Topical hydrogel

Abstract

To provide means of keeping a drug at an application site and allowing it to penetrate quickly, shortening the time it takes for the anesthetic effect to appear and improving the therapeutic effect of the affected area, when administering topical liquids or sprays to the skin or mucosa for the purposes of local anesthesia, pain relief, anti-inflammatory, antibacterial, and the like.SOLUTION: Provided are a porous composition obtained by freeze-drying or spray-drying a water-soluble polymer solution, a topical hydrogel obtained by mixing the porous composition with a liquid formulation, a medical kit combining the porous composition with a microneedle array, and a topical medical system comprising the topical hydrogel and a microneedle array.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to porous compositions obtained from aqueous polymer solutions for use as topical hydrogels. [Background technology]

[0002] Topical local anesthetics applied to the skin to provide local anesthesia include topical anesthetics such as Emla ointment and patch anesthetics such as Penless Tape. Lidocaine is a common drug. Both types of anesthetics require 30 minutes or more to take effect after application to the skin, and shortening this time has been a challenge from the perspective of both patient quality of life and physicians' perspectives in terms of shortening treatment times. Furthermore, while many sprays are used to treat skin diseases, the amount of drug remaining in the affected area is reduced due to the flow of the liquid, resulting in insufficient effectiveness.

[0003] For example, local anesthetics for dentistry are widely used, just as they are for skin applications. The drugs typically used are lidocaine and ethyl aminobenzoate (gel) ointments, but these are insufficient in terms of effectiveness even after 10 to 20 minutes, and both doctors and patients are seeking stronger anesthetic effects in a shorter time. Antibacterial sprays applied to treat periodontal disease quickly run off. The challenge is how to increase the viscosity of the liquid, retain the drug in the affected area, and allow it to penetrate quickly.

[0004] The present inventors have developed a microneedle array containing a local anesthetic for intraoral application, and have succeeded in achieving an anesthetic effect in a short period of time (Patent Document 1). Patent Documents 1 and 2 are inventions of dental microneedle preparations in which a local anesthetic is dissolved in microneedles, or dental preparations in which a local anesthetic is applied to microneedles. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 2019-084352 [Patent Document 2] Japanese Patent Application Publication No. 2017-061447 Summary of the Invention [Problem to be solved by the invention]

[0006] From the physician's standpoint, there is a need for a new administration method that can be prepared and applied appropriately in the medical field, allowing doctors to administer topical preparations consisting of various familiar ointments and liquids that have a proven track record and that can produce effects in a shorter period of time. The present invention has been made to solve problems related to topical drugs applied to the skin, oral cavity, etc., and aims to provide a means for allowing the drug to remain at the application site and penetrate rapidly, thereby shortening the time for the anesthetic effect to appear and improving the therapeutic effect of the affected area, when administering to the skin or mucosa preparations such as external liquids and sprays for topical administration for the purposes of local anesthesia, pain relief, anti-inflammatory, antibacterial, etc. [Means for solving the problem]

[0007] The present inventors have developed a gellable composition that allows topical liquid or spray formulations to be easily retained at the application site, and have completed the present invention. The present invention is as follows. [1] A porous composition obtained by freeze-drying or spray-drying a water-soluble polymer solution. [2] The porous composition according to [1], having an apparent specific gravity of 0.001 to 0.2. [3] The porous composition according to [1], wherein the water-soluble polymer is selected from the group consisting of polyacrylic acid, hyaluronic acid and its sodium salt, carboxymethylcellulose and its sodium salt, carboxyvinyl polymer, polyvinylpyrrolidone, sodium chondroitin sulfate, collagen, and hydroxypropylcellulose. [4] A hydrogel for topical application, comprising a mixture of the porous composition according to any one of [1] to [3] and a liquid preparation. [5] The topical hydrogel according to [4], wherein the viscosity of the hydrogel is 10 mPa·s or more, and the viscosity is measured when the porous composition is mixed with water to give a solids concentration of 1% by mass. [6] The topical hydrogel according to [4], wherein the liquid formulation is selected from the group consisting of a local anesthetic, an antibacterial aqueous solution, and an anti-inflammatory aqueous solution. [7] A medical kit comprising a combination of the porous composition according to any one of [1] to [3] and a microneedle array. [8] The medical kit according to [7], wherein the microneedle array is made of a water-insoluble thermoplastic polymer material. [9] The medical kit according to [8], wherein the water-insoluble thermoplastic polymeric material is selected from the group consisting of polyolefin, soft silicone, and polyurethane.

