JP6738120B2 - External pharmaceutical composition - Google Patents

Description

The present invention relates to a pharmaceutical composition for external use, in which the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof is enhanced.

In the modern society, more and more people are suffering from stiff shoulders, muscle pain, joint pain, etc. due to the same posture for a long time due to the spread of OA equipment, excessive stress, lack of exercise and the like. For such stiff shoulders, muscle and joint pains, etc., conventionally, anti-inflammatory analgesics have been applied 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 and analgesics. Among these non-steroidal anti-inflammatory drugs, diclofenac is known to have a high inhibitory activity against cyclooxygenase and to exhibit an excellent anti-inflammatory and analgesic action. Diclofenac, when administered orally or rectally, may cause gastrointestinal, renal, or hepatic disorders as side effects, and in particular, may have serious side effects on the gastrointestinal tract, so recently application as an external preparation has been increasing. There is. However, diclofenac has a drawback that it has a low transdermal absorbability, and that when it is applied transdermally, it cannot fully exhibit its original anti-inflammatory and analgesic action.

Therefore, various studies have hitherto been made on formulation techniques for improving the transdermal absorbability of diclofenac and improving its drug efficacy. For example, Patent Document 1 discloses that in an external composition containing diclofenac or a salt thereof, the transdermal absorbability of diclofenac or a salt thereof is improved by adding an alcohol and a carboxylic acid ester and/or a carboxylic acid. It is disclosed. In Patent Document 2, diclofenac or a pharmaceutically acceptable salt thereof is contained in an external pharmaceutical composition in an amount of 0.5 to 1.5% by weight and a cooling agent in an amount of 5 to 15% by weight. As a result, it is disclosed that the analgesic effect is improved.

However, with the increase in the number of people who suffer from stiff shoulders, muscle pain, arthralgia, etc., there is an increasing demand for an external preparation capable of exerting a superior anti-inflammatory and analgesic effect, and a formulation that further improves the transdermal absorbability of diclofenac. Expectations for technology development are high.

JP, 10-182450, A JP, 2011-074032, A

The present invention provides a pharmaceutical technique for improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for external use containing diclofenac and/or a pharmaceutically acceptable salt thereof. With the goal.

The present inventor has conducted extensive studies to solve the above-mentioned problems, and as a result, an external pharmaceutical composition containing monoterpene and lactic acid and/or a salt thereof together with diclofenac and/or a pharmaceutically acceptable salt thereof, , Diclofenac and/or the pharmaceutically acceptable salt thereof, was found to have dramatically improved transdermal absorbability. It has also been found that the percutaneous absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof is further improved by further containing a polar oil in the external pharmaceutical composition. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following modes.
Item 1. An external pharmaceutical composition comprising (A) diclofenac and/or a pharmaceutically acceptable salt thereof, (B) monoterpene, and (C) lactic acid and/or a salt thereof.
Item 2. Further, the external pharmaceutical composition according to Item 1, further comprising (D) a polar oil.
Item 3. Item 3. The external pharmaceutical composition according to Item 1 or 2, wherein the monoterpene is menthol.
Item 4. Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, containing 1 to 10% by weight of the monoterpene and 0.1 to 5% by weight of the lactic acid and/or its salt.
Item 5. Item 5. The external-use pharmaceutical composition according to any one of Items 2 to 4, containing 0.1 to 20% by weight of the polar oil.
Item 6. Item 6. The external pharmaceutical composition according to Item 2 or 5, wherein the polar oil is an aliphatic monocarboxylic acid ester.
Item 7. Item 7. The external pharmaceutical composition according to Item 6, wherein the aliphatic monocarboxylic acid ester is isopropyl myristate and/or isopropyl palmitate.
Item 8. Item 8. The external pharmaceutical composition according to any one of Items 1 to 7, which is a liquid agent or a gel agent.

