JPH082786B2 - Method for producing alginate hydrogel sheet - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an alginate hydrated gel sheet which is a base material for various patches used in medical products, cosmetics and the like.

(Prior Art) An aqueous solution containing alginate is a colloidal solution, and when this aqueous solution is gelled, a hydrous alginate gel is obtained. Here, the solution that is the matrix of the gel is called a gel matrix aqueous solution. It is also possible to obtain a hydrous gel sheet to which a drug component, an electrolyte component, a cosmetic component and the like can be added, if necessary, to an alginate-containing aqueous solution as a gel matrix aqueous solution. This hydrous alginate hydrogel sheet is useful as a base material for various patches used for medical purposes, cosmetics and the like.

The conventional method for producing an alginate hydrogel sheet from an aqueous gel matrix solution containing alginate was as follows.

British Patent Nos. 530889, 552770 and U.S. Patent No. 2403
The method disclosed in 5407 is a method in which an alginate-containing aqueous solution which is a gel matrix aqueous solution is extruded through a slit into an aqueous solution of a gelling agent such as calcium chloride to cause gelation.

However, this method cannot avoid the problem that active ingredients such as drugs contained in the alginate-containing aqueous solution are eluted into the aqueous gelling agent solution. The elution of the active ingredient causes instability in the quality of the obtained alginate hydrogel sheet. In addition, since the composition of the gelling agent aqueous solution gradually changes when the active ingredient is eluted into the gelling agent aqueous solution, it is necessary to continuously or periodically replace it with a new gelling agent aqueous solution. Furthermore, in order to carry out continuous operation by such a manufacturing method, there is a problem that the bath for gelling agent aqueous solution becomes large.

As another production method, a reagent that gradually dissolves a sparingly water-soluble calcium salt and / or a sparingly water-soluble salt (for example,
A method has been proposed in which an aqueous solution containing alginate in which gluconodeltalactone) is dissolved is cast into a sheet and gradually gelled over a long period of time (Food Industry vol. .Four).

This method has a problem that productivity is extremely low because the gelation time is generally 20 to 40 hours, which is very long. Therefore, a wide storage space is required to produce a fixed amount. Furthermore, since the gelation time is long, the product is easily affected by environmental conditions such as temperature and humidity, resulting in large variation in quality. In order to solve such a problem, it is possible to accelerate the gelation. However, when the gel matrix aqueous solution has a composition that rapidly gelates, the pot life of the solution becomes short, which causes new problems such as gelation during coating and partially gelled lumps.

The present inventors have attempted the following method in order to solve the above problems.

Using a non-permeable film, a flat plate or the like as a support, a water-soluble calcium salt as a gelling agent is applied to the surface of the support.
Then, on the surface of the layer consisting of this water-soluble calcium salt,
An alginate-containing aqueous solution, which is a gel matrix aqueous solution, is cast to form a sheet.

In this method, the formed body first gels at the interface between the water-soluble calcium salt layer and the alginate-containing aqueous solution, and then gelation proceeds to the inside of the alginate-containing aqueous layer. The time until the whole gels is shorter than before and is not significantly affected by environmental conditions.

However, in this method, the phenomenon that the gel matrix aqueous solution "slides" at the interface of the layer of the water-soluble calcium salt was observed. Due to this sliding phenomenon, the application of the gel matrix aqueous solution becomes insufficient.

The present inventors have also studied a method for producing an alginate hydrous gel sheet having excellent mechanical strength.

In order to increase the mechanical strength, it is conceivable to insert a non-woven fabric as a core material in the alginate hydrous gel sheet. As a general method for inserting a non-woven fabric, there is a dipping and lifting method. However, in this method, tension is applied to the non-woven fabric to stretch the non-woven fabric, air bubbles are caught between fibers of the non-woven fabric to impair the appearance, and the impregnation amount of the gel matrix aqueous solution into the non-woven fabric is not constant, so that the quality is not stable. There is a problem. In addition, there is a problem that the device becomes large and it is difficult to remove a large amount of the solution adhering to the guide roll or the like and keep it clean at all times.

