JPH0425929B2 - - Google Patents

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a poultice containing diclofenac sodium, and more specifically, the present invention relates to a poultice containing diclofenac sodium, and more specifically, it improves the solubility of diclofenac sodium in a base and improves the solubility of diclofenac sodium. release of fenatuc sodium,
Concerning a diclofenac poultice with extremely high absorption.

[Prior Art] Diclofenac sodium is widely used for various inflammatory diseases such as low back pain, osteoarthritis, rheumatoid arthritis, neuralgia, and throat inflammation.

Until now, diclofenac sodium has generally been administered orally in the form of tablets, but because of its strong medicinal efficacy, it can be used in cases where side effects are a concern, such as in patients with peptic ulcers or severe liver disorders. Its use is restricted to patients.

Therefore, in order to reduce side effects, there are ointments and poultices containing diclofenac sodium as an active ingredient as a treatment method using transdermal absorption.

[Problems to be Solved by the Invention] However, when using the ointment, it is complicated to apply it to the skin with your fingers and to secure it with a covering band to prevent the ointment from adhering to clothes. A lot of work is required.

Diclofenuc sodium is a substance that is solid at room temperature and poorly soluble in water. Therefore, while the poultice must contain diclofenac sodium, the conventional solvent is ethanol/
Since it is an aqueous mixed solvent, crystals of diclofenac sodium precipitate due to volatilization of ethanol during storage of the poultice, resulting in poor drug stability. Also,
Poultices are usually left on the skin for a long period of time, and the alcohol can irritate the skin. Therefore, poultices using an ethanol/water-based mixed solvent cannot necessarily be said to be suitable poultices.

[Means for Solving the Problems] The inventors continued their intensive research into developing a poultice containing diclofenac sodium in a water-containing base.

At the beginning of the research, we tried making a poultice by mixing diclofenac sodium propylene glycol solution as the main drug, sodium polyacrylate as the base, and glycerin and/or sorbit as a moisturizing agent. Although the formulation, retention, releasability of the release paper, prevention of bleeding from the back side, and feeling of use were good, the release and absorption of the drug were not satisfactory.

Therefore, the inventors conducted further research into the cause of this problem and found that glycerin and sorbit used as moisturizers and diclofenac sodium have poor compatibility, causing precipitation of diclofenac sodium in the poultice, resulting in It has been found that the above-mentioned glycerin, sorbitol, etc. are unsuitable as raw materials for poultices because they inhibit the absorption of drugs into the skin.

In addition, as a solvent for dissolving diclofenac sodium, a mixed solvent of water-propylene-1.3-butylene glycol was selected, but since diclofenac sodium has low solubility in water, the water used in the mixed solvent is amount is limited. For this reason, it has been found that sodium polyacrylate, carboxyvinyl polymer, sodium carboxymethyl cellulose, etc., which are widely used as bases for poultices, cannot be used together with the mixed solvent because they do not dissolve in the mixed solvent. .

Therefore, taking into account the above research results, the inventors conducted further intensive research into combinations of solvents and bases for solubilizing diclofenac sodium, which is sparingly soluble in water. The present invention was achieved by discovering that the solubility of diclofenac sodium can be increased in a drug.

The purpose of this invention is to stably dissolve diclofenac sodium, which is sparingly soluble in water, in a base material, so that crystals do not precipitate even after a long period of time, and to prevent the release of diclofenac sodium. The object of the present invention is to provide a poultice that is well absorbed into living organisms.

To achieve the above object, the present invention comprises diclofenac sodium, water, one or more moisturizing and dissolving agents of alkylene glycol having 3 or 4 carbon atoms, and any one of gelatin, polyvinyl alcohol and polyvinylpyrrolidone. This is a diclofenac poultice characterized by having one or more bases.

As the diclofenac sodium in this invention, ordinary ones can be used and there are no particular limitations.

As the water in this invention, ordinary purified water can be used, and deionized water can also be used.

The moisturizing and dissolving agent in this invention is one or a mixture of two or more alkylene glycols having 3 or 4 carbon atoms.

Examples of the alkylene glycol include
Examples include 1.2-propanediol, 1.3-propanediol, 1.2-butanediol, 1.3-butanediol, 1.4-butanediol, 2.3-butanediol, and the like.