According to the external pharmaceutical composition of the present invention, the transdermal absorbability of diclofenac and/or its pharmaceutically acceptable salt is dramatically improved by coexisting with monoterpene and lactic acid and/or its salt. Therefore, an excellent anti-inflammatory and analgesic action can be exerted, and stiff shoulders, muscle pain, joint pain, etc. can be effectively alleviated or cured. In addition, the external pharmaceutical composition of the present invention can further improve the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof by containing a polar oil in addition to the above-mentioned components, whereby It can exert an excellent anti-inflammatory and analgesic effect. Furthermore, since the external pharmaceutical composition of the present invention contains a monoterpene and can give a refreshing feeling to the applied skin, a good feeling of use can be obtained.

The external pharmaceutical composition of the present invention is characterized by containing (A) diclofenac and/or a pharmaceutically acceptable salt thereof, (B) monoterpene, and (C) lactic acid and/or a salt thereof. Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.

(A) Diclofenac and/or a pharmaceutically acceptable salt thereof The external pharmaceutical composition of the present invention comprises diclofenac and/or a pharmaceutically acceptable salt thereof as an anti-inflammatory and analgesic ingredient (hereinafter, “(A) ingredient”). Sometimes referred to as)) is included.

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

The pharmaceutically acceptable salt of diclofenac is not particularly limited, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; salts with ammonia; dimethylamine, diethylamine, Salts with primary, secondary or tertiary alkylamines such as trimethylamine and triethylamine; primary and secondary salts such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine and triisopropanolamine Examples thereof include salts with tertiary alkanolamines. Of these, alkali metal salts are preferable, and sodium salts are more preferable. These pharmaceutically acceptable salts of diclofenac may be used alone or in combination of two or more.

In the external pharmaceutical composition of the present invention, as the component (A), one may be selected from diclofenac and pharmaceutically acceptable salts thereof and used alone, or two or more kinds may be used in combination. You may. Among the component (A), a pharmaceutically acceptable salt of diclofenac is preferable, an alkali metal salt of diclofenac is more preferable, and sodium diclofenac 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) Monoterpene The external pharmaceutical composition of the present invention contains a monoterpene (hereinafter sometimes referred to as “component (B)”). By containing a monoterpene, it is possible to dramatically improve the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof by interacting with lactic acid and/or a salt thereof described below, It also makes it possible to impart a refreshing feel to the applied skin and improve the usability.

A monoterpene is a terpenoid compound having 2 isoprene units and 10 carbon atoms. The monoterpene used in the pharmaceutical composition for external use of the present invention is not particularly limited, and examples thereof include menthol, limonene, menthone, carvone, dihydrocarvone, pinene, geraniol, linalool, thymol, borneol, perillaldehyde, citral, citronellal. , Camphor, cineol and the like. The monoterpene used in the present invention may be in any of d-form, l-form and dl-form, if optical isomers are present.

Further, the external pharmaceutical composition of the present invention may use an essential oil containing monoterpene as the component (B). The essential oil containing a monoterpene can be appropriately selected and used from known ones. Examples of the essential oil containing menthol include mint oil, peppermint oil, spearmint oil and the like.

In the external pharmaceutical composition of the present invention, as the component (B), one type of monoterpene may be used alone, or two or more types of monoterpenes may be used in combination. Among components (B), from the viewpoint of further improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof, preferably menthol and an essential oil containing the same, more preferably 1-menthol and The essential oil containing this is mentioned.

The content of the component (B) in the pharmaceutical composition for external use of the present invention is not particularly limited, but is, for example, 1 to 10% by weight. In particular, from the viewpoint of further improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof, the content of the component (B) in the external pharmaceutical composition of the present invention is preferably 1 to 8 %, and more preferably 2 to 7% by weight. As the component (B), when using an essential oil containing a monoterpene, so that the content of the monoterpene in the pharmaceutical composition for external use of the present invention satisfies the above range, the amount of the terpene contained in the essential oil. The amount of essential oil to be blended may be appropriately set according to the above.

(C) Lactic acid and/or its salt The external pharmaceutical composition of the present invention contains lactic acid and/or its salt (hereinafter sometimes referred to as “component (C)”). By containing lactic acid and/or its salt, it becomes possible to dramatically improve the transdermal absorbability of diclofenac and/or its pharmaceutically acceptable salt by the interaction with the monoterpene described later. ..

