JPS6160608A - Diclofenac fomentation - Google Patents

Abstract

PURPOSE:A fomentation that contains a combination of diclofenac sodium, a specific humectant solubilizer and a base, thus keeping the active ingredients solubilized stably for a long period of time without precipitation and showing good releasability and absorption into the living body. CONSTITUTION:The objective fomentation contains diclofenacsodium which is effective in a variety of inflmmation such as low back pain, osteoarthritis, neurodynia, syanche, a humectant and solubilizer selected from water and 3 or 4C alkylene glycols, preferably a mixture of 1,2-propane diol and 1,3-butane diol, and a base selected from gelatin, polyvinyl alcohol and polyvinyl pyrrolidone. The amounts of individual components are 0.1-4wt% of the active ingredients, 10-50wt% of water, 2-40wt% of the humectant and 1.5-25wt% of the base. The resultant fomentation may include 0.1-10wt% of an absorption accelerator and up to 50wt% of inorganic fillers.

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 diclofenac poultice that increases the solubility of diclofenac sodium in a preparation and has extremely high release and absorption of the diclofenac sodium.

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

Until now, diclofenac sodium has generally been orally administered 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.

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 rub it on the skin IR with your finger and to wrap it in place with a covering band to prevent it from adhering to your clothes. It is necessary to have a good composition.

Diclofenac sodium is a substance that is solid at room temperature and poorly soluble in water. Therefore, where diclofenac sodium must be included in the poultice,
Since the conventional solvent is a mixed solvent of ethanol/water,
During storage of the poultice, crystals of dichloro-7ena-7-sodium precipitated due to the volatilization of ethanol, resulting in poor drug stability.
Also, since poultices are usually applied to each other for a long time, the alcohol can irritate the skin.

Therefore, a poultice that uses an ethanol/water-based mixed solvent cannot necessarily be said to be a suitable poultice.

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

At the beginning of the research, we tried making a poultice by mixing a propylene glycol solution of diclofenac sodium as the main drug solution, sodium polyacrylate as the base, and glycerin and/or sorbitol as the humectant. , shape retention, peelability of ', t, and qm paper, prevention of back bleeding, and usability were good, but
Drug release and absorption were not satisfactory.

Therefore, the inventors conducted further research into the cause of this problem and found that diclofenac sodium has poor compatibility with glycerin and sorbitol, which are used as moisturizers, and diclofenac sodium precipitates in the poultice, resulting in drug delivery to living organisms. It has been found that the above-mentioned glycerin, sorbitol, etc. are unsuitable as raw materials for poultices because they inhibit absorption.

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 amount of water used in the mixed solvent is 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 that solubilize diclofenac sodium, which is sparingly soluble in water. This invention was achieved by discovering that the solubility of diclofenac sodium could be increased.

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 diclofenac sodium from being released and absorbed into the body. The purpose of the present invention is to provide a good poultice.

To achieve the above object, the present invention comprises diclofenac sodium, water, one or more moisturizing solubilizers of alkylene glycols having 3 or 4 carbon atoms, and one or more of gelatin, polyvinyl alcohol and polyvinylpyrrolidone. This is a diclofenac poultice characterized by having a base consisting of two or more types.

As the diclofenac sodium in this invention, ordinary diclofenac sodium can be used and there is no particular limitation.

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.

As the alkylene glycol, for example, 1.2-
Propanediol, 1.3-propanediol, 1.2
-butanediol, 1.3-butanediol, 1.4-
Examples include butanediol, 2,3-butanediol, and the like.

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

Preferred moisturizing solubilizers include, for example, 1,2-propanediol, a mixture of 1,2-propanediol and 1,3-butanediol, particularly preferred moisturizing solubilizers include 1,2-propanediol and 1,3-butanediol. Mention may be made of mixtures with butanediol. This is because the 1,2-propanediol has a high solubilizing effect and is easily available commercially. In addition, since 1,2-propanediol may cause skin sensitization when used alone in large amounts, 1. A portion of 2-propanediol is replaced with 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.

Further, when this diclofenac poultice is made into a fixed type, the base 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 type of the moisturizing solubilizing agent and the base; Usually, in a diclofenac poultice, diclofenac sodium is 0.1 to 4% by weight, the water is 10 to 50%, the moisturizing solubilizer is 2 to 40% by weight, and the base is 1.5 to 2% by weight.
The amount of melon is 5%.

Choosing 1,2-propanediol and/or 1,3-butanediol as the preferred moisturizing solubilizer and a mixture of gelatin, polyvinyl alcohol and polyvinylpyrrolidone as the preferred base, each of the above in the diclofenac poultice The mixing ratio of the components is 0.1 to 4% by weight of diclofenac sodium, especially 1 to 2% by weight, 1 to 50% by weight of water, especially 20 to 40% by weight, and 1% by weight of water.
゜2-propanediol is 1 to 201Q%, especially 5 to 1
3! II amount%, 1,3-butanediol is 1-20fi
Amount%, especially 5-15% gelatin, 0.5-5ff gelatin
i amount%, especially 1 to 3 melon amount%, polyvinyl alcohol is 0
．． 5-10% by weight, especially 3-7% by weight, polyvinylpyrrolidone 0.5-10% by weight, especially 3-7'irX
is preferred.

