External aerosol

Abstract

To provide an emulsified topical aerosol containing loxoprofen as an active ingredient. [Solution] A topical aerosol containing the following components (A) to (F): (A) At least one selected from the group consisting of loxoprofen, pharmaceutically acceptable salts thereof, and solvates thereof. (B) Cooling agent; (C) Polysorbate, (D) Oily base, (E) Water; (F) Propellant.

Description

Technical Field

[0001] It relates to an external aerosol agent. In particular, it relates to an external aerosol agent containing loxoprofen and its salts as an active ingredient.

Background Art

[0002] At least one selected from the group consisting of loxoprofen, a pharmaceutically acceptable salt thereof, and a solvate thereof, which is a propionic acid-based non-steroidal anti-inflammatory, analgesic and antipyretic agent (NSAID) (hereinafter, these may be collectively referred to as "loxoprofen and its salts" in this specification) has antipyretic, analgesic and anti-inflammatory effects based on the inhibitory action on prostaglandin biosynthesis, like other NSAIDs.

[0003] Various external agents formulated with loxoprofen and its salts as an active ingredient for antipyretic, analgesic and / or anti-inflammatory effects have been proposed and developed. Among them, Patent Documents 1 to 3 describe external agents with improved percutaneous absorbability and effects of loxoprofen and its salts. Specifically, Patent Document 1 describes a loxoprofen-containing patch agent, and it is described that the percutaneous absorbability of loxoprofen and its salts is improved by blending a specific amount of bentonite and an organic acid into the adhesive base together with loxoprofen and its salts. Also, Patent Document 2 describes a loxoprofen-containing external agent, and it is described that the percutaneous absorbability of loxoprofen and its salts is improved by blending propylene glycol and propylene glycol fatty acid ester together with loxoprofen and its salts. Furthermore, Patent Document 3 describes a loxoprofen-containing external agent, and it is described that the anti-inflammatory effect of loxoprofen and its salts is improved by blending nonyl acid vanillylamide together with loxoprofen and its salts.

[0004] Furthermore, regarding topical aerosol preparations containing loxoprofen as an active ingredient, Patent Document 4 describes that by incorporating at least one selected from polyoxyethylene fatty acid esters with an HLB of 10 to 15 and polyoxyethylene hydrogenated castor oil with an HLB of 10 to less than 14, in addition to loxoprofen, the formation of precipitates over time can be suppressed, and a topical aerosol preparation with good spray properties can be prepared. Furthermore, Patent Document 5 describes that, regarding topical preparations containing loxoprofen with a high concentration of lower alcohol of 30.5% by mass or more, by incorporating carboxyvinyl polymer and diisopropanolamine, the precipitation of insoluble matter and the decrease in viscosity can be suppressed, and a topical aerosol preparation can be prepared. Furthermore, Patent Document 6 describes a foamy aerosol formulation consisting of 0.2-5% by weight of loxoprofen, 1-20% by weight of an absorption enhancer, 0.3-10% by weight of a surfactant, 0.01-5% by weight of a pH adjuster, 10-50% by weight of purified water, and 10-50% by weight of a propellant. It states that the foamy form eliminates irritation to the nasal mucosa, making it highly safe, and that the inclusion of an absorption enhancer allows for good transdermal absorption of the drug, providing an inflammatory disease treatment with superior pharmacological efficacy. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2013-147466 [Patent Document 2] Japanese Patent Publication No. 2016-79180 [Patent Document 3] Japanese Patent Publication No. 2014-224110 [Patent Document 4] Japanese Patent Publication No. 2012-193173 [Patent Document 5] Japanese Patent Publication No. 2018-188429 [Patent Document 6] Japanese Patent Application Publication No. 3-72433 [Overview of the project] [Problems that the invention aims to solve]

[0006] The object of this disclosure is to provide a topical aerosol formulation containing loxoprofen derivatives that has good sustained efficacy. [Means for solving the problem]