[10] A topical medical system comprising the topical hydrogel according to any one of [4] to [6] and a microneedle array.

[11] The topical medical system according to

[10] , wherein the drug contained in the topical hydrogel is lidocaine or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0008] According to the present invention, by administering a hydrogel containing an aqueous solution of lidocaine or a pharmaceutically acceptable salt thereof mixed with the porous composition of the present invention to the skin or mucosal surface and simultaneously compressing the administration site with a microneedle, the onset time of the surface anesthetic can be reduced to less than half of that of current methods. Here, current methods refer to administration methods in which a gel formulation is applied or a liquid formulation is sprayed. Current methods of applying a gel formulation include, for example, applying an appropriate amount of xylocaine jelly to the affected skin or mucosa, or spraying an appropriate amount of xylocaine pump spray onto the affected area. According to the present invention, by administering a hydrogel containing a mixture of a liquid formulation such as a local anesthetic or antibacterial agent and the porous composition of the present invention to the gingival area and simultaneously compressing the administration site with a microneedle, the amount of drug penetration into the gingival cavity can be improved. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention provides a porous composition obtained by freeze-drying or spray-drying a water-soluble polymer solution. The apparent specific gravity of the porous composition of the present invention is preferably 0.001 to 0.2, more preferably 0.004 to 0.1.

[0010] The apparent specific gravity is measured differently for freeze-dried porous compositions and spray-dried porous compositions. In the case of freeze-drying, the apparent specific gravity is calculated as the mass of the porous composition (g) / the volume of the solution before freeze-drying. In the case of spray drying, the bulk density of the porous composition is the value measured in accordance with the 18th Edition of the Japanese Pharmacopoeia, General Testing Methods, 3. Powder Property Measurement Methods, 3.01 Bulk Density Measurement Method.

[0011] The raw material for the porous composition of the present invention is a water-soluble polymer solution. The solvent for the solution is typically water, but other solvents may be included as long as they do not interfere with the drying process. The water-soluble polymer is preferably selected from the group consisting of polyacrylic acid, hyaluronic acid and its sodium salt, carboxymethylcellulose and its sodium salt, carboxyvinyl polymer, polyvinylpyrrolidone, sodium chondroitin sulfate, collagen, and hydroxypropyl cellulose. Carboxyvinyl polymer is particularly preferred.

[0012] The porous composition of the present invention can be produced as follows. A solvent such as water is added to a water-soluble polymeric substance to dissolve it, and the resulting homogeneous solution (typically an aqueous solution) is freeze-dried or spray-dried. In the drying step, the solvent is removed using a freeze-dryer or a spray-dryer. After the drying step, the porous composition of the present invention is obtained. The following describes a preferred embodiment of freeze-drying. The concentration of the water-soluble polymer in the solution is preferably 0.1% to 20% by mass. If the polymer concentration is less than 0.1% by mass, the content of the water-soluble polymer in the resulting porous composition will also be low. As a result, the topical hydrogel of the present invention, described below, will have low viscosity and may flow on the skin, potentially failing to achieve the object of the present invention. If the concentration exceeds 20% by mass, the content of the water-soluble polymer substance in the resulting porous composition will also be high. As a result, the topical hydrogel of the present invention, described below, will have high viscosity and low fluidity, potentially making it difficult to apply evenly to the skin. To improve the solubility of the water-soluble polymer substance in a solvent (typically water) or to promote solubility upon redissolution after drying, an appropriate amount of a basic substance, such as sodium hydroxide, may be added to the water-soluble polymer solution.

[0013] The present invention provides a topical hydrogel comprising the porous composition and a liquid preparation.

[0014] When the porous composition is mixed with water, a homogeneous hydrogel forms within about 5 minutes. When the porous composition is mixed with a liquid formulation containing water, a topical hydrogel is obtained. In the present invention, topical application means application to the skin and various tissue mucosa in the living body, including oral mucosa, palpebral conjunctiva, bulbar conjunctiva, nasal mucosa, vaginal mucosa, and anus.

