Oral cavity topical application system

Abstract

To provide means for shortening the time when the action of a local anesthetic, an antihistamine drug and the like on the oral mucosa is expressed.SOLUTION: A topical application system for shortening the time of a drug action on the oral mucosa comprises: a microspike patch that includes a substrate and microspikes bristling on the substrate, that is, the microspike patch for being applied to the oral mucosa, which is made of a water-insoluble thermoplastic polymeric substance; and the microspike patch, a liniment (gel, an ointment or the like containing a drug), and an adhesive tape for lining.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a patch having microprojections for topical application to the oral mucosa, and further to a topical application system utilizing the patch. [Background technology]

[0002] Local anesthetics for dentistry are widely used, just like those for the skin. The drugs are generally lidocaine and ethyl aminobenzoate in the form of a (gel) ointment, but the onset of effect is short, at 10 to 20 minutes, compared to the onset of effect on the skin. However, both doctors and patients are demanding an onset of action that occurs in a shorter time. The present inventors developed a microneedle array containing a local anesthetic for intraoral application, and succeeded in achieving an anesthetic effect in a short time (Patent Document 1). Patent Documents 1 and 2 are inventions of a microneedle preparation for skin in which a local anesthetic is dissolved in a microneedle, or a preparation in which a local anesthetic is applied to a microneedle. From the standpoint of doctors, there is a need for a new administration method that can be appropriately prepared and applied in the medical field, such as administering locally administered preparations consisting of various familiar (gel) ointments and liquids that have a proven track record and that can exert their effects in a shorter time by themselves. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2019-084352 A [Patent Document 2] JP 2017-061447 A Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention has been made to solve problems related to topical preparations, and has an object to provide a means for shortening the time it takes for preparations such as ointments, creams, liquids, and gels for topical administration intended for the purposes of local anesthesia, antihistamine, anti-inflammatory, antibacterial, pain relief, antipruritic, etc. to take effect when administered into the oral cavity. [Means for solving the problem]

[0005] The administration site of the topical formulation in the present invention is the oral cavity and gingiva. The outermost layer of the oral mucosa or gingiva is keratinized stratified squamous epithelium and mucous membrane, which is thinner than the stratum corneum of normal skin and has higher percutaneous absorption of local anesthetics than normal skin, but is sensitive to pain and prone to bleeding. On the other hand, the oral mucosa or gingiva is not flat and has more irregularities than normal skin, making it difficult to stably hold the formulation in the affected area. Furthermore, since it is in the oral cavity, it is always exposed to the moisture of saliva, and protection is required against peeling of patch-type formulations and against spillage of applied-type formulations. Due to the differences in various conditions as described above, the technical issues of topical formulations for oral mucosa are common to those of formulations for normal skin, but there are also many completely different technical issues. The present inventors have developed a microprojection patch to solve the above problems. In order to shorten the time it takes for local anesthetics, antihistamines, anti-inflammatory agents, antibacterial agents, pain relievers, antipruritics, etc. to act on the oral mucosa, when applying (gel) ointments or liquids containing these drugs to the affected area in the oral cavity, the microprojection patch of the present invention is overlaid on the application site. When applying a local anesthetic consisting of a solution to the skin, if the viscosity of the solution is too low, the anesthetic may not stay only in the intended local area even if it is applied to the oral cavity, as it may immediately flow off the mucosal surface. To avoid this, it is desirable to apply the formulation with a high viscosity so that it stays appropriately on the application surface. As a microprojection patch, a microneedle patch is known. The materials constituting the microneedle are silica, metal, plastic, biosoluble material, etc., but conventional microneedles are characterized by having a hardness that allows them to puncture the skin. In the present invention, the microprojections may have a hardness that allows them to puncture the oral mucosa even when applied to it, but more preferably have a hardness that does not allow them to puncture it. In the case of mucosal puncture, the drug effectively penetrates into the oral mucosa through the micropores opened in the oral mucosa. In the case of soft microneedles that cannot puncture the oral mucosa, the microprojections press the oral mucosa, locally stretching and thinning the oral mucosa, thereby improving the mucosal absorption of the drug administered at the same time. If the microneedle is made of a material with low hardness and flexibility, even if it punctures the oral mucosa, it will be only within a few μm from the surface, so it will not hurt or bleed. The microprojection patch of the present invention uses a water-insoluble polymer. Even if a water-soluble polymer, such as hyaluronic acid or carboxymethyl cellulose, is used to form a microprojection batch, when the microprojection batch is applied to a moist oral mucosa, the tips of the microprojections and then most of the needles soften and dissolve due to moisture, making it impossible to deform or puncture the oral mucosa, and therefore it is not possible to shorten the onset time of the drug action, which is the purpose of the present invention. The microprojection patch may be backed by an adhesive sheet that adheres strongly to the oral mucosa in the presence of saliva, thereby allowing the microprojections to pierce or press against the skin.

