HK1229216B - Pharmaceutical composition for external use - Google Patents

Description

External use pharmaceutical composition

Technical Field

The present invention relates to a pharmaceutical composition for external use which can suppress the precipitation of diclofenac and/or its salt even in the coexistence of diclofenac and/or its salt and lactic acid and/or its salt and has excellent stability.

Background Art

In modern society, the prevalence of OA (Office Automation) equipment has led to an increase in the number of people suffering from stiff shoulders, muscle pain, and joint pain due to prolonged periods of time spent in the same posture, excessive stress, and lack of exercise. Conventionally, the application of anti-inflammatory analgesics has been used to treat these stiff shoulders, muscle pain, and joint pain in order to suppress inflammation in the affected area and improve symptoms.

Nonsteroidal anti-inflammatory analgesics such as diclofenac, felbinac, dexamethasone, indomethacin, and ibuprofen have long been used as anti-inflammatory analgesics. Among these nonsteroidal anti-inflammatory analgesics, diclofenac is known to have high inhibitory activity against cyclooxygenase and to exhibit excellent anti-inflammatory and analgesic effects. Diclofenac, when administered orally or rectly, can cause gastrointestinal, renal, or hepatic damage as a side effect, with severe gastrointestinal side effects being particularly pronounced. Consequently, its use as a topical preparation has recently increased. However, diclofenac has the following disadvantages: low transdermal absorption and, when administered transdermally, its inherent anti-inflammatory and analgesic effects cannot be fully exerted.

Various formulation technologies have been investigated to improve the transdermal absorbability and efficacy of diclofenac. For example, Patent Document 1 discloses that the transdermal absorbability of diclofenac or its salts can be enhanced by adding an alcohol and a carboxylic acid ester and/or a carboxylic acid to a composition for external use containing diclofenac or its salts. Furthermore, Patent Document 2 discloses that the analgesic effect can be enhanced by including 0.5-1.5% by weight of diclofenac or its pharmaceutically acceptable salt and 5-15% by weight of a cooling agent in a composition for external use.

Prior art literature

Patent Literature

Patent Document 1: Japanese Patent Application Laid-Open No. 10-182450

Patent Document 2: Japanese Patent Application Laid-Open No. 2011-074032

Summary of the Invention

Problems to be solved by the invention

With the increasing number of people suffering from shoulder stiffness, muscle pain, and joint pain, there is a growing demand for topical preparations with superior anti-inflammatory and analgesic effects, and a growing desire for the development of formulation technologies that can further enhance the transdermal absorbability of diclofenac and/or its salts. Consequently, the present inventors investigated formulation technologies for enhancing the transdermal absorbability of diclofenac and/or its salts in topical pharmaceutical compositions containing diclofenac and/or its salts. As shown in Test Example 3 described below, lactic acid and/or its salts contribute to improved transdermal absorbability of diclofenac and/or its salts. However, when diclofenac and/or its salts are coexisted with 0.1% by weight or more of lactic acid and/or its salts, a new challenge arises: precipitation of diclofenac and/or its salts is likely to occur, compromising the stability of the formulation. While formulations containing high levels of lower alcohols, polyols, or polar oils are effective in inhibiting such precipitation, such formulations have the disadvantage of adversely affecting the feel of use and increasing limitations on formulation design.

Therefore, an object of the present invention is to provide a formulation technology that can suppress the precipitation of diclofenac and/or its salt even in the coexistence of diclofenac and/or its salt and lactic acid and/or its salt, thereby having excellent stability.

Solutions for solving problems

The present inventors conducted intensive research to address the aforementioned issues and discovered that the combined use of diclofenac and/or its salts, 0.1% by weight or greater of lactic acid and/or its salts, and menthol prevents precipitation of diclofenac and/or its salts and provides excellent stability. The present invention was completed based on this finding and further research.

That is, the present invention provides the inventions disclosed below.

Item 1. A pharmaceutical composition for external use, characterized in that it contains (A) diclofenac 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.

Item 2. The external pharmaceutical composition according to Item 1, further comprising (D) water.

Item 3. The external pharmaceutical composition according to Item 1 or 2, further comprising (E) a lower alcohol.

