JP6449554B2 - Pharmaceutical composition for external use - Google Patents

Description

  The present invention relates to a pharmaceutical composition for external use in which diclofenac and / or a salt thereof, tocopherol and / or a derivative thereof, and water are contained, and white turbidity and formation of precipitates are suppressed.

  In modern society, an increasing number of people suffer from stiff shoulders, muscle pain, joint pain, etc. due to the same posture for a long time, excessive stress, lack of exercise, etc. due to the spread of OA equipment. Conventionally, for such stiff shoulders, muscle and joint pains, etc., countermeasures have been taken to apply anti-inflammatory analgesics in order to suppress inflammation occurring in the affected area and improve symptoms.

  Conventionally, non-steroidal anti-inflammatory drugs such as diclofenac, felbinac, dexamethasone, indomethacin and ibuprofen have been put to practical use as anti-inflammatory analgesics. Among these non-steroidal anti-inflammatory drugs, diclofenac is known to have a high inhibitory activity against cyclooxygenase and to exert an excellent anti-inflammatory analgesic action. Diclofenac, when administered orally or rectally, may cause gastrointestinal, renal or hepatic damage as a side effect, especially for the gastrointestinal tract. Yes.

Non-Patent Document 1 reports the results and evaluation of a double-blind study using vitamin E, diclofenac sodium, and a combination of vitamin E and diclofenac sodium.

Von H. Bartsch, Fat Sci. Technol. 92 jahrgang Nr. 5 1990, 197-201

Diclofenac and / or a salt thereof and tocopherol and / or a derivative thereof have different polarities. Therefore, even if it can be formulated into an oral pharmaceutical composition such as a capsule or a tablet, an external medicine containing a relatively large amount of water When it mix | blends with a composition, there exists a fault that it cannot be solubilized but a cloudiness or a precipitate will produce | generate.

  Therefore, an object of the present invention is to provide a good external appearance property by suppressing white turbidity and precipitate formation while containing diclofenac and tocopherol and / or a derivative thereof in an external pharmaceutical composition containing water. The object is to provide a pharmaceutical technology.

  The present inventor has intensively studied to solve the above problems, and in an external pharmaceutical composition containing diclofenac and / or a salt thereof, tocopherol and / or a derivative thereof, and water, isopropanol is blended, and It has been found that by setting the pH to 5.0 or more, generation of white turbidity and precipitates due to diclofenac and / or a salt thereof and tocopherol and / or a derivative thereof can be suppressed, and an excellent appearance property can be provided. . The present invention has been completed by further studies based on this finding.

That is, this invention provides the invention of the aspect hung up below.
Item 1. It contains (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) tocopherol and / or a derivative thereof, (C) isopropanol, and (D) water, and has a pH of 5.0 or more. A pharmaceutical composition for external use.
Item 2. Item 2. The external pharmaceutical composition according to Item 1, wherein the pH is 5.3 to 11.5.
Item 3. Item 3. The external pharmaceutical composition according to Item 1 or 2, wherein the component (C) is contained in an amount of 50 to 80% by weight.
Item 4. Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, wherein the component (D) is contained in an amount of 15 to 45% by weight.
Item 5. Item 5. The external pharmaceutical composition according to any one of Items 1 to 4, wherein the component (B) is tocopherol acetate.
Item 6. Item 6. The external pharmaceutical composition according to any one of Items 1 to 5, which is a liquid agent or a gel agent.
Item 7. (A) Diclofenac and / or a pharmaceutically acceptable salt thereof, (B) Tocopherol and / or a derivative thereof, and (D) an external pharmaceutical composition containing water, (C) isopropanol is mixed, and the pH is 5 The method of suppressing the cloudiness and precipitation of an external pharmaceutical composition characterized by adjusting to 0.0 or more.

  According to the pharmaceutical composition for external use of the present invention, even when diclofenac and / or a salt thereof, tocopherol and / or a derivative thereof, and water coexist, white turbidity and precipitation can be suppressed, and an excellent appearance property is provided. be able to. Furthermore, the pharmaceutical composition for external use of the present invention can be provided with a highly transparent and excellent appearance property even when water is contained in a relatively large amount of 15% by weight or more. Less, it becomes possible to apply to various pharmaceutical formulations.

  Furthermore, the pharmaceutical composition for external use of the present invention contains diclofenac and / or a salt thereof and tocopherol and / or a derivative thereof, and can exhibit an excellent anti-inflammatory analgesic action, so that osteoarthritis, arthritis, joint pain, etc. It can be effectively relieved or cured.

