External solid preparation containing loxoprofen

Abstract

The present invention addresses the problem of providing a loxoprofen-containing solid preparation for external use, which has excellent solubility during production. According to the present invention, provided is a solid preparation for external use, which contains at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, a saturated fatty acid salt, polyoxyethylene hydrogenated castor oil, and a polyethylene glycol fatty acid ester.

Description

Technical Field

[0001] The present invention relates to a solid preparation for external use having excellent analgesic and anti-inflammatory effects, comprising at least one selected from loxoprofen, its salts and hydrates thereof. Background Art

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic and anti-inflammatory agent (NSAID), has antipyretic, analgesic and anti-inflammatory effects based on its inhibitory effect on prostaglandin biosynthesis, similar to other NSAIDs.

[0003] In addition, as preparations applied to the skin, there are known external preparations for skin application, which are broadly divided into patches and coatings. The coatings include external solid preparations (stick-shaped hard gels, hard gels), external liquid preparations (lotions, liniments), gels, ointments, creams, etc.

[0004] As an external preparation containing loxoprofen, for example, Patent Document 1 describes a solubilized and / or emulsified external preparation characterized by being blended with: a) loxoprofen and / or its medically acceptable salt, b) polyoxyethylene hydrogenated castor oil having an HLB value of 12.5 to 16.5, c) an acid and / or an acidic substance (which does not contain a carboxyvinyl polymer), and d) water.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent No. 6131522 Summary of the Invention

[0008] Problems to be solved by the invention

[0009] The present inventors have discovered that when a solid preparation for external use containing loxoprofen is blended with only polyoxyethylene hydrogenated castor oil as a surfactant, the solubility during production is poor, dissolution takes time, and the manufacturability is extremely poor. The present invention aims to provide a solid preparation for external use containing loxoprofen that exhibits excellent solubility during production.

[0010] Means for solving problems

[0011] The present inventors have discovered that when a solid preparation for external use containing at least one selected from loxoprofen, its salts, and hydrates thereof is blended with polyethylene glycol monostearate as a surfactant in addition to polyoxyethylene hydrogenated castor oil, solubility during production is improved, thereby significantly improving manufacturability. The present invention has been completed based on the above findings.

[0012] That is, according to the present invention, the following inventions are provided.

[0013] (1) A solid preparation for external use, comprising: at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof, a saturated fatty acid salt, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester.

[0014] (2) The solid preparation for external use according to (1), wherein the pH of the solution in which the solid preparation for external use is dissolved is 9.0 or higher.

[0015] (3) The solid preparation for external use according to (1) or (2), wherein each component contained in the solid preparation for external use is soluble.

[0016] (4) The solid preparation for external use according to any one of (1) to (3), wherein the polyethylene glycol fatty acid ester is polyethylene glycol monostearate.

[0017] (5) The solid preparation for external use according to any one of (1) to (4), wherein the saturated fatty acid salt is sodium stearate.

[0018] (6) The solid preparation for external use according to any one of (1) to (5), further comprising tocopherol acetate.

[0019] (7) The solid preparation for external use according to (6), wherein the content of tocopherol acetate is 0.05 to 5% by mass relative to the total mass of the solid preparation for external use.

[0020] (8) The solid preparation for external use according to any one of (1) to (7), further comprising ethanol.

[0021] (9) The solid preparation for external use according to (8), wherein the content of ethanol is 5 to 50% by mass relative to the total mass of the solid preparation for external use.

[0022] (10) A method for producing a solid dosage form for external use, comprising:

[0023] A step of mixing at least one selected from loxoprofen, its salts and hydrates thereof, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and saturated fatty acid salt to prepare composition A; and

[0024] A mixing process of mixing the composition A with water and / or ethanol.

[0025] (11) The method described in (10), wherein the polyethylene glycol fatty acid ester is polyethylene glycol monostearate.

[0026] (12) The method according to (10) or (11), wherein the saturated fatty acid salt is sodium stearate.

[0027] (13) The method according to any one of (10) to (12), wherein the composition A further contains tocopherol acetate.