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

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

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

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

Item 8. A method for inhibiting the precipitation of diclofenac and/or a pharmaceutically acceptable salt thereof, comprising: adding (C) menthol to a pharmaceutical composition for external use comprising (A) diclofenac and/or a pharmaceutically acceptable salt thereof and (B) 0.1% by weight or more of lactic acid and/or a salt thereof.

Effects of the Invention

The external pharmaceutical composition of the present invention can suppress the precipitation of diclofenac and/or its salts even when it coexists with lactic acid and/or its salts, thereby exhibiting a good appearance and excellent stability. Furthermore, the external pharmaceutical composition of the present invention, by containing menthol, suppresses the precipitation of diclofenac and/or its salts, thereby achieving stability. Therefore, in addition to formulation, the lower alcohol content can be reduced (e.g., to 80% by weight or less), making it possible to eliminate the need for polyols or polar oils. This reduces restrictions on formulation design and allows for application in a variety of formulations.

Furthermore, the external pharmaceutical composition of the present invention has significantly improved transdermal absorbability of diclofenac and/or its salts, and thus can exhibit excellent anti-inflammatory and analgesic effects, effectively alleviating or curing shoulder stiffness, muscle pain, joint pain, and the like.

DETAILED DESCRIPTION

1. External use pharmaceutical composition

The pharmaceutical composition for external use of the present invention is characterized by comprising (A) diclofenac 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. The pharmaceutical composition for external use of the present invention is described in detail below.

(A) Diclofenac and/or its salt

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

Diclofenac is a well-known nonsteroidal compound called 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid.

Salts of diclofenac are not particularly limited as long as they are pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; salts with ammonia; salts with primary, secondary, or tertiary alkylamines such as dimethylamine, diethylamine, trimethylamine, and triethylamine; and salts with primary, secondary, or tertiary alkanolamines such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, and triisopropanolamine. Among these, alkali metal salts are preferred, and sodium salts are even more preferred. 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 component (A), one species selected from diclofenac and its salts may be used alone, or two or more species may be used in combination. Among component (A), preferred examples include salts of diclofenac, more preferred examples include alkali metal salts of diclofenac, and particularly preferred examples include diclofenac sodium.

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, preferably 0.5 to 1.5% by weight, and more preferably 0.7 to 1.3% by weight.

(B) lactic acid and/or its salt

The external pharmaceutical composition of the present invention contains lactic acid and/or its salt (hereinafter also referred to as "component (B)") in an amount of 0.1% by weight or more.

There are no particular limitations on the salts of lactic acid as long as they are 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 salts with ammonia. These salts of lactic acid may be used alone or in combination of two or more.

In the external pharmaceutical composition of the present invention, as component (B), one selected from lactic acid and its salts can be used alone or in combination of two or more. Among component (B), from the viewpoint of further enhancing the effect of inhibiting the precipitation of diclofenac and/or its salts and its transdermal absorbability, preferably lactic acid and alkali metal salts of lactic acid are used, more preferably lactic acid and sodium lactate are used, and particularly preferably lactic acid is used.

The content of the component (B) in the external pharmaceutical composition of the present invention may be 0.1% by weight or more. From the viewpoint of further enhancing the effect of inhibiting the precipitation of diclofenac and/or its salts and its transdermal absorbability, the content is preferably 0.1 to 5% by weight, more preferably 0.1 to 4% by weight, particularly preferably 0.1 to 3% by weight, and particularly preferably 0.1 to 1% by weight.

(C) Menthol

The external pharmaceutical composition of the present invention contains menthol (hereinafter sometimes referred to as "component (C)"). The inclusion of menthol can suppress the precipitation of diclofenac and/or its salts in the presence of 0.1% by weight or greater of lactic acid and/or its salts, thereby imparting excellent stability to the external pharmaceutical composition. Furthermore, the inclusion of menthol can significantly improve the transdermal absorbability of diclofenac and/or its salts through interaction with 0.1% by weight or greater of lactic acid and/or its salts, thereby imparting a cooling sensation to the skin upon application and improving the feel during use.

Menthol may be in the d-isomer, l-isomer, or dl-isomer, and the l-isomer is preferred.

The external pharmaceutical composition of the present invention may also use an essential oil containing menthol as component (C). The essential oil containing menthol can be appropriately selected from known essential oils and can include, for example, peppermint oil, peppermint oil, and spearmint oil.