[0006] The present invention is as follows. [1] A microprojection patch comprising a substrate and a forest of microprojections on the substrate, the microprojection patch being made of a water-insoluble thermoplastic polymeric material and intended for application to the oral mucosa. [2] The microprojection patch according to [1], wherein the tip diameter of the microprojections is 10 μm to 300 μm, the length of the microprojections is 50 μm to 1500 μm, and the thickness of the substrate is 20 to 1000 μm. (3) The density of the micro-projections is 10 to 1,000 projections / cm 2 The microprojection patch according to [1], [4] The microprojection patch according to [1], wherein the water-insoluble thermoplastic polymeric material is selected from the group consisting of polyolefins, soft silicones, and polyurethanes. [5] The microprotrusion patch described in [1], wherein the water-insoluble thermoplastic polymeric material is selected from the group consisting of polyvinyl chloride, polyester, polyacetal, polylactic acid, polylactic acid-co-glycolic acid (PLGA), and polyglycolic acid. [6] The substrate is flexible and the water-insoluble thermoplastic polymeric substance is 5.0 × 10 4 kgf / cm 2 The microprojection patch described in [1] has the following elastic modulus: [7] The microprojection patch of [1], wherein the microprojection patch is backed by an adhesive tape. [8] The microprotrusion patch described in [7], wherein the adhesive constituting the adhesive tape contains a plasticizer. [9] The microprotrusion patch described in [7], wherein the adhesive constituting the adhesive tape contains a hydrophilic substance.

[10] The microprotrusion patch described in [9], wherein the hydrophilic substance is at least one selected from the group consisting of polyacrylic acid, hyaluronic acid and its sodium salt, carboxymethylcellulose and its sodium salt, polyvinyl alcohol, polyvinylpyrrolidone, dextrin, sodium chondroitin sulfate, collagen, and crosslinked products thereof.

[11] The microprotrusion patch according to [7], wherein the adhesive substrate constituting the adhesive tape is a foam.

[12] The microprotrusion patch described in [7], wherein the adhesive substrate constituting the adhesive tape is a nonwoven fabric.

[13] A topical application system for shortening the duration of drug action on the oral mucosa, comprising the microprojection patch according to any one of [1] to

[12] and a topical drug.

[14] A topical application system for shortening the duration of drug action on the oral mucosa, comprising the microprojection patch according to any one of [1] to

[12] and a mixture for application.

[15] The topical application system according to

[14] , wherein the viscosity of the application mixture is 5 to 300,000 mPa·s.

[16] The topical application system according to

[13] , wherein the drug is a local anesthetic or antihistamine and is intended to provide short-term pain relief or anti-itch relief.

[17] The topical application system according to

[14] , wherein the drug is a local anesthetic or antihistamine and is intended to provide short-term pain relief or anti-itch relief.

[18] The topical application system according to

[16] , wherein the local anesthetic is lidocaine or ethyl aminobenzoate.

