JPH0656660A - Patch containing sodium diclofenac - Google Patents

Abstract

(57) [Summary] [Structure] A patch containing sodium diclofenac, characterized in that a crosslinked hydrous gel in which a composition comprising water, a polyhydric alcohol fatty acid ester and sodium diclofenac is dispersed is spread on a support. . The composition may contain 1,3-butylene glycol as a solubilizing agent. [Effects] (1) Diclofenac sodium in a crosslinked hydrous gel should ensure stability without crystal precipitation and be capable of sustained release from the crosslinked hydrous gel for a long time. You can (2) It is possible to provide a patch that has good skin adhesion, does not leave a crosslinked hydrous gel on the affected area during peeling, and does not stain clothes. (3) Therefore, the effects of diclofenac sodium can be exerted continuously and stably without causing side effects such as rash and skin irritation during and after application.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a patch containing diclofenac sodium.

[0002]

BACKGROUND OF THE INVENTION Diclofenac sodium is a non-steroidal anti-inflammatory analgesic which is soluble in water and alcohols and has excellent anti-inflammatory and analgesic effects. The commercially available dosage forms are oral and I have a suppository.

[0003]

DISCLOSURE OF THE INVENTION However, diclofenac sodium absorbed into the body through the above administration route is
Once in the blood, it is distributed in high concentrations throughout the body as well as at the site of inflammation. Therefore, in order to increase the blood concentration at the inflammatory site, some overdose is required. In addition to this, diclofenac sodium absorbed in the body,
Since it passes through the detoxification and excretion route, it has been reported that various side effects, particularly gastrointestinal / liver / kidney disorders are caused.

Therefore, for the purpose of reducing the occurrence of side effects in these systemic administrations, local administration is considered, and diseases in which the site of inflammation is close to the epidermis, such as low back pain, osteoarthritis, rheumatoid arthritis, neuralgia. In the treatment of
Rather, transdermal absorption is recommended. In the case of transdermal administration, it is possible to cause a certain concentration of drug to exist at the inflammatory site by causing diclofenac sodium to act on the inflammatory site in a concentrated manner. Therefore, it is expected that the above-mentioned side effects associated with systemic administration can be avoided without distributing the drug to unnecessary sites. Examples of such transdermal agents include liquids, ointments (gels, creams), patches, etc., and these forms of diclofenac sodium are also being investigated.

However, the above-mentioned transdermal preparation has the following problems.

(1) In the case of liquid medicine and ointment: It is necessary to apply it to the affected area with a finger at the time of application, so depending on the affected area, it may be necessary to help others, and after application, do not stain clothes. This may be inconvenient because it may be necessary to cover the affected area with a suitable cloth piece or the like.

Percutaneous absorption of diclofenac sodium is transient, and is absorbed intensively when a liquid agent or the like is applied, and after a lapse of time after application, it becomes dry and poorly absorbed, and continuous absorption should be expected. I can't. Therefore, administration several times a day or more is required.

(2) In the case of poultices and patches In the case of poultices and patches, the solubility of diclofenac sodium is a problem. It is important to secure an effective dose without precipitating the drug in the preparation, and it is known that absorption is greatly affected. Although diclofenac sodium is soluble in water, its solubility is not enough to ensure an effective dose. Therefore, it is necessary to select an organic solvent, but it is necessary to avoid volatile and irritating substances, so that the kind and amount of the solubilizer for solubilization are strictly limited.

As one mode of the poultice and the patch, there is a form in which a pasty poultice plaster is spread on a cloth or the like, or a form in which the plaster is spread on a cloth in advance. It may be difficult to peel off the protective film pasted on the product during use, or it may become dull or sticky due to moisture absorption or softening of the plaster during use, and the plaster may remain on the skin when the patch is peeled off after use. May stain clothes.

In order to adhere to the skin, many require auxiliary means such as a plaster or a surgical tape,
It often causes skin irritation and rash.

The present invention has been made to solve all the above problems in the above-mentioned liquid preparation, ointment preparation, poultice preparation and patch preparation, and its purpose is physicochemical reaction in the preparation of diclofenac sodium. A patch containing sodium diclofenac that ensures stable release of the drug over a long period of time while ensuring stability, has excellent self-adhesiveness to the affected area, and does not leave a plaster on the affected area during peeling. To provide the agent.

[0012]

Means for Solving the Problems The topical patch for external use according to the present invention, which is suitable for the above purpose, comprises a composition comprising water, a polyhydric alcohol fatty acid ester, diclofenac sodium and optionally 1,3-butylene glycol dispersed therein. The gist of the invention lies in the fact that a crosslinked hydrous gel is spread on a support.