Diclofenac sodium is 0. l ifi%, the medicinal efficacy of this diclofenac poultice may decrease, and diclofenac sodium
! [If the amount exceeds Inx, it may become relatively difficult to dissolve in the moisturizing and dissolving agent. 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 50ii%, the solubility of diclofenac sodium in the base may decrease, and drug absorption may decrease. 1 m each of 1.2-propanediol and 1.3 butanediol
If ff is less than 1%, it may not be possible to completely dissolve the diclofenac sodium, and if it is more than 20%, skin sensitization may increase. If gelatin, polyvinyl alcohol and polyvinylpyrrolidone are each less than 0-5 mm%, the viscosity of the base required for the poultice may become small; If the amount of each pyrrolidone exceeds 10i1%, the viscosity of the base may become high.

In addition to the above ingredients, this diclofenac poultice contains:
Absorption enhancers, inorganic fillers, etc. can be included.

Examples of the absorption enhancer include isopropyl myristate, octadecyl myristate, 1-dodecyl azacyclohebutan-2-one, dimethyl sulfoxide, calcium thioglycolate, urea, diisopropyl adipate, mercaptoethanol, and the like. Can be mentioned.

Among the above-mentioned absorption enhancers of each family, inpropyl myristate, octadecyl myristate, diisopropyl adipate, etc. are preferred.

The amount of the absorption enhancer varies depending on the type, but is usually 0.1 to 10% by weight. The blending amount of Inpropyl is preferably 0.5 to 5 mFx%, especially 1
It is preferable that the amount of inpropyl myristate is less than 2%, although it is difficult to say more because it depends on the other ingredients to be mixed. If the amount is more than 1% by weight, isopropyl myristate may be liberated on the surface of the plaster.

Examples of the inorganic filler include carbonates such as calcium carbonate and calcium bicarbonate; silicates such as kaolin, talc, and clay; and oxides such as titanium oxide, zinc oxide, silica, and alumina. . Among the various inorganic fillers, preferred are orthocalcium carbonate, kaolin, titanium oxide, etc. 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 501 fi%, and when calcium bicarbonate, kaolin, titanium oxide, etc. are used as the preferred inorganic filler, the blend M'c is 10-50if in diclofenac poultice! m%, especially 20-4
0 melon amount% is preferable.

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

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

Furthermore, the fibers constituting the woven fabric, nonwoven fabric, and knitted fabric are:
It may be a natural fiber such as cotton, a synthetic fiber such as polyolefin, polyester, or nylon, or a semi-synthetic fiber such as rayon.

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 a fi 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 paste is spread on a support, release paper or plastic film is pasted on the surface of the paste, cut into a predetermined size, and stored in a packaging bag, such as an aluminum bag. In addition, in order to perform the kneading operation, a normal kneader, roll, mixer,
Mixed! ! l! In order to make the synthesis even more effective, during the synthesis operation, 50 to 7
Preferably, it is heated to 0°C.

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

The diclofenac poultice obtained by peeling can completely dissolve diclofenac sodium, which is sparingly soluble in water, without precipitation, and the moisturizing properties of the plaster are maintained well, so crystals do not precipitate. This makes it a poultice with good release and absorption of active ingredients.

[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 diclozena 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 diclofenac sodium was completely dissolved while shaking in a water bath at 80°C.Then, the dissolved mixture was cooled to room temperature. 1
．． 13 parts of 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. Ta.

7 parts of polyvinylpyrrolidone and 38 parts of orthocalcium carbonate were kneaded [KDHU-2 type, manufactured by Fuji Denki Kogyo Co., Ltd.]
The preliminary wire hardware obtained by preliminary kneading at room temperature for 5 minutes, and a solution obtained by previously mixing and dissolving 10 parts of 1,2-propanediol and 2 parts of diclofenac sodium on a 60°C water bath. , 13 parts of 1,3-butanediol,
The mixture was further kneaded in the kneader at room temperature for 5 minutes to obtain a primary kneaded product.Next, the above-mentioned caustic compound 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 mixed. The mixture was added and kneaded in the kneader at room temperature for zO minutes to obtain a secondary composite, and then the heating temperature of the kneader was increased to 6.
Maintaining the temperature at 0°C, the secondary composite, an aqueous gelatin solution obtained by mixing and dissolving 7 parts of water and 2 parts of gelatin, and 1 part of isopropyl myristate were kneaded in the kneader for 10 minutes. A plaster was obtained.

