Topical pharmaceutical composition

Abstract

With regard to an external pharmaceutical composition containing loxoprofen and / or a salt thereof and tocopherol acetate, the reduction in the amount of tocopherol acetate that may occur when the two are present together is suppressed. [Solution] A topical pharmaceutical composition containing (A) loxoprofen and / or a salt thereof, (B) tocopherol acetate, and (C) at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil.

Description

Technical Field

[0001] The present invention relates to an external pharmaceutical composition containing loxoprofen and / or a salt thereof and tocopherol acetate.

Background Art

[0002] Tocopherol acetate is a component known as a blood circulation-promoting ingredient, and is known to be formulated as an adjuvant in external pharmaceutical compositions for anti-inflammatory analgesia having an anti-inflammatory ingredient as the main active ingredient. However, when loxoprofen and / or a salt thereof is added as an anti-inflammatory ingredient in addition to tocopherol acetate to an external pharmaceutical composition, there is a problem that the stability of tocopherol acetate decreases and the content thereof is reduced. When the content of tocopherol acetate in the external pharmaceutical composition is reduced in this way, not only the expected blood circulation-promoting effect cannot be obtained, but also the effect that the entire external pharmaceutical composition should exert is weakened (Patent Document 1).

Prior Art Literature

Patent Literature

[0003]

Patent Document 1

Summary of the Invention

Problem to be Solved by the Invention

[0004] An object of the present invention is to provide a technique for suppressing reduction in the content of tocopherol acetate that may occur due to the coexistence of loxoprofen and / or a salt thereof and tocopherol acetate in an external pharmaceutical composition containing the same. Specifically, an object of the present invention is to provide an external pharmaceutical composition in which reduction in the content of tocopherol acetate caused by the coexistence of loxoprofen and / or a salt thereof and tocopherol acetate is suppressed.

Means for Solving the Problem

[0005] As a result of diligent research, the present inventors have found that the aforementioned problem can be solved by incorporating at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil into a topical pharmaceutical composition containing loxoprofen and / or a salt thereof and tocopherol acetate, thereby enabling the preparation of a topical pharmaceutical composition in which the reduction in tocopherol acetate is suppressed. The present invention was completed by further research based on this finding.

[0006] In other words, the present invention has the following embodiments. (I) Topical pharmaceutical compositions (I-1) A topical pharmaceutical composition containing (A) loxoprofen and / or a salt thereof, (B) tocopherol acetate, and (C) at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil. (I-2) The topical pharmaceutical composition according to (I-1), wherein (C) is at least two selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil. (I-3) Furthermore, (D) a topical pharmaceutical composition according to (I-1) or (I-2), comprising 60% by mass or more of a monohydric lower alcohol. (I-4) Furthermore, (E) an external pharmaceutical composition according to any one of (I-1) to (I-3), comprising at least one acid selected from the group consisting of lactic acid, citric acid, phosphoric acid, and boric acid. (I-5) A liquid external pharmaceutical composition as described in any one of items (I-1) to (I-4). (I-6) A topical pharmaceutical composition contained in any one of (I-1) to (I-5), which is housed in a polyolefin resin container.

[0007] (II) Methods to suppress the reduction in the amount of tocopherol acetate (II-1) A method for suppressing the reduction of tocopherol acetate in a topical pharmaceutical composition comprising (A) loxoprofen and / or a salt thereof, and (B) tocopherol acetate, characterized in that at least one, preferably two or more, selected from the group consisting of (C) diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil is incorporated into the topical pharmaceutical composition. (II-2) The method according to (II-1), wherein the topical pharmaceutical composition further contains (D) a monohydric lower alcohol in a proportion of 60% by mass or more. (II-3) The method according to (II-1) or (II-2), wherein the topical pharmaceutical composition is a liquid preparation further containing (F) water. (II-4) The method according to one of the items (II-1) to (II-3), characterized in that, in addition to component C, the external pharmaceutical composition further contains (E) at least one acid selected from the group consisting of lactic acid, citric acid, phosphoric acid, and boric acid. [Effects of the Invention]

