JP7186024B2 - External pharmaceutical composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an external pharmaceutical composition containing loxoprofen and/or a salt thereof and an ester derivative of nicotinic acid in water while suppressing generation of insoluble matter.

Loxoprofens (loxoprofen and/or salts thereof) typified by loxoprofen sodium are known as drugs having excellent analgesic and anti-inflammatory effects, and are also used as topical pharmaceutical compositions. Also, loxoprofens are known to be soluble in water and ethanol.

Esters of nicotinic acid such as nicotinic acid benzyl ester are known as agents having a blood circulation-promoting effect and are also used as topical pharmaceutical compositions. It is also known that esters of nicotinic acid are almost insoluble in water and miscible with ethanol.

In external compositions containing loxoprofens, nicotinic acid esters such as benzyl nicotinate may be blended in order to impart a blood circulation promoting action to the analgesic/anti-inflammatory action of loxoprofens. In such cases, it is common to include ethanol as a base in order to dissolve both components in water.

Furthermore, in order to improve the storage stability of an externally applied composition containing loxoprofens, the use of isopropanol instead of ethanol has been proposed, for example, in Patent Document 1. Patent Document 1 also discloses a formulation containing benzyl nicotinate in such a loxoprofen skin preparation for external use containing isopropanol.

JP 2017-200909 A

Loxoprofen formulations containing a large amount of ethanol are concerned about skin irritation due to ethanol. In addition, even in formulations of loxoprofens containing isopropanol instead of ethanol, isopropanol is more irritating than ethanol, and thus there is concern about skin irritation more than ethanol formulations.

Therefore, the present invention provides a formulation capable of suppressing the formation of insoluble matter without using a large amount of ethanol or isopropanol in an external composition containing loxoprofen and/or a salt thereof and an ester derivative of nicotinic acid in water. intended to provide

As a result of extensive studies, the present inventors have found that the use of N-methyl-2-pyrrolidone in an external pharmaceutical composition containing nicotinic acid ester derivatives together with loxoprofen and/or salts thereof in water suppresses the formation of insoluble matter. found to get. The present invention was completed by further studies based on this finding.

That is, the present invention provides inventions in the following aspects.
Section 1. An external pharmaceutical composition comprising (A) loxoprofen and/or salts thereof, (B) an ester derivative of nicotinic acid, (C) N-methyl-2-pyrrolidone, and (D) water.
Section 2. Item 2. The topical pharmaceutical composition according to Item 1, wherein the component (B) is benzyl nicotinate.
Item 3. Item 3. The topical pharmaceutical composition according to Item 1 or 2, wherein the component (C) is contained in an amount of 0.1 to 20% by weight.
Section 4. Item 4. The topical pharmaceutical composition according to any one of items 1 to 3, wherein the component (C) is contained in an amount of 20 to 1000 parts by weight per 1 part by weight of the component (B).
Item 5. A pharmaceutical composition for external application, in which (A) loxoprofen and/or a salt thereof, (B) an ester derivative of nicotinic acid and (D) water, and (C) N-methyl-2-pyrrolidone coexist in the pharmaceutical composition for external application. A method for suppressing the formation of insoluble matter in a substance.

According to the present invention, a pharmaceutical composition for external application containing loxoprofen and/or a salt thereof and an ester derivative of nicotinic acid in water can suppress the formation of insoluble matter by using N-methyl-2-pyrrolidone. A prescription is provided.

1. External pharmaceutical composition The external pharmaceutical composition of the present invention comprises (A) loxoprofen and/or a salt thereof (hereinafter sometimes referred to as "component (A)") and (B) an ester derivative of nicotinic acid (hereinafter referred to as sometimes referred to as "(B) component"), (C) N-methyl-2-pyrrolidone (hereinafter sometimes referred to as "(C) component"), and (D) water (hereinafter referred to as " (D) It is characterized by containing "ingredient"). The pharmaceutical composition for external application of the present invention is described in detail below.

(A) Loxoprofen and/or its salt The external pharmaceutical composition of the present invention contains loxoprofen and/or its salt as component (A). Loxoprofen and/or its salt is a component known as a kind of non-steroidal anti-inflammatory drug (NSAID). 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 thereof include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts. Also, the salt of loxoprofen may be a hydrate.

In the topical pharmaceutical composition of the present invention, as component (A), loxoprofen and/or salts thereof may be selected and used singly or in combination of two or more. . (A) Among the components, preferably loxoprofen salts, more preferably loxoprofen sodium, and still more preferably loxoprofen sodium hydrate.