[19] The topical application system according to

[17] , wherein the local anesthetic is lidocaine or ethyl aminobenzoate.

[20] The topical application system according to

[16] , wherein the antihistamine is selected from the group consisting of diphenhydramine and its salts, and chlorpheniramine and its salts.

[21] The topical application system according to

[17] , wherein the antihistamine is selected from the group consisting of diphenhydramine and its salts, and chlorpheniramine and its salts. Effect of the Invention

[0007] The topical application system of the present invention can shorten the time it takes for topical medications such as local anesthetics, antihistamines, anti-inflammatory agents, antibacterial agents, pain relievers, and antipruritic agents to take effect on the oral mucosa. [Brief description of the drawings]

[0008] [Figure 1] 1 is a drawing of a microprojection patch of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The microprojection patch applied to the oral mucosa of the present invention is water-insoluble. Water-insoluble is a necessary condition for the material of the present invention because the microprojections do not dissolve or swell when in contact with the oral mucosa for several minutes to several tens of minutes. Water-soluble microprojections tend to swell and dissolve due to the moisture on the surface when applied to the mucosa, and the drug may diffuse toward the mucosa while at the same time back-diffusion to the microprojections may occur.

[0010] The material of the microprojection patch of the present invention is a water-insoluble thermoplastic polymeric substance. Specifically, microprojection patches made of polyolefins such as polyethylene (0.3-1.2), polypropylene (1.1-1.5), ethylene propylene rubber (0.9-1.3), soft silicone, polyurethane, etc. are suitable. The numbers in parentheses indicate the tensile modulus of elasticity (unit: 10 4 kgf / cm 2 ) value. These resins are relatively soft thermoplastic polymers, and are characterized by their low tendency to puncture the mucous membrane when administered into the oral cavity. 4 kgf / cm 2 It is characterized by having the following elastic modulus: Polyvinyl chloride, polycarbonate, polyester, 6-nylon, polyacetal, PS (polystyrene), PPS (polyphenylene sulfide), PAI (polyamide imide), PEEK (polyether ether ketone), PSU (polysulfone), polylactic acid, lactic acid-glycolic acid copolymer (PLGA), polyglycolic acid, etc. are hard, and microprojections made from these materials are likely to puncture the skin, but can be used for this purpose. The water-insoluble thermoplastic polymeric material is also preferably selected from the group consisting of polyvinyl chloride, polyester, polyacetal, polylactic acid, lactic acid-glycolic acid copolymer (PLGA), and polyglycolic acid. These thermoplastic resins have a molecular weight of 1.5×10 4 kgf / cm 2 The elastic modulus is greater than . In particular, polyethylene and polypropylene are highly safe for the human body, have flexibility, and are preferable as raw material resins for microneedles that will not pierce the oral cavity.

[0011] The microprojection patch includes a substrate and a forest of microprojections on the substrate. The thickness of the substrate is 20 μm to 1000 μm, preferably 20 μm to 500 μm, and more preferably 50 μm to 300 μm. If the thickness of the substrate is 20 μm or more, it is easy to handle, and if it is 1000 μm or less, it is a thickness that makes it easy to adhere to the oral mucosa part with large irregularities. Furthermore, if the thickness of the substrate is 20 μm or more and 500 μm or less, it is more preferable because the flexibility of the sheet makes it easy to fit the irregularities in the oral cavity. The length of the microprotrusions is preferably 50 μm to 1500 μm, more preferably 100 μm to 1,000 μm. Furthermore, in order to prevent the oral mucosa from being deeply punctured, it is more preferably 500 μm or less. If the length of the microprotrusions is 50 μm or more, it is sufficient for the epidermis thinning effect and the convex height of the protrusions for puncturing the mucosa as necessary. If the length of the microprotrusions is 1500 μm or less, bending of the microprotrusions can be prevented. The shape of the minute projections is preferably a cone or a truncated cone. In the case of projections having such a shape, the diameter of the tip is preferably 10 μm or more and 300 μm or less, and more preferably 30 μm to 200 μm. The density of the micro-projections ranges from 1 to 3000 / cm 2 10 to 1000 pieces / cm 2 is preferable, and 50 to 800 fibers / cm 2 is more preferable. 2 If the density is 3000 fibers / cm or more, the effect of the present invention can be exhibited. 2 If the density is less than 50 / cm, it is easy to adapt to the unevenness of the mucosa. When applying a normal gel or cream to the tip of the microprojections and applying it to the mucosa, the density of the microprojections is 50 / cm. 2 If the number of microprojections is small, taking into consideration the viscosity of a typical applied preparation, the microprojections will accumulate at the bottom rather than the top, reducing the contact area with the mucosa and the permeability of the drug.

