TW202228668A - Pharmaceutical composition for external use - Google Patents

Abstract

To provide a pharmaceutical composition for external use, which comprises loxoprofen and/or a salt thereof, isopropyl myristate, and water, and which has improved dispersion stability. A pharmaceutical composition for external use which comprises loxoprofen and/or a salt thereof, isopropyl myristate and water and to which N-methyl-2-pyrrolidone is further added so that the dispersion stability is improved and a uniform suspended state can be achieved.

Description

External pharmaceutical composition

The present invention relates to a pharmaceutical composition for external use, which comprises loxoprofen and/or its salt, isopropyl myristate, and water, and has improved dispersion stability.

Loxoprofen and/or its salts are non-steroidal anti-inflammatory analgesics with antipyretic, analgesic and anti-inflammatory effects, and are used in external pharmaceutical compositions. On the other hand, it is known that the feeling of use can be improved by adding a liquid oil to a pharmaceutical composition for external use. Therefore, various prescriptions of external pharmaceutical compositions containing loxoprofen and/or its salts and liquid oils have been previously reported. For example, Patent Document 1 describes that a pharmaceutical composition for external use including loxoprofen and/or its salt, tocopherol acetate, liquid oil, and water can have excellent transdermal permeability .

In addition, among liquid oils, isopropyl myristate is known to be excellent in emollient action, imparting a soft and refreshing touch, and the like, and it is known that isopropyl myristate can be formulated into external pharmaceutical compositions by formulating isopropyl myristate. Propyl ester gives a good feeling of use. Therefore, in order to improve the feeling of use or the like in a pharmaceutical composition for external use containing loxoprofen and/or a salt thereof, it has been desired to develop a preparation formulation in which isopropyl myristate is further formulated. [Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2019-206496

[The problem to be solved by the invention] The inventors of the present invention have made intensive studies to develop a pharmaceutical composition for external use comprising loxoprofen and/or a salt thereof, isopropyl myristate, and water, and as a result, have found the following problem: , the dispersion stability of isopropyl myristate (the characteristic of stably maintaining the state after dispersion) is low, and a uniform suspension state cannot be formed.

Therefore, an object of the present invention is to provide a pharmaceutical composition for external use comprising loxoprofen and/or a salt thereof, isopropyl myristate, and water, and with improved dispersion stability.

[Means of Solving Problems] As a result of diligent studies to solve the above-mentioned problems, the present inventors have found that N-methylmethacrylate can be prepared by mixing loxoprofen and/or its salts, isopropyl myristate, and water in a pharmaceutical composition for external use. yl-2-pyrrolidone, and the dispersion stability is improved, and a uniform suspension state can be formed. The present invention is based on the above-mentioned knowledge and has been completed by further repeated studies.

That is, this invention provides invention of the aspect disclosed below. Item 1. A pharmaceutical composition for external use, comprising: (A) loxoprofen and/or a salt thereof, (B) isopropyl myristate, (C) N-methyl-2-pyrrolidone, and ( D) water. Item 2. The pharmaceutical composition for external use according to Item 1, wherein the content of the component (C) is 2% by weight to 15% by weight. [Effect of invention]

According to the present invention, in the external pharmaceutical composition comprising loxoprofen and/or its salt, isopropyl myristate, and water, the dispersion stability of isopropyl myristate is improved, and a uniform suspension state can be formed .

1. External pharmaceutical composition The external pharmaceutical composition of the present invention is characterized by containing: (A) loxoprofen and/or a salt thereof, (B) isopropyl myristate, (C) N-methyl-2-pyrrolidone, and (D) Water. Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.

[(A) Loxoprofen and/or its salts] The external pharmaceutical composition of the present invention contains loxoprofen and/or its salt (it may also be expressed as (A) component). Loxoprofen is a non-steroidal anti-inflammatory analgesic also known as 2-[p-(2-oxocyclopentylmethyl)phenyl]propionic acid.

The salt of loxoprofen is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts. In addition, the salt of loxoprofen may be a hydrate.

As the component (A), one of loxoprofen and/or a salt thereof may be selected and used alone, or two or more of them may be used in combination. Among the components (A), salts including loxoprofen are preferable, loxoprofen sodium is more preferable, and loxoprofen sodium hydrate is further preferable.

The content of the component (A) in the pharmaceutical composition for external use of the present invention may be appropriately set according to the medicinal effect to be possessed, for example, 0.1% by weight to 10% by weight, preferably 0.5% by weight to 3% by weight %, more preferably 0.5% by weight to 2% by weight.

[(B) Isopropyl myristate] The external pharmaceutical composition of this invention contains isopropyl myristate (it may also be expressed as (B) component). Isopropyl myristate is a fatty acid alkyl ester in which myristic acid and isopropyl alcohol are ester-bonded.

