JP2022036050A - External preparation for skin containing loxoprofen - Google Patents

Abstract

To provide an external preparation for skin that contains loxoprofen, and a lower alcohol of 60 mass% or more relative to the total amount of the external preparation for skin, where the external preparation for skin has improved storage stability.SOLUTION: An external preparation for skin contains loxoprofen or a salt thereof, a lower alcohol of 60 mass% or more relative to the total amount of the external preparation for skin, and at least one pH regulator selected from hydrochloric acid or malic acid and a salt thereof.SELECTED DRAWING: None

Description

The present invention relates to an external skin preparation containing loxoprofen, which has an excellent analgesic and anti-inflammatory effect and a feeling of use. More specifically, the present invention comprises loxoprofen with improved storage stability by incorporating a specific pH adjuster into a skin external preparation containing 60% by mass or more of lower alcohol based on the total amount of loxoprofen and the skin external preparation. Regarding external skin preparations.

Loxoprofen, which is a propionic acid-based non-steroidal antipyretic anti-inflammatory drug (NSAIDs), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibitory effect on prostaglandin biosynthesis, like other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosal stimulating effect after oral administration and becomes an active form in the body. Also known (see, for example, Non-Patent Document 1).

In recent years, loxoprofen has been commercially available as a poultice, a tape, and a gel as an external anti-inflammatory analgesic, and has been clinically used (see, for example, Non-Patent Document 2). It is known that loxoprofen is also converted into a trans-OH form (active form) by a ketone reductase in the skin (see, for example, Patent Document 1).

When producing a liquid or semi-solid preparation containing NSAIDs, it is often used by dissolving or dispersing a lower alcohol or purified water as a solvent. Since loxoprofen sodium has high solubility in ethanol, isopropanol, water and mixtures thereof, these components are often used as a solvent.

In addition, the liquid or semi-solid preparation of NSAIDs may additionally contain an ingredient that can be expected to have an anti-inflammatory and analgesic effect or an auxiliary effect. Among them, there are components such as menthol and tocopherol that are difficult to dissolve in water, and in such cases, it is necessary to add a large amount of a solvent other than water or to add an appropriate surfactant.

When producing an external preparation containing loxoprofen, a pH adjuster is added to adjust the pH to near neutrality. Known pH regulators include hydrochloric acid, lactic acid, phosphoric acid, malic acid, triethanolamine, diisopropanolamine and the like. (See Patent Document 2 and Patent Document 3)

Patent Document 2 contains (A) diclofenac, felbinac, loxoprofen and one or more selected from these salts, (B) one or more selected from malic acid and its salts, and (C) water. It is described that the composition for external use is 6 to 8 and may further contain (D) 30 to 80% by mass of ethanol. However, Patent Document 2 does not describe an example of an external composition containing loxoprofen. That is, there is no description of an example of an external composition containing loxoprofen and 60% by mass or more of ethanol based on the total amount of the external composition, and no specific disclosure is made.

Further, the external preparation of Patent Document 3 is a preparation in which the concentration of ethanol contained is less than 60% by mass based on the total amount of the external preparation. For external preparations in which the concentration of ethanol is 60% by mass or more based on the total amount of the external preparation, lactic acid and N-methyl-2-pyrrolidone are contained in the external pharmaceutical composition in which loxoprofen and / or a salt thereof and tocopherol acetate coexist. What to do is disclosed. (Patent Document 4 and Patent Document 5)

Japanese Patent Application Laid-Open No. 2008-074873 JP-A-2014-172857 JP-A-2018-188249 JP-A-2019-2064498 JP-A-2019-206499

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 JAPAN Prescription Drugs 2013 Maruzen 2012

An object of the present invention is to provide a skin external preparation having improved storage stability in a skin external preparation containing 60% by mass or more of a lower alcohol based on the total amount of loxoprofen and the skin external preparation.