1. External pharmaceutical composition The external pharmaceutical composition of the present invention comprises (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) tocopherol and / or a derivative thereof, (C) isopropanol, and (D) water. Containing, pH is 5.0 or more. Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.
(A) Diclofenac and / or salt thereof The external pharmaceutical composition of the present invention contains diclofenac and / or a salt thereof (hereinafter sometimes referred to as “component (A)”) as an anti-inflammatory analgesic component.

  Diclofenac is a known non-steroidal compound also called 2- (2- (2,6-dichlorophenylamino) phenyl) acetic acid.

  The salt of diclofenac is not particularly limited as long as it is pharmaceutically acceptable; for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; salt with ammonia; Salts with primary, secondary or tertiary alkylamines such as amine, diethylamine, trimethylamine, triethylamine; primary such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, And salts with secondary or tertiary alkanolamines. Among these, an alkali metal salt is preferable, and a sodium salt is more preferable. These pharmaceutically acceptable salts of diclofenac may be used alone or in combination of two or more.

  In the pharmaceutical composition for external use of the present invention, as the component (A), one kind selected from diclofenac and a salt thereof may be used alone, or two or more kinds may be used in combination. Among the components (A), a salt of diclofenac is preferable, an alkali metal salt of diclofenac is more preferable, and diclofenac sodium is particularly preferable.

The content of the component (A) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.2 to 2% by weight, preferably 0.5 to 1.5% by weight, more preferably 0.7. -1.3% by weight.
(B) Tocopherol and / or its derivative The pharmaceutical composition for external use of the present invention is tocopherol and / or its derivative (hereinafter referred to as “component (B)”) together with the above-mentioned component (A) in order to enhance anti-inflammatory analgesic action. May be included).

  Tocopherol is a known compound known as vitamin E. The tocopherol may be any of d-form, l-form, and dl-form, and preferably a dl-form. In addition, the tocopherol may be any of α-form, β-form, γ-form, and δ-form, and preferably α-form.

  The tocopherol derivative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include ester forms with carboxylic acids such as acetic acid, nicotinic acid and succinic acid, and diester forms with phosphoric acid. Among these tocopherol derivatives, an ester with a carboxylic acid is preferable, and tocopherol acetate is more preferable.

  The tocopherol derivative may be any of d-form, l-form, and dl-form, and preferably a dl-form. Furthermore, the derivative of tocopherol may be any of α-form, β-form, γ-form, and δ-form, and preferably α-form.

  In the pharmaceutical composition for external use of the present invention, as the component (B), one kind selected from tocopherol and its derivatives may be used alone, or two or more kinds may be used in combination. Among the components (B), a derivative of tocopherol, preferably an ester of tocopherol with a carboxylic acid, more preferably a tocopherol acetate, particularly preferably d-α-tocopherol acetate, 1-α-tocopherol acetate, dl acetate -Α-tocopherol.

The content of the component (B) in the external pharmaceutical composition of the present invention is not particularly limited, but for example 0.01 to 2% by weight, preferably 0.05 to 1.5% by weight, more preferably 0.1 Up to 1% by weight.
(C) Isopropanol The pharmaceutical composition for external use of the present invention contains isopropanol (hereinafter sometimes referred to as “component (C)”). By containing isopropanol and adjusting the pH to be described later, it is possible to suppress the formation of white turbidity and precipitates produced in the presence of diclofenac and / or a salt thereof, tocopherol and / or a derivative thereof, and water. Appearance characteristics can be provided.

The content of the component (C) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 50 to 80% by weight, preferably 50 to 75% by weight, more preferably 55 to 75% by weight, particularly preferably. 60-70 weight% is mentioned.
(D) water present invention to coexist said (A) ~ (C) component in water, water (hereinafter, "component (D)" and sometimes referred to) contains.

The content of the component (D) in the external pharmaceutical composition of the present invention may be appropriately set according to the formulation form, and examples thereof include 15 to 45% by weight. Usually, when diclofenac and / or a salt thereof and tocopherol and / or a derivative thereof are allowed to coexist under a condition where the water content is 15% by weight, particularly 20% by weight or more, the formation of white turbidity or precipitation appears remarkably. Thus, even if it contains a relatively large amount of water in this way, it is possible to suppress the generation of white turbidity or precipitation and to provide excellent appearance properties. In view of the effects of the present invention, the content of the component (D) in the external pharmaceutical composition of the present invention is preferably 20 to 45% by weight, more preferably 25 to 45% by weight, and particularly preferably 25 to 45% by weight. 40% by weight, most preferably 25 to 35% by weight.
(E) Menthol The external pharmaceutical composition of the present invention may contain menthol (hereinafter sometimes referred to as “component (E)”) as necessary. By containing menthol, it becomes possible to more effectively suppress the formation of white turbidity and precipitation. Moreover, by including menthol, it is possible to impart a refreshing feeling to the applied skin and to improve the feeling of use.