The content of component (B) in the pharmaceutical composition for external use of the present invention may be appropriately set according to the feeling of use to be imparted, for example, 0.1 to 30% by weight, preferably 0.5 to 20% by weight %, more preferably 1% by weight to 10% by weight.

In the pharmaceutical composition for external use of the present invention, the ratio of the (B) component to the (A) component is defined according to the respective contents of these components, for example, with respect to 1 part by weight of the (A) component, ( B) component is 0.01 to 1000 parts by weight, preferably 0.1 to 100 parts by weight, more preferably 0.5 to 20 parts by weight.

[(C)N-Methyl-2-pyrrolidone] The pharmaceutical composition for external use of the present invention also contains N-methyl-2-pyrrolidone (sometimes expressed as (C) component) in addition to the above-mentioned components. In the external pharmaceutical composition of the present invention, by including loxoprofen and/or its salt together with isopropyl myristate, and N-methyl-2-pyrrolidone, the isopropyl myristate can be increased. The dispersion stability of propyl ester forms a uniform suspension state. The N-methyl-2-pyrrolidone is a compound in which a methyl group is substituted on the nitrogen atom of 2-pyrrolidone.

As content of (C)component in the external pharmaceutical composition of this invention, 0.1 weight% - 20 weight% are mentioned, for example. From the viewpoint of further improving the dispersion stability of isopropyl myristate, it is preferably 1% by weight to 15% by weight, and the content of the component (C) in the pharmaceutical composition for external use of the present invention includes: It is preferably 2% by weight to 15% by weight, more preferably 5% by weight to 15% by weight.

In the pharmaceutical composition for external use of the present invention, the ratio of the component (C) to the component (A) is defined according to the respective contents of these components, for example, relative to 1 part by weight of the component (A), ( C) component is 0.01-1000 weight part, Preferably it is 0.1-100 weight part, More preferably, it is 1-20 weight part, More preferably, it is 5-15 weight part.

[(D) Water] The external pharmaceutical composition of the present invention contains water as a base. The content of water in the pharmaceutical composition for external use of the present invention may be the remainder after excluding other components to be prepared, for example, 5 to 99% by weight, preferably 10 to 92% by weight.

[monohydric lower alcohol] The external pharmaceutical composition of the present invention may further contain a monohydric lower alcohol. In the present invention, the term "monohydric lower alcohol" refers to a monohydric alcohol having 1 to 5 carbon atoms.

The type of the monovalent lower alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include ethanol, n-propanol, isopropanol, and the like. These monovalent lower alcohols may be used alone or in combination of two or more.

Among these monovalent lower alcohols, ethanol and isopropanol are preferably used, and ethanol is more preferably used.

When the external pharmaceutical composition of the present invention contains a monovalent lower alcohol, the content thereof is not particularly limited, but for example, 0.1 to 80% by weight, preferably 1 to 75% by weight can be mentioned.

[other ingredients] The pharmaceutical composition for external use of the present invention may contain, in addition to the above-mentioned components, other additives generally used as necessary. Examples of such additives include surfactants, vegetable oils, animal oils, mineral oils, fatty acid alkyl esters (other than component (B)), fatty acids, higher alcohols, pH adjusters, buffers, solubilizers, preservatives Agents, preservatives, antioxidants, stabilizers, fragrances, colorants, etc. When these additives are contained in the pharmaceutical composition for external use of the present invention, the content thereof may be appropriately set according to the types of additives to be used, and the like.

In addition, the pharmaceutical composition for external use of the present invention may contain pharmacological components in addition to the above-mentioned components. Examples of such pharmacological components include antihistamines, moisturizing agents, bactericides, antibacterial agents, antipruritic agents, skin protectants, blood circulation promoting components, vitamins, and the like. These pharmacological components may be used alone or in combination of two or more. In addition, when these pharmacological components are contained in the pharmaceutical composition for external use of the present invention, the concentration thereof may be appropriately set according to the type of the pharmacological component to be used, the expected effect, and the like.

[Preparation Form] The formulation form of the pharmaceutical composition for external use of the present invention is not particularly limited as long as it can be administered percutaneously, and examples thereof include liquids (suspensions), foams, ointments, creams, gels, and the like. . Among these, liquid preparations are preferably mentioned. These preparation forms can be prepared by using additives corresponding to the preparation forms according to the known methods described in the 17th revision of the Japanese Pharmacopoeia General Regulations for Prescriptions and the like. [Example]

Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited to these Examples.

Test Example 1 The external pharmaceutical composition (suspension) of the composition shown in Table 1 was prepared by the following method. Specifically, after mixing and dissolving loxoprofen sodium hydrate, water, and ethanol in predetermined amounts, isopropyl myristate was slowly added while mixing, and finally N-methyl-2- Pyrrolidone, propylene glycol, or glycerin is stirred until it becomes homogeneous, thereby preparing a pharmaceutical composition (suspension) for external use.

