JPS62111918A - Hydrous application agent - Google Patents

Abstract

PURPOSE:To hydrous application agent, containing a monovalent salt of polyacrylic acid and carboxyl-containing hydrophilic polymer, Al salt as a crosslinking agent and a given amount of water, obtained by incorporating a polyhydric alcohol and percutaneous absorption drug and having improved shape retaining property, application property and drug effect. CONSTITUTION:A hydrous application agent obtained by incorporating a monovalent salt of polyacrylic acid, preferably having >=1X10<6> weight-average molecular weight and 50-100% stoichiometric neutralization ratio with a carboxyl- containing hydrophilic polymer, e.g. polyacrylic acid, carboxyvinyl polymer, etc., Al salt, polyhydric alcohol and percutaneous absorption drug, e.g. nonsteroid beta-blocker, drug for asthma, etc., and having moisture content set to 20-80wt%. In this case, 3-30wt% monovalent salt of the polyacrylic acid and 0.005-0.2wt%, expressed in terms of Al, Al salt are preferably contained. The agent has a tough gel skeleton and rich shape retaining property and is capable of readily and effectively curing the body.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a water-containing patch used mainly for the purpose of removing or alleviating various disorders of the body by bringing it into direct contact with the body surface.

[Conventional technology]

Water-containing patches such as poultices are made of water-containing gel and are generally made from natural water-soluble polymers such as gum tragacanth, gum karaya, gum arabic, sodium alginate, mannan, gelatin, pectin, or polyacrylic acid, polyacrylate, polyvinyl alcohol. It is composed of a synthetic polymer such as polyacrylamide, which is mixed with a moisturizing agent such as polyhydric alcohol, water, a transdermal absorbable drug, etc.

[Problem that the invention seeks to solve]

However, since the natural water-soluble polymer is a natural product, its quality is not stable, and phenomena such as contamination due to contaminants and deterioration due to impurities occur. On the other hand, synthetic polymers do not have the above problems because they are synthetic products. However, since synthetic polymers lack cohesiveness, their use weakens the gel skeleton, and the 1:1 water-containing patch may cause irritation in the summer or leave adhesive residue on the skin. To solve the problem of doing something. In order to avoid staining, various crosslinking treatments are applied. For example, cross-linking of I) acrylates with polyvalent metal salts, cross-linking of boribi, :-luarnyl with dialdehyde starch, cross-linking of polyacrylates with epoxy cross-linking agents, cross-linking of polyethylene glycol with urethane compounds. etc. When crosslinking with polyvalent metal salts, increasing the crosslinking density makes the W film brittle, decreasing the crosslinking density causes adhesive residue on the skin, and physical properties change over time, so it takes time to reach the final physical property values. There are disadvantages in that the thickness is difficult to control. Crosslinking with dialdehyde starch has the disadvantage that the resulting base is hard and has weak adhesive strength. Further, crosslinking using an epoxy crosslinking agent or a urethane compound has safety problems and is not completely satisfactory in terms of reliability.

This invention was made in view of the above circumstances, and uses a synthetic polymer substance that has a strong gel skeleton, excellent shape retention, excellent water retention and adhesion, and can be easily and effectively applied. The purpose is to provide a water-containing patch that can treat the body.

[Means for Achieving Object 1] In order to achieve Object 1 above, the water-containing patch of the present invention is a water-containing patch whose main components are polyacrylic acid/alcohol and water, and - The water content is set to 20 to 80% by weight, and contains a hydrophilic polymer having a carboxyl group, alumina l, a salt, a polyhydric alcohol, and a transdermal absorbable drug. The structure is that

That is, as a result of repeated research focusing on hydrogels whose gel skeletons are polyacrylates, which are hydrophilic polymers among synthetic polymers, the present inventors found that monovalent polyacrylates among synthetic polymers In addition to using a salt and a hydrophilic polymer having a carboxyl group in combination, using an aluminum salt as a crosslinking agent for these, and limiting the water content to a certain range, polyhydric alcohol and a transdermal drug can be combined. It was discovered that the desired objective could be achieved by blending the above, and this invention was achieved.

The water-containing patch of the present invention is essentially a water-containing gel in which the liquid held between the gel skeletons contains water as a main component, and contains polyacrylic acid-alcohol salt and a hydrophilic gel having a carboxyl group. It is obtained using a polymer, an aluminum salt, water, a polyhydric alcohol, and a transdermal drug.

The polyacrylate needs to be a monovalent salt with effective hydrophilicity, in particular a weight average molecular weight of 1 x 10
It is preferable that it is 6 or more.

