TW201622713A - External pharmaceutical composition - Google Patents

Abstract

To provide a pharmaceutical technique which makes have an excellent stability by no precipitation of diclofenac and/or a salt thereof, in spite of coexistence of diclofenac and/or a salt thereof and lactic acid and/or a salt thereof. Combining menthol with diclofenac and/or a salt thereof, and 0.1% by weight or more of lactic acid and/or a salt thereof causes no precipitation of diclofenac and/or a salt thereof, and enables giving an excellent stability.

Description

External pharmaceutical composition

The present invention relates to a pharmaceutical composition for external use which can suppress the precipitation of ketone and/or a salt thereof even when diclofenac and/or a salt thereof is coexisted with lactic acid and/or a salt thereof.

In modern society, due to the popularity of office automation equipment, people who suffer from shoulder stiffness, muscle pain, and joint pain are increasing because they maintain the same posture for a long time, suffer from excessive stress, and lack of exercise. In the past, in order to suppress inflammation of the shoulders, muscles and joints, and the like, in order to suppress the symptoms of inflammation occurring in the affected part and to improve the symptoms, measures for applying an anti-inflammatory analgesic have been carried out.

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

To date, various reviews have been conducted on preparation techniques for improving the transdermal absorbability of Kevina and improving its efficacy. For example, in Patent Document 1, a topical composition containing ketone or a salt thereof is disclosed, and by adding an alcohol with a carboxylic acid ester and/or a carboxylic acid, the transdermal absorbability of ketone or a salt thereof can be improved. . Further, in Patent Document 2, it is disclosed that a pharmaceutical composition for external use contains 0.5 to 1.5% by weight of ketone or a pharmaceutically acceptable salt thereof, and 5 to 15% by weight of a cooling agent. Improve the analgesic effect.

[prior technical paper] [Patent Document]

[Patent Document 1] Japanese Patent Laid-Open No. Hei 10-182450

[Patent Document 2] Special Opening 2011-074032

With the increase in the number of people suffering from shoulder stiffness, muscle pain, and joint pain, the demand for agents that can exert more excellent anti-inflammatory and analgesic effects is increasing, and the development of Kefina and/or its salt can be further improved. The skin absorption preparation technology is expected to be higher and higher. Therefore, the present inventors reviewed the formulation technique for improving the transdermal absorbability of ketone and/or its salt for a pharmaceutical composition containing ketone and/or its salt. After the treatment, it was found that lactic acid and/or its salt can contribute to the improvement of the transdermal absorbability of ketone and/or its salt as described in Test Example 3 described later. However, it is only necessary to cope with ketone and/or its salt in an amount of 0.1% by weight or more of lactic acid and/or a salt thereof, and it is necessary to treat the ketone and/or its salt to be easily precipitated, thereby impairing the stability of the preparation. A novel subject. Inhibiting the precipitation of the ketone and/or its salt, the formulation of the formulation blended with a high content of the lower alcohol, and the formulation of the blended polyol or the polar oil can be effectively solved, however, the formulation of the formulations is present. The use of the product has an adverse effect, and there are many disadvantages such as limitations in the design of the formulation.

Therefore, the object of the present invention is to provide a formulation technique which can suppress the precipitation of ketone and/or its salt even if ketone and/or its salt coexist with lactic acid and/or a salt thereof, and which has excellent stability.

The inventors of the present invention conducted a thorough review to solve the above problems and found that by using menthol with ketone and/or its salt and 0.1% by weight or more of lactic acid and/or a salt thereof, Or its salt does not precipitate and has excellent stability. The present invention is based on the related knowledge and further accumulates the review and completed the invention.

That is, the present invention provides the invention of the embodiments disclosed below.

(1) A pharmaceutical composition for external use comprising (A) ketone 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) A pharmaceutical composition according to (1), which further contains (D) water.

(3) A pharmaceutical composition for (1) or (2) further comprising (E) a lower alcohol.

(4) A pharmaceutical composition for use in any one of (1) to (3), wherein the component (C) is contained in an amount of 1% by weight or more.