[0007] The inventors of the present invention conducted extensive research to solve the aforementioned problems and found that by preparing an emulsified composition (original ingredient) by emulsifying loxoprofen derivatives, a cooling agent, an oily base, and water using polysorbate as an emulsifier, and then combining this with a propellant to prepare an emulsified topical aerosol formulation, a topical preparation with good sustained efficacy can be obtained. In particular, the sustained efficacy of this topical emulsified aerosol formulation is significantly higher than that when the emulsified composition (original ingredient) is used without being in aerosol form. Furthermore, it was confirmed that when the formulation form of the original ingredient is an aqueous solution (lotion), the sustained efficacy does not improve significantly even when it is prepared in aerosol form. Moreover, it was confirmed that the significant improvement in sustained efficacy is an effect unique to the use of polysorbate as an emulsifier, and that such a large improvement is not observed when other nonionic surfactants are used. Furthermore, it was confirmed that the effect of improving the duration of effect of the topical emulsified aerosol formulation disclosed herein is particularly pronounced when loxoprofen is used as the active ingredient, and that no such significant effect is obtained when other anti-inflammatory and analgesic drugs are used. The inventions provided in this disclosure are the result of further investigation based on these various findings, and include, for example, the following embodiments.

[0008] I. Topical aerosols containing loxoprofen I-1. Topical aerosols containing the following components (A) to (F): (A) At least one selected from the group consisting of loxoprofen, pharmaceutically acceptable salts thereof, and solvates thereof. (B) Cooling agent; (C) Polysorbate, (D) Oily base, (E) Water; (F) Propellant. I-2. The topical aerosol agent described in I-1, wherein the component (D) is an ester oil. I-3. An external aerosol preparation according to I-1 or I-2, wherein the (D) component is isopropyl myristate. I-4. A topical aerosol agent according to any one of I-1 to I-3, wherein the (C) component is polysorbate 20. I-5. An external aerosol agent as described in any of I-1 to I-4, wherein the above-mentioned component (F) is liquefied petroleum gas. I-6. An emulsified composition containing components (A) to (E), and an external aerosol containing component (F) that is in an emulsified form, as described in any of I-1 to I-5.

[0009] II. Method for maintaining the effectiveness of topical emulsified compositions containing loxoprofen. II-1. A method for improving the duration of effect of an external emulsified composition containing the following components (A), (B), (D), and (E), as well as an emulsifier, (A) At least one selected from the group consisting of loxoprofen, pharmaceutically acceptable salts thereof, and solvates thereof. (B) Cooling agent; (D) Oily base, (E) Water; (C) Polysorbate is used as the emulsifier. The emulsion composition containing the components (A) to (E) is blended with a propellant (F) to prepare it in the form of an emulsified aerosol. The aforementioned method. II-2. The method for improving the duration of the effect as described in II-1, wherein component (D) is an ester oil. II-3. A method for improving the duration of effect according to II-1 or II-2, wherein component (D) is isopropyl myristate. II-4. A method for improving the duration of effect according to any one of II-1 to II-3, wherein the (C) component is polysorbate 20. II-5. A method for improving the duration of effect as described in any of II-1 to II-4, wherein the (F) component is liquefied petroleum gas. [Effects of the Invention]

[0010] According to the external aerosol agent and the method for improving the sustained effect of the present disclosure, for an emulsified external composition containing a cooling agent, an oily base, and water in addition to loxoprofen, its sustained effect can be improved.

Mode for Carrying Out the Invention

[0011] 1. Topical aerosol The external aerosol agent of the present disclosure (hereinafter sometimes referred to as "this aerosol agent") is characterized by containing (A) loxoprofen, (B) a cooling agent, (C) polysorbate, (D) an oily base, (E) water, and (F) a propellant. Among these components, the components (A) to (E) are an emulsified composition, and after being prepared as an emulsified composition, they are filled into a pressure-resistant container together with the component (F). Therefore, this aerosol agent is an external aerosol agent having an emulsified form (external emulsified aerosol agent). Hereinafter, in this specification, the emulsified composition containing the components (A) to (E) is referred to as a "drug" in order to distinguish it from the final preparation (emulsified aerosol agent) and the (F) propellant.

[0012] (A) Loxoprofen Loxoprofen (2-[4-(2-oxocyclopentylmethyl)phenyl]propionic acid) is a propionic acid-based non-steroidal antipyretic, analgesic and anti-inflammatory agent (NSAID) having antipyretic, analgesic and / or anti-inflammatory effects.