[0012] When the oral mucosa surface is pressed by the microprojections, the oral mucosa stretches in a concave shape and becomes thinner, so the penetration of the applied drug into the oral cavity is significantly improved. 4 kgf / cm 2When the elastic modulus of the microprojections exceeds 5.0×10, the microprojections are pierced into the oral mucosa, and the drug is highly permeated through the holes. Regarding the substrate, when the substrate is used in the oral mucosa, a hard substrate can be used for small-area treatment, and when a large-area treatment is performed, the substrate needs to be flexible and have an elastic modulus of 5.0×10 4 kgf / cm 2 The following polymeric substances are easier to apply: For the protrusions, materials with different hardness may be selected as required.

[0013] The area of ​​the microprojection patch corresponds to the area of ​​the substrate and is not particularly limited, but for intraoral application, it is 0.5 to 5 cm 2 is desirable.

[0014] In the microprojection patch of this embodiment, the applied drug can be securely retained at the site, and the drug administration efficiency can be significantly improved, and in the case of local anesthetics, the time for the anesthetic effect to appear can be shortened, and in the case of pain relief and antipruritic drugs, the time for pain relief and itch relief can be shortened.

[0015] To apply the microprojection patch to the skin, the patch may be backed with a peripheral adhesive tape to secure the patch to the skin. Although adhesive tape is not required, adhesive tape is preferred to stably secure the patch to the skin. The adhesive tape is composed of an adhesive and a substrate, and the adhesive is applied onto the substrate. The adhesive may be a rubber-based, silicone-based, acrylic-based, or urethane-based adhesive. The adhesive used in the adhesive tape is preferably a hydrophilic adhesive, since the oral mucosa itself is highly moist and the surrounding environment is extremely moist, and therefore the adhesive has strong adhesion to the oral mucosa on a moist surface and in a moist environment. Examples of hydrophilic adhesives include hydrophilic acrylic adhesives, HiPAS10 (trade name) adhesive (acrylic adhesive with methyl methacrylate as the main monomer, Cosmedi Pharmaceuticals), and HiPAS-PU (trade name) (urethane-based adhesive, Cosmedi Pharmaceuticals).

[0016] The adhesive is applied directly to a substrate film and used as an adhesive tape, but when applied to the oral cavity, the oral cavity is extremely hydrophilic and contains a lot of water on the surface, so that the water may cover the surface of the adhesive and cause the adhesive to lose its adhesiveness. In order to prevent this and enable stable application to the skin for a long time, it is effective to blend and mix a hydrophilic substance in the adhesive in advance and apply it to the substrate. In the present invention, the hydrophilic substance refers to a substance that dissolves or swells when added to water. As the hydrophilic substance, low molecular weight hydrophilic substances such as glucose and glycerin; hydrophilic polymeric substances such as polyacrylic acid, hyaluronic acid (sodium salt), and carboxymethylcellulose (sodium salt) are used. In particular, from the viewpoint of adding to a non-aqueous solution such as an acrylic adhesive, hydrophilic polymeric substances are more preferable. The role of the hydrophilic substance is to absorb moisture in the oral cavity and maintain the adhesiveness as an adhesive for a long time. The amount of hydrophilic substance added is preferably 3 to 80% by mass, more preferably 5 to 70% by mass. If the amount of hydrophilic substance added is small, it is difficult to achieve the above effects, and if it is too much, the adhesive loses its adhesiveness and the hydrophilic substance tends to remain on the skin. It is also good to use an adhesive in which a large amount of hydrophilic polymer is kneaded into a thermoplastic adhesive, such as a hydrocolloid.