If the weight average molecular weight is less than 1X10', the skeleton of the hydrogel obtained tends to be weak and the shape retention of the gel as a whole tends to be poor, and it is necessary to use a large amount of polyacrylic acid-alcohol salt to improve this. This is uneconomical. If a large amount of aluminum salt crosslinking agent is used to increase the crosslinking density, shape retention will be improved, but adhesiveness and flexibility will be deteriorated. Therefore, it is desirable to use a polyacrylic acid alcohol salt having a molecular weight as described above.

Particularly, among the above-mentioned polyacrylic acid-alcohol salts, it is preferable to use those having a stoichiometric neutralization rate of 50 to 100%. This is because those with a stoichiometric neutralization rate of less than 50% lack cohesiveness, resulting in a water-containing patch that has high fluidity and tends not to be used in applications requiring shape retention. This polyacrylic acid-alcohol salt is
Manufactured by conventional methods, such as pre-neutralized acrylic acid-tartar homopolymer or copolymer with acrylic acid, or polymerization of acrylic acid to form polyacrylic acid, followed by neutralization with various alkalis, etc. You can use the

Typical examples of such polyacrylic acid alcohol salts include alkali metal salts such as sodium salts and potassium salts, alkanolamine salts such as ethanolamine, jetanolamine, methyljetanolamine, and polyethanolamine, and ammonium salts. Salts and the like can be used alone or in combination.

- The hydrophilic polymer having a carboxyl group used together with the polyacrylic acid monovalent salt described in (g) forms the skeleton of the gel together with the polyacrylic acid monovalent salt described in (g), and by using it, shape retention is achieved. It becomes possible to obtain a water-containing patch that has high adhesive properties, leaves no adhesive residue when applied to the skin, and has high adhesive strength to the skin. Typical examples of this type of hydrophilic polymer include polyacrylic acid, carboxyvinyl polymer di-crosslinked polyacrylic acid, methoxyethylene-
Maleic Anhydride Copolymer 1 Examples include isoprene-maleic acid copolymers, which can be used alone or in combination. -1, Cross-linked polyacrylic acid has a cross-linked structure obtained by polymerizing an acrylic acid alkali metal salt in the presence of a cross-linking agent, whereas ordinary polyacrylic acid is linear. belongs to.

The polyhydric alcohol used in this invention is preferably one that does not dissolve the polyacrylic acid monovalent salt and disperses it uniformly. Suitable examples include glycerin, polyglycerin, ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene gelyl, volyl, ethylene glycol, 1'' pyrene glycol copolymer and the like. These polyhydric alcohols may be used singly or in combinations of two or more types without any problem. The polyhydric alcohol exemplified above does not substantially dissolve the polyacrylic acid monovalent salt and uniformly disperses it. Here, uniformly dispersing the polyacrylic acid monovalent salt without substantially dissolving it means that even if some of the low molecular weight portion of the polyacrylic acid monovalent salt is dissolved, most of the polyvalent monovalent salt is This means that it is insoluble and dispersed in alcohol.

The water used together with the polyhydric alcohol is not particularly limited, and water that is normally used for producing hydrogels can be used.

Aluminum salt 2 acts as a crosslinker and U7 on monovalent polyacrylic acid salts and hydrophilic polymers having carboxyl groups, and among various metal salts, it is more popular than monovalent metal salts. The valent metal salt was adopted from the viewpoint that it has a faster crosslinking speed and is superior to other metal salts in terms of safety, discoloration, etc. Representative examples include soda alum, potassium alum,
Examples include ammonia amicobium, aluminum sulfate, aluminum hydroxide, dry aluminum hydroxide gel, aluminum chloride, aluminum acetate, and the like. These can be used alone or in combination without any problem. Particularly, among the above compounds, the use of alums brings about good results.

Examples of transdermal drugs used with the above-mentioned raw materials include salicylic acid esters, menthol, camphor, pepper, chili pepper extract, and kabsaicin for poultices; Steroids, anginal drugs such as nitroglycerin and 15DN, local anesthetics such as pensicaine, prolactin, and xylocaine, antihistamines such as diphenhydramine, alprenolol, propranolol.

β-blockers such as pindolol, antihypertensive agents such as clonidine and nifedipine, and methylephedrine.

Bronchodilators such as chlorbrennaline, salbutamol, terbutaline, asthma drugs such as cromoglycic acid, benzalkonium chloride, benzethonium chloride.

Bactericidal agents such as silver sulfadiazine, antibiotics, sulfa drugs, antibacterial agents, prostaglandins, drugs such as hormones, water-soluble collagen, aloe extract, female hormones, skin beautifying ingredients such as loofah extract, allantoin, lecithin, vitamin E, A, D, B6, vitamins such as pantothenic acid, cam azulene, guaya azulene, r-oryzanol,
Urea, sulfur, salicylic acid, yellow oak, western horse chestnut, and toki.