  Menthol may be any of d-form, l-form, and dl-form, and preferably 1-form.

  In addition, the external pharmaceutical composition of the present invention may use an essential oil containing menthol as the component (E). The essential oil containing menthol can be appropriately selected from known ones, and examples thereof include peppermint oil, peppermint oil, spearmint oil, and the like.

  Among the components (E), 1-menthol and essential oils containing the same are preferable from the viewpoint of more effectively suppressing the formation of cloudiness and precipitation.

Although there is no restriction | limiting in particular about content of (E) component in the external pharmaceutical composition of this invention, For example, 1 weight% or more, Preferably 3-10 weight%, More preferably, 3-7 weight% is mentioned.
Other components The pharmaceutical composition for external use of the present invention may contain a pharmacological component, if necessary, in addition to the components described above, as long as the effects of the present invention are not hindered. The pharmacological component that can be blended in the external pharmaceutical composition of the present invention is not particularly limited. Pharmaceutically acceptable salts, antihistamines such as chlorpheniramine maleate; lidocaine and its pharmaceutically acceptable salts, dibucaine and its pharmaceutically acceptable salts, local anesthetics such as ethyl aminobenzoate; nicotine Blood circulation promoters such as acid benzyl ester, nonanoic acid vanillyl amide, red pepper tincture; Like herbal medicine, etc. is.

  In addition, the external pharmaceutical composition of the present invention may contain a base such as an aqueous base and an oil base other than the components (C) and (D) in order to obtain a desired pharmaceutical form.

  Examples of the aqueous base other than the components (D) and (F) include, for example, ethanol, propanol, n-butanol, sec-butanol, tert-butanol and other lower alcohols other than isopropanol; glycerin, propylene glycol, dipropylene glycol And polyhydric alcohols such as butylene glycol.

  Examples of oily bases include nonpolar oils and polar oils. Specific examples of the nonpolar oil include hydrocarbons such as paraffin and isoparaffin; squalane and wax. Specific examples of polar oils include aliphatic monocarboxylic acid esters, triglycerides, aliphatic dicarboxylic acid diesters, aliphatic dicarboxylic acid alkylene glycol esters, and higher fatty acids.

Furthermore, the external pharmaceutical composition of the present invention may contain other additives usually used in the external pharmaceutical composition, if necessary, in addition to the components described above. Examples of such additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, and coloring agents. Is mentioned. Although it does not restrict | limit especially about the thickener which can be mix | blended with the external pharmaceutical composition of this invention, For example, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a carboxy vinyl polymer, a hyaluronic acid, a xanthan gum etc. are mentioned.
pH
The pH of the external pharmaceutical composition of the invention is set to 5.0 or higher. By including the components (A) to (D) and setting the pH to 5.0 or more, it becomes possible to suppress the formation of white turbidity and precipitation in an external pharmaceutical composition, and to provide appearance properties Can do.

The pH of the external pharmaceutical composition of the invention is preferably 5.3 or more, more preferably 5.3 to 11.5, still more preferably 6.0 from the viewpoint of more effectively suppressing white turbidity and precipitation. 11.5, particularly preferably 6.4 to 11.5, most preferably 6.4 to 6.7.
Formulation Form The formulation form of the external pharmaceutical composition of the present invention is not particularly limited as long as it can be applied transdermally. For example, liquids (including lotions, sprays, aerosols, and emulsions), Examples include foams, ointments, creams, gels, patches and the like. Among these, Preferably a liquid agent or a gel agent is mentioned. These preparation forms can be prepared by formulating with additives according to the preparation form according to a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
Use Mode The pharmaceutical composition for external use of the invention is used by externally administering to the topical (skin) where analgesia is required. The dosage of the external pharmaceutical composition of the present invention is appropriately set according to the site to be administered, the degree of symptoms to be treated, etc., but per 1 cm ^{2 of} the local site to be administered, diclofenac and / or its pharmaceutically acceptable. It is desirable that the dose per salt of the salt is about 10 to 500 mg.