Among the components (C), from the viewpoint of further improving the transdermal absorbability of diclofenac and/or its pharmaceutically acceptable salt, preferably menthol and essential oils containing the same are mentioned, and more preferably 1-menthol and essential oils containing the same are mentioned.

The content of the component (C) in the external pharmaceutical composition of the present invention is, for example, 1% by weight or more, preferably 1 to 15% by weight, more preferably 3 to 10% by weight, and particularly preferably 5 to 10% by weight, from the viewpoint of further enhancing the effect of inhibiting the precipitation of diclofenac and/or its salts.

(D) Water

The pharmaceutical composition for external use of the present invention may contain water (hereinafter sometimes referred to as component (D)) as necessary in order to obtain a desired formulation form.

The content of component (D) in the external-use pharmaceutical composition of the present invention can be appropriately set according to the form of the preparation, and can be, for example, 5 to 50% by weight. Generally, when diclofenac and/or its salt coexists with 0.1% by weight or more of lactic acid and/or its salt under conditions of a water content of 15% by weight or more, particularly 20% by weight or more, there is a tendency for the formation of precipitates to become significant. However, the external-use pharmaceutical composition of the present invention can suppress the precipitation of diclofenac and/or its salt even when containing such a large amount of water. In view of the effects of the present invention, the content of component (D) in the external-use pharmaceutical composition of the present invention can preferably be 10 to 40% by weight, more preferably 15 to 40% by weight, particularly preferably 15 to 39% by weight, and most preferably 20 to 38.9% by weight.

(E) Lower alcohol

The external pharmaceutical composition of the present invention may contain a lower alcohol (hereinafter sometimes referred to as component (E)) as needed in order to improve the solubility of the components in water.

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, sec-butanol, and tert-butanol. Among them, ethanol, propanol, and isopropanol are preferred. These lower alcohols may be used alone or in combination of two or more.

The content of component (E) in the external pharmaceutical composition of the present invention can be appropriately set depending on the formulation form, and can be, for example, 30 to 90% by weight. The inclusion of components (A) to (C) in the external pharmaceutical composition of the present invention improves the solubility of diclofenac and/or its salt in water and reduces precipitation, thereby reducing the amount of lower alcohols contained. In view of the effects of the present invention, when the external pharmaceutical composition of the present invention contains component (E), its content can preferably be 45 to 80% by weight, more preferably 50 to 75% by weight, and particularly preferably 55 to 70% by weight.

Other ingredients

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

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

Examples of oily bases include non-polar oils and polar oils. Examples of non-polar oils include hydrocarbons such as paraffins and isoparaffins; squalane, wax, and the like. In addition, examples of polar oils include aliphatic monocarboxylic acid esters, triglycerides, aliphatic dicarboxylic acid diesters, aliphatic dicarboxylic acid alkylene glycol esters, and higher fatty acids. Polar oils are generally used to increase the solubility of fat-soluble components in water, but the pharmaceutical composition for external use of the present invention contains the aforementioned components (A) to (C), thereby increasing the solubility of diclofenac and/or its salts in water and making it less likely to precipitate. Therefore, formulations can be made without substantially containing polar oils. In view of the effects of the present invention, a suitable embodiment of the pharmaceutical composition for external use of the present invention includes a pharmaceutical composition for external use that does not substantially contain polar oils. Here, “substantially containing no polar oil” means that the content of the polar oil is an amount that does not affect the solubility of diclofenac and/or its salt in water, specifically, 5 wt % or less, preferably 3 wt % or less, and more preferably 0 wt %.

The external-use pharmaceutical composition of the present invention may contain pharmacological ingredients in addition to the aforementioned ingredients as needed, as long as they do not hinder the effects of the present invention. The pharmacological ingredients that can be incorporated into the external-use pharmaceutical composition of the present invention are not particularly limited, and examples thereof include: anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizate, ammonium glycyrrhizate, and stearyl glycyrrhizate; antihistamines such as diphenylimidazole, diphenhydramine and its pharmaceutically acceptable salts, and chlorpheniramine maleate; local anesthetics such as lidocaine and its pharmaceutically acceptable salts, dibucaine and its pharmaceutically acceptable salts, and ethyl aminobenzoate; blood circulation enhancers such as tocopheryl acetate, benzyl nicotinate, nonanoic acid vanillamide, and capsicum extract; and crude drugs such as arnica tincture, phellodendron amurense extract, gardenia jasminoides extract, horse chestnut extract, anisopus officinalis extract, belladonna extract, angelica extract, purple root extract, and sanshoum officinale extract.