The obtained plaster was coated with a non-woven fabric [Nippon Vilene Co., Ltd. 5! ]
Then, diclofenac sodium was applied at a concentration of 2 mg per square meter using a coating machine (Calendar Roll, J manufactured by Nippon Roll Co., Ltd.), and a polypropylene film was laminated on 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. Ta. As a result, no crystals of diclofenac sodium were found in the plaster.

As a drug release test for this diclofenac poultice, a 5 x 5 square CI test piece was taken from the diclofenac poultice, and this test piece was placed in a water/ethanol mixed solvent (water/ethanol +-3/2). The Erlenmeyer flask was placed in a shaker I device [Ira shaker 5B24, manufactured by Tokyo Rika Kikai Co., Ltd.] and heated to 37°C.
The amount of diclofenac sodium eluted into the solvent was measured using a liquid chromatography device [Shimadzu LS-3].
Afi, Shimadzu Corporation 11]. The results are shown in FIG.

As a drug absorption test for this diclofenac poultice, test pieces of 10 x 10 square C layers were taken from the diclofenac poultice, and two of these test pieces were fed to three domestic rabbits (Japanese white, male, weight: 3 kg). The patch is applied to the skin of the abdomen from which hair has been removed, and blood is collected at regular intervals after application, and the concentration of diclofenac sodium in the blood is measured using a liquid chromatograph device [Shimadzu LS-3Afi, manufactured by Shimadzu Corporation, 1
It was measured by 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 heavy carbon-based calcium, and 8 parts of water was 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 1 part and 2 parts of gelatin,
Example 1 Except that a mixture of 14 parts of water and 5 parts of polyvinyl alcohol dissolved in a water bath of 80°C was used instead of a mixture of 15 parts of water and 5 parts of polyvinyl alcohol dissolved in a water bath of 80°C. A diclofenac poultice was obtained in the same manner as in 1.

Regarding this diclofenac poultice, a drug solubility test was conducted 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) 76 parts of polyvinylpyrrolid was used instead of 7 parts of polyvinylpyrrolidone, 35 parts of calcium carbonate and 1 part of titanium oxide were used instead of 38 parts of calcium bicarbonate, and 7 parts of water and 2 parts of gelatin were used. Instead of the aqueous gelatin solution obtained by mixing and dissolving, use an aqueous gelatin solution obtained by mixing and dissolving 10 parts of water and 4 parts of gelatin, and a mixed solution of 15 parts of water and 5 parts of polyvinyl alcohol dissolved in a water bath at 80 ° C. water instead of 12
A diclofenac poultice was obtained in the same manner as in Example 1 above, except that a mixture of 5 parts of polyvinyl alcohol dissolved in a water bath at 80°C was used.

Regarding this diclofenac poultice, a drug solubility test was conducted 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 molding 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-
Put 10 parts of propanediol in an Erlenmeyer flask, and add 80 parts of propanediol.
Completely dissolved while shaking in a water bath at 100°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. This mixture was allowed to stand at room temperature, and the precipitation of crystals was visually inspected.

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.

With 6 parts of polyacrylic ugly soda with an average degree of polymerization of 30,000!
I! and 20 parts of calcium carbonate were preliminarily kneaded at room temperature for 2 minutes using the same kneader used in Example 1,
The obtained preliminary wire hardware, a solution obtained by previously mixing and dissolving 10 parts of 1,2-propanediol and 2 parts of diclofenac sodium on a 60°C water bath, and 40 parts of glycerin were heated in the kneader at room temperature. The kneaded product was further kneaded for 20 minutes to obtain a kneaded product.Next, the heating temperature of the kneader was maintained at 60°C, and the kneaded product was mixed and dissolved with 20 parts of water and 1 part of gelatin. An aqueous gelatin solution and 1 part of isopropyl myristate were kneaded in the kneader for 10 minutes to obtain a paste.

Using this paste, a poultice containing diclozener 7 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 diclofenac after one day had passed after the aluminum bag, 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 instead of the glycerin.

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

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 improve the solubility of diclofenac sodium in the base, and improve the release of diclofenac sodium from the normal body and into the living body. diclofenac sodium is stably contained in the plaster.
Moreover, they can continue to be dissolved for a long period of time without mutual precipitation. Moreover, this diclofenac poultice can be made into a safe poultice that does not cause sensitization to the skin.

[Brief explanation of the drawing]

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 in blood as a result of a drug absorption test. It is a graph showing the change over time. Patent applicant: Taisho Pharmaceutical Co., Ltd. Yabubo B8 group (min.)

Claims (2)

[Claims] (1) Diclofenac sodium, water, and carbon number 3
or 4. A diclofenac poultice characterized by having a moisturizing and dissolving agent of one or more alkylene glycols and a base consisting of one or more of gelatin, polyvinyl alcohol, and polyvinylpyrrolidone. (2) The moisturizing and dissolving agent comprises 1,2-propanediol and 1,3-butanediol.
Diclofenac poultice as described in section.