The external pharmaceutical composition of the present invention is used as an external anti-inflammatory analgesic, such as shoulder pain associated with stiff shoulders, joint pain, low back pain, muscle pain, tendonitis (hand / wrist pain), elbow pain (tennis elbow, etc.), bruise pain It can be used for the treatment of pain, fracture pain, neuralgia, osteoarthritis, arthritis and the like.
2. Cloudy and method for inhibiting precipitation Furthermore, the present invention is, of (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) tocopherol and / or derivatives thereof, and (D) external pharmaceutical composition comprising water A method for suppressing cloudiness and precipitation is provided. Specifically, the method for suppressing white turbidity and precipitation of the present invention comprises (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) tocopherol and / or a derivative thereof, and (D) an external application containing water. (C) Isopropanol is mix | blended with a pharmaceutical composition, and pH is adjusted to 5.0 or more, It is characterized by the above-mentioned. In the method for suppressing white turbidity and precipitation of the present invention, the types and amounts of components used, the pH of the external pharmaceutical composition, the formulation form, and the like are as described in the section of “1. External pharmaceutical composition”. is there.

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.
Test example 1
External pharmaceutical compositions having the compositions shown in Tables 1 and 2 were prepared. Specifically, a predetermined amount of diclofenac sodium was added and dissolved in a predetermined amount of isopropanol or ethanol, and a predetermined amount of tocopherol acetate (dl-α-tocopherol acetate) was added and stirred. Subsequently, water addition and pH adjustment were performed, and the external pharmaceutical composition (liquid form) was obtained.

Each external pharmaceutical composition was evaluated for appearance properties after being stored at 25 ° C. for 3 days under shading conditions. The appearance properties of the external pharmaceutical composition were evaluated according to the following criteria.
<Criteria for appearance properties>
(Double-circle): The production | generation of a deposit and white turbidity are not recognized, but it is a clear state.
◯: No precipitate was formed, and white turbidity was slightly observed, but it was in a translucent state acceptable for practical use.
(Triangle | delta): Although the precipitate was not produced | generated, it was the opaque state by which clear cloudiness is recognized.
X (1): Formation of precipitates was observed, and an opaque state was observed in which significant cloudiness was observed.
× (2): No precipitate was observed, but it was an opaque state in which significant cloudiness was observed.
× (3): No cloudiness was observed, but formation of significant precipitates was observed.

  The obtained results are shown in Table 1. When ethanol was allowed to coexist with diclofenac sodium and tocopherol acetate in the presence of water, generation of white turbidity and / or precipitates was observed (Comparative Examples 1 to 3). Moreover, even when isopropanol was allowed to coexist with diclofenac sodium and tocopherol acetate in the presence of water, the formation of precipitates was observed when the pH was less than 5.0 (Comparative Examples 4 and 5). On the other hand, in the presence of water, when isopropanol was coexisted with diclofenac sodium and tocopherol acetate and the pH was set to 5.0 or more, the formation of white turbidity and precipitates was not observed, and excellent appearance properties were exhibited. (Examples 1 to 5).

Formulation Example An external pharmaceutical composition having the composition shown in Table 2 was prepared (Formulation Examples 1, 3 and 5 were liquid, and Formulation Examples 2, 4 and 6 were gels). In any of the obtained external pharmaceutical compositions, no white turbidity or formation of precipitates was observed, and the appearance characteristics were excellent.

Claims (6)

(A) Diclofenac and / or a pharmaceutically acceptable salt thereof, (B) tocopherol and / or tocopherol acetate, (C) isopropanol 50 to 80% by weight, and (D) water, pH 5.0 A pharmaceutical composition for external use characterized by the above ( except when it contains an extract of a Curcuma plant ).   The external pharmaceutical composition according to claim 1, wherein the pH is 5.3 to 11.5.   The external pharmaceutical composition according to claim 1 or 2, wherein the component (D) is contained in an amount of 15 to 45% by weight.   The external pharmaceutical composition according to any one of claims 1 to 3, wherein the component (B) is tocopherol acetate.   The external pharmaceutical composition according to any one of claims 1 to 4, which is a liquid agent or a gel agent. (A) Diclofenac and / or a pharmaceutically acceptable salt thereof, (B) Tocopherol and / or tocopherol acetate, and (D) an external pharmaceutical composition containing water ( however, an extract of a Turmeric genus Curcuma plant) ( Excluding the case where it is included ) (C) Isopropanol is mixed so as to be 50 to 80% by weight, and the pH is adjusted to 5.0 or more, thereby suppressing the cloudiness and precipitation of an external pharmaceutical composition Method.