The moisturizing and dissolving agent may be any one of the various alkylene glycols, and
It may also be a mixture of two or more of the various alkylene glycols mentioned above.

Preferred moisturizing solubilizers include, for example, 1.2−
Propanediol, 1.2-propanediol and 1.3
A particularly preferred moisturizing solubilizer is a mixture of 1,2-propanediol and 1,3-butanediol. 1.2 above
- This is because propanediol has a high dissolving effect and is easily available commercially. In addition, since 1.2-propanediol may cause skin sensitization when used alone in large amounts, in order to maintain the same dissolving effect as when 1.2-propanediol is used alone, 1.2-propanediol is 1,3-butanediol is substituted for 1,3-butanediol.

As the base in this invention, any one of gelatin, polyvinyl alcohol, and polyvinylpyrrolidone may be used alone, or two or more of the above may be used.

Preferred bases for imparting self-adhesive properties to the diclofenac poultice include, for example:
Mixtures of gelatin and polyvinyl alcohol and/or polyvinylpyrrolidone may be mentioned.
Further, when this diclofenac poultice is made into a fixed type, the base material is, for example, gelatin.

The blending ratio of the diclofenac sodium, the water, the moisturizing solubilizing agent, and the base in the diclofenac poultice according to the present invention cannot be determined depending on the types of the moisturizing solubilizing agent and the base. , usually diclofenac sodium in diclofenac poultice is 0.1~
4% by weight, the water is 10-50%, the moisturizing and dissolving agent is 2-40% by weight, and the base is 1.5-25% by weight.

If 1.2-propanediol and/or 1.3-butanediol are selected as a preferred moisturizing solubilizer and a mixture of gelatin, polyvinyl alcohol and polyvinylpyrrolidone is selected as a preferred base, the mixing ratio of each of the above components in the diclofenac poultice will be contains diclofenac sodium 0.1 to 4% by weight, especially 1 to 2% by weight, and water 10 to 4% by weight.
50% by weight, especially 20-40% by weight, 1.2-propanediol 1-20% by weight, especially 5-13% by weight, 1.3
- 1 to 20% by weight of butanediol, in particular 5 to 15% by weight, 0.5 to 5% by weight of gelatin, in particular 1 to 3% by weight, 0.5 to 10% by weight of polyvinyl alcohol;
Especially 3-7% by weight, polyvinylpyrrolidone 0.5%
~10% by weight, especially 3-7% by weight is preferred.

When the diclofenac sodium content is less than 0.1% by weight, the medicinal efficacy of this diclofenac poultice may be reduced, and when the diclofenac sodium content is more than 4% by weight, it becomes relatively difficult to dissolve in the moisturizing dissolving agent. Sometimes. When the amount of water is less than 10% by weight, the paste becomes hard, its self-adhesiveness decreases, and drug absorption decreases. If it exceeds 50% by weight, the solubility of diclofenac sodium in the base may decrease, and drug absorption may decrease. When each of 1.2-propanediol and 1.3-butanediol is less than 1% by weight, it may not be possible to completely dissolve the diclofenac sodium, and when it is more than 20% by weight, skin sensitization increases. Sometimes. When gelatin, polyvinyl alcohol and polyvinylpyrrolidone are each less than 0.5% by weight, the viscosity of the base necessary for the poultice may become smaller, and
More than 5% by weight of gelatin, 10% each of polyvinyl alcohol and polyvinylpyrrolidone
If the amount exceeds 1% by weight, the viscosity of the base may become high.

This diclofenac poultice may contain an absorption enhancer, an inorganic filler, etc. in addition to the above-mentioned components.

Examples of the absorption enhancer include isopropyl myristate, octadecyl myristate,
Examples include 1-dodecyl azacycloheptan-2-one, dimethyl sulfoxide, calcium thioglycolate, urea, diisopropyl adipate, mercaptoethanol, and the like. Among the various absorption enhancers, isopropyl myristate,
Preferred are octadecyl myristate, diisopropyl adipate, and the like.