[0013] This aerosol agent can also use a pharmaceutically acceptable salt thereof or a solvate thereof instead of loxoprofen or together with loxoprofen. Pharmaceutically acceptable salts of loxoprofen include alkali metal salts of loxoprofen such as loxoprofen sodium. Examples of the solvent for forming a solvate with loxoprofen or its salt include water and lower alcohols such as ethanol. Water is preferred. The loxoprofen derivative is preferably loxoprofen sodium hydrate, and particularly preferably loxoprofen sodium dihydrate. These are known compounds and can be manufactured by known methods, or commercially available compounds can be used.

[0014] The loxoprofen content in this aerosol formulation can be appropriately set considering the effects of this disclosure and the analgesic and / or anti-inflammatory effects inherent in loxoprofen. However, it is not limited to these, but can be, for example, 0.1% to 10% by mass, preferably 0.5% to 5% by mass, more preferably 0.5% to 3% by mass, and even more preferably 0.5% to 2% by mass, on an anhydrous basis, per 100% by mass of the drug.

[0015] (B) Cooling agent Examples of cooling agents include menthol such as l-menthol, d-menthol, and dl-menthol; camphor such as d-camphor and dl-camphor; borneol such as d-borneol and dl-borneol; menthane, emulsified menthyl, geraniol, eucalyptus oil, terpene oil, bergamot oil, fennel oil, peppermint oil, rose oil, and cool mint. These cooling agents can be used individually or in any combination of two or more. The cooling agent to be incorporated into this aerosol is preferably menthol, and more preferably l-menthol.

[0016] The content of the cooling agent in this aerosol can be set as appropriate, taking into consideration the effects of this disclosure. However, it is not limited to the above, but can be, for example, 0.5% to 10% by mass, preferably 0.5% to 5% by mass, more preferably 0.5% to 3% by mass, and even more preferably 0.5% to 2% by mass, per 100% by mass of the drug.

[0017] (C) Polysorbate Polysorbate is an ethylene oxide condensation type polyoxyethylene sorbitan fatty acid ester produced by addition polymerization of ethylene oxide (approximately 20 moles) to a mixture of fatty acid esters of sorbitol and anhydrous sorbitol. Polysorbates are hydrophilic nonionic surfactants. These include polysorbate 20 (polyoxyethylene sorbitan monolaurate (20 E.O.)) with an HLB greater than 16 and 18 or less, preferably 16.5 to 17.5; polysorbate 40 (polyoxyethylene sorbitan monopalmitate (20 E.O.)) with an HLB in the range of 15.6 to 16.0; polysorbate 60 (polyoxyethylene sorbitan monostearate (20 E.O.)) with an HLB in the range of 14.9 to 15.7; polysorbate 65 (polyoxyethylene sorbitan tristearate (20 E.O.)) with an HLB of 10.6 to 11.0, preferably 10.5; and polysorbate 80 (polyoxyethylene sorbitan monooleate (20 E.O.)) with an HLB in the range of 13.0 to 15.7. HLB represents the molecular weight of the hydrophilic group portion of the total molecular weight of the surfactant and can be determined by Griffin's formula. Preferably, the HLB is greater than 16 for polysorbate 20.

[0018] The polysorbate content in this aerosol agent can be set as appropriate, taking into consideration the effects of this disclosure. However, it is not limited to the above, but can be, for example, 0.1% to 2% by mass, preferably 0.1% to 1% by mass, more preferably 0.1% to 0.8% by mass, and even more preferably 0.2% to 0.8% by mass per 100% by mass of the drug.

[0019] (D) Oily base Examples of oily bases include ester oils, hydrocarbon oils, higher fatty acids, animal and vegetable oils and fats, and silicone oils. These oily bases may be used individually or in combination of two or more. Among these oily bases, ester oils are preferred.

[0020] Examples of ester oils include esters of fatty acids with monohydric or polyhydric alcohols. Examples of fatty acids include aliphatic mono or dicarboxylic acids having 8 to 22 carbon atoms, examples of monohydric alcohols include linear or branched alcohols having 2 to 22 carbon atoms, and examples of polyhydric alcohols include dihydric to penhydric polyhydric alcohols having 3 to 5 carbon atoms.