[0013]

OPERATION AND PREFERRED EMBODIMENTS As described above, the present invention is
The composition is characterized in that a composition comprising water, a polyhydric alcohol fatty acid ester, diclofenac sodium, and, if necessary, 1,3-butylene glycol is dispersed in a crosslinked hydrous gel and used.

The polyhydric alcohol fatty acid ester is used here because diclofenac sodium is stably dissolved in the crosslinked hydrous gel at a constant concentration without crystallizing, and the diclofenac sodium from the crosslinked hydrous gel is stabilized. This is to ensure the release and thus to guarantee the long-term efficacy.

The use of 1,3-butylene glycol is expected to achieve the same effect as above by assisting the dissolution of diclofenac sodium.

The crosslinked hydrous gel stably holds a composition comprising water, a polyhydric alcohol fatty acid ester, and diclofenac sodium (diclofenac sodium dissolved in 1,3-butylene glycol if necessary), and at the same time, treats the affected area. It is used to secure self-adhesiveness, feel good for a long time, and prevent the plaster from remaining on the affected area when the patch is peeled off.

As the polyhydric alcohol fatty acid ester,
Preferably, a polyhydric alcohol medium chain fatty acid ester is used. As the polyhydric alcohol medium chain fatty acid ester, glycerin, ethylene glycol, propylene glycol,
There are fatty acid esters of polyhydric alcohols such as 1,3-butylene glycol, diglycerin, polyglycerin, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharides and reduced oligosaccharides. , The fatty acid has 6 carbon atoms
-12 are preferable. More preferred are polyhydric alcohol medium chain fatty acid monoesters.

The crosslinked hydrogel is not particularly limited in its constitution, but the most preferable one is a crosslinked product of polyacrylic acid, in which sodium carboxymethylcellulose, polyvinylpyrrolidone and gelatin coexist. Since it was particularly effective, this point will be supplemented below. The actions of the above four types of polymers are as follows.

[0019]

[Sodium polyacrylate] Sodium polyacrylate gives the crosslinked hydrogel a binding force and an adhesive force. As a result, the gel is prevented from flowing out of the plaster during use,
Further, the adhesiveness of the patch to the affected area is enhanced, and the patch can be directly applied to the skin or the like without the need for an auxiliary tool such as an adhesive tape or a bandage.

Any sodium polyacrylate can be used, and its molecular weight and linear or branched form are not particularly limited. Specifically, those having a molecular weight of 10,000 to 100,000 can be preferably used.

Further, the compounding amount is preferably 0.5 to 10% (% of the total weight of the paste, the same hereinafter), and more preferably 3 to 5%.

If the blending amount is too small (for example, less than 0.5%), the thickening effect is weak and sufficient adhesion to the skin cannot be obtained. When the blending amount becomes large (for example, exceeds 10%),
The thickening effect becomes too strong, making it difficult to spread it on the support, and the phenomenon that the adhesive strength decreases during use.

[Sodium carboxymethylcellulose] When sodium carboxymethylcellulose is used, it is possible to give the base a certain hardness.
As a result, it is possible to ensure the thixotropic properties of the crosslinked hydrous gel, it is possible to prevent the gel from protruding from the cutting edge in the patch obtained by applying and cutting the support, during storage, It is possible to prevent the gel from seeping into the support.

As sodium carboxymethyl cellulose, the molecular weight and the degree of etherification are not necessarily limited, and any of them can be used. The blending amount is preferably 0.5 to 10%, more preferably 2 to 5%
Is. When the blending amount is low (for example, less than 0.5%),
Sagging of the plaster and back streaking occur. If the blending amount is too large (for example, more than 10%), the viscosity becomes high and it becomes difficult to spread, and the adhesion to the skin becomes poor.
It may be difficult for diclofenac sodium to move to the affected part in the plaster, and the drug absorption may decrease.

[Polyvinylpyrrolidone] When polyvinylpyrrolidone is used, the stability of the polyhydric alcohol fatty acid ester and the diclofenac sodium dissolved in it is ensured in the gel, and the drug effect is maintained for a long period of time. The shape retention of the plaster can be improved.

The molecular weight of polyvinylpyrrolidone is not particularly limited, and any one can be used. As the compounding amount, 0.1-5%
Is preferable, and 0.5-4% is more preferable. When the compounding amount is small (for example, less than 0.1%), the adhesive force is lowered. When the blending amount becomes large (for example, exceeds 5%),
The physical stability of diclofenac sodium in the gel may be increased, and accordingly, the migration in the plaster may be reduced, which may reduce the drug absorption into the affected area.