[0008] According to the present invention, in a topical pharmaceutical composition comprising (A) loxoprofen and / or a salt thereof, and (B) tocopherol acetate, the reduction in the amount of tocopherol acetate produced in the topical pharmaceutical composition can be suppressed by incorporating (C) at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil. Therefore, the topical pharmaceutical composition of the present invention has suppressed reduction in the amount of tocopherol acetate and can exert the desired effects based on the inclusion of tocopherol acetate. [Modes for carrying out the invention]

[0009] (I) Topical pharmaceutical compositions The topical pharmaceutical composition of the present invention (hereinafter also referred to as "this composition") is characterized by containing (A) loxoprofen and / or a salt thereof (hereinafter also referred to as "component A"), (B) tocopherol acetate (hereinafter also referred to as "component B"), and (C) at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil (hereinafter also referred to as "component C"). The composition will be described below.

[0010] (A) Loxoprofen and / or salt thereof Loxoprofen and / or its salts are known components of nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is 2-[para-(2-oxocyclopentylmethyl)phenyl]propionic acid. The salt of loxoprofen is not particularly limited as long as it is a pharmaceutically acceptable salt of loxoprofen, and examples include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. Sodium salt is preferred. Furthermore, the salt of loxoprofen may be a hydrate.

[0011] In this composition, component A may be selected from the group consisting of loxoprofen and its salts and used alone, or two or more may be used in combination. While not limited, among component A, it is preferably a salt of loxoprofen. More preferably loxoprofen sodium, and even more preferably loxoprofen sodium hydrate.

[0012] The content of component A in this composition can be appropriately set according to the pharmacological effects to be provided to the topical pharmaceutical composition, and can be selected from a range of, for example, 0.1 to 10% by mass. Preferably, it can be 0.5 to 3% by mass, and more preferably 0.5 to 2% by mass.

[0013] (B) Tocopherol acetate Tocopherol acetate is a known component as a blood circulation-promoting ingredient. Specific examples of tocopherol acetate include d-α-tocopherol acetate, l-α-tocopherol acetate, and dl-α-tocopherol acetate, all of which can be used as tocopherol acetate in the present invention. Although not limited, dl-α-tocopherol acetate is preferable.

[0014] The content of component B in the present composition may be appropriately set according to the medicinal efficacy to be provided in the external pharmaceutical composition, and can be selected, for example, from the range of 0.01 to 1% by mass. Preferably 0.03 to 0.5% by mass, more preferably 0.05 to 0.3% by mass, and still more preferably 0.05 to 0.2% by mass can be mentioned.

[0015] In the present composition, the ratio of component A to component B is generally determined according to each content described above, and is not particularly limited, but can be appropriately set from the range of 0.01 to 1 part by mass as the ratio of component B per 1 part by mass of component A. Preferably 0.03 to 0.5 parts by mass, more preferably 0.05 to 0.3 parts by mass, and still more preferably 0.05 to 0.2 parts by mass can be mentioned.

[0016] As described above, in an external pharmaceutical composition containing component B together with component A, the content of component B decreases due to a decrease in the stability of component B, and as a result, the blood circulation-promoting effect of component B is attenuated. However, in the present composition, the decrease in the amount of component B can be suppressed by blending component C described later, so the desired effect (blood circulation-promoting effect) of component B can be obtained without increasing the amount of component B (or even when the amount of component B is reduced).

[0017] (C) Diisopropyl adipate, concentrated glycerin, polysorbate, and / or polyoxyethylene hydrogenated castor oil The composition contains, as component C, at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil. As described above, by blending and coexisting component C in an external pharmaceutical composition containing component B together with component A, it is possible to suppress a decrease in the amount of component B that may occur in the external pharmaceutical composition.

[0018] Diisopropyl adipate is a diester formed by dehydration condensation between two carboxy groups of adipic acid and the hydroxy group of isopropanol. Diisopropyl adipate is a liquid component that is used in external pharmaceuticals as a pharmaceutical additive for purposes such as base, oily solvent, or solubilization / dissolution aid.