The lactic acid salt is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include alkali metal salts of sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; salts with ammonia. Etc. These lactic acid salts may be used alone or in combination of two or more.

In the external pharmaceutical composition of the present invention, as the component (C), one type may be selected from lactic acid and salts thereof and used alone, or two or more types may be used in combination. Among components (C), from the viewpoint of further improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof, lactic acid, an alkali metal salt of lactic acid, more preferably lactic acid, sodium lactate. Particularly preferably, sodium lactate is used.

The content of the component (C) in the external pharmaceutical composition of the present invention is not particularly limited, but may be, for example, 0.1 to 5% by weight. In particular, from the viewpoint of further improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof, the content of the component (C) in the external pharmaceutical composition of the present invention is preferably 0.1. -4% by weight, more preferably 0.1-3% by weight, particularly preferably 0.2-3% by weight.

(D) Polar oil The external pharmaceutical composition of the present invention further contains a polar oil (hereinafter sometimes referred to as “(D) component”) in addition to the components (A) to (C). Good. By thus containing the polar oil, the transdermal absorbability of diclofenac and/or its pharmaceutically acceptable salt can be further improved.

The polar oil is a hydrocarbon-based oil containing a polar group such as a hydroxyl group, a carbonyl group, a carboxyl group, an ester group, an ether group and an amide group in the molecule. The IOB value (inorganic/organic balance) of the polar oil used in the pharmaceutical composition for external use of the present invention is not particularly limited, but for example, IOB value of 0.01 to 3.0, preferably 0.05. To 2.0, and more preferably 0.05 to 1.0.

Examples of the polar oil used in the pharmaceutical composition for external use of the present invention include aliphatic monocarboxylic acid esters, triglycerides, aliphatic dicarboxylic acid diesters, aliphatic dicarboxylic alkylene glycol esters, and higher fatty acids.

Examples of the aliphatic monocarboxylic acid ester include isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, isotridecyl isononanoate, isononyl isononanoate, cetyl 2-ethylhexanoate, myristyl myristate, hexadecyl isostearate, octanoate. Examples include cetyl and cetyl isooctanoate. These aliphatic monocarboxylic acid esters may be used alone or in combination of two or more.

Examples of the triglyceride include triacylglycerol, tripalmitin, glyceryl tripalmitate, glyceryl triisooctanoate, 1-palmitoyl-2,3-dioleoylglycerol, 1,3-dioleoyl-2-palmitoylglycerol, 1- Palmitooleoyl-2-stearoyl-3-linoleoylglycerol, 1-linoleoyl-2-palmitooleoyl-3-stearoylglycerol and the like can be mentioned. These triglycerides may be used alone or in combination of two or more.

Examples of the aliphatic dicarboxylic acid diesters include diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diethyl adipate, diisopropyl adipate, dibutyl adipate, diisobutyl adipate, dioctyl adipate, and the like. These aliphatic dicarboxylic acid diesters may be used alone or in combination of two or more.

Examples of the aliphatic dicarboxylic acid alkylene glycol ester include neopentyl glycol dioctanoate, propylene glycol dicaprate, ethylene glycol dioleate, ethylene glycol distearate and the like. These aliphatic dicarboxylic acid alkylene glycol esters may be used alone or in combination of two or more.

Examples of the higher fatty acid include fatty acids having 12 to 26 carbon atoms. Specific examples of such higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, oleic acid, linoleic acid, linoleic acid, docosahexaenoic acid and eicosapentaenoic acid. .. These higher fatty acids may be used alone or in combination of two or more.

In the external pharmaceutical composition of the present invention, as the component (D), one type of polar oil may be selected and used alone, or two or more types of polar oil may be used in combination. Among the components (D), from the viewpoint of further improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof, preferably an aliphatic monocarboxylic acid ester; more preferably, a carbon number of 10 An ester of a fatty acid of 17 and a monohydric alcohol having 1 to 5 carbon atoms; particularly preferred are isopropyl myristate and isopropyl palmitate.