[0015] The viscosity of the hydrogel is preferably 10 mPa·S or more, and more preferably 10,000 to 500,000 mPa·S. The viscosity of the hydrogel is the viscosity when the porous composition is mixed with water to a solid content of 1% by mass, and is a value measured with an E-type viscometer. In addition, by increasing the solid content, the viscosity of the hydrogel can be set within a desired range. As an example of practical use of the hydrogel, it is convenient to adjust the amounts of the porous composition of the present invention and the local anesthetic aqueous solution so that the viscosity is 5,000 mPa·S or higher. For this purpose, it is desirable to prepare the solids concentration to be 1 to 10 mass%. If the viscosity of the hydrogel is less than 10 mPa·S, the hydrogel will not easily remain at the application site when applied topically, making it difficult to achieve the object of the present invention.

[0016] As the liquid preparation, various liquid preparations used for topical application can also be used in the present invention, and for example, the liquid preparation can be selected from the group consisting of local anesthetics, antibacterial aqueous solutions, antihistamines, anti-inflammatory, antibacterial, pain-relieving, antipruritic solutions, and other liquid preparations for topical administration, such as liquids and sprays.

[0017] The present invention provides a medical kit comprising the porous composition and a microneedle array in combination.

[0018] The microneedle array is preferably made of a water-insoluble thermoplastic polymeric material, and examples of the water-insoluble thermoplastic polymeric material include those selected from the group consisting of polyolefin, soft silicone, and polyurethane. A suitable microneedle array for use in the present invention is the microprotrusion patch described in JP 2024-039002 A, which may be a microneedle array backed with adhesive tape. Rapid topical application can be achieved by compressing hundreds of fine needles against the surface of the skin or mucosal epithelium. A suitable commercially available product is Anespatch (registered trademark: manufactured by Cosmedi Pharmaceutical Co., Ltd.).

[0019] The medical kit of the present invention includes a porous composition and a microneedle array, and allows a hydrogel to be prepared from the porous composition using a topical liquid, and after the gel of appropriate viscosity is prepared and applied topically, the microneedle array can be used to compress the skin surface or mucosal epithelium for a predetermined period of time, thereby enabling adjustment of the onset time of the topical drug depending on the patient's condition and the severity of the disease in the medical field.

[0020] The present invention provides a topical medical system comprising the topical hydrogel and a microneedle array. The topical medical system of the present invention can be used in clinical settings by combining a topical hydrogel prepared in advance by mixing the porous composition with a liquid formulation with a microneedle array.

[0021] The preferred drug in the topical medical system of the present invention is a local anesthetic, such as lidocaine or a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt, or ethyl aminobenzoate, procaine, or a pharmaceutically acceptable salt thereof.

[0022] A local anesthetic aqueous solution is added to a certain amount of the porous composition of the present invention to form a uniform, thick gel. The concentration of the local anesthetic in the aqueous solution is preferably high, provided it is below the saturation solubility. The drug may be weighed and dissolved in water, or a commercially available local anesthetic aqueous solution, such as an 8% xylocaine spray, may be used. An appropriate amount of the local anesthetic aqueous solution is added to an appropriate amount of the porous composition and thoroughly stirred to form a uniform hydrogel. To prepare a gel for application to human tissue mucosa, such as the skin or oral mucosa, the porous composition should have a mass of 0.005 to 5 g. The amount of the local anesthetic aqueous solution added to the porous composition is preferably such that the solids concentration of the porous composition is 0.5 to 10% by mass. A viscosity of 0.5 to 5% by mass is even more preferable. While the objectives of the present invention can be achieved if the viscosity of the hydrogel is 10 mPa·s or higher, as shown in Example 1, porous compositions derived from carboxyvinyl polymers exhibit high viscosity even at low solids concentrations, making them very convenient.