[0021] Specific examples of ester oils include ethyl oleate, ethyl linoleate, isopropyl myristate, isopropyl palmitate, isopropyl isostearate, cetyl 2-ethylhexanoate, isocetyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, isostearyl 2-ethylhexanoate, cetyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl isostearate, isostearyl isostearate, trimethylolpropane triisostearate, myristyl myristate, cetyl myristate, octyldodecyl myristate, isostearyl myristate, isocetyl myristate, hexyl laurate, decyl oleate, octyldodecyl oleate, isostearyl pivalate, isopropyl isostearate, isononyl isononanoate, 2-ethylhexyl isononanoate Examples include isodecyl isononanoate, isotridecyl isononanoate, octyldodecyl erucate, neopentyl glycol didecanoate, pentaerythrityl tetraethylhexanoate, diisostearyl malate, trimethylolpropane triethylhexanoate, didecyl adipate, didecyl adipate, cholesteryl isostearate, batyl isostearate, hydrogenated castor oil monohydroxystearate, isostearyl lanolinate, isopropyl lanolinate, octyldodecyl lanolinate, cetyl ricinoleate, dioctyl succinate, cetyl lactate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dinonanoate, di(caprylic / capric acid)propylene glycol, propylene glycol diisostearate, and propylene glycol dioleate.

[0022] These ester oils may be used individually or in combination of two or more. Among these ester oils, preferred are esters of fatty acids and monohydric alcohols, more preferably aliphatic monocarboxylic acids having 8 to 22 carbon atoms (preferably 10 to 18, more preferably 12 to 16) and linear or branched (preferably branched) alcohols having 2 to 22 carbon atoms (preferably 2 to 10, more preferably 2 to 6, even more preferably 2 to 4), and particularly preferred isopropyl myristate.

[0023] The content of the oily base in this aerosol agent can be appropriately set considering the effects of this disclosure. While not limited to this extent, it can be selected from a range of, for example, 0.5% to 10% by mass per 100% by mass of the active ingredient. Preferably, it can be appropriately set and adjusted from a range of 1% to 5% by mass, more preferably 2% to 5% by mass, and even more preferably 2% to 3% by mass.

[0024] (E)Water The type of water and its amount can be appropriately set considering the effects of this disclosure. While not limited to these, examples of water types include purified water, deionized water, and distilled water. The water content in this aerosol agent can be appropriately set and adjusted from a range of, for example, 50% by mass or more, preferably 50% to 80% by mass, more preferably 60% to 80% by mass, and even more preferably 65% ​​to 75% by mass, per 100% by mass of the drug.

[0025] The agent in this aerosol may consist only of the components (A) to (E) above, but it may also contain any of the following components, either alone or in combination, as an optional component (G).

[0026] (G-1) Lower alcohol The lower alcohol can be any alcohol that can be used as a base, solvent, solubilizer, or solubilizer for a drug without interfering with the effects of the disclosure. Examples of lower alcohols include monohydric alcohols having 1 to 4 carbon atoms, such as ethanol, propyl alcohol, and isopropyl alcohol. These can be used individually or in any combination of two or more. The lower alcohol is preferably ethanol, and more preferably anhydrous ethanol.

[0027] When incorporating lower alcohols, the lower alcohol content can be appropriately set considering the effects of this disclosure. However, it is not limited to this extent, but can be, for example, 5% by mass or more and 40% by mass or less per 100% by mass of the drug, preferably 10% by mass or more and 40% by mass or less, more preferably 10% by mass or more and 35% by mass or less, and even more preferably 15% by mass or more and 30% by mass or less.

[0028] (G-2) Polyhydric alcohol Polyhydric alcohols are alcohols that have two or more hydroxyl groups in their molecule. Their type can be appropriately selected from the 2021 Dictionary of Pharmaceutical Additives, taking into consideration the effects of this disclosure. Examples include dihydric alcohols such as propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, and dipropylene glycol; and trihydric alcohols such as glycerin. These polyhydric alcohols can be used individually or in any combination of two or more. Preferably, glycerin, propylene glycol, dipropylene glycol, and 1,3-butylene glycol are used, and propylene glycol is particularly preferred. If polyhydric alcohols are included, their content can be appropriately set considering the effects of this disclosure. While not limited to this extent, the content can be selected from, for example, a range of 0.1% to 20% by mass per 100% by mass of the drug. Preferably, it can be appropriately set and adjusted from a range of 0.5% to 10% by mass, more preferably 0.5% to 5% by mass, and even more preferably 1% to 2% by mass.