[0028] Effects of the Invention

[0029] The solid preparation for external use of the present invention has good solubility during production and therefore has excellent manufacturability. DETAILED DESCRIPTION

[0030] The solid preparation for external use of the present invention is a solid preparation for external use containing loxoprofen or a salt thereof, a saturated fatty acid salt, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester.

[0031] In the present invention, "loxoprofen" refers to at least one selected from loxoprofen, its salts and hydrates thereof (including hydrated salts), preferably loxoprofen sodium or loxoprofen sodium dihydrate, more preferably loxoprofen sodium dihydrate.

[0032] Loxoprofen in the present invention is included in the 18th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0033] The saturated fatty acid salt in the present invention refers to a saturated fatty acid salt used in applications such as bases and emulsifiers, and is preferably a saturated fatty acid salt having 12 to 22 carbon atoms, examples of which include sodium stearate, which is included in the Japanese Pharmaceutical Excipients 2021.

[0034] It should be noted that when a saturated fatty acid salt is used to prepare a solid preparation for external use, the saturated fatty acid salt may be formed by containing a saturated fatty acid having 12 to 22 carbon atoms and a compound (sodium hydroxide, potassium hydroxide, etc.) that dissociates into cations and forms a salt therewith. It may also contain a saturated fatty acid salt (sodium salt of saturated fatty acid, etc.) or use a medicinal soap or a soap base (soap base).

[0035] Examples of the polyoxyethylene hydrogenated castor oil in the present invention include polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60, with polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 being preferred.

[0036] The polyethylene glycol fatty acid ester in the present invention refers to a nonionic surfactant having a structure obtained by addition polymerization of ethylene oxide and a fatty acid having 12 to 22 carbon atoms, or a structure obtained by bonding polyethylene glycol or ethylene glycol to a fatty acid ester having 12 to 22 carbon atoms. Examples of such compounds include polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol monooleate, and polyoxyl stearate (e.g., 40, 45, 55, etc.), which are included in the Pharmaceutical Additives Dictionary 2021 (Yakuji Nichiba, 2021), etc. Polyethylene glycol fatty acid ester is particularly preferably polyethylene glycol monostearate (also known as stearic acid glyceryl). Among polyethylene glycol monostearate, polyethylene glycol monostearate having an average added ethylene oxide mole number of 10 to 100 is preferred, more preferably 25 to 55, and particularly preferably 40 (also referred to as polyoxyl 40 stearate).

[0037] The solid preparation for external use of the present invention may further contain tocopherol acetate, or may not contain tocopherol acetate.

[0038] The tocopherol acetate in the present invention is included in the 18th edition of the Japanese Pharmacopoeia or the Dictionary of Pharmaceutical Additives 2021.

[0039] The solid preparation for external use of the present invention may further contain ethanol, or may not contain ethanol.

[0040] As ethanol (also called ethyl alcohol) in the present invention, it is used in external preparations for the purpose of solubilizing agent, base, solvent, and solubilizing agent, and examples thereof include ethanol and anhydrous ethanol. Ethanol and anhydrous ethanol in the present invention are included in the Dictionary of Pharmaceutical Additives 2021.

[0041] The content of at least one selected from loxoprofen, its salts, and hydrates thereof in the solid preparation for external use of the present invention is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.5 to 8.5% by mass, as loxoprofen sodium dihydrate, relative to the total mass of the solid preparation for external use.

[0042] The content of the saturated fatty acid salt in the solid preparation for external use of the present invention is not particularly limited, but is preferably 3 to 15% by mass, more preferably 4 to 12% by mass, and even more preferably 6 to 8% by mass relative to the total mass of the solid preparation for external use.

[0043] The content of the polyoxyethylene hydrogenated castor oil in the solid preparation for external use of the present invention is not particularly limited, but is preferably 1 to 20% by mass, more preferably 1 to 8% by mass, and even more preferably 3 to 6% by mass relative to the total mass of the solid preparation for external use.