Examples include extracts of herbal medicines such as purple root, fragrances, diagnostic agents for clinical tests, insect attractants and repellents, plant hormones, insecticides, fertilizers, and agricultural chemicals. These may be used alone or in combination without any problem.

The water-containing patch of the present invention can be produced using these raw materials, for example, in the following manner.

First, the above polyhydric alcohol is heated at room temperature or higher, preferably at 50%
Warming to a temperature of ~80°C reduces viscosity and reduces flowability. Next, the monovalent polyacrylic acid salt and aluminum salt described in 1. are added to this and thoroughly dispersed. In this case, it is preferable to use the polyacrylic acid monovalent salt in an amount of 3 to 30% by weight (hereinafter abbreviated as 1%) in the obtained water-containing patch to bring about good results. Further, the aluminum salt is preferably used so that the amount of aluminum contained in the produced water-containing patch is 0.005 to 0.2%. When the amount of aluminum salt is less than 0.005%, crosslinking becomes insufficient and the gel skeleton becomes weak.
The resulting water-containing patch tends to leave adhesive residue on the skin and has poor shape retention at high temperatures. On the other hand, if it exceeds 0.2%, the water-containing patch becomes too hard, has a weak adhesion to the skin, and tends to be difficult to mold.

Next, water and a hydrophilic polymer having a carboxyl group are added gradually or all at once to the mixture of polyacrylic acid monovalent salt and aluminum salt dipolyhydric alcohol obtained as described above.

The amount of water added is 20-80% water in the resulting water-containing patch.
Setting the amount of water to be contained imparts excellent properties to the resulting water-containing patch, and if the water content falls outside of the above range, the desired water-containing patch cannot be obtained. Further, it is appropriate to set the amount of the hydrophilic polymer having a carboxyl group so that the hydrophilic polymer is contained in the water-containing patch in an amount of 0.1 to 20%. If the amount of the hydrophilic polymer added is less than 0.1%, the skeleton components of the gel will decrease and at the same time the crosslinking rate with aluminum will slow down, so the skeleton strength of the gel will not increase much, whereas if it exceeds 20%, aluminum will crosslink. This is because the gel does not proceed uniformly and a non-uniform gel is likely to be formed.

After water and the hydrophilic polymer are gradually added in this way, the temperature is lowered to around 40 to 70°C and mixed under shear stress for 30 minutes or more. Mixing under this shear stress can be carried out by, for example, niegoo, co-kneader, kneader-ruder, etc.
, Ajihomo mixer.

This can be carried out by appropriately selecting and using a planetary mixer, a twin-screw kneader, or the like. In this case, lowering the temperature of the solution when adding water, etc. may cause discoloration of the base of the water-containing patch obtained by mixing at high temperatures for a long period of time, or deterioration or decomposition of the added ingredients. There is,
This is to avoid this.

Note that the transdermal absorbable drug may be added at any stage in the above manufacturing process. For example, if the drug is hydrophilic, it may be added at the same time as water is added; if it is lipophilic, it may be dissolved in polyhydric alcohol or the like and added together with the polyhydric alcohol, or the solution described in 1. Good results can be obtained by adding the surfactant together with the water addition.

In this way, a hydrogel composition for use in the hydrogel patch of the present invention is obtained. The composition is formed into a sheet by continuous extrusion using a device capable of imparting shear stress, such as a twin-screw extruder or twin-screw extruder, with a die attached to its discharge port. As a result, the water-containing patch of the present invention is obtained. This base is usually manufactured into a product by laminating it with a support. As the above support,
Examples include plastic films such as polyethylene, ethylene-vinyl acetate copolymer, vinyl chloride, polyurethane, and polyester, nonwoven fabrics such as nylon, Raycon, urethane, polyester, and absorbent cotton, cloth, elastic fabric, paper, cellophane, etc. It can be selected as appropriate depending on its use.

The water-containing patch of the present invention may further contain other water-soluble polymers, water-absorbing resins, inorganic fillers, tackifiers, pH regulators, surfactants, cleaning agents, various crosslinking agents, and transdermal absorption agents. Other additives such as accelerators and preservatives can be added as appropriate depending on the purpose.

