JPH09208542A - Clear aqueous solution of diclofenac sodium - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a transparent aqueous solution of diclofenac sodium useful for providing a preparation of a water-soluble pharmaceutics, etc., by blending diclofenac sodium with a specified stabilizer and water and by stably dissolving diclofenac sodium in water. SOLUTION: This transparent aqueous solution of diclofenac sodium is obtained by blending diclofenac sodium with a dialkylolamide of a fatty acid and water. These three components are preferably blended in the ratio represented by the point existing in the region surrounded by the hexagonal shape formed by tying A, B, C, D, E, F points of the figure. Moreover, a solubilizing agent is preferablly added to the liquid component. A lower alcohol, a polyfunctional alcohol and a nonion surfactant are preferable as the solubilizing agent. A diethanolamide of the fatty acid from coconut oil is preferable as the dialkylolamide of the fatty acid. A preparation for external use for skin such as a lotion, an emulsion, a suspension, an ointment, a gel ointment, a cream and a paste is produced by using this aqueous solution.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a transparent aqueous solution of diclofenac sodium, and more particularly to a transparent aqueous solution of diclofenac sodium useful for providing an aqueous pharmaceutical preparation in which diclofenac sodium is stably dissolved. .

[0002]

2. Description of the Related Art Diclofenac sodium itself dissolves in water in an amount of about 1.5% by weight (hereinafter referred to simply as "%"), but since it is used as a pharmaceutical preparation for external use,
When various base components are added, crystals are very likely to precipitate, and a solution which can be actually used as a preparation has not been obtained.

At present, as a method for dissolving diclofenac sodium in a solution, there is known a technique of dissolving it using a lower alcohol such as ethanol or isopropanol to prepare a formulation. However, lower alcohols have high volatility, have a limited dosage form, and have the drawback that they are likely to cause skin irritation, and cannot be said to be suitable for the production of pharmaceuticals.

[0004]

Therefore, it has been desired to develop a technique capable of stably dissolving and retaining diclofenac sodium in water even if a base component for formulation is further added without depending on a lower alcohol. .

[0005]

[Means for Solving the Problems] Initially, the present inventors thought that it was difficult to stably dissolve and maintain diclofenac sodium in water in the presence of a base component, and therefore dissolved diclofenac sodium in an oily component. And tried formulation.
In fact, indomethacin, ketoprofen, and the like are insoluble in water, and therefore, they are dissolved in oily ingredients such as peppermint oil to form a preparation.

However, in this attempt, it was found that diclofenac sodium is an ionic drug and therefore has low solubility in an oily component.

Therefore, when searching for a solvent for diclofenac sodium, a coconut oil fatty acid diethanolamide, which does not dissolve diclofenac sodium at all as an oily component, happens to be mixed with water. Therefore, they have found that diclofenac sodium can be dissolved, and that the obtained aqueous diclofenac sodium solution is a colorless, transparent and uniform aqueous solution, and completed the present invention.

Furthermore, when sodium polyacrylate or sorbitol, which is generally used as a base component of an external preparation and has poor compatibility with diclofenac sodium, is added to this aqueous solution, diclofenac sodium is also added. It was found that the above did not precipitate and kept a state of a colorless, transparent and uniform gel-like aqueous solution.

The present invention has been completed based on these findings, and the first object thereof is to provide a clear aqueous solution of diclofenac comprising diclofenac sodium, fatty acid dialkylolamide and water.

Another object of the present invention is to provide a transparent aqueous solution of diclofenac sodium, which is obtained by further adding a solubilizing agent to a liquid composition consisting of diclofenac sodium, fatty acid dialkylolamide and water. .

Still another object of the present invention is to provide an external preparation for skin prepared by using any of the above-mentioned clear aqueous solutions of sodium diclofenac.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION To prepare a clear aqueous solution of diclofenac sodium comprising diclofenac sodium, fatty acid dialkylolamide and water according to the present invention,
Diclofenac sodium may be added to a mixed solution of fatty acid dialkylolamide and water.

The fatty acid dialkylolamide is a compound obtained by condensing a fatty acid and a dialkylolamide, and the fatty acid portion thereof is coconut oil fatty acid, palm kernel oil fatty acid, palmitic acid, myristic acid, stearic acid, Examples include lauric acid, oleic acid, linoleic acid, isostearic acid, capric acid and caprylic acid, and the dialkylolamide moiety includes diethanolamine,
Examples thereof include di-lower alkanolamines such as diisopropanolamine. These fatty acid dialkylol amides can be used alone or in combination.