The content of component (A) in the topical pharmaceutical composition of the present invention may be appropriately set according to the efficacy and the like to be provided in the topical pharmaceutical composition. 5 to 3% by weight may be mentioned.

(B) Ester derivative of nicotinic acid The external pharmaceutical composition of the present invention contains an ester derivative of nicotinic acid as component (B). Ester derivatives of nicotinic acid are known ingredients known to have blood circulation promoting action, cell activating action, and the like. Since the ester derivative of nicotinic acid is oil-soluble, when it is contained in water together with loxoprofen and/or a salt thereof in a pharmaceutical composition for external use, insoluble matter is produced unless ethanol or isopropanol is added. It is possible to dissolve ester derivatives of nicotinic acid without using a large amount of ethanol or isopropanol.

The ester derivative of nicotinic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include benzyl nicotinic acid, β-butoxyethyl nicotinic acid, and methyl nicotinic acid. These nicotinic acid ester derivatives may be used singly or in combination of two or more. In the present invention, since it is possible to suppress the generation of insoluble matter in an external pharmaceutical composition containing loxoprofen and/or a nicotinic acid ester derivative in water, the nicotinic acid ester derivative is a highly hydrophobic substance. However, the generation of insoluble matter can be effectively suppressed. From this point of view, benzyl nicotinate is preferred among the components (B) in the topical pharmaceutical composition of the present invention.

The content of component (B) in the topical pharmaceutical composition of the present invention may be appropriately set according to the efficacy of the topical pharmaceutical composition, and is preferably 0.001 to 0.1% by weight, for example. is 0.003 to 0.05% by weight, more preferably 0.005 to 0.02% by weight.

(C) N-methyl-2-pyrrolidone The external pharmaceutical composition of the present invention contains N-methyl-2-pyrrolidone as component (C). A composition for external use containing loxoprofen and/or a salt thereof and an ester derivative of nicotinic acid in water produces insoluble matter unless ethanol or isopropanol is added. By containing -pyrrolidone, the ester derivative of nicotinic acid can be dissolved without using a large amount of ethanol or isopropanol.

The content of component (C) in the topical pharmaceutical composition of the present invention may be appropriately set according to the content of component (B) used, and is, for example, 0.01 to 20% by weight, preferably 0. .2 to 10% by weight, more preferably 0.5 to 6% by weight. In the present invention, component (C) has much better dissolving power than ethanol and isopropanol for nicotinic acid ester derivatives blended with loxoprofen and/or salts thereof in water. Even a small amount that cannot be solubilized can effectively suppress the generation of insoluble matter. Therefore, the topical pharmaceutical composition of the present invention can also suppress skin irritation that may be caused by ethanol, isopropanol, and the like.

In addition, in the pharmaceutical composition of the present invention, the ratio of the component (B) and the component (C) is determined according to the contents described above. The content of component (C) per 1 part by weight of component (B) is 20 to 1000 parts by weight, preferably 90 to 600 parts by weight.

(D) Water The topical pharmaceutical composition of the present invention contains water as component (D). Water is not particularly limited, and includes purified water, distilled water, ion-exchanged water, ultrapure water, sterilized water, and the like, preferably purified water. The content of the component (D) in the topical pharmaceutical composition of the present invention may be appropriately set according to the formulation form. INDUSTRIAL APPLICABILITY In the present invention, generation of insoluble matter in an external pharmaceutical composition containing loxoprofen and/or a salt thereof and an ester derivative of nicotinic acid in water can be suppressed. can be effectively suppressed. From such a viewpoint, the amount of component (D) in the topical pharmaceutical composition of the present invention is preferably 10% by weight or more, more preferably 30% by weight or more, still more preferably 60% by weight or more, and still more preferably 80% by weight. % by weight or more. Although the upper limit of the amount of component (D) is not particularly limited, it is, for example, 99% by weight or less, preferably 98% by weight or less. As described above, the topical pharmaceutical composition of the present invention can contain a large amount of water, and therefore can suppress skin irritation, which is a concern due to ethanol, isopropanol, and the like.

