Oral localized application system

Abstract

The present invention provides a means for shortening the onset time of action of a local anesthetic drug, an antihistamine drug, or the like on oral mucosa.　This microprotrusion patch comprises a substrate and microprotrusions densely standing on the substrate, and is composed of a water-insoluble thermoplastic polymer material and is applied to an oral mucosa. This localized application system for shortening the drug action time on an oral mucosa comprises: the microprotrusion patch; a coating drug (a gel or ointment containing a medication or the like); and an adhesive tape for backing.

Description

Oral topical application system

[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.

[0002] Local anesthetics for dentistry, like local anesthetics for the skin, are widely used. The most common drugs are lidocaine and ethyl aminobenzoate (gel) ointments, but their onset time is 10 to 20 minutes, which is shorter than the onset time for skin. However, both physicians and patients desire a faster onset of action. The present inventors developed a microneedle array containing a local anesthetic for oral application and successfully achieved an anesthetic effect in a short time (Patent Document 1). Patent Documents 1 and 2 describe inventions of microneedle preparations for the skin in which a local anesthetic is dissolved in microneedles, or preparations in which a local anesthetic is applied to microneedles. From the physician's perspective, new administration methods that can be prepared and applied in the medical field, such as administering locally administered preparations consisting of various familiar (gel) ointments and liquids with a proven track record, are desired, allowing for a shorter onset of effect.

[0003] JP 2019-084352 A JP 2017-061447 A

[0004] The present invention has been made to solve problems related to topical preparations, and aims to provide a means for shortening the time it takes for topical preparations such as ointments, creams, liquids, and gels to take effect when administered intraorally, the preparations providing local anesthesia, antihistamine, anti-inflammatory, antibacterial, pain relief, antipruritic, etc.

[0005] The administration sites for the topical formulation of the present invention are the oral cavity and gums. The outermost layer of the oral mucosa or gums is keratinized stratified squamous epithelium, which is thinner than the stratum corneum of normal skin. While transdermal absorption of local anesthetics is higher than that of normal skin, it is sensitive to pain and prone to bleeding. On the other hand, the oral mucosa and gums are less flat and more uneven than normal skin, making it difficult to stably retain the formulation at the affected area. Furthermore, because they are located inside the oral cavity, they are constantly exposed to saliva moisture, requiring protection against peeling of patch-type formulations and spillage of topical formulations. Due to the differences in conditions described above, the technical challenges of topical formulations for oral mucosa are some that are common to those for normal skin, but many that are completely different. The present inventors developed a microprojection patch to address the above challenges. To shorten the onset time of oral mucosal action of local anesthetics, antihistamines, anti-inflammatory agents, antibacterial agents, pain relievers, antipruritics, etc., the microprotrusion patch of the present invention is overlaid on the application site when applying (gel) ointments or liquids containing these drugs to the affected area in the oral cavity. When applying a solution-based local anesthetic to the skin, if the solution viscosity is too low, it may immediately flow off the mucosal surface after application to the oral cavity, and the anesthetic may not remain in the intended area. To avoid this, it is desirable to apply the applied formulation with a high viscosity so that it remains appropriately on the application surface. Microneedle patches are known as microprotrusion patches. Microneedles are made of materials such as silica, metal, plastic, and biosoluble substances, but conventional microneedles are characterized by their hardness allowing them to puncture the skin. In the present invention, the microprotrusions may be hard enough to puncture the oral mucosa when applied, but more preferably, they are hard enough to prevent puncture. In the case of mucosal puncture, the drug effectively penetrates the oral mucosa through micropores opened in the oral mucosa. In the case of soft microneedles that cannot puncture the oral mucosa, the microprotrusions compress the oral mucosa, locally stretching and thinning the mucosa, thereby improving mucosal absorption of simultaneously administered drugs. If the microneedle is made of a material with low hardness and flexibility, even if it punctures the oral mucosa, it will only puncture within a few μm from the surface, so it will not hurt or cause bleeding.The microprojection patch of the present invention uses a water-insoluble polymer as a constituent material. Even if a water-soluble polymer, such as hyaluronic acid or carboxymethyl cellulose, is used to form a microprojection patch, when it is applied to moist oral mucosa, the tips of the microprojections, followed by most of the needles, soften and dissolve due to the moisture, making it impossible to deform or puncture the oral mucosa, and therefore unable to shorten the intended drug onset time. The microprojection patch may be backed with an adhesive sheet. The adhesive sheet adheres strongly to the oral mucosa in the presence of saliva, thereby enabling the microprojections to puncture or press against the skin.

