TWI684448B - External pharmaceutical composition - Google Patents

Abstract

The object of the present invention is to provide a method for diclofenac and/or its salts to coexist with lactic acid and/or its salts, which does not cause the precipitation of diclofenac and/or its salts to cause excellent stability Sexual preparation technology.

The solution is to use menthol together with tocofina and/or its salt and 0.1% by weight or more of lactic acid and/or its salt, so that the tocofina and/or its salt does not precipitate out and has excellent stability Sex.

Description

External pharmaceutical composition

The present invention relates to a pharmaceutical composition for external use having excellent stability even if diclofenac and/or its salts coexist with lactic acid and/or its salts, and can suppress precipitation of diclofenac and/or its salts.

Due to the popularity of office automation equipment in modern society, the number of people suffering from stiff shoulders, muscle pain, and joint pain is increasing due to maintaining the same posture for a long time, suffering from excessive stress, and lack of exercise. In the past, in response to such stiff shoulders, pain in muscles and joints, etc., in order to suppress the inflammatory symptoms occurring in the affected part and improve the symptoms, countermeasures for applying anti-inflammatory analgesics have been implemented.

Previous anti-inflammatory analgesics have been put into practical use of non-steroidal anti-inflammatory drugs such as tocofina, biphenylacetic acid, dicortisol, indomethacin, and profen. Among these non-steroidal anti-inflammatory drugs, oxyfina is known to have a high inhibitory activity on cyclooxygenase and can exert an excellent anti-inflammatory and analgesic effect. In addition, by oral or rectal administration at the time of Kefir, sometimes side effects that caused damage to the gastrointestinal tract, kidney, or liver sometimes occurred, especially because of extremely serious side effects on the gastrointestinal tract, which have recently been gradually increased for external use Agent. However, due to the low transdermal absorbability of Kefena, when used for transdermal administration, there is a disadvantage that the original anti-inflammatory and analgesic effects cannot be fully exerted.

So far, various preparation technologies have been reviewed for improving the transdermal absorbability of tokefina and improving its efficacy. For example, Patent Document 1 discloses a composition for external use containing tocofina or its salt. By adding alcohol and carboxylic acid ester and/or carboxylic acid, the transdermal absorbability of tocofina or its salt can be improved . In addition, Patent Document 2 discloses that the external pharmaceutical composition contains 0.5% to 1.5% by weight of tokefina or a pharmaceutically acceptable salt thereof, and 5 to 15% by weight of a cooling agent. Improve the analgesic effect.

[Previous Technical Document] [Patent Document]

[Patent Document 1] Japanese Unexamined Patent Publication No. 10-182450

[Patent Document 2] JP 2011-074032

With the increase in the number of people suffering from stiff shoulders, muscle pain, and joint pain, the demand for external agents that can play a more excellent anti-inflammatory and analgesic role is increasing, and for the development of the experience that can improve the treatment of kefina and/or its salts The skin-absorbable preparation technology is expected to be higher and higher. Therefore, the team of the present invention has reviewed the preparation techniques for improving the transdermal absorbability of tocofina and/or its salts for external pharmaceutical compositions containing tocofina and/or its salts After the operation, it was found that as described in Test Example 3 described later, lactic acid and/or its salts can contribute to enhancing the transdermal absorbability of tocofina and/or its salts. However, if only to be co-existed with fenfina and/or its salt and 0.1% by weight or more of lactic acid and/or its salt, it must be faced with fenfina and/or its salt to become easily precipitated, which impairs the stability of the preparation Novel subject. Inhibition of the precipitation of tocofina and/or its salts, formulations formulated with high levels of lower alcohols and formulations formulated with polyols or polar oils can be effectively resolved, however, there are There is an adverse effect on the sense of use, and there are many shortcomings such as limitations in the design of the preparation.

Therefore, the object of the present invention is to provide a preparation technology with excellent stability that can prevent the precipitation of dioxin and/or its salts even if it coexists with lactic acid and/or its salts.