[0017] A plasticizer may be added to the adhesive. The plasticizer may be any commonly used plasticizer, such as isopropyl myristate, isopropyl palmitate, octyl myristate, octyldodecyl lactate, etc.

[0018] The substrate on which the adhesive is applied is preferably a flexible film, foam, or nonwoven fabric, from the viewpoint of application to curved parts of the skin, the oral cavity, etc. The use of foam or nonwoven fabric is more preferable, and water-absorbent materials are even more preferable, in order to stabilize the adhesion of the adhesive tape in the oral cavity by absorbing moisture in the oral cavity. Foam can prevent the flow of the formulation when applying topical medicines such as creams and liquids as an overlay. Since foam is thicker than film, it is required that its hardness is not too great so as not to cause discomfort in the oral cavity. The elastic modulus of the foam is 20 kgf / cm 2If the thickness is less than 100 μm, no discomfort will occur in the oral cavity. The elastic modulus can be measured from the stress-displacement curve when the foam is punched into a dumbbell shape and pulled with a tensile tester. The foam may be either an open-cell foam or a closed-cell foam. It is sufficient that the side that comes into contact with the oral cavity is porous. The thickness is preferably 300 μm or less and 5 μm or more (100 μm or less and 5 μm or more) for a film, and 10 mm or less and 0.1 mm or more for a foam. The thickness is preferably 20 mm or less and 0.05 mm or more for a nonwoven fabric. More preferably, the thickness is 100 μm or less and 10 μm or more for a film, and 6 mm or less and 0.5 mm or more for a foam. The size of the adhesive / base material is for fixing the microprojection patch, so it is desirable that the size is 1 to 10 mm from the edge of the microprojection patch.

[0019] In actual application, a liniment (gel, ointment, etc.) is placed on the microprojection surface and spread to form a flat surface, then applied to the oral mucosa and pressed from the back of the base to adhere the microprojection patch to the oral mucosa. The liniment may be applied directly to a specific part of the oral mucosa, and immediately pressed down from above with the microprojection patch. The shape of the microprojection patch may be square, rectangular, circular, elliptical, cylindrical, spherical, etc. This microprojection patch can be backed with adhesive tape to adhere to the oral mucosa for better adhesion. This will stretch or puncture the oral mucosa, promoting the penetration of the drug into the oral mucosa. If the liniment has a moderately high viscosity and does not flow off when applied to the microprojection surface, the above administration method is sufficient, but if the liniment is a liquid with low viscosity, it is desirable to perform the following pretreatment. That is, an appropriate amount of a powder of a hydrophilic substance (particularly a hydrophilic polymer substance) or a high-concentration aqueous solution of a hydrophilic substance is mixed with the liquid, and the resulting mixture for application is applied to the microprojection surface. The viscosity of the mixture for application in the present invention is preferably 15 to 300,000 mPa·s, more preferably 20 to 20,000 mPa·s. If the viscosity of the mixture for application is less than 15 mPa·s, the fluidity of the mixture for application is too high and it flows away from the affected area to be applied, or it is difficult to quantitatively apply it to the microprojection surface. If the viscosity is higher than 300,000 mPa·s, the fluidity of the mixture for application is low, making it difficult to apply it evenly to the microprojection surface, and it is difficult to spread it evenly on the oral cavity surface even when applied to the oral cavity. The viscosity of the coating mixture was measured using an E-type viscometer, and the value was measured 2 minutes after the start of the measurement.