[0019] When diisopropyl adipate is blended as component C in the present composition, the content of diisopropyl adipate in the present composition can be appropriately set so as to exhibit the effect of the present invention. Although not limited, it can be preferably selected from the range of 0.5 to 12% by mass. Preferably 1 to 10% by mass, more preferably 2 to 8% by mass, and even more preferably 2 to 4% by mass. In the present composition, the ratio of component B to diisopropyl adipate is determined according to each content described above, but from the viewpoint of better suppressing the decrease in the amount of component B, the ratio of diisopropyl adipate to 1 part by mass of component B can preferably be selected and adjusted from the range of 5 to 120 parts by mass. Preferably 10 to 100 parts by mass, more preferably 20 to 80 parts by mass, and still more preferably 20 to 50 parts by mass.

[0020] Concentrated glycerin is glycerin having a glycerin content of 95.0% or more. It is used in external pharmaceuticals as a pharmaceutical additive for purposes such as stabilization, solubilization, base, pH adjustment, shaping, preservation, and dissolution aid. In the present composition, as component C, concentrated glycerin conforming to the 18th Revised Japanese Pharmacopoeia or the Standards for Quasi-drug Ingredients 2021 may be used.

[0021] When concentrated glycerin is incorporated as component C in this composition, the amount of concentrated glycerin in this composition can be appropriately set to achieve the effects of the present invention. Preferably, it can be selected from a range of 0.5 to 12% by mass. Preferably, it can be 1 to 10% by mass, more preferably 2 to 8% by mass, even more preferably 3 to 6% by mass, and even more preferably 3 to 4% by mass. In this composition, the ratio of component B to concentrated glycerin is determined according to the above-mentioned amounts, but from the viewpoint of better suppressing the reduction of component B, preferably, the ratio of concentrated glycerin to 1 part by mass of component B can be selected and adjusted from a range of 5 to 120 parts by mass. Preferably, it can be 10 to 100 parts by mass, more preferably 20 to 80 parts by mass, even more preferably 25 to 55 parts by mass, and particularly preferably 25 to 35 parts by mass.

[0022] Polysorbate is a compound formed by bonding fatty acids to polyoxyethylene sorbitan, and is a type of nonionic synthetic surfactant. There are at least five types of polysorbates, including polysorbate 20 (polyoxyethylene sorbitan monolaurate (Tween 20)) (e.g., HLB 16.7-17.0), polysorbate 40 (polyoxyethylene sorbitan monopalmitate (20E.O.) (Tween 40)) (e.g., HLB 15.6-16.0), polysorbate 60 (polyoxyethylene sorbitan monostearate (Tween 60)) (e.g., HLB 14.9-15.7), polysorbate 65 (polyoxyethylene sorbitan tristearate (Tween 65)) (e.g., HLB 10.5-10.7), and polysorbate 80 (polyoxyethylene sorbitan oleate (Tween 80)) (e.g., HLB 13.0-15.7). All of these can be used as polysorbates in the present invention. While not limited, polysorbate 80 is preferred.

[0023] When polysorbate is incorporated as component C in this composition, the polysorbate content in this composition can be appropriately set to achieve the effects of the present invention, and is preferably selected from the range of 0.2 to 10% by mass. More preferably, it can be 0.5 to 8% by mass, even more preferably 1 to 5% by mass, and even more preferably 1 to 3% by mass. In this composition, the ratio of component B to polysorbate is determined according to the above-mentioned content, but from the viewpoint of better suppressing the reduction of component B, it is preferable to select and adjust the ratio of polysorbate to 1 part by mass of component B from the range of 2 to 100 parts by mass. Preferably, it can be 5 to 80 parts by mass, and more preferably 10 to 50 parts by mass.