After intensively reviewing to solve the aforementioned problems, the team of the present invention found that by using menthol together with tocofina and/or its salts and 0.1% by weight or more of lactic acid and/or its salts, Or its salt will not precipitate, and has excellent stability. The present invention is based on relevant knowledge and further accumulated and completed.

That is, the present invention provides the following disclosed embodiments.

(1) A pharmaceutical composition for external use containing (A) tocofina and/or a pharmaceutically acceptable salt thereof, (B) 0.1% by weight or more of lactic acid and/or a salt thereof, and (C) menthol .

(2) The pharmaceutical composition other than (1), which further contains (D) water.

(3) The pharmaceutical composition other than (1) or (2) further contains (E) a lower alcohol.

(4) The pharmaceutical composition for external use according to any one of (1) to (3), wherein the component (C) contains 1% by weight or more.

(5) The pharmaceutical composition for external use according to any one of (1) to (4), wherein the component (D) contains 5 to 50% by weight.

(6) The pharmaceutical composition for external use according to any one of (1) to (5), wherein the component (E) contains 30 to 90% by weight.

(7) The pharmaceutical composition for external use according to any one of (1) to (6), which is a liquid agent or a gel agent.

(8) A method for inhibiting the precipitation of dicofena and/or a pharmaceutically acceptable salt thereof, which contains (A) pharmacokinetic and/or a pharmaceutically acceptable salt thereof, and (B) 0.1% by weight The above-mentioned pharmaceutical composition for external use of lactic acid and/or its salt is blended with (C) menthol.

According to the pharmaceutical composition for external use of the present invention, even if co-fifina and/or its salt coexists with lactic acid and/or its salt, it can suppress the precipitate of co-fina and/or its salt and exhibit good appearance properties, and With excellent stability. In addition, the pharmaceutical composition for external use of the present invention, by containing menthol, can suppress the precipitation of tocofina and/or its salts and stabilize it. When it is formulated, the content of lower alcohols is reduced ( For example 80% by weight (Below), it becomes possible with unblended polyols and polar oils, there are fewer restrictions on the design of the formulation, and it can be applied to various formulations.

Furthermore, the pharmaceutical composition for external use of the present invention dramatically improves the percutaneous absorbability of tocofina and/or its salts, can exert excellent anti-inflammatory and analgesic effects, and can effectively relieve or cure stiff shoulders, muscle pain, Joint pain, etc.

1. Topical pharmaceutical composition

The pharmaceutical composition for external use of the present invention is characterized by containing (A) tocofina and/or a pharmaceutically acceptable salt thereof, (B) 0.1% by weight or more of lactic acid and/or a salt thereof, and (C) menthol . Hereinafter, the pharmaceutical composition for external use of the present invention will be described in detail.

(A) To be kefina and/or its salt

The pharmaceutical composition for external use of the present invention contains tocofina and/or its salt as an anti-inflammatory and analgesic component (hereinafter sometimes referred to as "(A) component").

The non-steroidal compound of the tocofina series, also known as 2-(2-(2,6-dichloroaniline) phenyl) acetic acid.

To the extent that the salt of Kefena is pharmaceutically acceptable No particular limitation, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; ammonia and its salts; dimethylamine, diethylamine, trimethylamine, triethylamine, etc. Grade 1, 2, or 3 alkylamine salts; monoethanol Salts of 1, 2, or 3 alkanolamines such as amine, diethanolamine, diisopropanolamine, triethanolamine, and triisopropanolamine. Among them, alkali metal salts are preferred, and sodium salts are more preferred. The pharmacologically acceptable salt of Kefena can be used alone or in combination of two or more.

In the pharmaceutical composition for external use of the present invention, the component (A) can be used alone or in combination of two or more kinds selected from tocofina and its salts. Among the components (A), the salt to be treated with kefina is preferred, the alkali metal salt to be treated with kefina is more preferred, and the sodium to be treated with kefina is particularly preferred.