[0006] The present invention is as follows. [1] A microprojection patch comprising a substrate and microprojections standing tall 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 diameter of the tip 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] A microprojection patch wherein the density of the microprojections is 10 / cm ２ ~1000 pieces / cm ２ [4] The microprojection patch according to any one of [1] to [3], wherein the water-insoluble thermoplastic polymeric material is selected from the group consisting of polyolefin, soft silicone, and polyurethane. [5] The microprojection patch according to any one of [1] to [3], 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 microprojection patch according to any one of [1] to [3], wherein the substrate is flexible and the water-insoluble thermoplastic polymeric material is 5.0 x 10 ４ kgf / cm ２The microprojection patch according to any one of [1] to [5], having the following elastic modulus. [7] A microprojection patch with adhesive tape, comprising the microprojection patch according to any one of [1] to [6] and an adhesive tape, wherein the microprojection patch is backed by the adhesive tape. [8] The microprojection patch with adhesive tape according to [7], wherein the adhesive constituting the adhesive tape contains a plasticizer. [9] The microprojection patch with adhesive tape according to [7] or [8], wherein the adhesive constituting the adhesive tape contains a hydrophilic substance.

[10] The microprojection patch with adhesive tape according to [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 with adhesive tape according to any one of [7] to

[10] , wherein the adhesive substrate constituting the adhesive tape is a foam.

[12] The microprojection patch with adhesive tape according to any one of [7] to

[10] , 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 with adhesive tape according to any one of [1] to [6] and a topical medication.

[14] A topical application system for shortening the duration of drug action on the oral mucosa, comprising the microprojection patch with adhesive tape according to any one of [7] to

[10] and a topical medication.

[15] A topical application system for shortening the duration of drug action on the oral mucosa, comprising the microprojection patch with adhesive tape according to any one of [1] to [6] and a topical medication.

[16] A topical application system for shortening the duration of drug action on the oral mucosa, comprising the microprojection patch with adhesive tape according to any one of [7] to

[10] and a topical medication.

[17] The topical application system according to

[15] or

[16] , wherein the viscosity of the topical medication mixture is 15 mPa·s to 300,000 mPa·s.

[18] The topical application system according to

[13] or

[14] , wherein the drug contained in the liniment is a local anesthetic or antihistamine, and is intended to provide pain relief or anti-itch relief in a short period of time.

[19] The topical application system according to

[16] or

[17] , wherein the drug contained in the mixture for application is a local anesthetic or an antihistamine, and is intended to relieve pain or relieve itching in a short period of time.

[20] The topical application system according to

[18] or

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

[21] The topical application system according to

[18] or

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

[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 antipruritics to take effect on the oral mucosa.

[0008] FIG. 1 is a diagram showing a schematic diagram of the microprotrusion patch with adhesive tape prepared in Example 1.

[0009] The microprojection patch to be applied to the oral mucosa of the present invention is water-insoluble. If the microprojections are water-insoluble, they will not dissolve or swell even when in contact with the oral mucosa for several minutes to several tens of minutes, and therefore water-insolubility is a necessary condition for the material of the present invention. Note that when water-soluble microprojections are applied to the mucosa, the microprojections tend to swell or dissolve due to moisture on their surface, and while the drug diffuses toward the mucosa, back-diffusion into the microprojections may also occur.