Preferred fatty acid dialkyrolamides include coconut oil fatty acid diethanolamide, palm kernel oil fatty acid diethanolamide, stearic acid diethanolamide, lauric acid diethanolamide, oleic acid diethanolamide, linoleic acid diethanolamide and isostearic acid diethanolamide. And coconut oil fatty acid diethanolamide is particularly preferable.

In the present invention, a completely transparent aqueous solution of diclofenac sodium can be obtained when the system is composed of diclofenac sodium, fatty acid dialkylolamide and water only, and these are within a specific compounding amount range. .

That is, as will be understood from the examples described later, the blending amount of them is A in the three-phase component system diagram.
(0, 0, 100), B (1.8, 0, 98.2), C
(8, 8, 84), D (10, 20, 70), E (10,
40, 50) and F (0, 20, 80) in the hexagonal region formed by connecting the points (the numbers in parentheses indicate diclofenac sodium, fatty acid dialkylolamide and water in order). The compounding amount (%) is shown).

However, for the system diclofenac sodium, fatty acid dialkylolamide and water,
By further adding a solubilizing agent, the range in which a transparent diclofenac sodium aqueous solution can be obtained can be expanded.

Examples of solubilizing agents that can be used for this purpose include lower alcohols such as ethanol and isopropyl alcohol; polyhydric alcohols such as propylene glycol, 1,3-butylene glycol and polyethylene glycol; propylene glycol fatty acid esters and glycerin fatty acids. Nonionic surfactants such as esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, Pluronics and the like can be mentioned.

These solubilizers are used as long as they do not interfere with the use of diclofenac sodium as a medicine.
It can be used in any amount.

The clear aqueous solution of diclofenac sodium obtained as described above can be used for preparing various drugs containing diclofenac sodium, for example, external preparations. This transparent diclofenac sodium solution is not only transparent in appearance but also excellent in absorption from the skin because it dissolves diclofenac sodium.

Even if the aqueous solution of diclofenac sodium is not completely dissolved, the residual diclofenac sodium is dissolved in the fatty acid dialkylolamide-water system in accordance with absorption of diclofenac sodium from the skin. Regardless of the point, an excellent effect can be obtained in terms of skin absorbability.

Examples of the medicine obtained by using the above diclofenac sodium transparent solution include lotions,
Emulsion, suspension, ointment, gel ointment, gel cream,
In addition to external preparations such as creams, pastes and poultices, oral liquids, suppositories and the like can be mentioned. In this case, carriers and additives for the above-mentioned preparations which are usually used can be used unless the effects of the present invention are impaired.

Among the above-mentioned preparations, when a dosage form such as lotion, gel ointment or gel cream is selected, it is possible to impart transparency to these preparations and further increase the commercial value. Therefore, it is preferable.

[0024]

[Examples] Next, more detailed description will be given with reference to Examples.
The present invention is not limited to these examples.

Example 1 Solubility test (1): As shown in Table 1 below, a composition was prepared in which the amounts of diclofenac sodium, fatty acid alkylolamide (coconut oil fatty acid diethanolamide) and water were changed, The state of the solution after storing them at 25 ° C. for 24 hours was visually inspected. The results are shown in Table 1 and FIG.

[0026] * The dissolution state was evaluated according to the following criteria. A: Completely dissolved. B: Dissolves during preparation, but some crystals precipitate after standing. C: It cannot be completely dissolved.

Example 2 Solubility test (2): Compositions of the present invention and comparative compositions shown in Tables 2 and 3 below were prepared, and 25 of them were prepared.
The state of the solution after storage at 24 ° C. for 24 hours was visually inspected.
Table 4 shows the results.

[0028] (Note) Numbers indicate compounding amount (%). 1) HCO-60 (manufactured by Nikko Chemicals) 2) BL-9EX (manufactured by Nikko Chemicals) 3) Manufactured by Asahi Denka Co., Ltd.

[0029] (Note) Numbers indicate compounding amount (%). 1), 2), 3) Same as Table 2.

[0030] * The dissolution state was evaluated in the same manner as in Table 1 of Example 1.

Example 3 Lotion: A transparent aqueous lotion was obtained by the following composition and production method. (Direction) Diclofenac sodium 2% Coconut oil fatty acid diethanolamide 2% Purified water 73% Oleyl alcohol 1% D-sorbitol 20% Hydroxypropyl cellulose 2%

(Production method) Diclofenac sodium,
Coconut fatty acid diethanolamide was added to purified water and mixed to obtain a transparent aqueous solution in which sodium diclofenac was dissolved. To this, oleyl alcohol, D-sorbitol and hydroxypropyl cellulose were added and dissolved. The obtained aqueous lotion was transparent.