The content of the component (A) in the pharmaceutical composition for external use of the present invention is not particularly limited, and examples thereof include 0.2 to 2% by weight, more preferably 0.5 to 1.5% by weight, and most preferably 0.7 to 1.3% by weight.

(B) Lactic acid and/or its salts

The pharmaceutical composition for external use of the present invention may contain lactic acid and/or a salt thereof in a content of 0.1% by weight or more (hereinafter, sometimes referred to as "(B) component").

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

In the pharmaceutical composition for external use of the present invention, component (B) may be selected from lactic acid and its salts and used alone or in combination of two or more. (B) From the viewpoint of having both the effect of inhibiting the precipitation of Kefna and/or its salts and the further improvement of its transdermal absorbability, the component is preferably lactic acid, an alkali metal salt of lactic acid, and more preferably the system Lactic acid and sodium lactate Listed as lactic acid.

The content of the component (B) in the pharmaceutical composition for external use of the present invention is preferably 0.1% by weight or more, which has both the effect of inhibiting the precipitation of kefina and/or its salts and the improvement of its transdermal absorbability From a viewpoint, the preferable system is, for example, 0.1 to 5% by weight, more preferably 0.1 to 4% by weight, preferably 0.1 to 3% by weight, and most preferably 0.1 to 1% by weight.

(C) Menthol

The pharmaceutical composition for external use of the present invention contains menthol (hereinafter sometimes referred to as "(C) component"). By containing menthol in the composition, it is possible to suppress the precipitation of kefena and/or its salt generated when coexisting with 0.1% by weight or more of lactic acid and/or its salt, so that the external pharmaceutical composition can have excellent stability . Furthermore, by containing menthol and using interaction with 0.1% by weight or more of lactic acid and/or its salt, the transdermal absorbability of tocofina and/or its salt can be dramatically improved. Gives the skin a refreshing sensation and gives it a good feel.

The menthol may be any of the d-body, the l-body, and the dl-body, preferably the l-body.

For the pharmaceutical composition for external use of the present invention, an essential oil containing menthol may also be used as the (C) component. The essential oil containing menthol can be appropriately selected and used among well-known persons, and examples thereof include peppermint oil, peppermint oil, and green mint oil.

In the component (C), from the viewpoint of further improving the transdermal absorbability of tocofina and/or its pharmaceutically acceptable salts, it is preferably thin Horitol and essential oil containing it are more preferably 1-menthol and essential oil containing it.

With regard to the content of the (C) component in the pharmaceutical composition for external use of the present invention, from the viewpoint of further enhancing the effect of inhibiting the precipitation of tocofina and/or its salts, it may be, for example, 1% by weight or more, preferably 1 to 15% by weight %, more preferably 3 to 10% by weight, and most preferably 5 to 10% by weight.

(D) water

In order to make the pharmaceutical composition for external use of the present invention into a desired formulation form, it may contain water as needed (hereinafter, sometimes referred to as "(D) component").

The content of the component (D) in the external pharmaceutical composition of the present invention can be appropriately set according to the type of preparation, for example, 5 to 50% by weight. Generally, when the water content is 15% by weight or more, especially at 20% by weight or more, when the co-existence of kefina and/or its salt and 0.1% by weight or more of lactic acid and/or its salt is found, the formation of precipitates changes. There is a significant tendency, but the pharmaceutical composition for external use of the present invention can suppress the precipitation of tocofina and/or its salts even when it contains a large amount of water. In view of the effects of the present invention, the content of the component (D) in the external pharmaceutical composition of the present invention may be preferably 10 to 40% by weight, more preferably 15 to 40% by weight, and particularly preferably 15 to 39 % By weight, preferably 20~38.9% by weight.

(E) Lower alcohol

In the pharmaceutical composition for external use of the present invention, in order to improve the solubility in water of the contained components, etc., a lower alcohol (hereinafter, sometimes written as As "(E) component").