When the component (D) is contained in the external pharmaceutical composition of the present invention, the content thereof is not particularly limited, but it may be, for example, 0.1 to 20% by weight. In particular, from the viewpoint of further effectively improving the transdermal absorbability of diclofenac and/or a pharmaceutically acceptable salt thereof, as the content of the (D) component in the external pharmaceutical composition of the present invention, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight.

Other Ingredients The external pharmaceutical composition of the present invention may contain pharmacological components, if necessary, in addition to the components described above, as long as the effects of the present invention are not impaired. The pharmacological components that can be incorporated into the external pharmaceutical composition of the present invention are not particularly limited, but for example, anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and the like. Pharmaceutically acceptable salts, antihistamines such as chlorpheniramine maleate; blood circulation promoters such as tocopherol acetate, nicotinic acid benzyl ester, nonanoic acid vanillylamide, capsicum tincture; arnica tincture, oak extract, sardine extract, horse chestnut extract, funnel. Herbal medicines such as an extract, a belladonna extract, a Japanese laurel extract, a Chinese radish extract, a salamander extract, etc. are mentioned.

In addition, the external pharmaceutical composition of the present invention may contain a base such as an aqueous base or an oil base in order to obtain a desired formulation form. Examples of the aqueous base include polyhydric alcohols such as water, glycerin, propylene glycol, dipropylene glycol and butylene glycol, lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol and isobutanol. Examples of the oily base material include nonpolar oils, specifically hydrocarbons such as paraffin and isoparaffin; squalane, wax and the like.

Furthermore, the pharmaceutical composition for external use of the present invention may contain, in addition to the above-mentioned components, other additives which are usually used in the pharmaceutical composition for external use, if necessary. Examples of such additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, colorants, etc. Are listed.

Formulation form The formulation form of the external pharmaceutical composition of the present invention is not particularly limited as long as it is transdermally applicable, and examples thereof include liquid formulations (including lotions, sprays, aerosols, and emulsions), Foams, ointments, plasters, creams, gels, patches and the like can be mentioned. Among these, a liquid agent and a gel agent are preferable, and a liquid agent is more preferable. Preparation into these dosage forms can be carried out according to a known method described in the 16th Revised Japanese Pharmacopoeia General Rules for Preparation etc. by using additives according to the dosage form.

When the external use pharmaceutical composition of the present invention is in the form of a liquid, it is desirable that the aqueous base comprises a mixed solution of water and a lower alcohol, preferably a mixed solution of water and ethanol, as an aqueous base. When the external pharmaceutical composition of the present invention is mixed with water and a lower alcohol to give a liquid preparation, the content of water and the lower alcohol is, for example, 0 to 50% by weight of water, preferably 0 to 40% by weight. Further preferably, the range is 1 to 30% by weight; the lower alcohol is 20 to 95% by weight, preferably 40 to 95% by weight, and more preferably 60 to 95% by weight. When the external pharmaceutical composition of the invention is in the form of a liquid, its pH is, for example, 3.0 to 9.0, preferably 4.0 to 9.0, and more preferably 4.5 to 9.0. Can be mentioned.

Use mode The external pharmaceutical composition of the present invention is used by externally administering it locally (skin) where analgesia is required. The dose of the external pharmaceutical composition of the present invention is appropriately set depending on the administration site, 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 of each salt of sodium chloride be about 10 to 500 mg.

The external pharmaceutical composition of the present invention is used as an external anti-inflammatory analgesic for shoulder pain associated with stiff shoulders, joint pain, low back pain, muscle aches, tendonitis (pain in the hands and wrists), elbow pain (tennis elbow etc.), bruising pain It can be preferably used for the purpose of analgesia for pain such as sprain pain, fracture pain and neuralgia.