The amount of the absorption enhancer varies depending on the type, but is usually 0.1 to 10% by weight. When isopropyl myristate is used as the preferred absorption enhancer, the amount of isopropyl myristate in the diclofenac poultice is The amount is 0.5-5
% by weight is preferred, particularly 1-2% by weight. Although it is not possible to say with certainty because it depends on the other ingredients included, if the amount of isopropyl myristate is less than 1% by weight, the absorption promoting effect may be small, and if it is more than 2% by weight, the effect of isopropyl myristate is May be released on the surface of the plaster.

Further, as the inorganic filler, for example,
Carbonates such as calcium carbonate and calcium bicarbonate,
Examples include silicates such as kaolin, talc, and clay, and oxides such as titanium oxide, zinc oxide, silica, and alumina. Among the various inorganic fillers, calcium bicarbonate, kaolin, titanium oxide, and the like are preferred. These various inorganic fillers may be used alone or in combination of two or more.

The blending amount of the inorganic filler varies depending on its type, but is usually 0 to 50% by weight. When calcium bicarbonate, kaolin, titanium oxide, etc. are used as the preferred inorganic filler, the blending amount of these fillers is , 10 to 50% by weight, especially 20 to 40% by weight in the diclofenac poultice.

The diclofenac poultice of the present invention comprises a support supporting a paste containing the diclofenac sodium, water, a moisturizing and dissolving agent, a base, and, if necessary, an absorption enhancer, an inorganic filler, etc. is preferred.

As the support, for example, any of woven fabrics such as flannel and lint fabrics, nonwoven fabrics, and knitted fabrics can be used.

Furthermore, the fibers constituting the woven fabric, non-woven fabric, and knitted fabric may be natural fibers such as cotton, synthetic fibers such as polyolefin, polyester, or nylon, or semi-synthetic fibers such as rayon. It's okay.

This diclofenac poultice can be produced, for example, as follows.

That is, diclofenac sodium, a moisturizing solubilizing agent, a part of the base, an absorption enhancer and an inorganic filler if necessary are kneaded, and then water is added to increase the viscosity of the kneaded mixture. This kneaded product with increased viscosity is kneaded with an aqueous solution of the base to obtain a paste having a desired viscosity, for example, a viscosity that does not ooze or run out from the support. The material is spread on a support, release paper or plastic film is attached to the surface of the material, cut into a predetermined size, and stored in a packaging bag, such as an aluminum bag. In addition,
For kneading operations, ordinary kneaders, rolls, mixers, kneaders, etc. can be used.
Further, during the kneading operation, it is preferable to heat the mixture to 50 to 70°C in order to make the kneading more effective.

Of course, this diclofenac poultice is not limited to the production method described above, and can be produced by various other methods.

The diclofenac poultice thus obtained is
Diclofenac sodium, which is sparingly soluble in water, can be completely dissolved without precipitation, and the moisturizing properties of the plaster are maintained well, so crystals do not precipitate and the active ingredient is released and absorbed. It makes a good poultice.

[Examples] Next, Examples and Comparative Examples of the present invention will be shown to specifically illustrate the present invention.

Example 1 Prior to manufacturing a diclofenac poultice, the solubility of diclofenac sodium in a moisturizing solubilizer was tested.

The solubility test was performed as follows.

That is, 2 parts of diclofenac and 10 parts of 1,2-propanediol were placed in an Erlenmeyer flask and heated to 80°C.
The diclofenac sodium was completely dissolved while shaking in a water bath. Next, the dissolved mixture was cooled to room temperature, and 13 parts of 1,3-butanediol and 22 parts of water were added and mixed uniformly. The mixed solution was left at room temperature and visually inspected for crystal precipitation.

As a result of this solubility test, 2 parts of diclofenac sodium dissolved in a mixture of 22 parts of water, 10 parts of 1,2-propanediol, and 13 parts of 1,3-butanediol was completely dissolved and did not precipitate.