The present inventors have developed a skin external preparation (combination agent) further containing an oil-soluble component such as tocopherol acetate and l-menthol for the purpose of imparting a blood circulation promoting action, etc., in a skin external preparation containing loxoprofen. Therefore, a preparation containing a high concentration of lower alcohol was investigated in order to solubilize those active ingredients. As a result, when a pH adjuster such as phosphoric acid and citric acid is added to the skin external preparation containing 60% by mass or more of lower alcohol based on the total amount of loxoprofen and the skin external preparation, storage stability is stable immediately after production and under low temperature storage. The sex was significantly reduced. Therefore, they have found that the storage stability is improved by adding hydrochloric acid or DL-malic acid instead of phosphoric acid and citric acid, and completed the present invention.

That is, according to the present invention, the following invention is provided.
(1) An external skin preparation containing the following [a] to [c].
[A] Loxoprofen or a salt thereof;
[B] 60% by mass or more of lower alcohol based on the total amount of external skin preparation; and [c] one or more pH regulators selected from hydrochloric acid or malic acid and salts thereof.
(2) The skin external preparation according to (1), wherein the content of the lower alcohol is 60 to 80% by mass based on the total amount of the skin external preparation.
(3) The external skin preparation according to (1) or (2), wherein malic acid and a salt thereof are DL-malic acid or a salt thereof.
(4) The external skin preparation according to any one of (1) to (3), which further contains an oil-soluble component.
(5) The skin external preparation according to (4), wherein the oil-soluble component is at least one selected from l-menthol and tocopherol or a derivative thereof.
(6) The external skin preparation according to any one of (1) to (5), which further contains a polyhydric alcohol.
(7) The external skin preparation according to any one of (1) to (6), which does not contain a surfactant as an additive.
(8) The external skin preparation according to any one of (1) to (7), which has a pH of 5.5 to 7.5.
(9) The external skin preparation according to any one of (1) to (8), which is for analgesia and anti-inflammatory.
(10) The skin external preparation according to any one of (1) to (9), wherein the dosage form is an external liquid agent, an ointment agent, a spray agent, a gel agent, an aerosol agent, or an external solid agent.

The skin external preparation of the present invention containing 60% by mass or more of lower alcohol, hydrochloric acid or malic acid and one or more pH regulators selected from the salt thereof based on the total amount of loxoprofen or a salt thereof and the total amount of the external preparation for skin is used. It has excellent sensation, can improve storage stability, and is extremely useful clinically.

The external skin preparation in the present invention contains the following [a] to [c].
[A] Loxoprofen or a salt thereof;
[B] 60% by mass or more of lower alcohol based on the total amount of external skin preparation; and [c] one or more pH regulators selected from hydrochloric acid or malic acid and salts thereof.

In the present invention, as "loxoprofen or a salt thereof", loxoprofen or a salt thereof, or a hydrate thereof can be used. The salt of loxoprofen is preferably a pharmacologically acceptable salt, more preferably loxoprofen sodium or loxoprofen sodium dihydrate, and even more preferably loxoprofen sodium dihydrate.

The loxoprofen sodium dihydrate in the present invention is listed in the 17th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate.

The lower alcohol in the present invention is an aliphatic alcohol having 1 to 4 carbon atoms used as an external preparation for applications such as a solubilizer, a base, a preservative, a solvent, and a solubilizing agent, and is, for example, methanol or ethanol. One or more selected from the group consisting of (also referred to as ethyl alcohol), propanol, isopropanol (also referred to as isopropyl alcohol), butyl alcohol and the like, preferably one selected from the group consisting of ethanol and isopropanol or more. There are two types. Those having an ethanol content of 99.5% by volume or more are also called absolute ethanol.

Examples of the hydrochloric acid in the present invention include hydrochloric acid, dilute hydrochloric acid and the like, which are used as external agents for the purposes of stabilizers, solubilizers, flavoring agents, solubilizers, solvents, solubilizing agents and pH adjusters. Hydrochloric acid in the present invention is listed in the 17th revised Japanese Pharmacopoeia and the Encyclopedia of Pharmaceutical Additives 2016 (Yakuji Nippo Co., Ltd., 2016).