(Problems to be Solved by the Invention) The present invention is to solve the above problems, and an object of the present invention is to show high productivity and stable quality of alginate hydrate without requiring large equipment. It is to provide a method by which a gel sheet can be manufactured. Another object of the present invention is to provide a method capable of producing an alginate hydrogel sheet having excellent mechanical strength, high productivity without requiring large-scale equipment, and stable quality.

(Means for Solving the Problems) The method for producing an alginate hydrous gel sheet of the present invention comprises
First step of forming a gelling agent layer on the surface of a support by applying an aqueous solution containing a water-soluble calcium salt and methylcellulose; at least 0.3% by weight of alginate on the surface of the gelling agent layer. A second step of forming a gel matrix layer by casting an aqueous gel matrix solution containing
And a third step of applying a gelling agent containing a water-soluble calcium salt to the surface of the gel matrix layer, thereby achieving the above object.

A method for producing a core material-containing alginate hydrogel sheet according to the present invention comprises a fourth step of laminating a non-woven fabric on the surface of a gel matrix layer after the first step and the second step; the alginate on the surface of the non-woven fabric. Fifth step of forming a second gel matrix layer by casting an aqueous gel matrix solution containing: a gelling agent containing a water-soluble calcium salt as a main agent on the surface of the second gel matrix layer. The above object is achieved by including the sixth step of applying.

 Hereinafter, the present invention will be described in detail.

The support used in the first step has a flat surface suitable for coating, and for example, a liquid-impermeable plastic film, a metal flat belt, a glass plate or a metal plate is used. The PET film is preferable because it has tensile strength and strength so that the subsequent steps can be easily performed. The surface of the support is preferably hydrophilic so that the aqueous solution can be easily applied, and it is effective to perform corona discharge treatment after mat processing. An aqueous solution containing a water-soluble calcium salt and methylcellulose is applied to the surface of such a support and dried to form a gelling agent layer. The gelling agent layer is a layer containing a gelling agent that gels the gel base aqueous solution to be applied next. The coating amount of this aqueous solution is determined by the amount of the gel matrix aqueous solution cast in the second step. Theoretically, 0.25 mol (10 g) of calcium atoms is required per 100 g of alginate, but practically, it is sufficient to apply an amount such that calcium atoms are 4 to 100 g.

The content ratio of water-soluble calcium salt and methyl cellulose (water-soluble calcium salt: methyl cellulose) is 98: 2 ~
30:70 (weight ratio) is preferable, and 95: 5 to 50:50 is particularly preferable. When the content ratio of methyl cellulose is less than the above range, a sliding phenomenon occurs at the interface with the gel matrix layer. When the content ratio of methyl cellulose exceeds the above range, the gelation of the gel matrix layer is delayed, resulting in a decrease in productivity.
The viscosity of this aqueous solution is preferably 20 to 20000 cps.

Examples of the water-soluble calcium salt that is a gelling agent include calcium chloride, calcium nitrate, calcium acetate and the like, and calcium chloride is preferable from the viewpoint of safety and economy.

The methyl cellulose used in the present invention may be any water-soluble polymer containing 50% by weight or more of a methyl cellulose component. However, a polymer having a functional group capable of reacting with calcium ions such as a carboxyl group is
It cannot be used.

Then, on the surface of the gelling agent layer, a gel base aqueous solution containing at least 0.3% by weight of alginate is cast,
A gel matrix layer is formed (second step).

The concentration of alginate in the gel matrix aqueous solution is 0.3% by weight.
It is above, and preferably 0.3 to 20% by weight. When it is less than 0.3% by weight, the strength of the obtained gel becomes too low. When it exceeds 20% by weight, the viscosity of the gel base aqueous solution becomes high and coating is difficult. The intrinsic viscosity of the gel matrix aqueous solution is 1
20% to 1200 cps at room temperature in a gel matrix aqueous solution of wt%.

Examples of the alginate include sodium alginate, potassium alginate, ammonium alginate and the like, and sodium alginate is particularly preferably used.

The alginic acid used preferably has a ratio of mannuronic acid, which is a constituent of alginic acid, to guluronic acid (mannuronic acid / guluronic acid) of 0.4 to 3.0, more preferably 0.5 to 2.0.

In addition to alginate, various components may be mixed with the gel base aqueous solution, if necessary.