And, for external-use medicinal composition of the present invention, in addition to the aforementioned components, other commonly used additives can also be included in the external-use medicinal composition as required. As such additives, for example, pH adjusting agents, surfactants, emulsifiers, solubilizers, preservatives, antiseptics, preservatives, antioxidants, stabilizers, chelating agents, thickeners, spices, coloring agents etc. can be enumerated. There is no particular restriction on the thickener that can be compounded in the external-use medicinal composition of the present invention, and for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxyvinyl polymer, hyaluronic acid, xanthan gum etc. can be enumerated.

pH

When the external pharmaceutical composition of the present 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 8.5.

Preparation form

For the preparation form of the external-use pharmaceutical composition of the present invention, as long as it can be applied to transdermal application, there is no particular limitation, and examples thereof include liquids (including lotions, sprays, aerosols, and emulsions), foaming agents, ointments, plasters, creams, gels, patches, etc. Among them, preferably, liquids or gels can be mentioned. For the preparation of these preparation forms, the known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, etc., can be used to prepare the additives that meet the preparation form.

Usage form

The topical pharmaceutical composition of the present invention is used by external application to the local area (skin) where analgesia is sought. The dosage of the topical pharmaceutical composition of the present invention can be appropriately determined based on the site of administration, the severity of the symptoms to be treated, and the like. It is desirable that the dosage of diclofenac and/or its pharmaceutically acceptable salts be approximately 10 to 500 mg per 1 ^cm² of the topical area administered and per dose.

The external medicinal composition of the present invention can be used as an external anti-inflammatory analgesic for the purpose of treating shoulder pain accompanied by shoulder stiffness, joint pain, low back pain, muscle pain, tenosynovitis (pain in the hand/wrist), elbow pain (tennis elbow, etc.), traumatic pain, sprain pain, fracture pain, neuralgia, osteoarthritis, arthritis, etc.

2. Methods for inhibiting precipitation

The present invention also provides a method for inhibiting the precipitation of diclofenac and/or its pharmaceutically acceptable salts. Specifically, the method for inhibiting precipitation of the present invention is a method for inhibiting the precipitation of diclofenac and/or its pharmaceutically acceptable salts, characterized by adding (C) menthol to a pharmaceutical composition for external use containing (A) diclofenac and/or its pharmaceutically acceptable salts and (B) 0.1% by weight or greater of lactic acid and/or its salts. Regarding the method for inhibiting precipitation of the present invention, the types of components used, the amounts added, the pH of the pharmaceutical composition for external use, the formulation form, etc. are as described above in the section "1. Pharmaceutical composition for external use."

Example

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Test Example 1

External pharmaceutical compositions having the compositions shown in Tables 1 and 2 were prepared. Specifically, predetermined amounts of diclofenac sodium and l-menthol were added to a predetermined amount of ethanol or isopropyl alcohol and dissolved. A predetermined amount of lactic acid was then added and stirred. Subsequently, predetermined amounts of water and hydroxypropylcellulose (only in the case of Example 3) were added and stirred to obtain external pharmaceutical compositions (liquid forms except for Example 3; gel form in Example 3).

The appearance of each external pharmaceutical composition was evaluated immediately after preparation and after storage at 25° C. under light-shielding conditions for 3 days. The appearance of the external pharmaceutical composition was evaluated based on the following criteria.

<Appearance Criteria>

⊚: No precipitate was observed, indicating an extremely good solubilized state.

○: A small amount of precipitates were observed, but the solubilized state was good enough to cause no problem in use.

Δ: Clear precipitates were observed, and the solution was not in a practically usable state.

×: Remarkable precipitation was observed, but the product was not dissolved.