[0024] Polyoxyethylene hydrogenated castor oil, also known as "POE hydrogenated castor oil" or "POE hydrogenated castor oil," is a type of nonionic surfactant obtained by adding hydrogen to castor oil to produce a hydrogenated oil, and then adding ethylene oxide through addition polymerization (hereinafter also referred to as "POE hydrogenated castor oil"). It is mainly used as an emulsifier, solubilizer, and dispersant in pharmaceuticals and other applications. In the present invention, while the POE hydrogenated castor oil is not limited, it is preferable that the average number of moles of ethylene oxide added to the hydrogenated castor oil is 20 or more. More preferably, the average number of moles of ethylene oxide added is 5 to 100, even more preferably 20 to 100, and even more preferably 40 to 60. The HLB of these POE hydrogenated castor oils is in the range of 6.0 to 16.5, preferably 10.5 to 16.5, and more preferably 12.5 to 14.0.

[0025] When POE hydrogenated castor oil is incorporated as component C in this composition, the content of POE hydrogenated castor oil in this composition can be appropriately set to achieve the effects of the present invention, and is preferably selected from the range of 0.5 to 12% by mass. More preferably 1 to 10% by mass, even more preferably 2 to 8% by mass, and even more preferably 2 to 5% by mass. In this composition, the ratio of component B to POE hydrogenated castor oil is determined according to the above-mentioned content, but from the viewpoint of better suppressing the reduction of component B, it is preferable to select and adjust the ratio of POE hydrogenated castor oil to 1 part by mass of component B from the range of 5 to 120 parts by mass. More preferably 10 to 100 parts by mass, even more preferably 20 to 80 parts by mass, and even more preferably 15 to 45 parts by mass.

[0026] The aforementioned diisopropyl adipate, concentrated glycerin, polysorbate, and POE hydrogenated castor oil can be used individually as component C in this composition, or two or more can be used in any combination. Of these, diisopropyl adipate, concentrated glycerin, and polysorbate are preferred, more preferably diisopropyl adipate and concentrated glycerin, and even more preferably diisopropyl adipate.

[0027] When two or more of these are combined, the manner of the combination is not particularly limited, but preferred examples include a combination of diisopropyl adipate and concentrated glycerin, a combination of diisopropyl adipate and polysorbate, and a combination of diisopropyl adipate and POE hydrogenated castor oil. More preferably, a combination of diisopropyl adipate and concentrated glycerin is used. When two or more C components are used in combination, the proportion of each C component in this composition can be reduced from the content of each component mentioned above, depending on the number and ratio of C components used in combination.

[0028] (D) Monohydric lower alcohols In addition to components A and B, and component C described above, this composition may further contain a monohydric lower alcohol (hereinafter also referred to as "component D"). The monohydric lower alcohol can be any pharmaceutically acceptable alcohol, and is not particularly limited to that extent. Examples include monohydric alcohols with 1 to 5 carbon atoms, such as ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, and pentanol. These monohydric lower alcohols may be used individually or in combination of two or more. Among these monohydric lower alcohols, ethanol and isopropanol are preferred, and ethanol is more preferred.

[0029] If the composition contains a monohydric lower alcohol, the content is not limited, but can be 60% by mass or more. Preferably, it can be 60-85% by mass, more preferably 65-80% by mass, and even more preferably 70-75% by mass.

[0030] (E) Acid This composition may further contain an acid in addition to the aforementioned components A and B (or components A, B and D), and component C (hereinafter also referred to as "component E"). The acids covered by this invention include organic acids and inorganic acids. Among these acids, lactic acid, citric acid, phosphoric acid, and boric acid are preferred. These may be used individually as component E, or two or more may be used in any combination. By adding these acids to the topical pharmaceutical composition containing components A and B (or components A, B and D) described above, in addition to component C, it becomes possible to more strongly, and preferably synergistically, enhance the effect of suppressing the reduction of component B.

[0031] Component E is more preferably lactic acid. The lactic acid may be in the d, l, or dl form, but the dl form is preferred.

[0032] When component E is incorporated into this composition, its content can be set as appropriate, but from the viewpoint of further suppressing the reduction of component B, for example, a range of 0.01 to 10% by mass can be given. Preferably, 0.05 to 5% by mass, more preferably 0.05 to 2% by mass, even more preferably 0.1 to 2% by mass, and even more preferably 0.5 to 1% by mass. When two or more types of component E are used in combination, the above content refers to their total amount.