[Gelatin] When gelatin is used,
In addition to increasing the hardness of the gel, it is possible to prevent dripping and stickiness due to moisture absorption and softening of the plaster during use of the adhesive patch and stain of clothes due to the gel remaining after peeling after use. The gelatin is not particularly limited in molecular weight and the like, and any commercially available product can be used. As the compounding amount, 0.5-4%
Is preferred, and more preferably 1 to 2%. If the blending amount is too small (for example, less than 0.5%), the gel strength becomes insufficient, and sagging or squeezing out from the support occurs. When the blending amount is large (for example, when it exceeds 4%), the gel strength becomes high and the adhesive strength becomes low.

As the polyvalent metal compound used as a cross-linking agent for polyacrylic acid, inorganic salts such as hydrochlorides, sulfates, phosphates and carbonates of polyvalent metals such as calcium, magnesium and aluminum. , Citrate, tartrate,
Examples thereof include organic acid salts such as gluconate and acetate, oxides and hydroxides, and aluminum compounds are particularly preferable. As the aluminum compound used here, any one can be preferably used. It is preferable to use one or more selected from the above. The blending amount is preferably 0.005 to 4%, more preferably 0.02 to 2%, although it varies depending on the kind.

When the blending amount is small (for example, less than 0.005%), the cohesive force of the gel may decrease, and when the blending amount is large (for example, more than 4%), the crosslinking ratio of the crosslinked hydrogel becomes high. Therefore, it may be difficult to spread it on the support or the adhesive strength may be reduced.

As the other components, the following commonly used appropriate components can be used in the patch of the present invention.

(1) Moisturizing Agent As a moisturizing agent, one or more polyhydric alcohols such as D-sorbitol, glycerin, propylene glycol and polyethylene glycol which are usually used for orthopedic poultices can be blended. Of these, D-sorbitol is particularly preferable. D-sorbitol usually uses a 70% solution, but is not limited thereto. Further, the compounding amount is preferably 5 to 60% as D-sorbitol. 20-40% is more preferable. When the amount of the humectant is small (for example, D-sorbitol is less than 5%), the moisturizing effect is insufficient, and when the amount is large (for example, D-sorbitol is more than 60%), the solubility of the polymer substance is decreased. It may be necessary to reduce the amount of water blended.

(2) Crosslinking gel stabilizer A urea or the like can be added as a crosslinking gel stabilizer. The blending amount is preferably 0 to 5%, more preferably 0.5 to 3%.

(3) Stabilizer for drugs and compositions thereof As a stabilizer for drugs and compositions thereof, a chelating agent such as EDTA can be added. The blending amount is preferably 0 to 1%, more preferably 0.01 to 2%.

(4) Inorganic filler As the inorganic filler, kaolin, bentonite, talc,
Titanium oxide, zinc oxide and the like can be added. The blending amount is preferably 0 to 30%, more preferably 0 to 15%
Is.

(5) Preservative As a preservative, parabens and the like can be added.
Regarding the blending amount of each of the above components, diclofenac sodium 0.2 to 4%, polyhydric alcohol fatty acid ester 5.0 to 1
0%, 1,3-butylene glycol 5-10%, and crosslinked hydrogel 30-80% are preferable. In addition, p of cross-linked hydrogel
It is preferable to adjust H to 7.0 to 9.0.

As the support used in the present invention,
It is desirable to use a flexible support that does not peel off depending on the feel at the time of application, the tightness of the affected area, and the movement of the human body. Nonwoven fabrics made of various natural or synthetic fibers, woven fabric flakes, and polyethylene films as these liners, ethylene vinyl acetate. A film, a polyvinyl chloride film, a laminate of polyurethane, a polyolefin, etc., and a product obtained by punching are used.

Next, a typical method for producing a patch containing sodium diclofenac according to the present invention will be described below.

Water is added to gelatin and polyvinylpyrrolidone, heated and dissolved at a predetermined temperature (for example, about 60 ° C.), and then sorbitol, a stabilizer, an inorganic filler, a preservative and the like are added as necessary to obtain a uniform mixture. , Sodium polyacrylate, sodium carboxymethyl cellulose, polyhydric alcohol fatty acid ester and diclofenac sodium (dissolved in 1,3-butylene glycol if necessary), aluminum compound, and sufficiently stirred and kneaded, Is evenly spread on a support such as a non-woven fabric, a lint cloth, and a knitted cloth, and a plastic film is attached to the coated surface and cut into an appropriate size to obtain the patch of the present invention.

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

In the following description, "part" means "part by weight".