The lower alcohol is not particularly limited, and examples thereof include monovalent lower alcohols having 1 to 4 carbon atoms, such as ethanol, propanol, isopropanol, n-butanol, second butanol, and third butanol. Among them, preferred examples include ethanol, propanol, and isopropanol. One type of these lower alcohols may be used alone, or two or more types may be used in combination.

The content of the component (E) in the pharmaceutical composition for external use of the present invention can be appropriately set according to the type of the preparation and the like, and may be, for example, 30 to 90% by weight. The pharmaceutical composition for external use of the present invention can reduce the composition by containing the aforementioned components (A) to (C) to increase the solubility of tocofina and/or its salts in water and make it difficult to precipitate. The amount of lower alcohol contained in. In view of the effects of the present invention, when the external pharmaceutical composition of the present invention contains the component (E), its content may be preferably 45 to 80% by weight, more preferably 50 to 75% by weight, and particularly preferably 55~70% by weight.

Other ingredients

In addition, the pharmaceutical composition for external use of the present invention may contain a base such as an aqueous base or an oily base other than the aforementioned components (D) and (E) in order to produce a desired formulation form.

Examples of the aqueous base other than the components (D) and (E) include polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and butylene glycol.

Examples of oily bases include non-polar oils and polar oils. Specific examples of the non-polar oil include hydrocarbons such as paraffin and isoparaffin; squalene and spermaceti. In addition, the polar oil specifically includes aliphatic monocarboxylic acid esters, triglycerides, Aliphatic dicarboxylic acid diester, aliphatic dicarboxylic acid alkylene glyceride, higher fatty acid, etc. Generally, polar oils are used in order to improve the solubility of fat-soluble components in water, etc. The pharmaceutical composition for external use of the present invention, by containing the aforementioned components (A) to (C), improves tocopheraline and/or its salts The solubility in water makes it difficult to precipitate, and it can actually be formulated without polar oil. In view of these effects of the present invention, one embodiment suitable for the external pharmaceutical composition of the present invention may be one that does not actually contain a polar oil. Here, "actually does not contain polar oil" means that the content of polar oil is an amount that does not affect the solubility of tokefina and/or its salts in water, and specifically means 5% by weight or less, preferably It is less than 3% by weight, more preferably 0% by weight.

In the pharmaceutical composition for external use of the present invention, in addition to the aforementioned components, pharmacological components may be contained as needed in a range that does not hinder the effects of the present invention. The pharmacological components that can be incorporated in the external pharmaceutical composition of the present invention are not particularly limited, and examples include anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and stearic acid glycyrrhizinate; two Phenimidazole, diphenhydramine and their pharmacologically approved salts, clofipramine and malic acid and other antihistamines; lidocaine and its pharmacologically approved salts, tobucaine and its Pharmaceutically approved salts, 4-aminobenzoic acid ethyl esters and other local anesthetics; tocopherol acetate, benzyl nicotinate, vanillyl nonanoate, capsaicin anhydride and other blood circulation promoting agents; Arnica tincture, Phellodendron chinense Extracts, extracts of gardenia extract, horse chestnut extract, scopolium extract, belladonna extract, angelica extract, purple root extract, mountain pepper extract and other crude drugs.

Furthermore, the pharmaceutical composition for external use of the present invention may contain, in addition to the aforementioned components, a pharmaceutical composition generally used for external use as needed Other additives. Examples of such additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, colorants, and the like. The tackifier that can be incorporated into the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and carboxyvinyl polymers. , Hyaluronic acid, xanthan gum, etc.

pH

When the pharmaceutical composition for external use of the present invention is made into a liquid dosage form, the pH may be, for example, 3.0 to 9.0, more preferably 4.0 to 9.0, and most preferably 4.5 to 8.5.