[0029] (G-3) Thickening agent Examples of thickeners include acrylic acid-based thickeners such as carboxyvinyl polymers; water-soluble or water-swellable cellulose-based thickeners such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, and carboxymethylcellulose; polyvinylpyrrolidone; colloidal aluminum silicate; gums such as xanthan gum, locust bean gum, tragacanth gum, guar gum, and gum arabic; alginic acid or its salts; and gelatin. These thickeners can be used individually or in any combination of two or more. Preferably, carboxyvinyl polymers, cellulose-based polymer compounds, and gums are used. More preferably, cellulose-based thickeners such as hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose are used. If a thickening agent is included, its content can be appropriately set considering the effects of this disclosure. While not limited to this extent, it can be selected from a range of, for example, 0.1% to 2% by mass per 100% by mass of the drug. Preferably, it can be appropriately set and adjusted from a range of 0.1% to 1% by mass, more preferably 0.2% to 1% by mass, and even more preferably 0.2% to 0.8% by mass.

[0030] (G-4) Other ingredients In addition to the above-mentioned components, the drug may contain other pharmacoactive ingredients besides loxoprofen, as long as they do not interfere with the effects of the present invention. Examples of such pharmacoactive ingredients include anti-inflammatory agents, blood circulation promoting components, local anesthetics, antiseptics, antipruritics, moisturizers, steroids, antihistamines, vitamins, mucopolysaccharides, etc. These pharmacoactive ingredients may be used individually or in combination of two or more. Among these pharmacoactive ingredients, anti-inflammatory agents, blood circulation promoting components, local anesthetics, and moisturizers are preferred. The specific components corresponding to these pharmacoactive ingredients can be any ingredients that can be applied to the skin (externally). Furthermore, when these pharmacoactive ingredients are included in the emulsified composition of the present invention, their content may be appropriately set according to the type of pharmacoactive ingredient used, the expected effect, etc.

[0031] Furthermore, the drug may also contain, as appropriate, other additives commonly used in topical compositions, such as pH adjusters, solubilizers, solubilizers, preservatives, skin protectants, antioxidants, and stabilizers, in addition to the above-mentioned components, provided that they do not interfere with the effects of the present invention. Specific examples of these components are listed in the 2021 Dictionary of Pharmaceutical Additives (Yakuji Nippo Co., Ltd.).

[0032] (F) Propellant Examples of propellants include liquefied petroleum gas, liquefied carbon dioxide, carbon dioxide, dimethyl ether, 1,1,1,2-tetrafluoromethane, and 1,1,1,2-heptafluoropropane. Liquefied petroleum gas is preferred. The propellant content in this aerosol can be set as appropriate, taking into consideration the effects of this disclosure. While not limited to this extent, it can be selected from a range of 80 to 300 parts per 100 parts per volume of the drug. Preferably, it is 80 parts to 200 parts, and more preferably 80 parts to 180 parts (under 25°C and atmospheric pressure conditions).

[0033] 2. Form and Manufacturing Method The aforementioned drugs containing components (A) to (E) and optionally component (G) are O / W type emulsion compositions. The pH is not particularly limited as long as it does not adversely affect the skin, but for example, under 25°C conditions, it is weakly acidic with a pH of 4 to 6.5, preferably 4.5 to 6, and more preferably 4.5 to 5.5.

[0034] The drug can be manufactured according to known methods for producing emulsified compositions. Examples, though not limited to these methods, include the following: First, an aqueous phase composition is prepared by mixing the water-soluble components (A), (E), and (G), which may be added as needed. Separately, an oil phase composition is prepared by mixing the oil-soluble components (B), (D), and (G), which may be added as needed. Component (C) may be added to either the oil phase composition or the aqueous phase composition, or both, but it is preferable to add it to the oil phase composition. Next, the obtained aqueous phase composition is heated to approximately 60-80°C, and then the oil phase composition is slowly added while stirring, and emulsified using an emulsification method such as a homomixer. This is then cooled to approximately 30°C. If a lower alcohol is included as component (G), it can be added to the cooled emulsified composition and stirred to produce an O / W type emulsified drug.

[0035] This aerosol agent can be manufactured, for example, by filling a pressure-resistant container with the emulsified agent produced by the method described above, together with the propellant (F) mentioned above.