After each prepared pharmaceutical composition for external use was allowed to stand at room temperature for 10 minutes, the appearance was observed, and "the oil (isopropyl myristate) was significantly separated, and a uniform suspension was not formed" was set as 1 point, and "" The separation of the oil component (isopropyl myristate) was not confirmed at all, and a uniform suspension was formed" was set as 10 points, and the dispersion stability was scored in ten stages from 1 to 10 points according to the degree of dispersion state. In addition, for reference, the photograph which image|photographed the external appearance of the external pharmaceutical composition in the state of the said score of 1 point and 10 points is shown in FIG. 1. FIG. In addition, in the said score, when it is 5 points or more, it can be judged that it has dispersion stability which is allowable for practical use.

The results are shown in Table 1. In addition, FIG. 1 shows the photograph which image|photographed the external appearance of the external medicine composition of Example 3 and Comparative Example 1. In the external pharmaceutical composition to which only isopropyl myristate was added, the oil component (isopropyl myristate) was remarkably separated into the upper layer, and a uniform suspension could not be formed (Comparative Example 1). In the external pharmaceutical composition to which only loxoprofen sodium hydrate and isopropyl myristate were added, the dispersion state was improved compared with that of Comparative Example 1, but most of the oil was separated and distributed in the upper layer, and it was not possible to form a uniform composition. Suspension (Comparative Example 2). In addition, even if loxoprofen sodium hydrate and isopropyl myristate, and propylene glycol or glycerin used as a dispersant are included, most of the oil is separated and distributed in the upper layer, and a uniform suspension cannot be formed ( Comparative Example 3 and Comparative Example 4). On the other hand, in the pharmaceutical composition for external use to which loxoprofen sodium hydrate, isopropyl myristate, and N-methyl-2-pyrrolidone were added together, separation of oil was not observed, and the formation of Homogeneous suspension (Example 1 to Example 7). In particular, when the content of N-methyl-2-pyrrolidone was 2% by weight or more, particularly 5% by weight or more, particularly excellent dispersion stability was confirmed (Examples 2 to 7). Furthermore, in Example 3, in the external pharmaceutical composition prepared by changing loxoprofen sodium hydrate into unprepared, most of the oil was separated and distributed in the upper layer, and a uniform suspension could not be formed (Comparative Example 5). ). Therefore, it was confirmed that loxoprofen sodium hydrate also improves the dispersion stability of isopropyl myristate. Also, in the pharmaceutical compositions for external use in which ethanol was changed to isopropanol in Examples 6 and 7, as in Examples 6 and 7, no separation of oil was observed, and a uniform suspension could be formed. liquid.

[Table 1] Comparative example Example 1 2 3 4 5 1 2 3 4 5 6 7 Loxoprofen Sodium Hydrate - 1 1 1 - 1 1 1 1 1 1 1 Isopropyl myristate 6 6 6 6 6 6 6 6 6 10 6 6 N-Methyl-2-pyrrolidone - - - - 5 1 2 5 7 8 5 5 Propylene Glycol - - 5 - - - - - - - - - glycerin - - - 5 - - - - - - - - Ethanol - - - - - - - - - - 50 70 purified water The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part Total (wt%) 100 100 100 100 100 100 100 100 100 100 100 100 Dispersion Stability (Score) 1 2 2 2 3 6 8 10 10 10 10 10

Prescription example The external pharmaceutical composition (suspension) of the composition shown in Table 2 was prepared by the same method as in Test Example 1, and the external appearance was observed by the same method as in Test Example 1. As a result, any one of Formulation Example 1 to Formulation Example 8 was used for external use. Dispersion stability was confirmed in all of the pharmaceutical compositions.

[Table 2] Prescription example 1 2 3 4 5 6 7 8 Loxoprofen Sodium Hydrate 1 1 1 1 1 1 1 1 Isopropyl myristate 5 5 10 10 5 5 10 10 N-Methyl-2-pyrrolidone 1 10 2 10 1 10 2 10 L-Menthol - - - - 3 3 3 3 Ethanol - - - - 70 70 70 70 purified water The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part The remaining part Total (wt%) 100 100 100 100 100 100 100 100

none

FIG. 1 is a photograph of the external appearance of the pharmaceutical compositions for external use in Example 3 and Comparative Example 1. FIG.

Claims (2)

A pharmaceutical composition for external use, comprising: (A) loxoprofen and/or a salt thereof, (B) isopropyl myristate, (C) N-methyl-2-pyrrolidone, and (D) water . The external pharmaceutical composition according to claim 1, wherein the content of the component (C) is 2% by weight to 15% by weight.

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