(5) A pharmaceutical composition for use in any one of (1) to (4), wherein the component (D) is contained in an amount of 5 to 50% by weight.

(6) A pharmaceutical composition for use in any one of (1) to (5), wherein the component (E) is contained in an amount of 30 to 90% by weight.

(7) A pharmaceutical composition, which is a liquid preparation or a gelling agent, as used in any one of (1) to (6).

(8) A method for inhibiting precipitation of ketone and/or a pharmaceutically acceptable salt thereof, which comprises (A) ketone and/or a pharmaceutically acceptable salt thereof, and (B) 0.1% by weight The medicinal composition other than the above lactic acid and/or its salt is blended with (C) menthol.

According to the pharmaceutical composition for external use according to the present invention, even if ketone and/or a salt thereof is coexisted with lactic acid and/or a salt thereof, precipitation of ketone and/or a salt thereof can be suppressed, and a good appearance property is exhibited, and Excellent stability. Further, in the pharmaceutical composition for external use of the present invention, since menthol is contained, precipitation of ketone and/or a salt thereof can be suppressed to stabilize, and when the formulation is formulated, the content of the lower alcohol can be lowered ( For example 80% by weight The following), with unblended polyols and polar oils, is less restrictive in formulation design and can be applied to a wide variety of formulation formulations.

Further, since the pharmaceutical composition for external use of the present invention drastically enhances the transdermal absorbability of ketone and/or its salt, it can exert an excellent anti-inflammatory and analgesic effect, and can effectively alleviate or cure shoulder stiffness and muscle pain. Joint pain and so on.

1. Topical pharmaceutical composition

A pharmaceutical composition for external use according to the present invention, which comprises (A) ketone 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 treated with kefin and/or its salt

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

A well-known compound of the non-steroidal system of 2-(2-(2,6-dichloroaniline)phenyl)acetic acid, which is also known as Keflon.

If the salt of Kefina is pharmaceutically acceptable, The alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt; ammonia and a salt thereof; dimethylamine, diethylamine, trimethylamine, triethylamine, etc. are not particularly limited. a salt of a grade 1, 2 or 3 alkylamine; monoethanol A salt of a grade 1, 2 or 3 alkanolamine such as an amine, diethanolamine, diisopropanolamine, triethanolamine or triisopropanolamine. Among them, an alkali metal salt is preferred, and a sodium salt is more preferred. The pharmaceutically acceptable salt may be used singly or in combination of two or more.

In the pharmaceutical composition for external use of the present invention, the component (A) may be used alone or in combination of two or more selected from the group consisting of ketone and its salt. Among the components (A), a salt of ketone is preferred, and an alkali metal salt of ketone is more preferred, and a particularly preferred one is kefenaldine.

The content of the component (A) in the external pharmaceutical composition of the present invention is not particularly limited, and is, for example, 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 salt

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

The salt of lactic acid 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; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonia and salts thereof. These salts of lactic acid may be used alone or in combination of two or more.

In the pharmaceutical composition for external use of the present invention, the component (B) may be used alone or in combination of two or more kinds selected from the group consisting of lactic acid and a salt thereof. Among the components (B), from the viewpoint of simultaneously suppressing the precipitation of ketone and/or its salt and increasing the transdermal absorbability, an alkali metal salt of lactic acid or lactic acid is preferred, and a system is preferred. Lactic acid, sodium lactate, especially good Give it 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, and has an inhibitory effect of precipitation of ketone and/or a salt thereof and an increase in transdermal absorbability. The viewpoint is preferably, for example, 0.1 to 5% by weight, more preferably 0.1 to 4% by weight, still more preferably 0.1 to 3% by weight, most preferably 0.1 to 1% by weight.

(C) menthol

The pharmaceutical composition for external use of the present invention contains menthol (hereinafter, referred to as "(C) component"). By containing menthol in the composition, precipitation of ketone and/or a salt thereof when coexisting with lactic acid and/or a salt thereof in an amount of 0.1% by weight or more can be suppressed, and the external pharmaceutical composition can have excellent stability. . Further, by containing menthol and utilizing an interaction with 0.1% by weight or more of lactic acid and/or a salt thereof, the transdermal absorbability of the ketone and/or its salt can be dramatically improved, further Gives the skin a cool feeling and gives it a good feeling of use.