7 parts polyvinylpyrrolidone and calcium bicarbonate
38 parts and a kneader [KDHU-2 type, Fuji Electric Industries
Co., Ltd.] for 5 minutes at room temperature, and the resulting pre-kneaded mixture was mixed with 10 parts of 1,2-propanediol and 2 parts of diclofenac sodium in advance for 60 min.
The solution obtained by mixing and dissolving on a water bath at ℃ and 13 parts of 1,3-butanediol were mixed in the kneader at room temperature for
The mixture was further kneaded for a minute to obtain a primary kneaded product. Then,
The above-mentioned primary kneaded product and a mixed solution prepared by dissolving 5 parts of polyvinyl alcohol in 15 parts of water in a water bath at 80°C were added and kneaded for 20 minutes at room temperature in the kneader to obtain a secondary kneaded product. , then the heating temperature of the kneader was changed to
Maintaining the temperature at 60°C, knead the secondary mixture, an aqueous gelatin solution obtained by mixing and dissolving 7 parts of water and 2 parts of gelatin, and 1 part of isopropyl myristate in the kneader for 10 minutes. A plaster was obtained.

The obtained plaster was applied to a nonwoven fabric [manufactured by Nippon Vilene Co., Ltd.] using a coating machine [calendar roll, manufactured by Nippon Roll Co., Ltd.] so that diclofenac sodium was 2 mg per square centimeter.
A polypropylene film was attached to the surface of the paste to obtain a diclofenac poultice.

As a drug solubility test for this diclofenac poultice, the diclofenac poultice was stored in an aluminum pack, and after one month, the diclofenac poultice was taken out and the surface of the plaster was observed with a polarizing microscope to examine the state of crystal precipitation. . As a result, no crystals of diclofenac sodium were found in the plaster.

Regarding this diclofenac poultice, as a drug release test, 5×
A test piece of 5 square cm was taken, and this test piece was soaked in water/
Ethanol mixed solution (water/ethanol = 3/2)
This Erlenmeyer flask was attached to a shaker [Irasiaker SB24, manufactured by Tokyo Rika Kikai Co., Ltd.] and shaken in a figure-8 shape in a water bath at 37°C for a certain period of time. The amount of diclofenac sodium eluted into the solvent was sampled at each time point using a liquid chromatogram device [Shimadzu LS-3A].
Mold, manufactured by Shimadzu Corporation]. The results are shown in FIG.

Regarding this diclofenac poultice, as a drug absorption test, 10 × 10
A square cm test piece was taken, and two of these test pieces were pasted on the dehaired abdominal skin of three domestic rabbits (Japanese white, male, weighing approximately 3 kg), and after a certain period of time had elapsed after the pasting. Blood was collected and the concentration of diclofenac sodium in the blood was measured using a liquid chromatography device [Shimadzu LS-
3A, manufactured by Shimadzu Corporation]. The results are shown in FIG.

Example 2 37 parts of kaolin and 1 part of titanium oxide were used instead of 38 parts of calcium bicarbonate, and 8 parts of water and 2 parts of gelatin were used instead of an aqueous gelatin solution obtained by mixing and dissolving 7 parts of water and 2 parts of gelatin. Using an aqueous gelatin solution obtained by mixing and dissolving 5 parts of polyvinyl alcohol in 14 parts of water at 80°C, instead of a mixture of 15 parts of water and 5 parts of polyvinyl alcohol dissolved in a water bath at 80°C.
A diclofenac poultice was obtained in the same manner as in Example 1, except that the mixture dissolved in the water bath was used.

This diclofenac poultice was subjected to a drug solubility test in the same manner as in Example 1, and as a result, no crystals of diclofenac sodium were found in the plaster.

This diclofenac poultice was subjected to a drug solubility test in the same manner as in Example 1, and the results are shown in FIG.

This diclofenac poultice was subjected to a drug absorption test in the same manner as in Example 1, and the results are shown in FIG.

Example 3 6 parts of polyvinylpyrrolidone was used instead of 7 parts of polyvinylpyrrolidone, 35 parts of calcium bicarbonate and 1 part of titanium oxide were used instead of 38 parts of calcium bicarbonate.
Instead of an aqueous gelatin solution obtained by mixing and dissolving 7 parts of water and 2 parts of gelatin, use an aqueous gelatin solution obtained by mixing and dissolving 10 parts of water and 4 parts of gelatin, and add polyvinyl alcohol to 15 parts of water. The procedure was repeated in the same manner as in Example 1, except that a mixture of 12 parts of water and 5 parts of polyvinyl alcohol dissolved in a water bath of 80°C was used instead of the mixture of 5 parts of polyvinyl alcohol dissolved in a water bath of 80°C. A diclofenac poultice was obtained.