In addition, in the pharmaceutical composition of the present invention, the ratio of the component (B) and the component (D) is determined according to each content described above. In the present invention, it is possible to suppress the generation of insoluble matter in an external pharmaceutical composition containing loxoprofen and/or a salt thereof and an ester derivative of nicotinic acid in water. It is possible to effectively suppress the generation of substances. From this point of view, the content of component (D) per 1 part by weight of component (B) is preferably 1000 parts by weight or more, more preferably 3000 parts by weight or more, still more preferably 6000 parts by weight or more, and still more preferably 8000 parts by weight or more. The upper limit of the amount of component (D) per 1 part by weight of component (B) is not particularly limited. As described above, the topical pharmaceutical composition of the present invention can contain a large amount of water, and therefore can suppress skin irritation, which is a concern due to ethanol, isopropanol, and the like.

Other Ingredients The topical pharmaceutical composition of the present invention may optionally contain other pharmacological ingredients in addition to the above-described ingredients, as long as they do not interfere with the effects of the present invention. Other pharmacological ingredients that can be blended in the topical pharmaceutical composition of the present invention are not particularly limited, but for example, anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, antihistamines such as chlorpheniramine maleate; lidocaine and its pharmaceutically acceptable salts, dibucaine and its pharmaceutically acceptable salts, local anesthetics such as ethyl aminobenzoate capsaicinoids (specifically, nonanoic acid vanillylamide; and capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, etc.), blood circulation promoters such as tocopherol acetate (other than the above component (B)) herbal medicines such as arnica tincture, Phellodendron bark extract, Sanshishi extract, Horse chestnut extract, Rohto extract, Belladonna extract, Angelica extract, Chikon extract, Sansho extract.

Furthermore, the pharmaceutical composition for external application of the present invention may contain, if necessary, solvents and other additives that are commonly used in pharmaceutical compositions for external application, in addition to the components described above. Examples of such solvents include monohydric lower alcohols having 1 to 5 carbon atoms such as ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol; propylene glycol, dipropylene glycol, 1,3 - dihydric alcohols having 2 to 8 carbon atoms such as butylene glycol; In the present invention, it is possible to suppress the generation of insoluble matter in an external pharmaceutical composition containing nicotinic acid ester derivatives together with loxoprofen and/or a salt thereof in water. , or even if it is not contained, the generation of insoluble matter can be effectively suppressed. From such a viewpoint, the content of the monohydric lower alcohol in the topical pharmaceutical composition of the present invention is 0 to 70% by weight, preferably 0 to 55% by weight, more preferably 0 to 40% by weight, and still more preferably 0% by weight. to 20% by weight, more preferably 0 to 5% by weight. This can satisfactorily suppress skin irritation. When the topical pharmaceutical composition of the present invention contains a dihydric alcohol, the amount of the dihydric alcohol is, for example, 0.01 to 20% by weight, preferably 0.3 to 10% by weight, more preferably 0.5 to 20% by weight. 8% by weight. Additives include, for example, pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, perfumes, colorants, and the like. mentioned.

Formulation Form The formulation form of the topical pharmaceutical composition of the present invention is not particularly limited as long as it can be applied transdermally. Examples include foams, ointments, creams, gels, patches and the like. Among these, liquid agents or gel agents are preferred, and liquid agents are particularly preferred. Preparation into these formulations can be carried out according to known methods described in the Japanese Pharmacopoeia 17th Edition, General Rules for Formulations, etc., by using additives suitable for the formulations.

Container The container for containing the pharmaceutical composition for external use of the present invention is not particularly limited, and can be appropriately determined according to the formulation form. When the pharmaceutical composition for external use of the present invention is prepared as an external pharmaceutical composition, it can be contained in an applicator container having an applicator part to which a porous member or a ball member is attached. In particular, in the present invention, it is preferable that the coating material is housed in an application container having an application section to which a porous member is attached. Since the generation of insoluble matter is suppressed in the topical pharmaceutical composition of the present invention, the active ingredient is dammed up by the porous member and stays in the container at the time of application. can be suppressed, and clogging of insoluble matter in the porous member can also be suppressed.

As the porous member attached to the application portion of the application container, any member may be used as long as it has fine continuous pores to exhibit porosity. Moreover, the porous member is preferably a flexible member from the viewpoint of facilitating application. Examples of such a porous member include a sponge member and a mesh member, preferably a sponge member. The material of the porous member is also not particularly limited, but includes synthetic resin materials such as urethane and rubber, and natural materials such as cellulose, preferably synthetic resin materials such as urethane and rubber. A particularly preferable example of the porous member is a rubber sponge member.