Example 4 Gel Agent: A transparent gel agent was obtained by the following composition and production method. (Composition) Diclofenac sodium 2% Coconut oil fatty acid diethanolamide 2% Purified water 60% Oleyl alcohol 1% D-sorbitol 20% Sodium polyacrylate 5% Propylene glycol 10%

(Production method) Diclofenac sodium,
Coconut oil fatty acid diethanolamide was added to purified water and mixed to obtain a transparent aqueous solution in which diclofenac sodium was dissolved. To this, oleyl alcohol and D-sorbitol were added and dissolved, and further, a solution in which sodium polyacrylate was uniformly suspended in propylene glycol was added, and the mixture was stirred and mixed to obtain a gel agent. This gel was transparent in which diclofenac sodium was dissolved.

Practical Example 5 Pap agent: A poultice was prepared by the following composition and production method. (Composition) Amount (%) A Diclofenac sodium 2.0 Coconut oil fatty acid diethanolamide 2.0 Purified water 33.65 B Gelatin 3.0 Purified water 12.0 C D-sorbitol 30.0 Light anhydrous silicic acid 2.0 D oleyl alcohol 1.0 Propylene glycol 7.0 Sodium polyacrylate 5.0 Sodium carboxymethyl cellulose 1.0 Polybutene 1.0 Tartaric acid 0.15 Aluminum hydroxide 0.2

(Production method) A was mixed to obtain a transparent aqueous solution of diclofenac sodium. Next, B in another container
Was heated to obtain a gelatin solution. A, B and C were mixed, and the mixed solution of D was added with stirring to obtain a uniform gel.
This gel was spread on a non-woven fabric to obtain a poultice.

[0037]

INDUSTRIAL APPLICABILITY The clear aqueous solution of diclofenac sodium of the present invention not only stably dissolves diclofenac sodium, but also improves its transdermal absorbability as compared with that in which it is not dissolved. Therefore, the transparent aqueous solution of the present invention,
As such, it can be used not only as a liquid agent for external use or as an internal use agent, but also as various drugs by combining with other known pharmaceutical carriers. Further, in particular, by utilizing its transparent appearance, if it is made into a lotion, gel ointment, gel cream, etc., it is possible to prepare a transparent formulation containing diclofenac sodium, which has never existed before. It is also possible to improve the commercial value.

[Brief description of drawings]

FIG. 1 is a drawing showing a range in which a transparent aqueous solution is obtained in the system of diclofenac sodium, fatty acid dialkylolamide and water.

[Explanation of symbols]

In the figure, each point is A (0, 0, 100), B
(1.8, 0, 98.2), C (8, 8, 84), D (1
0, 20, 70), E (10, 40, 50) and F
Indicates each point of (0, 20, 80) (The numbers in parentheses are
The amounts (%) of diclofenac sodium, fatty acid dialkylolamide and water are shown in that order). that's all

 ─────────────────────────────────────────────────── (72) Inventor Kazuyuki Ishikawa 3586 Yoshihara, Ami-cho, Inashiki-gun, Ibaraki Prefecture Tsumura Co., Ltd. (72) Inventor Takaaki Matsumoto 3586 Yoshiwara, Ami-cho, Inashiki-gun, Ibaraki Tsumura Co., Ltd.

Claims (8)

[Claims] 1. A clear aqueous solution of diclofenac sodium consisting of diclofenac sodium, a fatty acid dialkyrolamide and water. 2. Diclofenac sodium, fatty acid dialkyrolamide and water are added at points A, B and C in FIG.
A transparent aqueous solution of diclofenac sodium contained in a hexagonal region formed by connecting points D, E, and F. 3. A transparent aqueous solution of diclofenac sodium obtained by further adding a solubilizing agent to a liquid composition comprising diclofenac sodium, a fatty acid dialkylolamide and water. 4. The solubilizing agent is a lower alcohol, a polyhydric alcohol or a nonionic surfactant.
Item 5. A transparent aqueous solution of diclofenac sodium according to any one of items 1 to 3. 5. The fatty acid dialkylol amide is a coconut oil fatty acid diethanol amide, according to any one of claims 1 to 4.
A transparent aqueous solution of diclofenac sodium according to any one of the items. 6. An external preparation for skin, which is produced by using a transparent aqueous solution of sodium diclofenac according to any one of claims 1 to 5. 7. A lotion, an emulsion, a suspension, an ointment,
The external skin preparation according to claim 6, which is a gel ointment, cream, paste or poultice. 8. Diclofenac sodium, fatty acid dialkylol amide and water are added at points A, B and C in FIG.
A method for dissolving diclofenac sodium, characterized in that the compounding amount is such that it is contained in a hexagonal region connecting points D, E and E.