[0020] For application to the oral mucosa, the microprojection patch is preferably a rectangular patch with a minor axis of 0.5 cm or more and a major axis of 5 cm or less in order to closely fit the tooth base. If the microprojection patch is circular, the diameter is preferably 0.4 cm or more and 3 cm or less. The thickness of the substrate is preferably 500 μm or less, and particularly preferably 300 μm or less.

[0021] The method for forming the microprojections in the present invention includes press molding using a mold, injection molding, solution molding, and the like.

[0022] Drugs that can be used in the present invention include local anesthetics such as lidocaine, mepivacaine, dibucaine, bupivacaine, ropivacaine, procaine, chloroprocaine, tetracaine, and benzocaine (ethyl aminobenzoate). As the antihistamine, diphenhydramine and its salts, chlorpheniramine and its salts, isothipendyl and its salts, diphenylpyraline and its salts, and diphenylimidazole and its salts are preferred. As anti-inflammatory, pain relieving and antipruritic drugs, corticosteroids such as betamethasone ester, non-steroidal drugs such as diclofenac and indomethacin, vitamins for the skin such as vitamin A, and antibacterial agents such as antibiotics are preferred.

[0023] The method of use may be to apply a liniment to the oral mucosa, then place the microprojection patch on top of it to cover it and press it from the back of the base, or the liniment may be applied directly to the microprojection surface, applied to the oral mucosa, and backed with an intraoral adhesive tape. EXAMPLES

[0024] The present invention will now be described in more detail with reference to the following examples. These examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these examples.

[0025] Example 1 The microprojection patch shown in FIG. 1 is a circular substrate on which multiple microprojections with a length of 300 μm stand. Each projection is shaped like a truncated cone, the diameter of the projection tip is 35 μm, and the projection spacing is 500 μm. base The plate thickness is 60 μm. For production, a 100μm thick polypropylene sheet was placed on a metal concave mold, heated to 180℃, and pressed to form a sheet filled with microprojections, which was then cut to a diameter of 10mm to produce a microprojection patch. This microprojection patch was made by backing a bandage made of polyethylene film coated with 100μm of acrylic adhesive (a mixture of 100g of HiPAS10 adhesive, manufactured by Cosmedi Pharmaceuticals) and 30g of isopropyl myristate, with tape cut to a diameter of 16mm. To actually use this microprojection patch, 0.1 g of the topical local anesthetic "Hurricane Gel" (containing 200 mg of ethyl aminobenzoate in 1 g of gel ointment) was spread over the entire surface of the microprojections. In this state, the microprojections with the drug were applied to the upper jaw of three volunteers, and the base (the back of the microprojections) was pressed to attach the ointment and microprojection patch to the mucosa with adhesive tape. After application, the tape was partially peeled off at 1 minute, 3 minutes, and 5 minutes, and the area where the drug was applied was lightly pressed with a toothpick, and the participants were asked to self-evaluate whether or not they felt pain. The time when all three participants no longer felt pain was 3 minutes. For comparison, 0.1 g of Hurricane Gel was simultaneously applied to a circular area with a diameter of 1 cm on the upper jaw, and the time when pain no longer felt was evaluated every 1 minute, 3 minutes, and 5 minutes, but all three participants felt pain after 5 minutes.

[0026] Comparative Example 1 A hyaluronic acid solution was cast on a metal concave mold, a sheet of microprojections was formed by drying, and cut to a diameter of 10 mm to produce a microprojection patch. This microprojection patch had a needle length of 300 μm, needle tip diameter of 35 to 40 μm, needle interval of 500 μm, and substrate thickness of 80 μm. A bandage made by applying acrylic adhesive (a mixture of 100 g of HiPAS10 adhesive (manufactured by Cosmedi Pharmaceutical) and 30 g of isopropyl myristate) to a thickness of 100 μm on a polyethylene film was used, backed with tape cut to a diameter of 16 mm. The subsequent operations were performed in the same manner as in Example 1. When the Hurricane gel was placed on the surface, the microprojections at the contact area melted, and the Hurricane gel was applied to the mucous membrane first, and then the microprojection patch was applied and evaluated (3 volunteers). The time until the pain disappeared was evaluated, and all three people felt pain after 5 minutes.