The malic acid in the present invention may be D-malic acid, L-malic acid, or DL-malic acid, and is preferably DL-malic acid. DL-malic acid is a pharmaceutical additive used as an external preparation for the purpose of stabilizers, buffers, flavoring agents, excipients, and pH regulators, and is listed in the Encyclopedia of Pharmaceutical Additives 2016. Examples of the malate salt include sodium malate, potassium malate and the like.

In the external skin preparation according to the present invention, one or more pH regulators selected from hydrochloric acid or malic acid and salts thereof are used. In the external skin preparation according to the present invention, for example, hydrochloric acid, malic acid and a salt thereof may be used as a pH adjuster. In the external skin preparation according to the present invention, for example, malic acid and a salt thereof (for example, DL-malic acid) may be used as a pH adjuster. Further, in the external skin preparation according to the present invention, for example, it is preferable to use hydrochloric acid as a pH adjuster from the viewpoint of easier dissolution in water and ethanol.

The external skin preparation according to the present invention may contain an oil-soluble component.
The oil-soluble component in the present invention is a component that is difficult to dissolve in water and easily dissolves in oil and can be blended in an external preparation for skin. For example, l-menthol, tocopherol or a derivative thereof, nonyl acid vanillylamide, etc. Can be mentioned.
In the external skin preparation according to the present invention, the oil-soluble component may be one or more selected from l-menthol and tocopherol or a derivative thereof.
The l-menthol in the present invention is listed in the 17th revised Japanese Pharmacopoeia and the Encyclopedia of Pharmaceutical Additives 2016 (Yakuji Nippo Co., Ltd., 2016).

Examples of tocopherol or a derivative thereof in the present invention include tocopherol, d-δ-tocopherol, tocopherol acetate, and the like, and tocopherol acetate is preferable. Tocopherol, d-δ-tocopherol, and tocopherol acetate are listed in the 17th revised Japanese Pharmacopoeia and the Encyclopedia of Pharmaceutical Additives 2016.

The external skin preparation of the present invention may contain a polyhydric alcohol. The polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used as an external preparation for applications such as a solubilizer, a base, a wetting agent, a viscous agent, a solvent, and a solubilizing agent. For example, propylene glycol, 1,3-butylene glycol, macrogol (also referred to as polyethylene glycol), glycerin, and D-sorbitol, which are listed in the Encyclopedia of Pharmaceutical Additives 2016.

The content of loxoprofen in the present invention is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total amount of the external preparation for skin as loxoprofen sodium dihydrate. %.

The content of the lower alcohol in the present invention (when two or more kinds of alcohols are contained, the total amount of alcohol added) is 60% by mass or more, preferably 60 to 80% by mass, based on the total amount of the external preparation for skin. Yes, more preferably 60 to 73% by mass, still more preferably 60 to 71% by mass. The content of the lower alcohol may be 61% by mass or more, 62% by mass or more, 63% by mass or more, 64% by mass or more, or 65% by mass or more based on the total amount of the external skin preparation. The content of the lower alcohol may be 70% by mass or less, 69% by mass or less, 68% by mass or less, 67% by mass or less, or 66% by mass or less based on the total amount of the external skin preparation. If the concentration of the lower alcohol is less than 60% by mass based on the total amount of the external skin preparation, for example, it is necessary to add a surfactant when blending a poorly soluble oil-soluble component. In addition, when the concentration of lower alcohol is high, the content of lower alcohol should be the total amount of external skin preparation from the viewpoint that more attention must be paid to the bulk containing the ingredients and the storage and transportation of the product due to fire and temperature. As a reference, it is preferably 80% by mass or less.

The content of one or more pH regulators selected from hydrochloric acid or malic acid and salts thereof in the present invention is preferably 0.01 to 5% by mass, more preferably 0, based on the total amount of the external skin preparation. It is 0.05 to 3% by mass.

When the external skin preparation of the present invention contains l-menthol, the content of l-menthol is preferably 0.01 to 10% by mass, more preferably 0.5, based on the total amount of the external skin preparation. It is about 7.5% by mass.

When the external skin preparation of the present invention contains tocopherol or a derivative thereof, the content of tocopherol or a derivative thereof is usually 0.001 to 5% by mass, preferably 0.05, based on the total amount of the external skin preparation. It is about 3% by mass, more preferably 0.1 to 1% by mass.