The results are shown in Tables 1 and 2. These results confirm that no precipitate formation was observed when diclofenac sodium was not present in the presence of lactic acid or when diclofenac sodium was present in less than 0.1% by weight of lactic acid (Reference Examples 1 and 2). However, significant precipitate formation was observed immediately after preparation and after three days of storage when diclofenac sodium was present in the presence of 0.1% by weight or more of lactic acid and without l-menthol (Comparative Examples 1 to 6). On the other hand, when diclofenac sodium, 0.1% by weight or more of lactic acid, and l-menthol were present, precipitate formation was suppressed immediately after preparation and after three days of storage (Examples 1 to 9). In particular, when diclofenac sodium, 0.1% by weight or more of lactic acid, and 5% by weight or more of l-menthol were present, the precipitate formation suppression effect was significant, resulting in an extremely favorable solubilized state.

[Table 1]

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

[Table 2]

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

Test Example 3

An external-use pharmaceutical composition (liquid) with the composition shown in Table 3 was prepared. In order to evaluate the transdermal absorbability of each external-use pharmaceutical composition, the following test was performed. The YMP (Yucatan Micropig) skin (manufactured by Charles River, Japan) frozen at -30°C was placed at room temperature for about 30 minutes. After natural thawing, the fat and meat pieces attached to the subcutaneous tissue were removed and used as test skin. The test skin was installed in a Franz-type diffusion cell (effective penetration diameter of about 25 mm, made of glass), the receiver was filled with 0.2M PBS buffer (pH 7.4), and the Franz-type diffusion cell was immersed in warm water at 37°C ± 3°C. After the temperature in the Franz-type diffusion cell reached 37°C ± 3°C, 1 g of the external-use pharmaceutical composition was applied to the epidermal side of the test skin and kept at 37°C ± 3°C for 5 hours. Three and five hours after application of the topical pharmaceutical composition, 0.5 ml of PBS buffer was collected from the receiver. The diclofenac concentration in the PBS buffer was measured by liquid chromatography to calculate the amount of diclofenac sodium permeating the test skin (percutaneous absorption of diclofenac sodium, μg). It should be noted that in this experiment, all test skin used was from the same lot.

The results are shown in Table 3. As is clear from Table 3, the transdermal absorption of diclofenac sodium dramatically increased when diclofenac sodium, l-menthol, and lactic acid were included (Example 10) compared to when no lactic acid was present (Comparative Example 7). On the other hand, the transdermal absorption of diclofenac sodium did not increase as much as when lactic acid was used when diclofenac sodium, l-menthol, and acetic acid were included (Comparative Example 8). Furthermore, even when diclofenac sodium and lactic acid were included, the transdermal absorption of diclofenac sodium did not increase when l-menthol was not present (Comparative Example 9). These results clearly demonstrate that a dramatic increase in the transdermal absorption of diclofenac sodium can be achieved by including diclofenac sodium, l-menthol, and lactic acid in an integral and inseparable manner.

[Table 3]

In Table A, the unit of the amount of each component is "weight %".

Preparation Examples

External pharmaceutical compositions having the compositions shown in Table 4 were prepared (Preparation Examples 1, 3, and 5 were liquid, and Preparation Examples 2, 4, and 6 were gel). The resulting external pharmaceutical compositions all exhibited excellent transdermal absorbability of diclofenac sodium, suppressed precipitate formation, and exhibited excellent stability.

[Table 4]

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

Claims (5)

1. A topical pharmaceutical composition, characterized in that it contains (A) 0.2 to 2% by weight of diclofenac and/or its pharmaceutically permissible salt, (B) 0.1 to 1% by weight of lactic acid and/or its salt, (C) 1 to 15% by weight of menthol, and (D) 5 to 50% by weight of water, and does not contain propylene glycol. 2. The topical pharmaceutical composition according to claim 1, further comprising (E) lower alcohols. 3. The topical pharmaceutical composition according to claim 1 or 2, wherein it is a liquid or a gel. 4. The topical pharmaceutical composition according to claim 2, comprising 30 to 90% by weight of the (E) component. 5. A method for inhibiting the precipitation of diclofenac and/or its pharmaceutically permissible salts, characterized in that it comprises mixing (B) 0.1-1% lactic acid and/or its salts into a topical pharmaceutical composition comprising (A) 0.2-2% by weight of diclofenac and/or its pharmaceutically permissible salts and (C) 1-15% by weight of menthol, and adding (D) 5-50% by weight of water, and The topical pharmaceutical composition does not contain propylene glycol.