[0027] Example 2 Polylactic acid was dissolved in dichloromethane at 10% by mass, cast onto a silicon mold (having a conical hole with a depth of 0.3 mm, tip diameter: 0.04 mm, base diameter: 0.18 mm, hole spacing: 0.5 mm), and dried at 60°C to form a microneedle sheet. The substrate thickness was 0.1 mm. The microneedle patch was cut to a diameter of 10 mm. It was used after being backed with the same adhesive tape as in Example 1. To actually use this microprojection patch, 0.15 g of a dental local anesthetic, "Neozalocaine Paste" (containing 250 mg of ethyl aminobenzoate and 50 mg of diethylaminoethyl parabutylaminobenzoate hydrochloride per 1 g of pasta) was spread over the entire surface of the microprojections. In this state, the microprojections with the drug were applied to the upper jaw of three volunteers, and the base (the back of the microprojections) was pressed to press the ointment and the microprojection patch, and the patch was attached with adhesive tape. After application, the tape was partially peeled off every 1, 3, and 5 minutes, and the area where the drug was applied was lightly pressed with a toothpick, and the volunteers were asked to evaluate whether or not there was pain. The time when all three volunteers no longer felt pain was 3 minutes. For comparison, 0.15 g of Neozalocaine Paste was simultaneously applied to a circular area with a diameter of 1 cm in the oral cavity, and the time when pain no longer felt was evaluated every 5 minutes, but all three volunteers felt pain after 5 minutes.

[0028] Examples 3-5, Comparative Examples 2-3 The microprojections shown in Table 1 were manufactured and backed with the same adhesive tape as in Example 1, and for practical use were evaluated in the same manner as in Example 2. In all cases, the microprojection tip diameter was 0.04 mm, the microprojection base diameter was 0.15 mm, and the microprojection spacing was 0.6 mm.

[0029] [Table 1]

[0030] Examples 6-7, Comparative Example 4 Application and Evaluation Methods The mixture for application was 0.05 g of gel (containing 79 mg of lidocaine in 1 g of gel) made by adding polyacrylic acid powder to the spray-type surface anesthetic "Xylocaine Pump Spray 8%" (aqueous spray containing 8% lidocaine). The mixture for application was spread and placed on the entire surface of microprojections (diameter 10 mm) made of a polypropylene sheet by the same heat press as in Example 1. The back of the microprojections was lined with adhesive tape with a diameter of 16 mm. The adhesive tape was made of the adhesive composition of Example 1, except that 40 g of polyacrylic acid was added as a hydrophilic substance. In this state, the microprojections were pressed against the upper jaw of three volunteers with the substrate (back of the microprojections), and the ointment and microprojection patch were adhered to the mucosa with tape. Two minutes after application, the tape was partially peeled off, and the drug application area was lightly pressed with a toothpick, and the presence or absence of pain was evaluated by the volunteers. The viscosity of the coating mixture was measured at 25° C. using a TVE-25 E-type viscometer manufactured by Toki Sangyo Co., Ltd. The sample amount was 0.2 ml. The results are shown in Table 2.

[0031] [Table 2]

[0032] Examples 8-9, Comparative Example 5 (Test on adhesive strength of peripheral adhesive tape in wet environment) sample (Sample 1) the adhesive tape used in Example 1, (Sample 2) the tape used in Example 6, and (Sample 3) a rubber-based craft tape were used and each was cut to a size of 10 x 40 mm. Test Method Approximately 8mg / cm2 on the entire surface of a vertically fixed white paper 2 Water was sprayed onto the sample so that the surface was moistened. A 10x30mm portion of the sample was attached vertically to the bottom edge of the white paper and lightly pressed down. After 5 minutes, weights of 10g and 20g were placed on the bottom of each sample, and the peeling and falling behavior of the sample from the white paper was observed. The results are shown in Table 3.

