JPH07121860B2 - Topical drug composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a pharmaceutical composition for external use containing diclofenac or a salt thereof having good transdermal absorbability.

[Problems to be Solved by Prior Art and Invention]

Diclofenac or a salt thereof is a non-steroidal anti-inflammatory drug and is currently on the market as an oral preparation or a suppository. However, when administered orally or rectally, various side effects such as gastrointestinal disorders have become a problem,
In order to reduce such side effects, various external pharmaceutical compositions have been proposed, which are intended to be absorbed from the outer skin and act locally or systemically. However, all of them are difficult to be percutaneously absorbed, so that they have not been put on the market yet, and an external preparation containing diclofenac or a salt thereof having good transdermal absorbability is desired.

[Means for Solving the Problems]

Under such circumstances, the present inventors have earnestly studied the percutaneous absorption promotion of an external preparation containing diclofenac or a salt thereof, and as a result, when adding a nonionic surfactant, its HLB
Depending on the value, the absorption of diclofenac or a salt thereof is affected, and particularly when an HLB value of 14.5 or less is added to the nonionic surfactant, the transdermal absorbability of diclofenac or a salt thereof is found to be improved, and the present invention has been completed. .

Therefore, the present invention provides diclofenac or a salt thereof, and HL
The present invention provides a pharmaceutical composition for external use, which comprises a nonionic surfactant having a B value of 14.5 or less.

The salt of diclofenac used in the present invention includes various pharmaceutically acceptable inorganic or organic salts, for example, sodium, potassium, calcium, ammonium, dimethylamine, diethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, Alkali metals such as diisopropanolamine, triethanolamine, triisopropanolamine,
Salts with alkaline earth metals, ammonia, primary, secondary or tertiary alkylamines or primary, secondary or tertiary alkanolamines are preferably used.

Further, the nonionic surfactant used in the present invention, the HLB value is required to be 14.5 or less, depending on the type, specifically, although not particularly limited, the HLB value is 14.5 or less sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan trioleate, glyceryl monostearate, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, polyoxyethylene cetyl Ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, polyoxyethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene monooleate, polyoxye Rensorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene glyceryl monooleate, polyoxyethylene glyceryl monostearate, polyoxyethylene phytosterol, polyoxyethylene Nonyl phenyl ether, polyoxyethylene octyl phenyl ether, etc. are mentioned. These may be used alone or in combination.

The external drug base used in the present invention is usually used as a gel base, for example, in addition to a gelling agent,
Generally, it is composed of water, a lower alcohol, a neutralizing agent and a cosolvent. Among these, examples of the gelling agent include carboxyvinyl polymer, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol and the like.
These gelling agents are used alone or in combination of two or more, and among these, a carboxyvinyl polymer is particularly preferably used. Examples of commercially available products include Wako Pure Chemical Industries, Ltd.
Hibiswako 103, 104, 105 manufactured by Goodrich Chemical Co., USA, and Carbopol 934, 940, 941 manufactured by Goodrich Chemical Co.

As lower alcohols, ethanol, propanol,
Examples of the neutralizing agent include isopropanol and the like.
Ammonia, primary, secondary or tertiary alkylamines and primary, secondary or tertiary alkanolamines such as aqueous ammonia, dimethylamine, diethylamine, triethylamine, monoethanolamine, Diethanolamine, diisopropanolamine,
Examples thereof include triethanolamine and triisopropanolamine. Further, examples of the cosolvent include glycerin, propylene glycol, polyethylene glycol and 1,3-butylene diol.

If necessary, a solubilizing agent, a thickener, a stabilizer, a flavoring agent, a coloring agent and the like can be added to the external pharmaceutical composition of the present invention.

The method for producing the external pharmaceutical composition of the present invention is not particularly limited, but for example, a lower alcohol solution in which diclofenac or a salt thereof is dissolved, an aqueous solution of a gelling agent, a cosolvent and a nonionic surfactant are added, After adding other components and stirring well, a neutralizing agent is added to adjust the pH of the preparation to 5.5 to 8.

Next, the compounding example of the external pharmaceutical composition of the present invention will be shown.

[Action and Effect] The thus obtained external-use pharmaceutical composition of the present invention has extremely good skin permeability and transdermal absorbability of diclofenac or a salt thereof.

〔Example〕

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

Example 1 A gel formulation of diclofenac sodium having a pH of about 7.5 was obtained by a conventional method with the following composition.

(Composition) Diclofenac sodium 1.0g Sorbitan trioleate 5.0g Propylene glycol 5.0g Isopropanol 20.0g Hibiswako 105 2.0g Ammonia water (10%) 6.0g Total amount 100.0g with purified water Example 2 A gel formulation of diclofenac sodium with a pH of about 7.5 was obtained according to.