[0033] Furthermore, when component E is incorporated into this composition, the ratio of component B to component E is determined according to the respective content amounts described above. However, from the viewpoint of further suppressing the reduction of component B, the ratio of component E to 1 part by mass of component B can be selected and adjusted from the range of 0.1 to 100 parts by mass. Preferably, it is 0.5 to 50 parts by mass, more preferably 0.5 to 20 parts by mass, even more preferably 1 to 20 parts by mass, and even more preferably 4.5 to 10 parts by mass.

[0034] Furthermore, when component E is incorporated into this composition, the ratio of component C to component E is determined according to the respective content described above. However, from the viewpoint of further suppressing the reduction of component B, the ratio of component E to 1 part by mass of component C can be selected and adjusted from the range of 0.001 to 50 parts by mass. Preferably, it is 0.005 to 10 parts by mass, more preferably 0.01 to 3 parts by mass, even more preferably 0.05 to 2 parts by mass, and even more preferably 0.07 to 0.7 parts by mass.

[0035] (F)Water This composition may further contain water. The water is not particularly limited and includes purified water, distilled water, ion-exchanged water, ultrapure water, and sterile water, with purified water being preferred. When water is added to this composition, its content can be appropriately set depending on the formulation, but for example, 5 to 35% by mass is a possible amount. Topical pharmaceutical compositions containing component B together with component A tend to have a deterioration in the stability of component B, making them prone to weight reduction when water is added. However, in this composition, the stability of component B is improved, so even when water is added, the reduction in the blood circulation promoting effect can be effectively suppressed. In view of these effects of the present invention, the water content in the topical pharmaceutical composition of the present invention is preferably 5 to 30% by mass, more preferably 5 to 25% by mass, and even more preferably 5 to 20% by mass.

[0036] (G) Other ingredients In addition to the components described above, this composition may optionally contain other pharmacological components, provided that they do not interfere with the effects of the present invention. Other pharmacological components that can be incorporated into this composition are not particularly limited, but examples include anti-inflammatory agents (other than component A above) such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and stearyl glycyrrhetinate; antihistamines such as diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, and chlorpheniramine maleate; local anesthetics such as lidocaine and pharmaceutically acceptable salts thereof, dibucaine and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate; blood circulation promoters (other than component B above) such as benzyl nicotinate, vanillylamide nonanoate, and capsicum tincture; analgesics (other than component A above) such as L-menthol; and crude drugs such as arnica tincture, Phellodendron amurense extract, Gardenia fruit extract, Aesculus hippocastanum extract, Belladonna extract, Angelica acutiloba extract, Lithospermum erythrorhizon extract, and Zanthoxylum piperitum extract.

[0037] Furthermore, in addition to the components described above, this composition may optionally contain other additives commonly used in topical pharmaceutical compositions. Examples of such additives include pH adjusters (other than component E above), surfactants (other than component C above), emulsifiers, solubilizers, preservatives, antioxidants, oils, stabilizers, chelating agents, thickeners, fragrances, colorants, etc. Preferred additives that can be incorporated into this composition include dibutylhydroxytoluene and isopropyl myristate. There are no particular limitations on the thickeners that can be incorporated into this composition, but examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxyvinyl polymer, hyaluronic acid, xanthan gum, etc.

[0038] Formulation The formulation form of this composition is not particularly limited, as long as it is applicable transdermally. Examples include liquids (including lotions, sprays, aerosols, and emulsions), foams, ointments, creams, gels, and patches. Among these, liquids or gels are preferred, and liquids are particularly preferred. These formulations can be prepared by compounding with additives appropriate to the formulation form, according to known methods described in the General Provisions for Formulations of the 18th Revised Japanese Pharmacopoeia, etc.

[0039] This composition can be packaged in a polyolefin resin container to produce the product. Polyolefin resin is a polymer obtained by polymerizing olefins (alkene hydrocarbons), which are a type of unsaturated hydrocarbon. Preferred polyolefin resins include polyethylene (PE) and polypropylene (PP). Polyethylene is more preferred.