When the skin external preparation of the present invention contains a polyhydric alcohol, the content of the polyhydric alcohol is not particularly limited, but is preferably 0.5 to 20% by mass, more preferably, based on the total amount of the skin external preparation. , 1.0 to 15% by mass.

The pH range of the external preparation for skin of the present invention is preferably 5.0 to 8.0, more preferably 5.5 to 7.5, and even more preferably, from the viewpoint of reducing irritation to the skin. , 6.0-7.0.

In the external skin preparation of the present invention, drugs and pharmaceutical additives usually used for external skin preparations for analgesia and anti-inflammatory other than the above components can be added.
Examples of the drug include anti-inflammatory agents such as glycyrrhetinic acid, antihistamines such as chlorpheniramine maleate, blood circulation improving components such as nicotinic acid benzyl ester, local stimulating components such as capsaicin and capsaicin, and crude drug components such as arnica tincture. These drugs can be blended within a range that does not impair the effects of the present invention.

Pharmaceutical additives other than the above components are added as needed for the purpose of, for example, content stability over time and further improvement of usability, and are, for example, wetting agents, antioxidants and refreshing agents. And so on.
As the wetting agent, for example, dl-sodium pyrrolidone carboxylate or the like can be added.

Examples of the antioxidant include ascorbic acid, ascorbic acid palmitate, sodium hydrogen sulfite, sodium pyrosulfate, sodium edetate, citric acid hydrate, anhydrous citric acid, dibutylhydroxytoluene, butylhydroxyanisole, benzotriazole, and galvanic acid. Propyl acid or the like can be used.
Examples of the refreshing agent include camphor, dl-camphor, peppermint oil, eucalyptus oil and the like.

The external skin preparation of the present invention may or may not contain a surfactant, but from the viewpoint of reducing irritation to the skin, it is preferable not to contain the surfactant. ..

Specific dosage forms of the external skin preparation of the present invention include, for example, external liquids, ointments, creams, sprays (pump sprays, etc.), gels, aerosols (external aerosols, etc.), and patches (paste (external aerosols, etc.)). Tape agents, pap agents), external solid agents, and the like can be mentioned. The above dosage form can be produced according to the usual method described in the 17th revised Japanese Pharmacopoeia, etc., by appropriately using additives and bases suitable for each dosage form. As the dosage form of the external skin preparation of the present invention, an external liquid agent, an ointment, a spray agent, a gel agent, an aerosol agent, or an external solid agent is preferable, and an external liquid agent is particularly preferable.
Further, the formulation of the external preparation for skin of the present invention can be contained in a container / packaging made of a metal such as aluminum or a container / packaging made of an olefin resin such as polyethylene or polypropylene and sealed.

The external skin preparation of the present invention should be used for analgesic and anti-inflammatory patients with pain and inflammation, such as low back pain, bruise, sprain, shoulder pain associated with stiff shoulders, tendonitis, elbow pain, and arthralgia. Can be done. The external skin preparation of the present invention is applied or affixed to the affected area in an appropriate amount once to several times a day for the patient.
Hereinafter, the present invention will be described in more detail with reference to examples.

<Test Example 1> Property confirmation test 1 for external skin preparation containing loxoprofen
(1) Preparation of test materials and specimens Loxoprofen sodium / dihydrate is made by KOLON LIFE SCIENCE Co., Ltd., l-menthol is made by Suzuki Ushiro Co., Ltd., and tocopherol acetate is Riken Vitamin Co., Ltd. ), Absolute ethanol from Imazu Yakuhin Kogyo Co., Ltd., Hydrochloric acid, phosphoric acid and 1,3-butylene glycol from Kanto Kagaku Co., Ltd., DL-apple acid and citric acid The ones manufactured by Tokyo Kasei Kogyo Co., Ltd. were used.
The components listed in Table 1 below were mixed and dissolved to obtain an external solution shown in the table. An appropriate amount of each pH adjuster was added to adjust the pH of the pharmaceutical product to 6.5.