[Effects of the Invention] As described above, the water-containing patch of the present invention contains a polyacrylic acid monovalent salt, a hydrophilic polymer having a carboxyl group, an aluminum salt, a polyhydric alcohol, and a transdermal absorption drug. Moreover, since the total water content is set to 20 to 80%, the gel skeleton is strong and has excellent shape retention at high temperatures, making it easy to use. Moreover, since it has high water-retention properties and can maintain a cooling sensation for a long time, the effect of the transdermal drug contained in the gel is also long-lasting. Furthermore, it has excellent adhesion properties and can adhere well to the skin. Therefore, the body can be easily and effectively treated using the water-containing patch of the present invention. Furthermore, this water-containing patch does not use an epoxy crosslinking agent or a urethane crosslinking agent, so it is highly safe. In addition, this water-containing patch can be made into a sheet even after salt crosslinking reaches the end point by adjusting shear stress and temperature, and because it contains a high proportion of polyhydric alcohol, it can be used as a transdermal drug with lipophilic properties. It has the advantage that it is possible to dissolve both highly hydrophilic and highly hydrophilic materials, and a wide range of raw materials can be used. Further, during its production, the pl+ of the liquid can be arbitrarily controlled by adjusting the amount of the hydrophilic polymer having a carboxyl group or the degree of neutralization of the monovalent polyacrylic acid salt, so that the production is easy.

Next, examples will be described together with comparative examples.

[Example, comparative example]

A water-containing patch was manufactured in the following manner using the raw materials shown in the table below.

(The following is a blank space) That is, using a planetary mixer, the temperature of the sodium polyacrylate, glycerin, and potassium alum fine powders was raised to 60'C, uniformly mixed and dispersed, and mixing was continued in that state for 1 hour. Next, the temperature was lowered to 50°C, and a 20% aqueous solution of polyacrylic acid, water, and a surfactant were added and mixed. When the whole was homogeneous, the above drug was added and emulsified, and mixed in that state for 1 hour. A hydrogel composition was produced. Next, the thus obtained hydrogel composition was applied onto a nonwoven fabric using a single screw extruder to obtain a sample.

The sample obtained in this way is cut to a certain size,
A panel of 10 people applied the adhesive to their faces for 3 hours, and evaluated its condition in three grades: ◯, △, and ×.

In addition, in order to examine shape retention at high temperatures, these samples were left at 60° C. for 24 hours, and the state thereafter was observed. The results are shown in Table 2.

(Left below) First--Shio! iIj standard O: Good, △: Fairly good, ×: Poor (
From Table 2, it can be seen that the example products according to the present invention have excellent shape retention at high temperatures, excellent adhesion to the skin, and are easy to use. On the other hand, in Comparative Example 1, potassium alum fine powder as a crosslinking agent was not used, and in Comparative Example 2, the water content was below the range of this invention, and in Comparative Example 3, the water content was Since the results exceed the scope of this invention, the results in both cases are poor.

[Example 7] Clonidine was used as a drug to be contained in a water-containing patch at a concentration of 2.5
% by weight was used. A water-containing patch was produced in the same manner as in Example 2 except for the above. This water-containing patch (clonidine content: 100 μg/cat) was cut into 4 x 4 cm squares and applied to the shaved back of a Wistar male rat (weight 200-250 g), and the caudal artery pressure was measured over time. did.

The results are shown in the drawing. As is clear from this drawing,
It can be seen that when the water-containing patch of the present invention is used, the blood pressure lowering effect is exerted over a long period of time.

[Example 8] Fluocinolone acetonide was used as a drug to be contained in a water-containing patch in an amount of 0.2 times. A water-containing patch was produced in the same manner as in Example 1 except for the above.

This water-containing patch was used by Christle and Moore Robinson (Christle and Moore Rob+).
A test piece of 20 x 20 cm was prepared according to the method of N5ON) and was attached to the oil side of the forearm of 10 panelists for the time shown in Table 3 below. Two hours after the peeling, the pallor of the adhered surface was observed and evaluated as follows.

0 points...No change.

1 point...the surface it was pasted on looks a little like its own.

2 points: Two corners of the surface where it was pasted have relatively clear white discoloration.

3 points: All the corners of the surface where it was pasted have turned white very clearly.

The evaluation results are shown in Table 3.

(See blank space below) From the results shown in Table 4, it can be seen that when the water-containing patch of the present invention is used, the medicinal effect is expressed within a short time after application, and this medicinal effect is sustained for a long time.

[Brief explanation of drawings]

Figure [F] 1 is a diagram of the bush octopus of the 11th regular season Koto. Time after administration

Claims (4)

[Claims] (1) A water-containing patch containing polyacrylic acid monovalent salt and water as main components, the water content being set to 20 to 80% by weight, and a hydrophilic polymer having a carboxyl group; A water-containing patch characterized by containing an aluminum salt, a polyhydric alcohol, and a transdermally absorbable drug. (2) Polyacrylic acid monovalent salt has a weight average molecular weight of 1×1
0^4 or more and the stoichiometric neutralization rate is 50-100%
The water-containing patch according to claim 1, which is (3) The water-containing patch according to claim 1 or 2, wherein the content of polyacrylic acid monovalent salt is set to 3 to 30% by weight. (4) The water-containing patch according to any one of claims 1 to 3, wherein the content of the aluminum salt is set to 0.005 to 0.2% by weight as aluminum.