[0040] Usage This composition is used by topical administration to the local area (skin) where anti-inflammatory and analgesic effects are required. As a topical anti-inflammatory and analgesic agent, this composition can be used for the treatment of 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, neuralgia, osteoarthritis, arthritis, etc.

[0041] (II) Methods to suppress the reduction in the amount of tocopherol acetate The present invention provides a method for suppressing the reduction of component B in a topical pharmaceutical composition containing loxoprofen and / or a salt thereof (component A) and tocopherol acetate (component B). This method can be carried out by incorporating at least one (component C), preferably two or more, selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil into the topical pharmaceutical composition.

[0042] The aforementioned topical pharmaceutical composition may contain 60% by mass or more of a monohydric lower alcohol (component D) in addition to components A and B. Furthermore, the aforementioned topical pharmaceutical composition may contain water (component F) in addition to components A and B, or components A, B, and D. The aforementioned topical pharmaceutical composition may also be in liquid form.

[0043] The above method, by incorporating at least one acid (component E) selected from the group consisting of lactic acid, citric acid, phosphoric acid, and boric acid in addition to component C into the topical pharmaceutical composition, can more effectively suppress the reduction of component B than when component C is incorporated alone.

[0044] In this method, the types and amounts of each component used, as well as the formulation form of the topical pharmaceutical composition, are as described in the "(I) Topical Pharmaceutical Composition" section above, and these descriptions shall be applied accordingly.

[0045] In this specification, the terms “contains” and “includes” include the meanings of “consisting of” and “substantially consisting of.” [Examples]

[0046] 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 under atmospheric pressure conditions. Unless otherwise specified, "%" below means "mass percent" and "parts" means "parts by mass".

[0047] Test method (1) Evaluation of the effect of tocopherol acetate on preventing weight loss The prepared topical pharmaceutical composition is placed in a polyolefin resin container (polyethylene container), sealed, and stored in an airtight container in a dark place at 50°C in an incubator for one month. Take 5g each of the topical pharmaceutical composition before storage (pre-storage composition) and the topical pharmaceutical composition after storage (post-storage composition), add 5mL of internal standard solution, and add ethanol (95) to make up to a total volume of 50mL, then mix. This solution is subjected to HPLC under the following conditions to measure the amount of tocopherol acetate.

[0048] (HPLC conditions) Equipment: UV absorbance spectrophotometer (manufactured by Shimadzu Corporation) Column: Wakosil-II 5C18 RS (4.6mm x 150mm, 5μm) (Manufactured by Wako Pure Chemical Industries, Ltd.) Mobile phase: methanol / diluted acetic acid (diluted 100 times with water) = 98 / 2 (volume ratio) Flow rate: 1.1ml / min Detection: UV284nm

[0049] The amount of tocopherol acetate (component B) lost due to storage is determined from the difference in the amount of tocopherol acetate (component B) measured in the pre-storage composition and the post-storage composition (amount of component B in the pre-storage composition - amount of component B in the post-storage composition). The "component B reduction inhibition rate %" is calculated using the following formula from the reduction rate obtained for each topical pharmaceutical composition (example) and the reduction rate obtained for the topical pharmaceutical composition set as a comparative example (comparative example), and rounded to the first decimal place. If this inhibition rate % exceeds 100%, it can be evaluated that the reduction inhibition effect of tocopherol acetate (component B) is high compared to the comparative example used as the reference for the comparative example's reduction value.

[0050] B component weight loss suppression rate% = {(Comparative example weight loss - Example weight loss) / Example weight loss} × 100 + 100

[0051] Test Example 1: Evaluation of the effect of component C on inhibiting the reduction of tocopherol acetate Topical pharmaceutical compositions with the compositions shown in Table 1 (Comparative Example 1, Examples 1-4) were prepared. Specifically, the following procedure was followed for preparation. First, loxoprofen sodium hydrate (hereinafter also referred to as "loxoprofen Na hydrate") was mixed with ethanol (ethanol (95)) and stirred until homogeneous. To the resulting solution, tocopherol acetate (dl-α-tocopherol acetate) and each of the G components listed in Table 1 were mixed and stirred until homogeneous (Comparative Example 1). For the Examples, each of the C components listed in Table 1 was further mixed in and stirred until homogeneous. Polysorbate 80 was used as the polysorbate listed in Table 1. In both the comparative examples and the examples, purified water was added at the end to bring the total volume to 100g, and the mixture was stirred until uniform to prepare it as a liquid, which was then placed in a polyethylene container (Comparative Example 1 and Examples 1-4).