[0023] Topical liquid and spray formulations of local anesthetics contain large amounts of alcohols and polyhydric alcohols, such as ethanol, glycerin, and butylene glycol. When such liquid formulations are added to a porous composition to form a uniform hydrogel, the alcohols may inhibit gel formation. The porous composition of the present invention is preferred because it can form a hydrogel even in a liquid formulation containing approximately 20% alcohol by mass. Porous compositions obtained from carboxyvinyl polymers are more preferred because they are alcohol-resistant.

[0024] The microneedle array included in the medical kit of the present invention can be either a water-soluble microneedle array or a water-insoluble microneedle array, but water-insoluble microneedles are more preferred.

[0025] Water-soluble microneedle arrays are made by dissolving water-soluble polymeric substances such as hyaluronic acid, gelatin, and sodium chondroitin sulfate in an aqueous solution and molding them into microneedle arrays. Water-insoluble microneedle arrays are made by heating and melting thermoplastic polymeric substances such as polyethylene, polypropylene, nylon, and polyethylene terephthalate, and molding them into microneedle arrays by injection molding, press molding, or the like. Furthermore, microneedle arrays are made by molding 1.5 × 10 microneedles selected from the group consisting of polyolefin, soft silicone, and polyurethane. 4 kgf / cm 2 The thermoplastic polymer material having the following elastic modulus can be used and produced by press molding.

[0026] The needle length of a microneedle array is preferably 0.1 mm to 2.0 mm. Microneedles shorter than 0.1 mm do not exert sufficient pressure on the skin or mucosa to stretch the stratum corneum or epithelium. Microneedles longer than 2.0 mm may pierce the skin or mucosa when pressure is applied, raising concerns about bleeding. The area of ​​the microneedle array substrate is preferably 30 square cm or less, but this is not essential. The needle density is preferably 10 needles / square cm or more. A needle density that is too low is disadvantageous in terms of applying pressure to the skin or mucosa.

[0027] Using the medical kit of the present invention, a hydrogel containing a local anesthetic is applied to the skin or mucosa, and then the microneedle array is placed over the applied hydrogel and applied pressure, stretching and thinning the stratum corneum or mucosal epithelium. This effect promotes the penetration of the local anesthetic into the body and shortens the time it takes for the local anesthetic to take effect. [Example]

[0028] The present invention will be described in more detail below 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. The gel compositions prepared in the examples are synonymous with hydrogels.

[0029] Example 1 Carboxyvinyl polymer (Nikko Chemicals Co., Ltd.) was measured and water was added to prepare a solution with a solid content of 0.5% by mass. A small amount of 10% by mass aqueous sodium hydroxide solution was added to the solution to adjust the pH of the solution to 4.5 to 7. 1 g of the solution was placed in a 2 ml tube and freeze-dried to prepare a porous composition.

[0030] Examples 2 to 4 Sodium hyaluronate, sodium carboxymethylcellulose, and hydroxypropylcellulose were each weighed and added with water to prepare a solution with a solid content of 10% by mass. 1 g of the solution was placed in a 2 ml tube and freeze-dried to prepare a porous composition.

[0031] Example 5 Carboxyvinyl polymer (Nikko Chemicals Co., Ltd.) was measured and water was added to prepare a solution with a solid content of 0.1% by mass. A small amount of 10% by mass aqueous sodium hydroxide solution was added to the solution to adjust the pH of the solution to 4.5 to 7. 3 g of the solution was placed in a 5 ml tube and freeze-dried to prepare a porous composition.

[0032] Reference examples 1~3 Porous compositions using polyvinylpyrrolidone, sodium chondroitin sulfate, and collagen were prepared in the same manner as in Examples 2 to 4.

[0033] Test Example 1: Viscosity measurement of gel composition after dissolution The porous compositions obtained in Examples 1 to 5 and Reference Examples 1 to 3 were dissolved in water in an amount such that the concentration of the water-soluble polymer after dissolution was 1% by mass or 10% by mass. The viscosity of the dissolved composition was measured using an E-type viscometer TV-25 type L (manufactured by Toki Sangyo Co., Ltd.). The apparent specific gravity and viscosity after dissolution of each porous composition are shown in Table 1. As Comparative Example 1, a commercially available spray (xylocaine pump spray 8%) was used.