The menthol may be any of a d body, a l body, and a dl body, and preferably one body.

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

Among the components (C), from the viewpoint of further improving the transdermal absorbability of the salt to be ketone and/or its pharmaceutically acceptable salt, it is preferred to be thin. The alcohol and the essential oil containing the same, more preferably 1-menthol and essential oils thereof.

The content of the component (C) in the pharmaceutical composition for external use of the present invention is, for example, 1% by weight or more, preferably 1 to 15% by weight, from the viewpoint of further suppressing the effect of inhibiting the precipitation of ketone and/or its salt. %, 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, water may be contained as needed (hereinafter, referred to as "(D) component").

The content of the component (D) in the external pharmaceutical composition of the present invention can be appropriately set depending on the formulation type, for example, 5 to 50% by weight. In general, when the water content is 15% by weight or more, particularly 20% by weight or more, when the ketone and/or its salt is coexisted with 0.1% by weight or more of lactic acid and/or a salt thereof, precipitate formation is observed. There is a significant tendency, but the pharmaceutical composition for external use of the present invention can suppress the precipitation of ketone and/or its salt even in the case of containing 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 is preferably 10 to 40% by weight, more preferably 15 to 40% by weight, and particularly preferably 15 to 39%. The weight % is preferably 20 to 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 components to be contained, a lower alcohol may be contained as needed (hereinafter, it may be noted "(E) component").

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

The content of the component (E) in the pharmaceutical composition for external use according to the present invention can be appropriately set depending on the form of the preparation, and examples thereof include, for example, 30 to 90% by weight. In the pharmaceutical composition for external use of the present invention, by containing the components (A) to (C), the solubility of the ketone and/or its salt in water is improved, and it is difficult to precipitate, and the composition can be lowered. The amount of lower alcohol contained in the product. In view of the effects of the present invention, when the external pharmaceutical composition of the present invention contains the component (E), the content thereof is preferably from 45 to 80% by weight, more preferably from 50 to 75% by weight, particularly preferably 55 to 70% by weight.

Other ingredients

Further, in the pharmaceutical composition for external use of the present invention, a base such as an aqueous base or an oil base other than the components (D) and (E) may be contained in order to obtain a desired formulation form.

The aqueous base other than the components (D) and (E) may, for example, be a polyhydric alcohol such as glycerin, propylene glycol, dipropylene glycol or butylene glycol.

The oily base may, for example, be a nonpolar oil or a polar oil. Specific examples of the non-polar oil include hydrocarbons such as paraffin and isoparaffin; squalene and cetyl wax. Further, specific examples of the polar oil include aliphatic monocarboxylic acid esters and triglycerides. An aliphatic dicarboxylic acid diester, an aliphatic dicarboxylic acid alkene glyceride, a higher fatty acid or the like. In general, a polar oil is used to enhance the solubility of a fat-soluble component in water, and the pharmaceutical composition for external use of the present invention is improved by containing the above components (A) to (C). The solubility in water is difficult to precipitate, and it can be formulated without actually containing a polar oil. In view of the effects of the present invention, one embodiment of the external pharmaceutical composition of the present invention is preferably one which does not substantially contain a polar oil. Here, "the fact that the polar oil is not contained" means that the content of the polar oil does not affect the solubility of the ketone and/or its salt to water, and specifically means 5% by weight or less, preferably It is 3% by weight or less, more preferably 0% by weight.

The pharmaceutical composition for external use of the present invention may contain a pharmacological component as needed in addition to the above components, within a range not inhibiting the effects of the present invention. The pharmacological component which can be blended in the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include an anti-inflammatory agent such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and glycyrrhizic acid stearate; Phenylimidazole, diphenhydramine and its pharmaceutically acceptable salts, antihistamines such as chlorphenamine dexamethasone; lidocaine and its pharmaceutically acceptable salts, to be buckin and Pharmaceutically acceptable salt, local anesthetic such as ethyl 4-aminobenzoate; tocopherol acetate, benzyl nicotinic acid, vanillyl citrate, capsaicin, etc. to promote blood circulation; arnica flower bud, cork Extracts, crab apple extract, horse chestnut extract, sorghum extract, belladonna extract, angelica extract, purple root extract, pepper extract and other crude drugs.