For example, polyethylene glycol, polypropylene glycol, poly (ethylene-propylene) glycol,
Plasticizers such as glycerin, diglycerin, polyglycerin, sorbit, reduced maltose; hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polypropylene glycol, pectin, arabic gum, guar gum, dextran, carboxymethyl cellulose, carboxymethylated Adhesion-enhancing components such as starch; steroid hormones, vasodilators, anti-inflammatory agents, anti-allergic agents, antihistamines, antibacterial agents, anti-inflammatory analgesics, analgesics and other medicinal ingredients; sodium chloride when used for skin electrodes, Conductive ingredients such as magnesium chloride and sodium salicylate; hyaluronic acid, collagen, loofah water, various skin moisturizers, various skin astringents, various vitamin agents, and other cosmetic effect promoting ingredients; preservatives such as methyl paraoxybenzoate Stabilizer; skin protectants; absorption enhancer; a variety of water-soluble non-toxic dye colorant such like; perfumes.
The amount of the plasticizer added is 0 to 2000 parts by weight per 100 parts by weight of alginate, and the amount of the tackiness enhancing component added is 0 to 100 parts by weight.

A gelling agent containing a water-soluble calcium salt is applied to the surface of the gel matrix layer formed by casting such a gel matrix aqueous solution (third step).

As the application method, a method of laminating a plastic film or sheet having a surface layer uniformly coated with a gelling agent; and an aqueous solution of the gelling agent so as to be uniform on the surface of the layer containing the gel matrix aqueous solution. , There is a method of directly spraying.

The gelling agent used here may be the same as or different from the gelling agent used in the first step.

The alginate hydrogel sheet thus obtained can be cut into a desired size to obtain a product.

Next, a method for producing an alginate hydrous gel sheet having excellent mechanical strength will be described.

After the first step and the second step, a nonwoven fabric is laminated on the surface of the gel matrix layer (fourth step).

The layer of the gel matrix aqueous solution obtained in the second step is the first gel matrix layer described in claim 2.

The nonwoven fabric used in the present invention is preferably lightweight, has high porosity, and has high elasticity in order to improve strength and elasticity without impairing the "suppleness" of the hydrogel sheet. Polyether polyurethane non-woven fabric is most suitable. The amount is preferably 100 g / m ² or less.

On the surface of this non-woven fabric, a gel base aqueous solution containing the same or different alginate as used in the second step is cast to form a second gel base layer (fifth step).

At this time, the viscosity of the gel matrix aqueous solution used is preferably 2000 cps or less so that air bubbles are not entrained.

Then, a gelling agent containing a water-soluble calcium salt is applied to the gel matrix aqueous solution to cause gelation (6th step).
By the process), an alginate-containing hydrogel sheet containing a core material is obtained.

As the method for applying the gelling agent, there are a method of using the support having the gelling agent layer formed in the first step and a method of spraying an aqueous solution of the gelling agent. The composition of the gelling agent and the addition amount thereof may be the same as or different from those in the first step. Methylcellulose is not particularly required because the slippage phenomenon does not occur in this step.

The alginate hydrated gel sheet or the alginate hydrated gel sheet containing the core material thus obtained may contain an active ingredient such as a drug. In that case, the water content is once reduced by drying the obtained alginate hydrogel sheet. After drying, apply an aqueous solution containing the active ingredient to one or both sides of this sheet,
It is attached by a method such as spraying, dipping, and transferring, and a protective film is laminated and left standing for a certain period of time to be integrated with the gel sheet. Another method may be such that another film coated with an aqueous solution containing an active ingredient is laminated on the gel sheet and left standing for a certain period of time to be integrated with the gel sheet.

The obtained alginate hydrous gel sheet or the alginate hydrous gel sheet containing a core material is cut into a predetermined size. Each cut sheet or a plurality of cut sheets are packaged as a unit to obtain a product. At this time, the support used in the first step and / or the third or sixth step may remain attached.

In the present invention, not only gelation of the gel matrix aqueous solution is achieved by the gelling agent, but also the gel matrix aqueous solution itself may be gelled. For example, when it is desired to increase the thickness of the gel matrix layer, gelation from the surface is not sufficient, so it is preferable to promote gelation also from inside the layer. In such a case, unlike the conventional case, strict conditions for adjusting the gelation rate and the like are not required for the composition of the base aqueous solution.

