or spraying a lubricating component on the microneedle. The manufacturing method of the microneedle array of any one of Claims 1-6.   7. The method according to claim 1, wherein a lubricating component is applied to a mold in which the shape of the microneedle is perforated, an aqueous solution of a water-soluble or water-swellable resin is cast, dried, and then peeled off. A method for producing the microneedle array according to claim 1.   The lubricating component is dispersed in an aqueous solution of a water-soluble or water-swellable resin, cast into a mold having a microneedle shape, dried, peeled off, and the lubricating component is bleed on the surface of the microneedle. The manufacturing method of the microneedle array of any one of Claims 1-6 to do.

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