[0036] This aerosol formulation is prepared as a topical preparation (pharmaceutical, quasi-drug) in spray form and can be administered topically. The dosage of this aerosol formulation depends on the severity of the symptoms to be treated, but it is desirable that the amount of loxoprofen-like active ingredients applied per application be 20 mg or less.

[0037] This aerosol can be suitably used as a topical anti-inflammatory and analgesic agent for pain such as shoulder pain associated with stiff shoulders, joint pain, lower back pain, muscle pain, tenosynovitis (hand / wrist pain), elbow pain (tennis elbow, etc.), bruise pain, sprain pain, fracture pain, and neuralgia, for the purpose of pain relief and / or anti-inflammatory action.

[0038] 3. Method for maintaining the effect of topical emulsified compositions containing loxoprofen. The method disclosed herein is a method for improving the duration of effect of an external emulsified composition containing the aforementioned components (A), (B), (D), and (E), as well as an emulsifier. This method can be carried out by using (C) polysorbate as the emulsifier and preparing an emulsified aerosol by adding a propellant (F) to an emulsified composition containing these components (A) to (E). In addition to components (A) to (F), the external emulsified composition may also contain the aforementioned component (G) as an optional component.

[0039] The components (A) to (E) and (G), as well as component (F), that are incorporated into the external emulsified composition are as described in Section 1 above, and that description can be incorporated herein by reference. The process of preparing an emulsified composition (pharmaceutical) by incorporating component (C) into components (A), (B), (D), and (E), and the method of producing this aerosol by incorporating component (F) therein, are as described in Section 2 above.

[0040] In this specification, the terms “contains” and “includes” include the meanings of “consisting of” and “substantially consisting of.” [Examples]

[0041] The present invention will be described below using experimental examples to aid in understanding its structure and effects. However, the present invention is not limited in any way by these experimental examples. Unless otherwise specified, the following experiments were conducted at room temperature (25±5℃) and atmospheric pressure.

[0042] Test Example 1: Manufacturing of pharmaceuticals and aerosols, and evaluation of efficacy duration. (1) Manufacturing of pharmaceuticals (1-1) Manufacturing of liquid-form drugs (Comparative Examples 1' and 2') As shown in Table 1, all components except (F) liquefied petroleum gas were mixed to prepare liquid compositions (Comparative Examples 1' and 2'). The liquid composition of Comparative Example 1' was used as is as a liquid formulation (Comparative Example 1) in the tests described later. The liquid composition of Comparative Example 2' was used as a raw material (liquid drug) for the manufacture of an aerosol formulation (Comparative Example 2).

[0043] (1-2) Preparation of emulsified drugs (Example 1', Comparative Examples 3' and 4') Of the components shown in Table 1, the water-soluble components (A) loxoprofen sodium dihydrate, (G-2) propylene glycol, and (G-3) hydroxypropyl methylcellulose were dissolved in (E) purified water to prepare an aqueous phase composition. Separately, the oil-soluble components (B) l-menthol and (D) isopropyl myristate were mixed with (C) an emulsifier to prepare an oil phase composition. The aqueous phase composition was heated to 80°C, and then the oil phase composition was slowly added to it while stirring with a tornado stirrer ("Tornado PM-202", manufactured by AS ONE Corporation) and emulsified by mixing. Next, it was left at room temperature to cool to 30°C, and then (G-1) ethanol was added and stirred with a tornado stirrer at a rotation speed of 500 rpm for 30 minutes to prepare an O / W type emulsion composition. The emulsified composition of Comparative Example 3' was used as is as the emulsified formulation (Comparative Example 3) in the tests described later. The emulsified compositions of Example 1' and Comparative Example 4' were used as raw materials (emulsifying agents) for the manufacture of aerosols (Example 1 and Comparative Example 4).

[0044] (2) Manufacturing of aerosols The liquid agent (Comparative Example 2') and emulsifying agent (Example 1', Comparative Example 4') prepared above were filled into pressure-resistant aerosol containers, and then liquefied petroleum gas was sealed in so that the volume ratio was 1:1 (agent:propellant) to produce various aerosol agents (Comparative Example 2, Example 1, and Comparative Example 4).