[0044] The mass ratio of the saturated fatty acid salt to the polyoxyethylene hydrogenated castor oil is preferably 0.30 or more, more preferably 0.60 or more, and preferably 2.0 or less, more preferably 1.0 or less, and even more preferably 0.80 or less, from the perspective of improving solubility during production. The mass ratio of the saturated fatty acid salt to the polyoxyethylene hydrogenated castor oil is preferably 0.30 to 2.0, more preferably 0.30 to 1.0, and even more preferably 0.30 to 0.80.

[0045] The content of the polyethylene glycol fatty acid ester in the solid preparation for external use of the present invention is not particularly limited, but is preferably 1 to 30 mass %, more preferably 1 to 25 mass %, further preferably 2 to 20 mass %, and even more preferably 3 to 18 mass % relative to the total mass of the solid preparation for external use.

[0046] The mass ratio of the saturated fatty acid salt to the polyethylene glycol fatty acid ester in the solid preparation for external use of the present invention is preferably 0.30 or more, preferably 3.0 or less, more preferably 2.0 or less, and even more preferably 1.8 or less, from the viewpoint of improving solubility during production.

[0047] The mass ratio of the saturated fatty acid salt to the polyethylene glycol fatty acid ester in the solid preparation for external use of the present invention, polyethylene glycol fatty acid ester / saturated fatty acid salt, is preferably 0.30 to 3.0, more preferably 0.30 to 2.0, and even more preferably 0.30 to 1.8.

[0048] In addition, the mass ratio of the saturated fatty acid salt, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester in the external solid dosage form of the present invention is preferably 0.60 or more, more preferably 0.90 or more, and even more preferably 1.1 or more, and preferably 5.0 or less, and even more preferably 3.0 or less, from the perspective of improving solubility during production. The mass ratio of the saturated fatty acid salt, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester in the external solid dosage form of the present invention is preferably 0.60 to 5.0, more preferably 0.90 to 3.0, and even more preferably 1.1 to 3.0.

[0049] When the solid preparation for external use of the present invention contains tocopherol acetate, the content of tocopherol acetate in the solid preparation for external use is not particularly limited, but is preferably 0.05 to 5% by mass, more preferably 0.1 to 2% by mass, and even more preferably 0.5 to 1% by mass, relative to the total mass of the solid preparation for external use.

[0050] In addition, from the viewpoint of making each component contained in the external use solid preparation more easily solubilized, tocopherol acetate may not be contained.

[0051] When the solid preparation for external use of the present invention contains ethanol, the content of ethanol in the solid preparation for external use is not particularly limited, but is preferably 5 to 50 mass %, more preferably 5 to 40 mass %, further preferably 7.5 to 40 mass %, and particularly preferably 7.5 to 15 mass %, relative to the total mass of the solid preparation for external use.

[0052] The water content in the solid preparation for external use of the present invention is not particularly limited, but is preferably 30 to 90% by mass, more preferably 45 to 90% by mass, and even more preferably 60 to 75% by mass relative to the total mass of the solid preparation for external use.

[0053] The solid preparation for external use of the present invention may contain a basic substance.

[0054] The alkaline substance in the present invention is not particularly limited and refers to a substance commonly used in external preparations to increase pH, for example, potassium hydroxide, calcium hydroxide, sodium hydroxide, diisopropanolamine, diethanolamine, triisopropanolamine, triethanolamine, etc., which are included in the Dictionary of Pharmaceutical Additives 2021.

[0055] The amount of the alkaline substance added to the external solid preparation of the present invention is not particularly limited, but is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, based on the total amount of the external solid preparation. It should be noted that the above amount is the converted amount of the undiluted alkaline substance itself, and substances diluted in a solvent such as water can be used during manufacture. Furthermore, one or more alkaline substances may be used in combination.

[0056] The pH of the solution in which the external solid dosage form of the present invention is dissolved is preferably 9.0 or more, more preferably 9.5 or more, and even more preferably 10.0 or more, from the viewpoint of easy solidification when producing the external solid dosage form. In addition, from the viewpoint of skin irritation when using the external solid dosage form, it is preferably 13.0 or less, more preferably 12.5 or less, and even more preferably 12.0 or less. The pH of the solution in which the external solid dosage form of the present invention is dissolved is preferably 9.0 to 13.0, more preferably 9.5 to 12.5, and even more preferably 10.0 to 12.0. The pH of the solution in which the external solid dosage form is dissolved can be measured by adding 15 mL of purified water to 0.5 g of the external solid dosage form and heating and dissolving the resulting liquid in a water bath at 70°C, and then allowing it to stand at room temperature.