(2) Evaluation method The properties of each obtained sample were visually confirmed. The properties were evaluated based on the following criteria regarding the presence or absence of insoluble matter precipitation and precipitation, and only ○ was regarded as the allowable range.
◯: Colorless and clear liquid, no precipitates or precipitates ×: White turbid liquids or precipitates or precipitates are observed. In addition, the properties are all immediately after production, after 24 hours at room temperature, and after 24 hours at 5 ° C. If it was 〇, it was passed.

(3) Test results The results are shown in Table 1.

By comparing Examples 1, 2 and 5 in Table 1 with Comparative Examples 1, 2 and 5, it contains loxoprofen sodium hydrate, 70% by mass of absolute ethanol and 1,3-butylene glycol based on the total amount of the external preparation. In the external preparation to be used, the properties immediately after production and after 24 hours at room temperature were significantly improved by adding hydrochloric acid and DL-malic acid as compared with the case of adding citric acid or phosphoric acid as a pH adjuster.

The blending amount of loxoprofen sodium hydrate corresponds to 1 g of loxoprofen sodium (anhydrous equivalent).

By comparing Examples 3 and 4 of Table 1 with Comparative Examples 3 and 4, the pH of the external preparation containing 70% by mass of anhydrous ethanol and l-menthol based on the total amount of loxoprofen sodium hydrate and external preparation was adjusted. Compared with the case where citric acid or phosphoric acid was added as an agent, the properties immediately after production and after 24 hours at room temperature were significantly improved when hydrochloric acid and DL-malic acid were added.

The blending amount of loxoprofen sodium hydrate corresponds to 1 g of loxoprofen sodium (anhydrous equivalent).

<Test Example 2> Property confirmation test 2 for external skin preparation containing loxoprofen
(1) Preparation of test materials and samples The same procedure as in Test Example 1 was carried out. For the sample not containing loxoprofen sodium hydrate, the same amount of pH regulator as the sample containing loxoprofen sodium hydrate was added in the same formulation.
(2) Evaluation method The same procedure as in Test Example 1 was performed.

(3) Test results The results are shown in Table 2.

From Reference Examples 1 to 5 in Table 2, the properties of the external preparation containing no loxoprofen sodium hydrate were stable regardless of the type of pH adjuster to be added.

<Test Example 3> Property confirmation test 3 for external skin preparation containing loxoprofen
(1) Preparation of test materials and samples Based on the components shown in Table 3, preparations were made in the same manner as in Test Example 1.
(2) Evaluation method The same procedure as in Test Example 1 was performed.

(3) Test results The results are shown in Table 3.

From Table 3, comparing Example 6 and Comparative Example 6 in which the concentration of absolute ethanol is 60% by mass based on the total amount of the external preparation, when phosphoric acid is added, the properties are obtained when stored at 5 ° C. for 24 hours. On the other hand, when hydrochloric acid was added, the properties could be kept stable. In Comparative Example 7 in which the concentration of absolute ethanol was 61% by mass based on the total amount of the external preparation and phosphoric acid was added, the properties deteriorated immediately after production and when stored at room temperature or 5 ° C. for 24 hours. .. Comparing Example 7 and Comparative Example 8 in which the concentration of absolute ethanol is 70% by mass based on the total amount of the external preparation, when phosphoric acid is added, both immediately after production and when stored at room temperature for 24 hours. While the properties deteriorated, the properties could be kept stable in all cases when hydrochloric acid was added. From the above results, when absolute ethanol is contained in an amount of 60% by mass or more based on the total amount of the external preparation, if the pH adjuster is phosphoric acid, the property stability of the external preparation containing loxoprofen sodium hydrate is deteriorated. I understood. Furthermore, it was also clarified that the properties are stabilized by changing the pH adjuster from phosphoric acid to hydrochloric acid.

<Test Example 4> Property confirmation test 4 for external skin preparation containing loxoprofen
(1) Preparation of test materials and samples Each sample was prepared in the same manner as in Test Example 1 based on the components in Table 4 by substituting isopropanol (manufactured by Kosakai Pharmaceutical Co., Ltd.) for absolute ethanol in Test Example 1.
(2) Evaluation method The same procedure as in Test Example 1 was performed.