[0010] The material of the microprojection patch of the present invention is a water-insoluble thermoplastic polymer. 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 (unit: 10 ４ kgf / cm ２ These resins are relatively soft thermoplastic polymers, and are characterized by their resistance to puncturing the mucous membrane when administered to the oral cavity. These thermoplastic polymers have a viscosity of 1.5 × 10 ４ kgf / cm ２They are characterized by having the following elastic modulus: polyvinyl chloride, polycarbonate, polyester, 6-nylon, polyacetal, PS (polystyrene), PPS (polyphenylene sulfide), PAI (polyamideimide), 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 prone to puncture the skin, but can be used for this purpose. The water-insoluble thermoplastic polymeric substance 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 modulus of elasticity of 1.5 x 10 ４ kgf / cm ２ In particular, polyethylene and polypropylene are highly biosafe and flexible, making them 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. More specifically, in the microprojection patch, the microprojections are forested on a first surface of the substrate. In the microprojection patch, the substrate and the microprojections are preferably an integrally molded product. That is, in the microprojection patch, the substrate and the microprojections are preferably an integrally molded product made of a water-insoluble thermoplastic polymer. 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 substrate is 20 μm or more thick, it is easy to handle, and if it is 1000 μm or less, it is easy to adhere to the oral mucosa, which has large irregularities. Furthermore, if the substrate is 20 μm or more thick and 500 μm or less thick, 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 microprojections is preferably 50 μm to 1500 μm, more preferably 100 μm to 1000 μm. Furthermore, the length of the microprotrusions is more preferably 500 μm or less so as not to puncture the oral mucosa too deeply. If the length of the microprotrusions is 50 μm or more, the convex height of the protrusions is sufficient for thinning the epidermis and, if necessary, for puncturing the mucosa. If the length of the microprotrusions is 1500 μm or less, bending of the microprotrusions can be prevented. The shape of the microprotrusions is preferably conical or truncated conical. In the case of protrusions of such shapes, the diameter of the tip of the microprotrusion is preferably 10 μm or more and 300 μm or less, more preferably 30 μm to 200 μm. The density of the microprotrusions is 1 protrusion / cm ２ ~3000 lines / cm ２ 10 strands / cm ２ ~1000 pieces / cm ２ is preferable, and 50 fibers / cm ２ ~800 pieces / cm ２ It is more preferable that the density of the micro-projections is 1 / cm. ２ If the density of the micro-projections is 3000 / cm or more, the effect of the present invention can be exhibited. ２ When a normal gel or cream is applied to the tip of the microprojections and applied to the mucosa, the density of the microprojections is 50 / cm ２If the number of microprojections is small, considering the viscosity of a typical topical formulation, the microprojections will accumulate at the base rather than the tip, reducing the contact area with the mucosa and the drug permeability.

[0012] When the surface of the oral mucosa is pressed by the microprojections, the oral mucosa stretches in a concave shape and becomes thin, which significantly improves the penetration of the applied drug into the oral cavity. ４ kgf / cm ２ When the microprojections have an elastic modulus of more than 5.0 × 10, they puncture the oral mucosa and the drug penetrates through the holes to a high degree. Regarding the substrate, when used on the oral mucosa, a hard substrate can be used for small-area treatments, and when treatment is performed on a large area, the substrate needs to be flexible and have a modulus of more than 5.0 × 10. ４ kgf / cm ２ The following polymeric substances are easier to apply: Materials with different hardness may be selected for the protrusions as needed.

[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] This type of microprotrusion patch can reliably retain the applied drug at the site, significantly improve drug administration efficiency, and in the case of local anesthetics, shorten the time it takes for the anesthetic effect to appear. In the case of pain relief and antipruritic drugs, shorten the time it takes for pain relief and itch relief to occur.