According to the production method of the present invention, since the alginate-containing aqueous solution is cast on the strong gelling agent layer, gelation occurs instantaneously at the interface, and then gelation proceeds inside the gel matrix aqueous solution layer. Therefore, the time until the gelation of the gel matrix aqueous solution is completed is short. In addition, since the gelling agent layer contains methyl cellulose, a part of the methyl cellulose molecule enters and the gel matrix aqueous solution instantly gels at the interface in a state where the anchor of the methyl cellulose molecule is driven. The anchoring effect of this methylcellulose can prevent the sliding phenomenon of the gel matrix aqueous solution.

Even when compared with the conventional method, since the step of eluting the active ingredient such as a drug is not included, the quality of the finally obtained product is stable. Also, no large-scale device or equipment is required for gelation.

Also, when preparing the alginate hydrous gel sheet containing the core material, there is no concern that air bubbles are involved as in the dipping method.

(Example) Hereinafter, the present invention will be described in detail based on examples.

Example 1 First step; <Supporting film (support)> The surface of a PET film having a thickness of 50 μm is matted and then subjected to corona discharge treatment to impart hydrophilicity to the surface of the film to support it. A supporting film as a body was obtained.

<Preparation and coating of aqueous solution for gelling agent layer> 28% calcium chloride aqueous solution and common count # 100 (2
% Aqueous solution of 5% methyl cellulose having a viscosity of 100 cps at 20 ° C. was mixed at a ratio of 41.7: 58.3 (weight ratio) to prepare an aqueous solution for a gelling agent layer. In this aqueous solution, the weight ratio of calcium chloride to methyl cellulose is 8:
Is 2. The concentration of solids in the aqueous solution was 14.6% by weight, of which the concentration of calcium chloride was 11.7% by weight.

The prepared aqueous solution for gelling agent layer was applied on the surface of the above-mentioned supporting film at 40 g / m ² and dried. On this coated surface, the solid content was 5.8 g / m ² , and the calcium chloride was 4.7 g / m ^2.
It is contained.

Second step: <Preparation of gel base aqueous solution> 3% sodium alginate (Kimitsu algin-I-5 manufactured by Kimitsu Chemical Industry Co .; 1% aqueous solution has a viscosity of 500 to 60 at 20 ° C).
0 cps) 100 parts by weight of aqueous solution, diglycerin 50 as a plasticizer
30 parts by weight of a 3% aqueous solution of polyvinylpyrrolidone (Kollidon-K-90 manufactured by BASF) as an adhesion promoter, 0.08 parts by weight of methyl paraoxybenzoate as a preservative, and 20 parts by weight of 10% diphenhydramine hydrochloride as a drug. The mixture was mixed to give an aqueous gel matrix solution.

This gel base aqueous solution was applied to the surface of the gelling agent layer prepared in the first step. The coating amount is 1 per 1 m ^{2 of} gelling agent layer.
It was 200g. The amount of sodium alginate was 18 g per 1 m ^{2 of the} gelling agent layer. No slippage phenomenon of the base solution was observed at the time of application.

Third step: After the second step, the third step was performed subsequently.

On the surface of the mother solution layer, a carrier film of the same type as that prepared in the first step was laminated.

When this was stored and aged for 3 hours or more, gelation proceeded throughout and a usable hydrous gel sheet was obtained. When it was stored and aged for 5 hours or more, it had a sufficiently practical strength. In this example, the amount of sodium alginate in the hydrous alginate gel sheet was 18 g / m ² and the amount of calcium chloride was 9.4 g / m ² (1.9 times the theoretical amount). The obtained sheet contains a medicinal component and is therefore useful as a medicated patch.

Example 2 First step; <Preparation of aqueous solution for gelling agent layer> A 35% calcium chloride aqueous solution and a 2% aqueous solution of methylcellulose having a common count of # 1500 were mixed at a ratio of 25:75 (weight ratio). Thus, an aqueous solution for gelling agent layer was prepared. In this aqueous solution, the weight ratio of calcium chloride to methyl cellulose was 85.4: 14.6. The concentration of solids in the aqueous solution is 10.3% by weight, of which the concentration of calcium chloride is 8.
It was 75% by weight.