Further, the pharmaceutical composition for external use of the present invention may contain, in addition to the aforementioned components, a composition generally used for external use as needed. Other additives in the product. Examples of such additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, tackifiers, perfumes, coloring materials, and the like. The tackifier which can be blended in the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and carboxyvinyl polymer. , hyaluronic acid, xanthan gum, etc.

pH

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

Formulation type

The formulation form of the external pharmaceutical composition of the present invention is not particularly limited as long as it is percutaneously applicable, and examples thereof include a liquid preparation (including a lotion, a spray, a gel, and an emulsion), and a foaming agent. , ointments, plasters, creams, gels, patches, etc. Among these preparations, a liquid preparation or a gel preparation is preferred. The method of preparing the preparation forms can be formulated according to the formulation method in the Japanese Pharmacopoeia of the sixteenth revision, and the preparation is carried out in accordance with the formulation type.

Way of use

The pharmaceutical composition for external use of the present invention is applied to a part (skin) for analgesia by a topical administration method. The dosage of the external pharmaceutical composition of the present invention can be appropriately set depending on the site to be administered, the degree of the symptom to be treated, and the like, and it is desirable to carry out the administration of the local portion of the drug per 1 cm ² , to be kefinal and/or its pharmaceutically acceptable salt. The dosage can be about 10~500mg.

The external use pharmaceutical composition of the present invention is an anti-inflammatory analgesic for external use, which can be used for shoulder pain, joint pain, back pain, muscle pain, tendonitis (pain of the hand and wrist), and pain of the elbow (tennis elbow) Etc.), heavy pain, sprain pain, fracture pain, neuralgia, osteoarthritis, arthritis, etc.

2. Control the precipitation method

Further, the present invention provides a method of inhibiting the precipitation of ketone and/or its pharmaceutically acceptable salt. Specifically, the method for inhibiting precipitation according to the present invention is characterized by comprising (A) ketone 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, which is a method for inhibiting the precipitation of ketone and/or its pharmaceutically acceptable salt. In the method for inhibiting precipitation according to the present invention, the type of the component to be used, the blending amount, the pH of the external pharmaceutical composition, the formulation type, and the like are as described in the column "1. External pharmaceutical composition".

[Examples]

The invention is more specifically illustrated by the following examples, but the invention is not limited by the examples.

Test example 1

The composition shown in Tables 1 and 2 was prepared by using a pharmaceutical composition. Specifically In a predetermined amount of ethanol or isopropyl alcohol, a predetermined amount of ketophene sodium and 1-menthol are added and dissolved, and then a predetermined amount of lactic acid is added and stirred. Then, a predetermined amount of water and hydroxypropylcellulose (Example 3 only) were added and stirred to obtain a pharmaceutical composition for external use (liquid form other than Example 3, and only Example 3 was gel-like).

The appearance properties of each of the externally applied pharmaceutical compositions immediately after the preparation were evaluated, and the external appearance of the externally applied pharmaceutical composition was evaluated at 3 ° C for 3 days, and the appearance properties after storage under light-shielding conditions were evaluated. The evaluation of the appearance properties of the external pharmaceutical composition was carried out according to the following criteria.

<Criteria for judging traits>

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

○: Some micro-precipitates were found, but they were in a practically usable soluble state.

△: The precipitate was clearly found and could not be made soluble.

×: Significant precipitates were found and did not exhibit a soluble state.