(Composition) Sodium diclofenac 1.0g Sorbitan monooleate 5.0g Propylene glycol 5.0g Isopropanol 20.0g Hibiswako 105 2.0g Ammonia water (10%) 6.0g Total amount of purified water 100.0g Example 3 A gel formulation of diclofenac sodium with a pH of about 7.5 was obtained according to.

(Composition) Sodium diclofenac 1.0 g Glyceryl monostearate 5.0 g Propylene glycol 5.0 g Isopropanol 20.0 g Hibiswako 105 2.0 g Ammonia water (10%) 5.5 g Total amount of purified water 100.0 g Example 4 A gel formulation of diclofenac sodium with a pH of about 7.5 was obtained according to.

(Composition) Diclofenac sodium 1.0g Polyoxyethylene (10) monostearate 5.
0g Propylene glycol 5.0g Isopropanol 20.0g Hibiswako 105 2.0g Ammonia water (10%) 6.0g Total amount with purified water 100.0g Example 5 A gel preparation of diclofenac sodium having a pH of about 7.5 was obtained according to a conventional method by the following composition. It was

(Composition) Sodium diclofenac 1.0 g Polyoxyethylene (10) monolaurate 5.0 g Propylene glycol 5.0 g Isopropanol 20.0 g Hibiswako 105 2.0 g Ammonia water (10%) 6.0 g Total amount 100.0 g in purified water Example 6 Composition below According to a conventional method, a gel preparation of diclofenac sodium having a pH of about 7.5 was obtained.

(Composition) Sodium diclofenac 1.0 g Polyoxyethylene (10) cetyl ether 5.0 g Propylene glycol 5.0 g Isopropanol 20.0 g Hibiswako 105 2.0 g Ammonia water (10%) 6.0 g Total amount of purified water 100.0 g Example 7 A gel preparation of diclofenac sodium having a pH of about 7.5 was obtained according to a conventional method.

(Composition) Sodium diclofenac 1.0g Polyoxyethylene (9) lauryl ether 5.0g Propylene glycol 5.0g Isopropanol 20.0g Hibiswako 105 2.0g Ammonia water (10%) 5.5g Total amount of purified water 100.0g Comparative example 1 A gel preparation of diclofenac sodium having a pH of about 7.5 was obtained according to a conventional method.

(Composition) Diclofenac sodium 1.0 g Polyoxyethylene (20) sorbitan monooleate 5.0 g Propylene glycol 5.0 g Isopropanol 20.0 g Hibiswako 105 2.0 g Ammonia water (10%) 7.0 g Total amount 100.0 g in purified water Comparative Example 2 According to a conventional method, a gel preparation of diclofenac sodium having a pH of about 7.5 was obtained from the following composition.

(Composition) Sodium diclofenac 1.0 g Polyoxyethylene (10) nonylphenyl ether 5.0 g Propylene glycol 5.0 g Isopropanol 20.0 g Hibiswako 105 2.0 g Ammonia water (10%) 7.0 g Total amount with purified water 100.0 g Test Example 1 Example The diclofenac skin absorption of the preparations obtained in 1 to 7 and Comparative Examples 1 to 2 was measured as follows.

That is, a hairless mouse excised skin was attached to a glass permeation cell filled with a pH 7.2 phosphate buffer solution, the gel preparation was applied to the epidermal surface, and the amount of diclofenac in the dermis and the buffer solution after 16 hours was changed to a high-speed liquid. It was quantified by chromatography. The results are shown in Table 1.

As described above, the external pharmaceutical composition of the present invention showed good skin permeability.

Examples 8 to 10 and Comparative Examples 3 to 4 According to a conventional method, gel formulations of diclofenac sodium having a pH of about 7.5 were obtained according to a conventional method.

(Composition) Diclofenac sodium 1.0g Polyoxyethylene (10) oleyl ether 5.0g Propylene glycol 5.0g Isopropanol 20.0g Hibiswako 105 2.0g Ammonia water (10%) 7.0g Total amount in purified water 100.0g Ethylene oxide Table 2 shows the results of a skin permeation test conducted in the same manner as in Test Example 1 for Examples 8 to 10 and Comparative Examples 3 to 4 containing five different polyoxyethylene oleyl ethers.

From this result, as in Test Example 1, it was revealed that good absorption was exhibited when a nonionic surfactant having an HLB value of 14.5 or less was used.

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Claims (2)

[Claims] 1. Diclofenac or a salt thereof and an HLB value of 1
A pharmaceutical composition for external use containing a nonionic surfactant which is 4.5 or less. 2. The external pharmaceutical composition according to claim 1, wherein the dosage form is a gel preparation.