The prepared gelling agent layer solution was applied on the surface of the carrier film prepared in Example 1 at a rate of 55 g / m ² and dried.
The coated surface contained 5.7 g / m ² as solid content and 4.8 g / m ² as calcium chloride.

Second step: <Preparation of gel base aqueous solution> 5% sodium alginate (Kimitsu algin G-1-H manufactured by Kimitsu Chemical Industry Co .; 1% aqueous solution has a viscosity of 500-
600 cps) aqueous solution 100 parts by weight, polyethylene glycol (polymerization degree 400) 60 parts by weight as a plasticizer, 3% polyacrylic acid (polymerization degree 1000) 3 parts by weight as an adhesion promoter, methyl paraoxybenzoate 0.1 parts by weight as a preservative , And 10 parts by weight of sodium chloride as an electrolyte were mixed to obtain a gel matrix aqueous solution. The concentration of sodium alginate in this solution was about 2.24% by weight.

This gel base aqueous solution was applied to the surface of the gelling agent layer prepared in the first step. The coating amount is 1 per 1 m ^{2 of} gelling agent layer.
It was 100 g. The amount of sodium alginate was 24.6 g per 1 m ^{2 of the} gelling agent layer. No slippage phenomenon of the base solution was observed at the time of application.

Third step: After the second step, the third step was performed subsequently.

The carrier film prepared in the first step was laminated on the surface of the mother solution layer.

When this was cut into a predetermined size and then aged for storage, gelation proceeded throughout. After 6 hours, it had a sufficiently practical strength. In this Example, the amount of sodium alginate in the alginate hydrous gel sheet was 24.6.
g / m ^2, calcium chloride amount is 9.6g / m ² (1.9 times the stoichiometric amount). The obtained sheet has electrical conductivity and is useful as a skin electrode for medical devices.

Example 3 First step; <Preparation of aqueous solution for gelling agent layer> 24 parts by weight of calcium chloride aqueous solution having a concentration of 25%, 66 parts by weight of 3% aqueous solution of methylcellulose having a common count of # 400, and 10% aqueous solution of polyvinylpyrrolidone 10 The parts by weight were mixed to prepare an aqueous solution for gelling agent layer. In this aqueous solution,
The weight ratio of calcium chloride to methyl cellulose is 75:25.
Is. The concentration of solids in the aqueous solution was 9%, of which the concentration of calcium chloride was 6%.

The prepared gelling agent layer solution was applied to the surface of the above-mentioned carrier film at a rate of 60 g / m ² and dried. This coated surface is
It contains 3.6 g / m ^{2 of} calcium chloride.

Second step; <Preparation of gel base aqueous solution> 50 parts by weight of 2% sodium alginate (Kimitsu algin-IS manufactured by Kimitsu Chemical Industry Co., Ltd.) aqueous solution, 50% by weight of 10% sodium alginate (Kimitsu algin-IL ₂ manufactured by Kimitsu Chemical Industry Co., Ltd.) aqueous solution Parts, 60 parts by weight of polypropylene glycol # 400 (Uniol D400 made by NOF CORPORATION) as a plasticizer, 0.1 part by weight of methyl paraoxybenzoate as a preservative, 5 parts by weight of natural hemima stock solution, 0.1 part by weight of sodium hyaluronate, and sodium glycyrrhizinate. 0.3 part by weight was mixed to obtain a gel matrix aqueous solution.

The concentration of sodium alginate in this gel matrix aqueous solution was about 3.6% by weight.

This gel base aqueous solution was applied to the surface of the gelling agent layer prepared in the first step. The coating amount is 8 per 1 m ^{2 of} gelling agent layer.
It is 00g. No slippage phenomenon of the base solution was observed at the time of application.

Third step: After the second step, the third step was performed subsequently.

A 10% calcium chloride aqueous solution as a gelling agent for spraying was sprayed onto the surface of the base solution layer at a rate of 40 g / m ² . Immediately after spraying, it was laminated so that the hydrophilic surface of the carrier film used in the first step was in contact with this surface.