[0015] When applying the microprojection patch to the skin, the microprojection patch may be backed with adhesive tape around the periphery to secure it in the oral cavity. While adhesive tape is not essential, it is preferable to use adhesive tape to stably secure the microprojection patch to the skin. That is, it is preferable to use a microprojection patch with adhesive tape, which comprises the above-described microprojection patch and adhesive tape and is backed by the adhesive tape. "The microprojection patch being backed by adhesive tape" means that the adhesive tape is disposed on the second surface of the substrate in the microprojection patch. Note that the first surface of the substrate in the microprojection patch is the surface on which the microprojections are forested, as described above. The second surface of the substrate is the surface opposite the first surface of the substrate. The adhesive tape is composed of an adhesive and a substrate (adhesive substrate), and the adhesive is applied to the substrate. The adhesive contains an adhesive component. The adhesive component in the adhesive may be a rubber-based, silicone-based, acrylic-based, or urethane-based adhesive, etc. Because the oral mucosa itself is highly moist and the surrounding area is an extremely moist environment, the adhesive component used in adhesive tapes is preferably a hydrophilic adhesive component, and one that adheres strongly to the oral mucosa on a moist surface or in a moist environment is preferred. Examples of hydrophilic adhesive components include hydrophilic acrylic adhesives, HiPAS10 (trade name) adhesive (an acrylic adhesive with methyl methacrylate as the main monomer, Cosmedy Pharmaceutical), and HiPAS-PU (trade name) (a urethane-based adhesive, Cosmedy Pharmaceutical).

[0016] In adhesive tapes, the substrate (adhesive substrate) is preferably a substrate film. In this case, the adhesive is directly applied to the substrate film to form the adhesive tape. However, particularly when applied to the oral cavity, the oral cavity is extremely hydrophilic and contains a large amount of water on its surface, which can cover the surface of the adhesive and cause it to lose its adhesiveness. To prevent this and enable stable application to the skin for a long period of time, it is effective to blend a hydrophilic substance into the adhesive beforehand 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. That is, the adhesive preferably contains an adhesive component and a hydrophilic substance. Examples of hydrophilic substances include low-molecular-weight hydrophilic substances such as glucose and glycerin; and hydrophilic polymeric substances such as polyacrylic acid, hyaluronic acid (sodium salt), carboxymethylcellulose (sodium salt), polyvinyl alcohol, polyvinylpyrrolidone, dextrin, sodium chondroitin sulfate, collagen, and crosslinked forms thereof. Hydrophilic polymeric substances are more preferred, especially from the perspective of adding them to non-aqueous solutions such as acrylic adhesives. The role of the hydrophilic substance is to absorb moisture in the oral cavity and maintain the adhesive properties of the adhesive for a long time. The content of the hydrophilic substance is preferably 3 to 80% by mass, more preferably 5 to 70% by mass, based on 100% by mass of the adhesive. If the content of the hydrophilic substance is too low, the above effect is difficult to achieve, but if it is too high, the adhesive properties of the adhesive are lost and the hydrophilic substance is likely to remain on the skin. It is also possible to use an adhesive in which a large amount of hydrophilic polymer is kneaded into a thermoplastic adhesive, such as a hydrocolloid.

[0017] The adhesive may contain a plasticizer, and examples of the plasticizer that can be used include commonly used plasticizers such as isopropyl myristate, isopropyl palmitate, octyl myristate, and octyldodecyl lactate.

[0018] The substrate to 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. In order to stabilize the adhesion of the adhesive tape in the oral cavity by absorbing moisture in the oral cavity, it is more preferable to use foam or nonwoven fabric, and a water-absorbent material is even more preferable. Foam can prevent the formulation from flowing when using topical medications 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 ２ If the thickness is less than 100 μm, no discomfort will occur in the oral cavity. The modulus of elasticity 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 to 5 μm (or 100 μm to 5 μm) for films, and 10 mm to 0.1 mm for foams. For nonwoven fabrics, the thickness is preferably 20 mm to 0.05 mm. More preferably, the thickness is 100 μm to 10 μm for films, and 6 mm to 0.5 mm for foams. For nonwoven fabrics, the thickness is preferably 10 mm to 0.08 mm. The size of the adhesive / substrate is for fixing the microprojection patch, so it is desirably 1 to 10 mm from the edge of the microprojection patch.