This diclofenac poultice was subjected to a drug solubility test in the same manner as in Example 1, and as a result, no crystals of diclofenac sodium were found in the plaster.

This diclofenac poultice was subjected to a drug release test in the same manner as in Example 1, and the results are shown in FIG.

This diclofenac poultice was subjected to a drug absorption test in the same manner as in Example 1, and the results are shown in FIG.

Comparative Example 1 Prior to manufacturing a diclofenac poultice, the solubility of diclofenac sodium in a mixed solvent was tested.

The solubility test was performed as follows.

That is, 2 parts of diclofenac sodium and
1.2-propanediol (10 parts) was placed in an Erlenmeyer flask and completely dissolved while shaking in a water bath at 80°C. The dissolved mixture was cooled to room temperature, and 40 parts of glycerin and 20 parts of water were added thereto and mixed uniformly. The mixture was left at room temperature and visually inspected for crystal precipitation.

As a result of this solubility test, 2 parts of diclofenac sodium was not completely dissolved in a mixed solvent of 20 parts of water, 10 parts of 1,2-propanediol, and 40 parts of glycerin, and crystals remained.

6 parts of sodium polyacrylate and 20 parts of calcium bicarbonate having an average degree of polymerization of 30,000 were preliminarily kneaded at room temperature for 2 minutes in the same kneader used in Example 1, and the obtained pre-kneaded product was obtained. A solution obtained by mixing and dissolving 10 parts of 1,2-propanediol and 2 parts of diclofenac sodium in advance on a 60°C water bath, and 40 parts of glycerin were mixed in the kneader at room temperature.
The mixture was further kneaded for 20 minutes to obtain a kneaded product. Next, while maintaining the heating temperature of the kneader at 60° C., the kneader mixed and dissolved the gelatin aqueous solution obtained by mixing and dissolving 20 parts of water and 1 part of gelatin, and 1 part of isopropyl myristate. A paste was obtained by kneading for 10 minutes.

Using this paste, a diclofenac poultice was obtained in the same manner as in Example 1 above.

Regarding this diclofenac poultice, a drug solubility test was carried out in the same manner as in Example 1. As a result, crystals began to precipitate in the paste one day after the aluminum pack was applied, and the amount of precipitated crystals increased over time.

This diclofenac poultice was subjected to a drug release test in the same manner as in Example 1, and the results are shown in FIG.

This diclofenac poultice was subjected to a drug absorption test in the same manner as in Example 1, and the results are shown in FIG.

Comparative Example 2 A diclofenac poultice was obtained in the same manner as in Comparative Example 1 except that sorbitol was used in place of the glycerin.

Regarding this diclofenac poultice, a drug solubility test was carried out in the same manner as in Example 1. As a result, crystals began to precipitate in the paste one day after the aluminum pack was applied, and the amount of precipitated crystals increased over time. .

This diclofenac poultice was subjected to a drug release test in the same manner as in Example 1, and the results are shown in FIG.

This diclofenac poultice was subjected to a drug absorption test in the same manner as in Example 1, and the results are shown in FIG.

[Effects of the Invention] As detailed above, the diclofenac poultice according to the present invention can increase the solubility of diclofenac sodium in the base, and can also improve the release of diclofenac sodium from the paste. It has excellent properties and absorbability into the body, and can stably dissolve diclofenac sodium in the plaster without precipitating over a long period of time. Moreover, this diclofenac poultice can be made into a safe poultice that does not cause sensitization to the skin.

[Brief explanation of drawings]

Figure 1 is a graph showing the change over time in the amount of diclofenac sodium dissolved in a water/ethanol mixed solvent as a result of a drug release test, and Figure 2 is a graph showing the amount of diclofenac sodium dissolved in blood as a result of a drug absorption test. It is a graph showing the change in the amount of Natsuku sodium over time.

Claims (1)

[Scope of Claims] 1. Diclofenac sodium, water, one or more moisturizing and dissolving agents of alkylene glycol having 3 or 4 carbon atoms, and one or more of gelatin, polyvinyl alcohol, and polyvinylpyrrolidone. A diclofenac poultice characterized by having a base consisting of the above. 2. The diclofenac poultice according to claim 1, wherein the moisturizing and dissolving agent contains 1,2-propanediol and 1,3-butanediol.