[0045] [Table 1]

[0046] (3) Evaluation of the duration of the effect The duration of effect of each formulation manufactured as described above was evaluated using a panel of three panelists. Specifically, on the skin of the inner forearm (area approximately 25 cm²) for each panel. 2 Each formulation was applied to the skin at a rate of 1g (aerosol formulations were sprayed). Each panelist was asked to measure the duration of the skin irritation they felt upon application, which was defined as the drug's effect, and the average value for the panel was calculated. The duration (average value) of Comparative Example 1 (liquid formulation) was set to 100, and the relative duration of each formulation (Example 1, Comparative Examples 2-4) was calculated and rounded to the first decimal place. The results are shown in Table 2.

[0047] [Table 2]

[0048] As can be seen from these results, it was confirmed that preparing an aerosol formulation (Comparative Example 2) using a liquid formulation (Comparative Example 1) as the drug slightly improved the duration of effect, but the improvement was minimal. On the other hand, the duration of effect of the emulsified formulation (Comparative Example 3) decreased to about half that of the liquid formulation (Comparative Example 1). In contrast, preparing an aerosol formulation (Example 1) using the emulsified formulation (Comparative Example 3) as the drug significantly improved the duration of effect, and its duration far exceeded that of the liquid aerosol formulation of Comparative Example 2. On the other hand, while the duration of effect of the emulsified aerosol formulation (Comparative Example 4), which used an emulsified formulation with a nonionic surfactant other than polysorbate as the drug, improved, the degree of improvement was significantly better in the emulsified aerosol formulation using polysorbate (Example 1). As these experiments demonstrate, by preparing an emulsified composition containing loxoprofen using polysorbate as an emulsifier and then forming it into an aerosol, the sustained effect of loxoprofen can be significantly improved.

[0049] Test Example 2: Comparative Evaluation with Other Anti-inflammatory and Analgesic Drugs As an anti-inflammatory and analgesic agent, indomethacin, glycol salicylate, and diclofenac sodium were used instead of loxoprofen sodium dihydrate to prepare emulsified formulations and emulsified aerosol formulations, and their duration of effect was evaluated in the same manner as in Test Example 1.

[0050] (1) Manufacturing of emulsified aerosols Following the method described in Test Example 1(1), emulsified compositions were prepared by mixing all components except (F) liquefied petroleum gas shown in Table 3 (Comparative Example 3', Example 1', Reference Examples 1'-6'). Of these emulsified compositions, Comparative Example 3', Reference Examples 1', 3', and 5' were used as emulsified formulations (Comparative Example 3, Reference Examples 1, 3, and 5) in the tests described later. On the other hand, Examples 1', Reference Examples 2', 4', and 6' were filled into pressure-resistant aerosol containers in the same manner as described in Test Example 1(2), and then liquefied petroleum gas was sealed in so that the volume ratio was 1:1 (agent:propellant) to produce various emulsified aerosol agents (Example 1, Reference Examples 2, 4, and 6).

[0051] [Table 3]

[0052] (2) Evaluation of the duration of the effect The duration of effect of each formulation manufactured as described above was evaluated using the method described in Test Example 1(3). In addition, for each anti-inflammatory analgesic, the duration of effect of the emulsified aerosol formulation was calculated as the "degree of improvement in duration of effect of the emulsified aerosol formulation," with the duration of effect of the emulsified formulation set to 1. The results are shown in Table 4.

[0053] [Table 4]

[0054] As shown in Table 4, even when using anti-inflammatory analgesics other than loxoprofen, a tendency was observed for improved duration of effect when an emulsified formulation was used as the drug to create an emulsified aerosol. However, the degree of improvement in duration was small, and it was confirmed that the remarkable improvement in duration obtained in Example 1 was a unique effect of using loxoprofen as the anti-inflammatory analgesic.

Claims

1. Topical aerosols containing the following ingredients (A) to (F): (A) At least one selected from the group consisting of loxoprofen, pharmaceutically acceptable salts thereof, and solvates thereof. (B) a refreshing agent; (C) Polysorbate, (D) Oily base, (E) Water; (F) Propellant.

2. The topical aerosol agent according to claim 1, wherein component (D) is an ester oil.

3. The topical aerosol agent according to claim 1, wherein component (D) is isopropyl myristate.

4. The topical aerosol agent according to claim 1, wherein the (C) component is polysorbate 20.

5. The external aerosol agent according to claim 1, wherein the (F) component is liquefied petroleum gas.

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