[0033] [Table 3]

[0034] It was clear that the tested HiPAS adhesive tape was extremely hydrophilic and therefore had good adhesion to wet surfaces, whereas the rubber adhesive tape was non-polar and its adhesion rapidly decreased when it came into contact with water.In Example 9, it was found that the addition of a hydrophilic resin to the HiPAS adhesive tape further improved the adhesiveness of the adhesive tape in wet environments. [Explanation of symbols]

[0035] 1 Microprotrusion 2 Adhesive tape

Claims

1. A microprojection patch comprising a substrate and a forest of microprojections on the substrate, the microprojection patch being made of a water insoluble thermoplastic polymeric material for application to an oral mucosa.

2. 2. The microprojection patch of claim 1, wherein the tip diameter of the microprojections is 10 μm to 300 μm, the length of the microprojections is 50 μm to 1500 μm, and the thickness of the substrate is 20 to 1000 μm.

3. The density of the microprojections is 10 to 1000 / cm ２ 2. The microprojection patch of claim 1 , wherein:

4. 10. The microprojection patch of claim 1, wherein the water insoluble thermoplastic polymeric material is selected from the group consisting of polyolefins, soft silicones, and polyurethanes.

5. 2. The microprojection patch of claim 1, wherein the water insoluble thermoplastic polymeric material is selected from the group consisting of polyvinyl chloride, polyester, polyacetal, polylactic acid, polylactic-co-glycolic acid (PLGA), and polyglycolic acid.

6. The substrate is flexible, and the water-insoluble thermoplastic polymeric material is 5.0×10 ４ kgf / cm ２ 10. The microprojection patch of claim 1 having an elastic modulus of:

7. 10. The microprojection patch of claim 1, wherein the microprojection patch is backed by an adhesive tape.

8. The microprojection patch according to claim 7 , wherein the adhesive constituting the adhesive tape contains a plasticizer.

9. The microprojection patch according to claim 7 , wherein the adhesive constituting the adhesive tape contains a hydrophilic substance.

10. The microprotrusion patch of claim 9, wherein the hydrophilic substance is at least one selected from the group consisting of polyacrylic acid, hyaluronic acid and its sodium salt, carboxymethylcellulose and its sodium salt, polyvinyl alcohol, polyvinylpyrrolidone, dextrin, sodium chondroitin sulfate, collagen, and crosslinked products thereof.

11. The microprojection patch according to claim 7, wherein the adhesive base material constituting the adhesive tape is a foam.

12. The microprotrusion patch according to claim 7, wherein the adhesive base material constituting the adhesive tape is a nonwoven fabric.

13. A topical application system for shortening the time of drug action on the oral mucosa, comprising the microprojection patch according to any one of claims 1 to 12 and a topical medicine.

14. A topical application system for shortening the duration of drug action on the oral mucosa, comprising the microprojection patch according to any one of claims 1 to 12 and a coating mixture.

15. The topical application system according to claim 14, wherein the viscosity of the application mixture is from 15 to 300,000 mPa·s.

16. 14. The topical application system of claim 13, wherein the drug is a local anesthetic or antihistamine and is intended to provide short-term pain relief or relief from itching.

17. 15. The topical application system of claim 14, wherein the drug is a local anesthetic or antihistamine and is intended to achieve short-term pain relief or anti-itch relief.

18. 17. The topical application system of claim 16, wherein the local anesthetic is lidocaine or ethyl aminobenzoate.

19. 18. The topical application system of claim 17, wherein the local anesthetic is lidocaine or ethyl aminobenzoate.

20. 17. The topical application system of claim 16, wherein the antihistamine is selected from the group consisting of diphenhydramine and its salts, and chlorpheniramine and its salts.

21. 18. The topical application system of claim 17, wherein the antihistamine is selected from the group consisting of diphenhydramine and its salts, and chlorpheniramine and its salts.

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