[0052] For each topical pharmaceutical composition (Comparative Example 1, Examples 1-4), the effect of inhibiting weight loss of tocopherol acetate (component B) was evaluated using the test method described above. The results obtained are also shown in Table 1.

[0053] [Table 1]

[0054] As is clear from Table 1, by incorporating one or more types of component C (diisopropyl adipate, concentrated glycerin, and polysorbate 80) in addition to components A and B, the reduction in component B was dramatically suppressed compared to the case without component C (Comparative Example 1). Thus, it was confirmed that a high effect in suppressing the reduction of component B can be obtained by incorporating diisopropyl adipate alone or in combination with other component C (concentrated glycerin, polysorbate 80) as component C, or by incorporating concentrated glycerin alone or in combination with other component C (diisopropyl adipate) as component C in an external pharmaceutical composition containing components A and B.

[0055] Test Example 2: Evaluation of the effect of components C and E on inhibiting the reduction of tocopherol acetate Topical pharmaceutical compositions with the compositions shown in Table 2 (Comparative Examples 1 and 2, Examples 5-15) were prepared. The topical pharmaceutical composition of Comparative Example 1 was prepared by the method described in Test Example 1. The topical pharmaceutical compositions of Comparative Example 2 and Examples 5-15 were prepared by the following procedure. First, loxoprofen sodium hydrate was mixed with ethanol (ethanol (95)) and stirred until homogeneous. To the resulting solution, tocopherol acetate (dl-α-tocopherol acetate), lactic acid (dl-lactic acid), and each of the G components listed in Table 2 were mixed and stirred until homogeneous (Comparative Example 2). For the Examples, each of the C components listed in Table 2 was further mixed and stirred until homogeneous. Polysorbate 80 was used as the polysorbate listed in Table 2. In both Comparative Example 2 and the Examples, purified water was added at the end to bring the total volume to 100g, and the mixture was stirred until uniform to prepare it as a liquid, which was then placed in a polyethylene container (Comparative Example 2 and Examples 5-15).

[0056] For each topical pharmaceutical composition (Comparative Examples 1 and 2, Examples 5-15), the effect of inhibiting weight loss of tocopherol acetate (component B) was evaluated using the test method described above. The results obtained using the weight loss value of Comparative Example 2 as the comparative example weight loss value are also shown in Table 2.

[0057] [Table 2]

[0058] As shown in Table 2, it was confirmed that by adding component C (diisopropyl adipate, concentrated glycerin, polysorbate 80, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, and POE hydrogenated castor oil 60) in addition to components A and B, the reduction in component B was dramatically suppressed compared to the case without component C (Comparative Example 2) (Examples 5-15). Furthermore, as shown in Table 2, Comparative Example 2, which added component E (lactic acid) in addition to components A and B, showed significantly suppressed reduction in component B compared to Comparative Example 1, which did not contain component E, confirming that lactic acid also contributes to suppressing the reduction of component B. Thus, by combining components C and E in an external pharmaceutical composition containing components A and B, a high effect of suppressing the reduction of component B can be obtained.

[0059] Test Example 3: Evaluation of the effect of component C (2 components) and component E on inhibiting the reduction of tocopherol acetate Topical pharmaceutical compositions with the compositions shown in Table 3 (Comparative Examples 1 and 2, Examples 16-25) were prepared using the methods described in Test Examples 1 and 2, and placed in polyethylene containers. Polysorbate 80 was used as the polysorbate shown in Table 3. For each of these topical pharmaceutical compositions, the effect of inhibiting the reduction of tocopherol acetate (component B) was evaluated using the test method described above. The results obtained using the reduction value of Comparative Example 2 as the comparative example reduction value are also shown in Table 3. Table 3 also shows the theoretical value of the reduction inhibition rate of component B when two types of component C are used in combination.