[0019] The topical application system of the present invention is a topical application system for shortening the time a drug acts on the oral mucosa, comprising the above-mentioned microprojection patch and a topical medication. However, the microprojection patch may be backed with an adhesive tape. That is, the topical application system of the present invention may be a topical application system for shortening the time a drug acts on the oral mucosa, comprising the above-mentioned microprojection patch with adhesive tape and a topical medication.

[0020] 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 down from the back of the substrate to adhere the microprojection patch to the oral mucosa. The liniment may be applied directly to the desired site on the oral mucosa, followed immediately by pressing down from above with the microprojection patch. The microprojection patch may be square, rectangular, circular, oval, cylindrical, spherical, or other shapes. Backing the microprojection patch with adhesive tape to adhere it to the oral mucosa provides better adhesion. This allows the oral mucosa to stretch or puncture, promoting drug penetration into the oral mucosa. If the liniment has a moderately high viscosity and does not flow out when placed on the microprojection surface, the above administration method is sufficient. However, if the liniment is a liquid with a low viscosity, the following pretreatment is recommended. Specifically, an appropriate amount of a hydrophilic substance (especially a hydrophilic polymer) powder or a highly concentrated aqueous solution of the hydrophilic substance is mixed with the liquid, and the resulting application mixture is placed on the microprojection surface. The viscosity of the application mixture in the present invention is preferably 15 mPa·s to 300,000 mPa·s, and more preferably 20 mPa·s to 20,000 mPa·s. If the viscosity of the application mixture is less than 15 mPa·s, the application mixture will have too much fluidity and will flow away from the affected area or will be difficult to apply quantitatively to the microprojection surface. If the viscosity is higher than 300,000 mPa·s, the application mixture will have poor fluidity, making it difficult to apply evenly to the microprojection surface and making it difficult to spread evenly over the oral surface when applied to the oral cavity. The viscosity of the application mixture was measured at 25°C using an E-type viscometer, and the value was measured 2 minutes after the start of measurement.

[0021] For application to the oral mucosa, the microprojection patch is preferably rectangular, with a minor axis of 0.5 cm or more and a major axis of 5 cm or less, so as to fit closely to the tooth base. If the microprojection patch is circular, its 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.

[0022] The method for forming the micro-projections in the present invention includes press molding using a mold, injection molding, solution molding, and the like.

[0023] The topical application includes drugs. Drugs that can be used in the present invention include local anesthetics, antihistamines, anti-inflammatory, pain-relieving, and antipruritic drugs. Local anesthetics include lidocaine, mepivacaine, dibucaine, bupivacaine, ropivacaine, procaine, chloroprocaine, tetracaine, and benzocaine (ethyl aminobenzoate). Preferred antihistamines include diphenhydramine and its salts, chlorpheniramine and its salts, isothipendyl and its salts, diphenylpyraline and its salts, and diphenylimidazole and its salts. Preferred anti-inflammatory, pain-relieving, and antipruritic drugs include corticosteroids such as betamethasone ester, non-steroidal drugs such as diclofenac and indomethacin, dermatological vitamins such as vitamin A, and antibacterial agents such as antibiotics.

[0024] The method of use may involve applying a liniment to the oral mucosa, then placing the microprojection patch on top of it to cover it and pressing it down from the back of the base, or alternatively, applying the liniment directly to the microprojection surface, applying it to the oral mucosa, and then backing it with intraoral adhesive tape.

[0025] The present invention will be described in more detail below with reference to the following examples. These examples are merely examples for specifically explaining the present invention, and the scope of the present invention is not limited to these examples.