[0057] In the solid preparation for external use of the present invention, it is preferred that each component contained in the solid preparation for external use is soluble. In other words, the solid preparation for external use of the present invention is preferably not an emulsified type.

[0058] The solid preparation for external use of the present invention may contain drugs or pharmaceutical additives other than the above-mentioned ingredients that are generally used in solid preparations for external use for analgesia and anti-inflammatory purposes.

[0059] Examples of the drug include anti-inflammatory agents such as glycyrrhetinic acid, antihistamines such as chlorpheniramine maleate, blood circulation improving ingredients such as benzyl nicotinate, local irritating ingredients such as nonanoic acid vanillamide, and herbal medicinal ingredients such as arnica montana tincture. These drugs may be contained within a range that does not impair the effects of the present invention.

[0060] Pharmaceutical additives other than the above-mentioned ingredients are substances added as needed for the purpose of further improving the content stability over time or the feeling during use, and examples thereof include wetting agents, antioxidants, and cooling agents.

[0061] As the wetting agent, for example, sodium dl-pyrrolidonecarboxylate or the like may be added.

[0062] As the antioxidant, for example, tocopherol etc. can be used.

[0063] Examples of the cooling agent include camphor, dl-camphor, peppermint oil, and eucalyptus oil.

[0064] Examples of the dosage form of the solid preparation for external use of the present invention include stick-shaped hard gels and hard gels.

[0065] The present invention further relates to a method for producing a solid dosage form for external use, comprising: a step of preparing a composition A by mixing at least one selected from loxoprofen, its salts, and hydrates thereof, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, and saturated fatty acid salts; and a mixing step of mixing the composition A with water and / or ethanol. Specific examples and preferred embodiments of the at least one selected from loxoprofen, its salts, and hydrates thereof, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, and saturated fatty acid salts are described above in this specification. Composition A may further contain tocopherol acetate. For example, a mixture containing at least one selected from loxoprofen, its salts, and hydrates thereof, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, and saturated fatty acid salts can be heated in a water bath or under steam at a temperature of 65°C or above while stirring to prepare a uniform composition A. Subsequently, the composition A can be mixed with water and / or ethanol to dissolve the components. Furthermore, the mixture can be solidified to produce the solid dosage form for external use.

[0066] The solid dosage form for external use of the present invention is housed in a container, and a sealed container is preferably used as the container. Examples of sealed containers include tubular containers, bottles, can bottles, and extrusion-type or turntable-type lifting containers. Among these, extrusion-type or turntable-type lifting containers are preferred for the solid dosage form for external use from the perspective of its use and storage.

[0067] The external solid dosage form of the present invention can be housed in, for example, a glass container / package, or a metal container / package such as aluminum, or a container / package made of an olefin resin such as polyethylene or polypropylene and sealed, and can further be housed in a moisture-proof bag containing a metal such as aluminum. In addition, the container / package can use a container / package containing environmentally friendly raw materials / materials such as recycled plastics or biomass raw materials. If necessary, a laminated structure material or a gas barrier material can be used to prevent the external solid dosage form from being deteriorated by factors / elements / environmental changes from the container / package of the pharmaceutical product, such as heat or light in a high temperature environment, and any material that appropriately maintains the quality of the external solid dosage form. In one embodiment of the present invention, a preparation / composition of an external solid dosage form can be prepared and housed in a suitable container / package.

[0068] The solid dosage form for external use of the present invention is used for analgesia and anti-inflammatory purposes and can be used for patients experiencing pain or inflammation, such as low back pain, contusions, sprains, shoulder pain with stiff shoulders, tenosynovitis, elbow pain, and arthralgia. For these patients, an appropriate amount of the solid dosage form for external use of the present invention is applied to the affected area once to several times a day.