Formulation

The formulation type of the pharmaceutical composition for external use of the present invention is not particularly limited as long as its range is transdermally applicable. For example, liquid formulations (including lotions, sprays, aerosols, and emulsions) and foams can be mentioned. , Ointment, plaster, cream, gel, patch, etc. Examples of such preparations are preferably liquid or gel. The preparation method for these types of preparations can be formulated according to the well-known methods described in the Sixteenth Revision of the Japanese Pharmacopoeia, such as the General Principles of Preparations, using additives according to the type of preparation.

How to use

The pharmaceutical composition for external use of the present invention is applied to an analgesic part (skin) by external administration. The dosage of the pharmaceutical composition for external use of the present invention can be appropriately set according to the administration site, the degree of symptoms to be treated, etc., and the local area where administration is desired is to be given once per 1 cm ² of kefina and/or its pharmaceutically acceptable salts The dosage can be about 10~500mg.

The pharmaceutical composition for external use of the present invention is an anti-inflammatory analgesic for external use, which can be used for shoulder pain, arthralgia, lumbago, muscle pain, tendonitis (pain in the hands and wrists) accompanied by stiff shoulders, and pain in the elbow (tennis elbow) Etc.), severe pain, sprain pain, fracture pain, neuralgia, deformed arthritis, arthritis, etc.

2. Control precipitation method

Further, the present invention provides a method for inhibiting the precipitation of tocofina and/or its pharmaceutically acceptable salts. Specifically, the method for inhibiting precipitation of the present invention is characterized in that it contains (A) tokefina and/or a pharmaceutically acceptable salt thereof, and (B) 0.1% by weight or more of lactic acid and/or a salt thereof. In the composition, (C) menthol is blended to suppress the precipitation of tocofina and/or its pharmaceutically acceptable salts. In the method for suppressing precipitation according to the present invention, the types and blending amounts of the components used, the pH of the external pharmaceutical composition, the form of the preparation, etc., are as described in the column of "1. External pharmaceutical composition".

[Examples]

The following disclosed embodiments more specifically illustrate the present invention, but the present invention is not limited by these embodiments.

Test Example 1

A pharmaceutical composition other than the compositions shown in Tables 1 and 2 was prepared. Specific In other words, after adding a predetermined amount of kefina sodium and 1-menthol to a predetermined amount of ethanol or isopropanol and dissolving it, add a predetermined amount of lactic acid and stir. Next, by adding a predetermined amount of water and hydroxypropylcellulose (only Example 3) and stirring, a pharmaceutical composition for external use was obtained (other than Example 3 was in liquid form, and only Example 3 was in gel form).

The external appearance of each pharmaceutical composition just after preparation was evaluated, and the external appearance of the pharmaceutical composition after being stored at 25° C. for 3 days under shading conditions was also evaluated. The external appearance pharmaceutical composition was evaluated in accordance with the following criteria.

<Judgment criteria for appearance characteristics>

◎: No precipitate was found, and it was in an excellent soluble state.

○: Slight precipitates were found, but they were in a good soluble state in practical use.

△: Precipitates are clearly found and cannot be used in a soluble state.

×: Significant precipitates were found, and no soluble state was exhibited.

The obtained results are shown in Tables 1 and 2. From this result, it can be seen that when Kefena sodium does not coexist with lactic acid, and when Kefena sodium coexists with less than 0.1% by weight of lactic acid, no precipitates are generated (refer to Examples 1 and 2). When sodium coexists with 0.1% by weight or more of lactic acid and does not contain 1-menthol, a significant amount of precipitates were found immediately after the preparation was completed or stored for 3 days (Comparative Examples 1 to 6). On the contrary, when Kfina sodium coexists with more than 0.1% by weight of lactic acid and contains 1-menthol, the preparation is completed and stored 3 Days later, it was found that the formation of precipitates was suppressed (Examples 1 to 9). That is, when Kefena sodium coexists with 0.1% by weight or more of lactic acid and contains 5% by weight or more of 1-menthol, it has a significant effect of suppressing the formation of precipitates and exhibits an excellent soluble state.