Mode of Use The topical pharmaceutical composition of the invention is used by topical administration to the local area (skin) where anti-inflammatory analgesia is required. The topical pharmaceutical composition of the present invention is used as an external anti-inflammatory analgesic to treat shoulder pain associated with stiff shoulders, joint pain, lumbago, muscle pain, tenosynovitis (hand/wrist pain), elbow pain (tennis elbow, etc.), and bruise pain. , sprain pain, fracture pain, neuralgia, osteoarthritis, arthritis and the like.

2. Method for Suppressing the Generation of Insoluble Matters As described above, N-methyl-2-pyrrolidone suppresses the generation of insoluble matter in an external pharmaceutical composition containing loxoprofen and/or a salt thereof in water together with an ester derivative of nicotinic acid. can do. Therefore, the present invention further provides a topical pharmaceutical composition comprising loxoprofen and/or a salt thereof as component (A), an ester derivative of nicotinic acid as component (B), and water as component (D), Provided is a method for suppressing the formation of insoluble matter in a pharmaceutical composition for external use, in which component (C) N-methyl-2-pyrrolidone is present.

In the present invention, suppressing the formation of insoluble matter means that the external pharmaceutical composition has a transparent appearance, specifically transparent (clear) or translucent, more preferably transparent (clear). Say things.

In the method for suppressing the formation of insoluble matter, the types and amounts of components used, the form of the pharmaceutical composition for external application, etc. are as shown in the section "1. Pharmaceutical composition for external application."

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these.

Test example 1
[Preparation of topical pharmaceutical composition]
A topical pharmaceutical composition having the composition shown in Table 1 was prepared. Specifically, it was prepared by the following procedure. First, purified water and loxoprofen sodium hydrate (loxoprofen sodium hydrate) were mixed and stirred until uniform. A mixed solution of an ester derivative of nicotinic acid (benzyl nicotinate) and N-methyl-2-pyrrolidone was mixed with the resulting solution and stirred until uniform. Finally, purified water was added so that the total amount was 100 g, and the mixture was stirred until uniform.

[Evaluation of Insoluble Matter Generation Suppression]
100 g of the prepared external pharmaceutical composition was placed in a transparent screw tube with a barrel diameter of 40 mm, and the appearance was visually observed to evaluate suppression of formation of insoluble matter according to the following criteria.
◎: transparent, clear (formation of insoluble matter is extremely well suppressed)
○: Translucent (the generation of insoluble matter is suppressed)
△: Insoluble matter dispersed and opaque (precipitated insoluble matter floats)
×: Separation of insoluble matter (precipitated insoluble matter precipitates)

Table 1 shows the results obtained. As is clear from Table 1, the external pharmaceutical composition containing loxoprofen sodium hydrate together with benzyl nicotinate in water (Comparative Example 1) caused separation of insoluble matter. In addition, the external pharmaceutical composition containing 75% by weight of ethanol and 75% by weight of benzyl nicotinic acid in water (Reference Example 2) inhibited the formation of insoluble matter very well. ), resulting in separation of the insolubles. In addition, topical pharmaceutical compositions containing loxoprofen sodium hydrate and benzyl nicotinate in water together with polyhydric alcohols such as glycerin, D-sorbitol and polyvinyl alcohol (Comparative Examples 2-4) also caused separation of insolubles. On the other hand, in the topical pharmaceutical compositions containing N-methyl-2-pyrrolidone together with loxoprofen sodium hydrate and benzyl nicotinate in water (Examples 1 and 2), the amount of N-methyl-2-pyrrolidone was as low as 5% or 1% by weight, the formation of insolubles was very well suppressed.

Claims (5)

(A) loxoprofen and/or salts thereof, (B) benzyl nicotinate, β-butoxyethyl nicotinate, and/or methyl nicotinate, ( C) N-methyl-2-pyrrolidone, and (D) water An external pharmaceutical composition comprising: 2. The pharmaceutical composition for external application according to claim 1, wherein the component (B) is benzyl nicotinate. 3. The pharmaceutical composition for external application according to claim 1, wherein said component (C) is contained in an amount of 0.1 to 20% by weight. The topical pharmaceutical composition according to any one of claims 1 to 3, wherein said component (C) is contained in an amount of 20 to 1000 parts by weight per 1 part by weight of said component (B). In the external pharmaceutical composition, together with (A) loxoprofen and/or salts thereof, (B) benzyl nicotinate, β-butoxyethyl nicotinate, and/or methyl nicotinate, and (D) water, ( C) A method for suppressing the formation of insoluble matter in a pharmaceutical composition for external application, in which N-methyl-2-pyrrolidone is coexistent.