When this was stored at room temperature for 2 hours, a hydrogel sheet having a sufficiently practical strength was obtained. In this example, the amount of calcium chloride in the alginate hydrous gel sheet is 0.95 times the theoretical amount. The obtained sheet is
It is useful as a cosmetic for face (packing agent).

Example 4 First step; Example 1 was formed on the surface of the carrier film prepared in Example 1.
The aqueous solution for gelling agent layer prepared in the above was applied at a rate of 55 g / m ² .
Dried. This coated surface is 6.4g as calcium chloride
/ m ² contained.

Second step: The gel matrix aqueous solution prepared in Example 1 was applied to the surface of the gelling agent layer prepared in the first step. The coating amount is 800 g per 1 m ^{2 of the} gelling agent layer. The amount of sodium alginate is 12 g per 1 m ^{2 of the} gelling agent layer. No slippage phenomenon of the base solution was observed at the time of application.

Fourth step: After the second step, the fourth step was performed subsequently.

As the core material, a polyether polyurethane non-woven fabric (density: 40 g / m ² , diameter of one fiber; average 10 microns) was used. The stretch ratio of this non-woven fabric up to breaking is 1000% or more in both the vertical and horizontal directions.

This non-woven fabric was laminated on the surface of the base solution layer after the second step without applying tension to the non-woven fabric. The laminating speed at this time was 50 cm / min. One third of the non-woven fabric sank into the matrix solution layer. At this time, no entanglement of bubbles that could be visually discerned occurred.

Fifth step: The aqueous solution of the gel matrix used in the second step was applied to the surface of the non-woven fabric so as to have a concentration of 800 g / m ² . The coating speed was 50 cm / min.

Sixth step: The film obtained in the first step was laminated on the surface of this gel matrix aqueous solution so that the gelling agent layer formed on the film was in close contact. The laminating speed at this time was 50 cm / min.

When this was stored and aged at room temperature for 3 hours or more, gelation proceeded throughout and a hydrogel sheet having a usable strength was obtained. In this example, the amount of calcium chloride in the alginate hydrous gel sheet is 1.9 times the theoretical amount. The obtained sheet contains a medicinal component and is therefore useful as a medicated patch.

Even when 10 gel sheets were stacked and stored and aged, the sheets did not flow or deform. In addition, the tensile strength was increased to 5 times or more by laminating the nonwoven fabrics, and the flexibility was not changed by laminating the nonwoven fabrics.

(Effect of the invention) As described above, according to the present invention, due to the anchoring effect of methylcellulose contained in the gelling agent layer, in the step of casting the gel matrix aqueous solution, the matrix aqueous solution slides on the surface of the gelling agent layer. And the application of the aqueous base solution can be performed satisfactorily. Therefore, since gelation proceeds efficiently from the interface,
The gelation time of the gel matrix aqueous solution is shortened and the production efficiency is high. In addition, since the active ingredients such as drugs are not eluted, the quality of the obtained gel sheet is stable.

Further, according to the present invention, a core material can be inserted without entraining air bubbles, and a gel sheet having deformation resistance can be obtained.

Claims (2)

[Claims] 1. A step of forming a gelling agent layer by applying an aqueous solution containing a water-soluble calcium salt and methylcellulose onto the surface of a support, wherein the surface of the gelling agent layer contains at least 0.3% by weight. A step of casting a gel matrix aqueous solution containing an alginate to form a gel matrix layer, and a step of applying a gelling agent containing a water-soluble calcium salt to the surface of the gel matrix layer, Method for producing hydrogel sheet. 2. A step of forming a gelling agent layer by applying an aqueous solution containing a water-soluble calcium salt and methylcellulose onto the surface of a support, wherein the surface of the gelling agent layer contains at least 0.3% by weight. A step of casting an aqueous gel matrix solution containing alginate to form a first gel matrix layer, laminating a nonwoven fabric on the surface of the first gel matrix layer, and containing the alginate on the surface of the nonwoven fabric Forming a second gel matrix layer by casting an aqueous gel matrix solution, and applying a gelling agent containing a water-soluble calcium salt to the surface of the second gel matrix layer. A method for producing a hydrous gel sheet of alginate included.