[0069] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0070] Example

[0071] <Test Materials>

[0072] Loxoprofen sodium dihydrate was manufactured by KOLON LIFE SCIENCE, tocopherol acetate was manufactured by Mitsubishi Chemical Corporation, sodium stearate was manufactured by NOF Corporation, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, and polyethylene glycol monostearate (the average number of added moles of ethylene oxide was 40) were manufactured by Nikko Chemical Co., Ltd., sodium hydroxide was manufactured by Kanto Chemical Co., Ltd., and ethanol was manufactured by FUJIFILM Wako Chemical Corporation.

[0073] <Preparation of Samples>

[0074] (1) Loxoprofen sodium dihydrate, tocopherol acetate, sodium stearate, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyethylene glycol monostearate, and a 10% aqueous solution of sodium hydroxide (using the types and amounts listed in Tables 1 and 2) were weighed into a beaker in advance, heated in a water bath at 80°C, and stirred uniformly with a stirring rod.

[0075] (2) Make the purified water into hot water at 80 - 85°C and put it in. Scrape the preparation adhering to the inner wall of the beaker with a stirring rod, and stir with a Three-One Motor to confirm dissolution (stirring speed: 300 ± 10 rpm, stirring blade: propeller).

[0076] (3) Measure the weight of the test sample, correct the moisture in the evaporation part, add ethanol as required, and stir with a Three-One Motor for filling (stirring speed: 300 ± 10 rpm, stirring blade: propeller).

[0077] <Evaluation of solubility>

[0078] Measure the time (minutes) required from the start of stirring with the Three-One Motor to the confirmation of dissolution in the above (2).

[0079] <pH measurement method>

[0080] Add 15 mL of purified water to 0.5 g of the solidified test sample, heat and dissolve it in a water bath at 70°C. Let the liquid stand at room temperature and measure the pH.

[0081] [Table 1]

[0082]

[0083]

[0084] [Table 2]

[0085]

[0086]

[0087] The values in Table 1 and Table 2 represent the blending amount (g) in 100 g of the preparation.

[0088] In Examples 1 - 9, 11 - 12 and Comparative Example 1, there was no turbidity and it was solubilized. In Example 10, there was turbidity and there was a possibility that it was not completely solubilized.

[0089] In Examples 1 - 12 containing polyethylene glycol monostearate, the dissolution time was less than 30 minutes and the solubility was good. In Comparative Example 1 without polyethylene glycol monostearate, the dissolution time was 30 minutes and the solubility was poor.

Claims

1. A solid preparation for external use, comprising: at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof, a saturated fatty acid salt, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester.

2. The solid preparation for external use according to claim 1, wherein The pH of the solution in which the external solid preparation is dissolved is 9.0 or higher.

3. The solid preparation for external use according to claim 1 or 2, wherein All ingredients contained in the solid preparation for external use are soluble.

4. The solid preparation for external use according to claim 1 or 2, wherein The polyethylene glycol fatty acid ester is polyethylene glycol monostearate.

5. The solid preparation for external use according to claim 1 or 2, wherein The saturated fatty acid salt is sodium stearate. The solid preparation for external use according to claim 1 or 2, further comprising tocopherol acetate.

7. The solid preparation for external use according to claim 6, wherein The content of tocopherol acetate is 0.05 to 5% by mass based on the total mass of the solid preparation for external use. The solid preparation for external use according to claim 1 or 2, further comprising ethanol.

9. The solid preparation for external use according to claim 8, wherein The content of ethanol is 5 to 50% by mass relative to the total mass of the solid preparation for external use.

10. A method for producing a solid dosage form for external use, comprising: A step of mixing at least one selected from loxoprofen, its salts and hydrates thereof, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and saturated fatty acid salt to prepare composition A; and A mixing process of mixing the composition A with water and / or ethanol.

11. The method according to claim 10, wherein: The polyethylene glycol fatty acid ester is polyethylene glycol monostearate.

12. The method according to claim 10 or 11, wherein: The saturated fatty acid salt is sodium stearate.

13. The method according to claim 10 or 11, wherein: Composition A further contains tocopheryl acetate.

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