[0026] Example 1 The microprotrusion patch shown in Figure 1 has a circular substrate on which multiple 300 μm long microprotrusions stand. Each protrusion is frustoconical, with a tip diameter of 35 μm, a protrusion spacing of 500 μm, and a substrate thickness of 60 μm. To manufacture the microprotrusion patch, a 100 μm thick polypropylene sheet was placed on a metal concave mold, heated to 180 °C, and press-molded to form a microprotrusion-filled sheet. The microprotrusion patch was then cut to a diameter of 10 mm. The resulting microprotrusion patch was backed with adhesive tape cut to a diameter of 16 mm to obtain a microprotrusion patch with adhesive tape. The adhesive in the adhesive tape was a mixture of 100 g of acrylic adhesive (HiPAS10 adhesive, manufactured by Cosmedy Pharmaceuticals) and 30 g of isopropyl myristate, and the substrate was a 100 μm thick polyethylene film. Next, 0.1 g of topical local anesthetic "Hurricane Gel" (liniment) (containing 200 mg of ethyl aminobenzoate in 1 g of gel ointment) was spread over the entire surface of the microprotrusions. In this state, the microprotrusions with the local anesthetic were applied to the upper jaw of three volunteers, and the base (the back of the microprotrusions) was pressed to adhere the ointment and microprotrusion patch to the mucosa with adhesive tape. After application, the tape was partially peeled off at 1, 3, and 5 minutes, and the applied area was lightly pressed with a toothpick to self-assess the presence or absence of pain. All three volunteers felt no pain after 3 minutes. For comparison, 0.1 g of Hurricane Gel (without the microprotrusion patch) was simultaneously applied to a 1 cm diameter circular area on the upper jaw. The time until pain was relieved was assessed every 1, 3, and 5 minutes. All three volunteers felt pain after 5 minutes.

[0027] Comparative Example 1: A hyaluronic acid aqueous solution was cast onto a metal concave mold, dried to form a sheet of microprojections, and then cut to a diameter of 10 mm to produce a microprojection patch. The resulting microprojection patch had a needle length of 300 μm, needle tip diameter of 35-40 μm, needle spacing of 500 μm, and substrate thickness of 80 μm. Using the resulting microprojection patch, a microprojection patch with adhesive tape was obtained in the same manner as in Example 1. Subsequent procedures were also performed in the same manner as in Example 1. When Hurricane Gel was placed on the microprojections, the microprojections dissolved at the contact points. Therefore, Hurricane Gel was first applied to the mucosa, and then the microprojection patch was applied and evaluated (three volunteers). The time until pain disappeared was evaluated, and all three volunteers felt pain after five minutes.

[0028] Example 2: Polylactic acid was dissolved in dichloromethane at 10% by mass, cast onto a silicon mold (with 0.3 mm deep truncated conical holes, tip diameter: 0.04 mm, base diameter: 0.18 mm, hole spacing: 0.5 mm), and dried at 60°C to produce a microneedle sheet. The substrate thickness was 0.1 mm. Microprotrusion patches (microneedle patches) were cut to 10 mm diameter and used with a backing of adhesive tape similar to that used in Example 1. Next, 0.15 g of dental local anesthetic "Neozalocaine Paste" (liniment) (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 microprotrusions. In this state, the microprotrusions loaded with the local anesthetic were applied to the upper jaws of three volunteers, and the substrate (the back of the microprotrusions) was pressed against the ointment and microprotrusion patch, which were then adhered with adhesive tape. After application, the tape was partially removed every 1, 3, and 5 minutes, and the patient was gently pressed with a toothpick on the applied area to assess whether pain was present or absent. All three patients felt no pain after 3 minutes. For comparison, 0.15 g of Neosalocaine paste was simultaneously applied to a 1 cm diameter circular area in the oral cavity, and the time to pain relief was assessed every 5 minutes. All three patients felt pain after 5 minutes.

[0029] Examples 3-5, Comparative Examples 2-3 The microprojections shown in Table 1 were manufactured, backed with the same adhesive tape as in Example 1, and evaluated for actual use 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.