[0060] [Table 3]

[0061] As shown in Table 3, it was confirmed that by combining two types of component C (diisopropyl adipate, concentrated glycerin, polysorbate 80, POE hydrogenated castor oil 40, and POE hydrogenated castor oil 60) in addition to components A and B, the reduction in component B was dramatically suppressed compared to the case without component C (Comparative Example 2) (Examples 16-25). Similar to Test Example 2, it was confirmed that lactic acid also contributed to the suppression of component B reduction. Thus, in topical pharmaceutical compositions containing components A and B, a high effect of suppressing component B reduction can be obtained by combining component E with two or more types of component C. In particular, the combined use of diisopropyl adipate and concentrated glycerin as component C (Example 16), diisopropyl adipate and polysorbate 80 (Example 17), and diisopropyl adipate and POE hydrogenated castor oil 40 or POE hydrogenated castor oil 60 (Examples 19-21) synergistically improves the effect of each component C on suppressing the reduction of component B.

[0062] Test Example 4: Evaluation of the effect of components C and E on inhibiting the reduction of tocopherol acetate. External pharmaceutical compositions (Comparative Examples 1 and 3, Examples 1-3, 26-34) with the compositions shown in Tables 4 and 5 were prepared according to the methods described in Test Examples 1 and 2 (however, citric acid, phosphoric acid, and boric acid were used instead of lactic acid as component E) and placed in polyethylene containers. For each of these topical pharmaceutical compositions, the effect of inhibiting weight loss of tocopherol acetate (component B) was evaluated using the test method described above. Table 4 shows the results obtained using the weight loss value of Comparative Example 3 as the comparative example weight loss value, and Table 5 shows the results obtained using the weight loss value of Comparative Example 1 as the comparative example weight loss value.

[0063] [Table 4]

[0064] [Table 5]

[0065] The results from Comparative Examples 1 and 3 shown in Table 4 confirm that, like lactic acid, citric acid also contributes to suppressing the reduction of component B. As shown in Table 4, it was confirmed that by combining one or two types of component C (diisopropyl adipate, concentrated glycerin) with component E (citric acid) in addition to components A and B, the reduction of component B was dramatically suppressed compared to the case without component C (Comparative Example 3) (Examples 26-28).

[0066] Furthermore, as shown in Table 5, it was confirmed that inorganic acids such as phosphoric acid and boric acid can have similar effects to organic acids such as lactic acid and citric acid mentioned above. Specifically, as can be seen from the comparison of the results of Examples 1-3 and Examples 29-34 in Table 5, by combining component E with component C (diisopropyl adipate, concentrated glycerin) in an external pharmaceutical composition containing components A and B, the effect of suppressing the reduction of component B can be significantly improved (Examples 29-34).

Claims

1. A topical pharmaceutical composition containing (A) loxoprofen and / or a salt thereof, (B) tocopherol acetate, and (C) at least one selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil.

2. The topical pharmaceutical composition according to claim 1, wherein (C) is at least two selected from the group consisting of diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil.

3. Furthermore, the topical pharmaceutical composition according to claim 1, further comprising (D) a monohydric lower alcohol in a proportion of 60% by mass or more.

4. Furthermore, the topical pharmaceutical composition according to claim 1 or 3, further comprising (E) at least one acid selected from the group consisting of lactic acid, citric acid, phosphoric acid, and boric acid.

5. A topical pharmaceutical composition according to claim 1 or 3, which is a liquid formulation.

6. An external pharmaceutical composition according to claim 1 or 3, housed in a polyolefin resin container.

7. A method for suppressing the reduction of tocopherol acetate in a topical pharmaceutical composition comprising (A) loxoprofen and / or a salt thereof, and (B) tocopherol acetate, characterized in that the topical pharmaceutical composition contains at least one, preferably two or more, selected from the group consisting of (C) diisopropyl adipate, concentrated glycerin, polysorbate, and polyoxyethylene hydrogenated castor oil.

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