The results obtained are shown in Tables 1 and 2. From the results, it was found that when kefinal sodium was not coexisted with lactic acid, and when kefinal sodium was coexisted with less than 0.1% by weight of lactic acid, no precipitate formation was observed (Reference Examples 1 and 2), to Kefner When sodium and 0.1% by weight or more of lactic acid coexisted, and 1-menthol was not contained, remarkable precipitate formation was observed immediately after preparation or storage for 3 days (Comparative Examples 1 to 6). On the other hand, when kofene sodium is coexisted with 0.1% by weight or more of lactic acid, and 1-menthol is contained, it is just completed and stored. After the day, it was found that the formation of precipitates was suppressed (Examples 1 to 9). That is, when kevina sodium is coexisted with 0.1% by weight or more of lactic acid and contains 5% by weight or more of 1-menthol, it has an effect of suppressing the formation of precipitates and exhibits an excellent soluble state.

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

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

Test example 2

The composition shown in Table 3 was prepared by using a pharmaceutical composition (liquid). The following experiment was conducted in order to evaluate the transdermal absorbability of each external pharmaceutical composition. The skin of YMP (Yucatan Micropig, yikatan micropigs) frozen at -30 ° C (manufactured by Charles River, Japan) was naturally thawed at room temperature for about 30 minutes to remove the fat and muscle attached to the skin and used as test skin. . The test skin device was placed in a Franz-type diffusion tank (effective permeation diameter of 25 mm, made of glass), and the receiving side tank was filled with 0.2 M PBS buffer (pH 7.4), and the Franz-type diffusion tank was immersed in Warm water at 37 °C ± 3 °C. After the inside of the Franz type diffusion tank was 37 ° C ± 3 ° C, 1 g of the external pharmaceutical composition was applied to the epidermis side of the test skin and maintained at 37 ° C ± 3 ° C for 5 hours. After administration of the topical pharmaceutical composition for 3 hours and 5 hours, 0.5 ml of the PBS buffer in the receiving side tank was taken, and the concentration of the ketone to be used in the PBS buffer was measured by a liquid chromatograph, and the Kefir was calculated. The amount of sodium that passed through the test (the amount of transdermal absorption of kefinal sodium, μg). In this test, the same batch number was used for the skin for the test.

The results obtained are shown in Table 3. It can be clearly seen from Table 3 that when kevinate and 1-menthol are added, when lactic acid is contained (Example 10), compared with when lactic acid is not contained (Comparative Example 7), the ketone sodium solution is compared. The amount of skin absorption has increased dramatically. On the other hand, when acetic acid was contained together with ketophene sodium and 1-menthol (Comparative Example 8), the transdermal absorption amount of kefinal sodium was not increased as in the case of using lactic acid. Further, even if it contains Nasal and lactic acid did not increase the transdermal absorption of koffinna when the content of 1-menthol was not contained (Comparative Example 9). From the above results, it is clear that the transdermal absorption of koffinnab can be dramatically increased by containing Kefina sodium, 1-menthol and lactic acid in an integral and inseparable form.

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

Formulation example

The composition shown in Table 4 was prepared by using a pharmaceutical composition (formulations 1, 3, and 5 in liquid form, and preparation examples 2, 4, and 6 in a gel form). The pharmaceutical composition for external use has excellent percutaneous absorption of kefferenadine, and further inhibits the formation of precipitates, and has excellent stability.

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

Claims (8)

A pharmaceutical composition for external use comprising (A) ketone 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. A pharmaceutical composition, which further contains (D) water, is used in addition to claim 1. A pharmaceutical composition is further contained in addition to claim 1 or 2, which further contains (E) a lower alcohol. The pharmaceutical composition according to any one of claims 1 to 3, wherein the component (C) is contained in an amount of 1% by weight or more. The pharmaceutical composition according to any one of claims 1 to 4, wherein the component (D) is contained in an amount of 5 to 50% by weight. The pharmaceutical composition according to any one of claims 1 to 5, wherein the component (E) is contained in an amount of 30 to 90% by weight. A pharmaceutical composition, a liquid preparation or a gelling agent, for use in any one of claims 1 to 6. A method for inhibiting precipitation of ketone and/or a pharmaceutically acceptable salt thereof, which comprises (A) ketone and/or a pharmaceutically acceptable salt thereof, and (B) 0.1% by weight or more of lactic acid And (/) menthol is blended in a pharmaceutical composition for use in addition to/or its salt.