[0030]

[0031] Examples 6-7 and Comparative Example 4 Application and Evaluation Methods The application mixture was 0.05 g of a gel (containing 79 mg of lidocaine per 1 g of gel) prepared by adding polyacrylic acid powder to the spray-type topical anesthetic "Xylocaine Pump Spray 8%" (an aqueous spray containing 8% lidocaine). The application mixture was spread over the entire surface of microprojections (10 mm in diameter) fabricated using a polypropylene sheet using the same heat press as in Example 1. The back of the microprojections was lined with 16 mm in diameter adhesive tape. The adhesive tape consisted of the same adhesive composition as in Example 1, except that 40 g of polyacrylic acid was added as a hydrophilic substance. In this state, the microprojections were pressed against the base (back of the microprojections) on the upper jaws of three volunteers, and the ointment and microprojection patch were adhered to the mucosa with the tape. Two minutes after application, the tape was partially removed, and the application site was lightly pressed with a toothpick, and the patient self-evaluated for pain. The viscosity of the coating mixture was measured at 25° C. using an E-type viscometer TVE-25 manufactured by Toki Sangyo Co., Ltd. The sample amount was 0.2 ml. The results are shown in Table 2.

[0032]

[0033] Examples 8-9, Comparative Example 5 (Test on adhesive strength of peripheral adhesive tape in a wet environment) Samples (Sample 1) The adhesive tape used in Example 1, (Sample 2) The tape used in Example 6, and (Sample 3) Rubber-based Kraft tape were used, each cut to 10 x 40 mm. Test method A sheet of high-quality white paper was fixed vertically and coated with a tape of approximately 8 mg / cm2. ２ Water was sprayed onto the surface to moisten it. A 10 x 30 mm portion of the sample was attached vertically to the bottom edge of the white paper and lightly pressed down. After 5 minutes, 10 g and 20 g weights 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.

[0034]

[0035] It was clear that the HiPAS adhesive tape tested was highly 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 a wet environment.

[0036] 1 Microprotrusion patch 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. 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 micro-projections is 10 projections / cm ２ ~1000 pieces / cm ２ 3. The microprojection patch of claim 1 or 2, wherein:

4. The microprojection patch of any one of claims 1 to 3, wherein the water insoluble thermoplastic polymeric material is selected from the group consisting of polyolefins, soft silicones, and polyurethanes.

5. The microprojection patch of any one of claims 1 to 3, 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 x 10 ４ kgf / cm ２ The microprojection patch of any one of claims 1 to 5, having an elastic modulus of:

7. A microprojection patch with adhesive tape, comprising: the microprojection patch according to any one of claims 1 to 6; and an adhesive tape, wherein the microprojection patch is backed by the adhesive tape.

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

9. The microprotrusion patch with adhesive tape according to claim 7 or 8, wherein the adhesive constituting the adhesive tape contains a hydrophilic substance.

10. The microprotrusion patch with adhesive tape according to 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 microprotrusion patch with adhesive tape according to any one of claims 7 to 10, wherein the adhesive substrate constituting the adhesive tape is a foam.

12. The microprotrusion patch with adhesive tape according to any one of claims 7 to 10, wherein the adhesive substrate 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 6 and a topical medicine.

14. A topical application system for shortening the time of drug action on the oral mucosa, comprising the microprojection patch with adhesive tape according to any one of claims 7 to 12 and a topical medicine.

15. 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 6 and a coating mixture.

16. A topical application system for shortening the duration of drug action on the oral mucosa, comprising a microprojection patch with adhesive tape according to any one of claims 7 to 12 and a coating mixture.

17. The topical application system according to claim 15 or 16, wherein the viscosity of the application mixture is from 15 mPa·s to 300,000 mPa·s.

18. The topical application system according to claim 13 or 14, wherein the drug contained in the liniment is a local anesthetic or antihistamine, and is intended to provide short-term pain relief or anti-itch relief.

19. The topical application system according to claim 16 or 17, wherein the drug contained in the application mixture is a local anesthetic or antihistamine, and is intended to provide short-term pain relief or anti-itch relief.

20. A topical application system according to claim 18 or 19, wherein the local anesthetic is lidocaine or ethyl aminobenzoate.

21. The topical application system according to claim 18 or 19, wherein the antihistamine is selected from the group consisting of diphenhydramine and its salts, and chlorpheniramine and its salts.

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