[0041]

【Example】

Example 1 Gelatin 1 part, polyvinylpyrrolidone 3 parts, methylparaben 0.1 part, propylparaben 0.05 part,
1 part of urea was added, and 24.35 parts of water was added to this to obtain about 6 parts.
Dissolve by heating at 0 ° C. To this mixed solution, a solution prepared by previously dissolving 2 parts of diclofenac sodium in 5 parts of propylene glycol monocaprylate and 70% sorbitol solution 1
5 parts and 0.5 parts of aluminum hydroxide are added and mixed uniformly to obtain a mixed solution A. A mixed solution B obtained by adding and mixing 5 parts of 1,3-butylene glycol, 4 parts of sodium polyacrylate and 4 parts of sodium carboxymethyl cellulose to the mixed solution A was added and kneaded with a universal mixer. A crosslinked hydrogel containing diclofenac sodium is obtained. The obtained hydrous gel was applied onto a nonwoven fabric so that the amount of diclofenac sodium was 2 mg per square centimeter, and a plastic film was attached to the application surface to obtain a diclofenac sodium-containing patch.

[0042]

Example 2 To 1 part of gelatin and 4 parts of polyvinylpyrrolidone, 27.35 parts of water was added and dissolved by heating at about 60 ° C., then 2 parts of diclofenac sodium, 8 parts of propylene glycol monocaprylate, 0.1 part of methylparaben, propylparaben. 0.05 part is added to obtain a mixed solution C. Then, mixed solution D obtained by mixing and dispersing 10 parts of kaolin, 43 parts of 70% sorbitol solution, and 5 parts of sodium carboxymethyl cellulose is added to the mixed solution C, and the mixture is stirred and kneaded to obtain a hydrogel containing diclofenac sodium. . The obtained hydrous gel was spread in the same manner as in Example 1 to obtain a diclofenac sodium-containing patch.

[0043]

[Example 3] 1.0 part of gelatin and 3 parts of polyvinylpyrrolidone
Parts, 0.1 parts of methylparaben, 0.05 parts of propylparaben, and 19.85 parts of water are added and dissolved by heating at about 60 ° C.
To get Furthermore, a dispersion F obtained by mixing 47 parts of a 70% sorbitol solution and 6 parts of propylene glycol monocaprylate with 2 parts of diclofenac sodium, 1 part of urea and 10 parts of kaolin and mixing and dispersing the mixture was added to the solution E. Then, the mixture is uniformly kneaded to obtain a kneaded product. Next, a mixed solution obtained by mixing and dispersing 5 parts of 1,3-butylene glycol and 5 parts of sodium carboxymethyl cellulose is added to the kneaded product,
The mixture was stirred and kneaded until it became uniform to obtain a hydrous gel. The obtained gel was spread in the same manner as in Example 1 to obtain a diclofenac sodium-containing patch.

[0044]

Example 4 2.5 parts of gelatin, 4 polyvinylpyrrolidone
28.15 parts of water is added to the above parts and dissolved by heating at about 60 ° C. to obtain a solution G. Diclofenac sodium 2 parts, propylene glycol monocaprylate 8 parts, methyl paraben 0.1
Parts and 0.05 parts of propylparaben are mixed and dissolved, and the resulting solution is added to the solution G and mixed uniformly, and then 40 parts of 70% sorbitol solution and 0.2 parts of sodium edetate are added to obtain a mixed solution H. 5 parts of sodium carboxymethyl cellulose mixed and dispersed in 10 parts of 1,3-butylene glycol was added to the mixed solution H, and the mixture was stirred and kneaded until it became homogeneous to obtain a hydrogel. The obtained gel was spread in the same manner as in Example 1 to obtain a diclofenac sodium-containing patch.

[0045]

Example 5 Gelatin 1.5 parts, polyvinylpyrrolidone 2
Part, methylparaben 0.1 part, propylparaben 0.05 part,
After mixing 0.5 parts of urea, 0.5 parts of aluminum hydroxide and 25.35 parts of water with heating and dissolving, 10 parts of kaolin and 35 parts of 70% sorbitol solution are added and uniformly mixed to obtain a mixed solution I. Then, propylene glycol monocaprylate 8
Parts, 7 parts of 1,3-butylene glycol, 2 parts of diclofenac sodium, 7 parts of sodium polyacrylate and 1 part of sodium carboxymethyl cellulose were added and mixed and dispersed to the above mixed solution I, and these were uniformly stirred and kneaded. To obtain a hydrogel. The obtained gel was spread in the same manner as in Example 1 to obtain a diclofenac sodium-containing patch.