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Test example 1
A topical pharmaceutical composition (liquid form) having the composition shown in Table 1 was prepared. The following tests were conducted to evaluate the transdermal absorbability of each external pharmaceutical composition. YMP (Yucatan Micropig) skin (manufactured by Charles River Japan) frozen at −30° C. is left at room temperature for about 30 minutes and allowed to thaw naturally, and then fat and meat fragments attached to the skin are removed, and this is used as test skin. And A test skin was attached to a Franz diffusion cell (effective permeation diameter of about 25 mm, made of glass), the inside of the receptor was filled with 0.2 M PBS buffer solution (pH 7.4), and the Franz diffusion cell was 37° C.±3° C. Soaked in warm water. After the inside of the Franz diffusion cell reached 37° C.±3° C., 1 g of the external pharmaceutical composition was applied to the epidermis side of the test skin and kept at 37° C.±3° C. for 5 hours. After 3 hours and 5 hours from the application of the external pharmaceutical composition, 0.5 ml of the PBS buffer solution in the receptor was sampled, and the concentration of diclofenac in the PBS buffer solution was measured by liquid chromatography to test diclofenac sodium. The amount of permeation through the skin (transdermal absorption of diclofenac sodium, μg) was calculated. In addition, in this test, all the test skins used were of the same lot.

The results obtained are shown in Table 1. As is clear from Table 1, in the case where lactic acid was included in addition to diclofenac sodium and 1-menthol (Example 1), diclofenac sodium content was higher than that in the case where lactic acid or sodium lactate was not included (Comparative Example 1). The percutaneous absorption increased dramatically. Further, when diclofenac sodium, 1-menthol, and lactic acid or sodium lactate are further contained, and isopropyl myristate or isopropyl palmitate is further contained (Examples 2 to 7), the transdermal absorption amount of diclofenac sodium may be further improved. confirmed. On the other hand, when citric acid or acetic acid was contained together with diclofenac sodium and 1-menthol (Comparative Examples 4 and 5), the transdermal absorption amount of diclofenac sodium could not be increased as in the case of using lactic acid or sodium lactate. .. Furthermore, even if it contained diclofenac sodium and lactic acid but did not contain 1-menthol (Comparative Example 6), the transdermal absorption amount of diclofenac sodium did not increase. From the above results, a dramatic increase in the percutaneous absorption of diclofenac sodium was realized by including diclofenac sodium, 1-menthol, and lactic acid or sodium lactate in an inseparable relationship, and the percutaneous absorption was further increased. It was revealed that the inclusion of polar oil increased even more.

Test example 2
A topical pharmaceutical composition (liquid form) having the composition shown in Table 2 was prepared, and the transdermal absorption amount of diclofenac sodium (permeation amount after 3 hours) was determined by the same method as in Test Example 1 above. The YMP skin used in this test example is of a different lot from that used in test example 1, and the transdermal absorption amount of diclofenac sodium is about 1/5 lower than that used in test example 1. It has been confirmed that

The obtained results are shown in Table 2. From these results, the percutaneous absorption of diclofenac sodium increased dramatically when diclofenac sodium, 1-menthol and lactic acid were contained, and the percutaneous absorption of diclofenac sodium was further increased when isopropyl myristate was contained. It was confirmed that it would be further improved.

Formulation Example An external pharmaceutical composition having the composition shown in Table 3 (Preparation Examples 1, 3 and 5 was liquid, Formulation Examples 2, 4 and 6 were gel) was prepared. All of the obtained external pharmaceutical compositions had excellent transdermal absorbability of diclofenac sodium.

Claims (6)

An external pharmaceutical composition comprising (A) diclofenac sodium, (B) menthol 2 to 7% by weight, (C) lactic acid and/or its salt 0.1 to 5% by weight, and water (however, , Except when containing a zirconium compound that functions as a zirconium ion donor). The external pharmaceutical composition according to claim 1, further comprising (D) a polar oil. The external pharmaceutical composition according to claim 1 or 2 , containing 0.1 to 20% by weight of the polar oil. The pharmaceutical composition for external use according to claim 2 or 3 , wherein the polar oil is an aliphatic monocarboxylic acid ester. The external pharmaceutical composition according to claim 4 , wherein the aliphatic monocarboxylic acid ester is isopropyl myristate and/or isopropyl palmitate. A liquid or gel, topical pharmaceutical composition according to any one of claims 1-5.