(3) Test results The results are shown in Table 4.

By comparing Example 8 and Comparative Example 9 in Table 4, even when isopropyl alcohol was added as the lower alcohol instead of absolute ethanol, it was better to add hydrochloric acid than when phosphoric acid was added as the pH adjuster. It was found that the properties immediately after and after 24 hours at room temperature were significantly improved.

(Example of pharmaceutical product)
After stirring and mixing the components shown in Tables 5 and 6 below to dissolve them, the external skin preparations of Pharmaceutical Examples 1 to 18 can be obtained.
As a manufacturing method, the above-mentioned components and amounts can be taken and manufactured according to the sections of "External liquid preparation" and "Gel preparation" of the Japanese Pharmacopoeia general rules.

In Tables 5, 6 and 7, the blending amount of loxoprofen sodium hydrate corresponds to 1 g of loxoprofen sodium (anhydrous equivalent).

<Test example> Property confirmation test for external skin preparation containing loxoprofen 5
(1) Preparation of test materials and specimens Preparations were made in the same manner as in Test Example 1 based on the components shown in Table 8.
(2) Evaluation method The same procedure as in Test Example 1 was performed.

(3) Test results The results are shown in Table 8.

By comparing Examples 9 to 11 and Comparative Examples 10 to 11 in Table 8, phosphoric acid was used as the pH adjuster regardless of whether the concentration of anhydrous ethanol was 60% by mass or 80% by mass based on the total amount of the external preparation. When blended, the properties deteriorated immediately after production or when stored at room temperature or 5 ° C for 24 hours, whereas when hydrochloric acid or DL-malic acid was blended, immediately after production and at room temperature and 5 ° C. The properties after 24 hours were significantly improved.

<Test example> Property confirmation test for external skin preparation containing loxoprofen 6
(1) Preparation of test materials and specimens Preparations were made in the same manner as in Test Example 1 based on the components shown in Table 8.
(2) Evaluation method The same procedure as in Test Example 1 was performed.

(3) Test results The results are shown in Table 9.

According to the comparison between Examples 12 to 15 and Comparative Examples 12 to 15 in Table 9, when phosphoric acid or citric acid is blended as a pH adjuster regardless of whether the pH is 5.5 or 7.5, immediately after production. In addition, the properties deteriorated even when stored at room temperature or 5 ° C for 24 hours, whereas when hydrochloric acid or DL-malic acid was added, the properties immediately after production and after 24 hours at room temperature and 5 ° C. Significantly improved.

Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. It is possible to add, omit, replace, and make other changes to the configuration without departing from the spirit of the present invention.

The external skin preparation containing loxoprofen of the present invention is extremely useful because it has an excellent feeling of use and excellent storage stability in appearance.

Claims (10)

An external skin preparation containing the following [a] to [c].
[A] Loxoprofen or a salt thereof;
[B] 60% by mass or more of lower alcohol based on the total amount of external skin preparation; and [c] one or more pH regulators selected from hydrochloric acid or malic acid and salts thereof. The skin external preparation according to claim 1, wherein the content of the lower alcohol is 60 to 80% by mass based on the total amount of the skin external preparation. The external skin preparation according to claim 1 or 2, wherein the malic acid and a salt thereof are DL-malic acid or a salt thereof. The external skin preparation according to any one of claims 1 to 3, further containing an oil-soluble component. The external skin preparation according to claim 4, wherein the oil-soluble component is at least one selected from l-menthol and tocopherol or a derivative thereof. The external skin preparation according to any one of claims 1 to 5, further containing a polyhydric alcohol. The external skin preparation according to any one of claims 1 to 6, which does not contain a surfactant as an additive. The external skin preparation according to any one of claims 1 to 7, wherein the pH is 5.5 to 7.5. The external skin preparation according to any one of claims 1 to 8, which is used for analgesia and anti-inflammatory. The skin external preparation according to any one of claims 1 to 9, wherein the dosage form is an external liquid, an ointment, a spray, a gel, an aerosol, or an external solid.