[0046]

[Comparative example]

[Comparative Example 1] 15 parts of water was added to 5 parts of gelatin and dissolved by heating, and then 45 parts of kaolin and 15 parts of glycerin were added and uniformly mixed.
Parts and 1 part of diclofenac sodium in 3 parts of a surfactant, 5 parts of sodium polyacrylate were further added and mixed and dispersed, and the mixture was stirred and kneaded uniformly to obtain a diclofenac sodium hydrogel. The obtained hydrous gel was spread in the same manner as in Example 1 to obtain a patch containing diclofenac sodium.

[0047]

[Comparative Example 2] 18 parts of water was added to 7 parts of gelatin and 5 parts of polyvinyl alcohol and dissolved by heating. A solution obtained by dissolving 15 parts of 1,3-butylene glycol and 2 parts of diclofenac sodium in the solution is obtained. In advance, 30 parts of glycerin, 17 parts of kaolin, 1 part of sodium polyacrylate, 2 parts of methyl cellulose and 3 parts of polybutene were added to the above solution, and the mixture was stirred and kneaded to give a diclofenac sodium-containing hydrogel. Obtained. The obtained hydrous gel was spread in the same manner as in Example 1 to obtain a patch containing diclofenac sodium.

[0048]

COMPARATIVE EXAMPLE 3 20 parts of water was added to 5 parts of gelatin, dissolved by heating, and then 25 parts of kaolin and 18 parts of glycerin were added and uniformly mixed to obtain a mixed solution. After 2 parts of diclofenac sodium was added to 25 parts of propylene glycol and dissolved, then 5 parts of polybutene were added and mixed and dispersed to obtain the above liquid, and the mixture was stirred and mixed until uniform to give a hydrogel containing sodium diclofenac. Obtained. The obtained hydrous gel was spread in the same manner as in Example 1 to obtain a diclofenac sodium-containing patch.

[0049]

Example 6 With respect to the patches obtained in Examples 1 to 5 and Comparative Examples 1 to 3, immediately after production, the presence or absence of precipitation of crystals of sodium diclofenac in the preparation was observed with the naked eye and a microscope, and Put it in a bag and seal it in the refrigerator (5
Store at ℃) for 1 month. After the storage, the temperature was returned to room temperature, the package was opened, and the presence or absence of crystal precipitation was similarly inspected. The test results are shown in Table 1.

[0050]

[Table 1]

[0051]

Example 7 (Carrageenin Paw Edema Inhibition Test) Male Wistar rats weighing 140 to 160 g were used as one group of 10 rats.
After measuring the paw volume of the right hind leg of the rat, 0.1 ml of a 1% carrageenin suspension was subcutaneously injected into the footpad. The volume of the same paw was measured again 4 hours after the injection of the inflammatory agent, and the edema rate and the inhibition rate of each agent with respect to the control group were determined from the difference before and after that.

The diclofenac sodium-containing patch and the base obtained in Examples 1 to 3 were administered 2.5 x 2 4 hours before injection.
(Cm ² ) was applied to the right hind leg. The test results are shown in Table 2.

[0053]

[Table 2]

[0054]

Example 8 (Adjuvant Arthritis Suppressing Effect) Mycoba suspended in liquid paraffin at the tail of SD female rat 8 weeks old.
cterium butyricum (1% / 0.06m
l) after intradermal injection, the patch containing diclofenac sodium obtained in Examples 4 and 5 and the same base 2 × 2.5 (cm ² ) were continuously patched once a day for 6 hours from the 15th day to the 21st day. . Mycobacterium butyricum
The edema rate on the 15th day after the inoculation was set to 100%, the paw volume was measured daily, and the edema rate was calculated and compared with the untreated control group.
The test results are shown in Table 3.

[0055]

[Table 3]

[0056]

Since the present invention is constructed as described above, the following excellent effects are exhibited.

(1) Diclofenac sodium in a crosslinked hydrous gel should ensure stability without causing crystal precipitation and enable sustained release from the crosslinked hydrous gel for a long time. You can

(2) It is possible to provide a patch which has good skin adhesion and does not leave the crosslinked hydrous gel on the affected area at the time of peeling and does not stain clothes.

(3) Therefore, the effect of diclofenac sodium can be exerted continuously and stably without causing side effects such as rash and skin irritation during and after application.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 47/14 J 7433-4C C 7433-4C 47/32 F 7433-4C 47/38 F 7433- 4C

Claims (2)

[Claims] 1. A patch containing sodium diclofenac, which is obtained by spreading a crosslinked hydrous gel in which a composition comprising water, a polyhydric alcohol fatty acid ester and sodium diclofenac is dispersed on a support. 2. The composition comprises 1,3-as a solubilizing agent.
The patch according to claim 1, comprising butylene glycol.