In the table, the unit of each component is "% by weight".

In the table, the unit of each component is "% by weight".

Test Example 2

A pharmaceutical composition (liquid) other than the composition shown in Table 3 was prepared. In order to evaluate the percutaneous absorbability of each external pharmaceutical composition, the following experiment was performed. YMP (Yucatan Micropig) skin (manufactured by Charles River Corporation, Japan) frozen at -30℃ was left at room temperature for about 30 minutes to thaw naturally, and the fat and muscle attached under the skin were removed to be used as the test skin . Then place the skin for the test in a Franz-type diffusion tank (effective permeation diameter 25mm, made of glass), fill the receiving side tank with 0.2M PBS buffer (pH7.4), and soak the Franz-type diffusion tank in 37℃±3℃ in warm water. After the Franz-type diffusion tank became 37°C±3°C, 1 g of the external pharmaceutical composition was applied to the epidermal side of the test skin and maintained at 37°C±3°C for 5 hours. After 3 hours and 5 hours after the application of the external pharmaceutical composition, 0.5 ml of PBS buffer in the receiving side tank was taken, and the concentration of tocopherol in the current PBS buffer was measured using a liquid chromatograph, and the tocopherol was calculated. The amount of sodium that penetrates the test skin (to be absorbed percutaneously with Kfina sodium, μg). In this test, the same batch number was used for the test skin.

The results obtained are shown in Table 3. It can be clearly seen from Table 3 that after adding fenfina sodium and 1-menthol, when lactic acid is contained (Example 10), compared with when lactic acid is not included (Comparative Example 7), the The amount of skin absorption increases dramatically. On the other hand, when acetic acid was simultaneously contained with tocopheraline sodium and 1-menthol (Comparative Example 8), the percutaneous absorption of tocopheraline sodium did not increase as when lactic acid was used. Further, even if it contains When sodium lactic acid and lactic acid did not contain 1-menthol (Comparative Example 9), the amount of percutaneous absorption of kefina sodium did not increase. From the above results, it is clear that the transdermal absorption amount of tocofina sodium can be increased dramatically, which is achieved by containing tocofina sodium, 1-menthol and lactic acid in an integral and indivisible form.

In the table, the unit of the blending amount of each contained component is "% by weight".

Preparation example

A pharmaceutical composition for external use other than the composition shown in Table 4 was prepared (Formulation Examples 1, 3 and 5 were in liquid form, and Preparation Examples 2, 4 and 6 were in gel form). The pharmaceutical compositions obtained for external use have excellent percutaneous absorption of tocofina sodium, can further suppress the formation of precipitates, and have excellent stability.

In the table, the unit of each component is "% by weight".

Claims (7)

A pharmaceutical composition for external use containing (A) tokefina and/or pharmaceutically acceptable salts thereof, (B) 0.1% by weight or more of lactic acid and/or its salts, and (C) 1% by weight or more Menthol; and does not contain zirconium compounds. If the pharmaceutical composition is used outside of claim 1, it further contains (D) water. If the pharmaceutical composition is used outside of claim 1 or 2, it further contains (E) a lower alcohol. The pharmaceutical composition for use other than claim 2, wherein the aforementioned (D) component system contains 5 to 50% by weight. The pharmaceutical composition for use other than claim 3, wherein the aforementioned (E) component system contains 30 to 90% by weight. If the pharmaceutical composition is used outside of claim 1 or 2, it is a liquid agent or a gel agent. A method for inhibiting the precipitation of dioxin and/or its pharmaceutically acceptable salts, which contains (A) oxyphena and/or its pharmaceutically acceptable salts, and (B) 0.1% by weight or more of lactic acid And/or its salt, and does not contain a zirconium compound, the pharmaceutical composition for external use is blended with (C) 1% by weight or more of menthol.