[0034] [Table 1]

[0035] Test Example 2 0.5 ml or 1 ml of 8% lidocaine spray (trade name: Xylocaine Pump Spray 8%, containing ethanol) was added to 0.005 g or 0.1 g of the porous compositions obtained in Examples 1 to 4 and Reference Examples 1 to 3, respectively, and dissolved to prepare a gel composition with a solids concentration of 1 to 10% by mass. This gel composition was spread on a microneedle patch (trade name: Anespatch, manufactured by Cosmedy Pharmaceutical, microneedle patch, needle length 0.3 mm, area: 15.5 x 13 mm, polypropylene needle) With informed consent, the gel compositions were applied to the inside of the upper arms of three volunteers, and an Anes patch was pressed against them. The gel compositions of Examples 1 to 4 were highly viscous and rarely spilled out of the microneedle patch, but Reference Examples 1 to 3 had low viscosity, and when pressed, the gel composition flowed across the skin, preventing the medicinal effect from being concentrated in the target skin area. Therefore, these were excluded from evaluation. Five, 10, and 20 minutes after the gel compositions of Examples 1 to 4 were administered by pressing with an Anes patch, the administration site was lightly pressed with a needle and the subjects were asked to self-report the presence or absence of pain, which was defined as the time to onset of effect. With informed consent, three other volunteers underwent the same treatment on their upper gums as on the skin, and two minutes after administration, the injection site was lightly pressed with a needle and the subjects were asked to self-report whether or not they felt any pain, which was determined as the time it took for the drug to take effect. Separately, as Comparative Example 1, an appropriate amount of a commercially available preparation (xylocaine pump spray 8%) was sprayed onto the skin and gums for comparison with the Examples.

[0036] Test Example 3 An 8% lidocaine solution was prepared using water containing 20% ​​ethanol as a solvent. 0.5 ml of the lidocaine solution was added to 0.002 g of the porous composition obtained in Example 5 and dissolved to prepare a gel composition with a solids concentration of 1% by mass. The following procedures were performed in the same manner as in Test Example 2, and the presence or absence of pain on the skin and gums was evaluated. The results of Test Examples 2 and 3 are shown in Table 2.

[0037] [Table 2]

[0038] It was found that the use of the hydrogel of the present invention significantly enhances the local anesthetic effect. The porous composition of Example 5 had a large thickening effect even in the presence of high concentrations of ethanol due to the carboxyvinyl polymer used as the material, and was also effective in use. The viscosity of the hydrogel in the formulation of Test Example 3 was 94,000 mPa·s.

Claims

1. A porous composition obtained by freeze-drying or spray-drying a water-soluble polymer solution.

2. 2. The porous composition according to claim 1, having an apparent specific gravity of 0.001 to 0.

2.

3. 2. The porous composition according to claim 1, wherein the water-soluble polymer is selected from the group consisting of polyacrylic acid, hyaluronic acid and its sodium salt, carboxymethylcellulose and its sodium salt, polyvinylpyrrolidone, carboxyvinyl polymer, sodium chondroitin sulfate, collagen, and hydroxypropylcellulose.

4. A hydrogel for topical application, comprising a mixture of the porous composition according to any one of claims 1 to 3 and a liquid preparation.

5. 5. The topical hydrogel according to claim 4, wherein the viscosity of the hydrogel is 10 mPa·s or more, and the viscosity is measured when the porous composition is mixed with water to a solids concentration of 1% by mass.

6. 5. The topical hydrogel of claim 4, wherein the liquid formulation is selected from the group consisting of a local anesthetic, an aqueous antibacterial agent, and an aqueous anti-inflammatory agent.

7. A medical kit comprising a combination of the porous composition according to any one of claims 1 to 3 and a microneedle array.

8. The medical kit according to claim 7 , wherein the microneedle array is made of a water-insoluble thermoplastic polymeric material.

9. 9. The medical kit of claim 8, wherein the water-insoluble thermoplastic polymeric material is selected from the group consisting of polyolefins, soft silicones, and polyurethanes.

10. A topical medical system comprising the topical hydrogel of claim 4 and a microneedle array.

11. 11. The topically applied medical system according to claim 10, wherein the drug contained in the topically applied hydrogel is lidocaine or a pharmaceutically acceptable salt thereof.

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