JP2024096496A - Aqueous patch - Google Patents

Abstract

To provide an aqueous patch with a small amount of ointment applied thereto, which excellently retains adhesion in use and prevents the ointment from striking through a substrate during manufacture or storage even when a thin nonwoven fabric without a film or the like laminated is used as the substrate.SOLUTION: A low water content ointment whose water content is 25-45 wt.% contains, as ointment components, water-soluble polymers of 10-20 wt.%, and polyalcohols of 20-50 wt.%, where the polyalcohols at least include glycerin of 10-40 wt.%. An aqueous patch is obtained by applying the low water content ointment to a substrate having a thickness of 0.4-0.7 mm (a mass per unit area of 80-110 g/m2), in an applied amount in the range of 300-600 g/m2.SELECTED DRAWING: Figure 1

Description

The present invention relates to an aqueous patch that requires a small amount of coating, does not show through of the paste during storage, and maintains good adhesive strength during use, even when a thin support is used.

In general, patches with a thinner thickness are preferred because they are less likely to get tangled with clothing and have a better feel when used. For this reason, efforts are being made to reduce the amount of plaster applied as much as possible, to make the plaster layer thinner, and also to make the support thinner, thereby reducing both thicknesses.
However, in the case of aqueous patches such as poultices, the paste that serves as the patch base is kept in a highly fluid state until it is crosslinked, which means that the paste seeps out to the back of the support, causing problems such as sticky hands when applied, and the patch preparation is prone to sticking to the inside of the packaging bag during storage.
Furthermore, there is a problem in that the adhesiveness decreases if the paste sinks too deeply into the support.

Therefore, when considering thin aqueous patches, the use of a support laminated with a film to prevent the paste from bleeding through the support has been considered (e.g., Patent Documents 1 and 2).
However, even in this case, laminating a film layer onto a support such as a commonly used nonwoven fabric reduces the patch's ability to conform to the skin, and the skin at the application site becomes steamy due to the lamination of the film, and furthermore, there are problems such as increased manufacturing costs.

JP 2001-213768 A JP 2005-224981 A

In view of the above-mentioned current situation, the present invention aims to provide an aqueous patch that requires a small amount of application of the paste, and that does not allow the paste to bleed through the support during production or storage, even when a thin nonwoven fabric that is not laminated with a film or the like is used as the support, and that maintains good adhesive strength during use.

As a result of intensive research conducted by the present inventors to solve these problems, they have discovered that an aqueous patch that can solve the above problems can be obtained by reducing the amount of water contained in the plaster of an aqueous patch, using specific amounts of both a water-soluble polymer and a polyhydric alcohol as plaster base components, preparing a plaster with a low water content that contains a specific amount of glycerin as at least one of the polyhydric alcohols, and applying this plaster to a thin support that is not laminated with a film or the like, thereby completing the present invention.

Thus, the basic aspect of the present invention is
(1) An aqueous patch comprising a low-water content paste having a water content of 25 to 45% by weight, the paste components of which include 10 to 20% by weight of a water-soluble polymer and 20 to 50% by weight of a polyhydric alcohol, and which also contains 10 to 40% by weight of at least glycerin as one type of polyhydric alcohol, and which is applied to a support having a thickness of 0.4 to 0.7 mm (basis weight: 80 to 110 g/m ² ) in a coating amount of 300 to 600 g/m ² ;
It is.

More specifically, the present invention relates to
(2) The aqueous patch according to the above (1), wherein the water-soluble polymer is one or more selected from gelatin, agar, pullulan, various gums (xanthan gum, gum arabic, locust bean gum, etc.), carmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, sodium polyacrylate, partially neutralized polyacrylic acid, polyacrylic acid, polyvinyl alcohol, and polyvinylpyrrolidone;
(3) The aqueous patch according to the above (1), wherein the other polyhydric alcohol is one or more selected from D-sorbitol solution, propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, polyethylene glycol, polypropylene glycol, and 1,3-butanediol;
(4) The aqueous patch according to any one of the above (1) to (3), further comprising a medicinal ingredient in the paste;
(5) The aqueous patch according to the above (4), wherein the medicinal ingredient is selected from the group consisting of loxoprofen sodium, ketoprofen, flurbiprofen, ibuprofen, zaltoprofen, fenbufen, pranoprofen, piroxicam, meloxicam, felbinac, mefenamic acid, indomethacin, and diclofenac sodium;
It is.

According to the present invention, a thin aqueous patch can be provided which uses a thin nonwoven fabric that is not laminated with a film or the like as a support and which has a small amount of applied paste, and which is free from bleed-through of the paste onto the support during production and storage, and which further maintains excellent adhesive strength.
Therefore, the aqueous patch of the present invention, which contains medicinal ingredients such as anti-inflammatory and analgesic agents in the plaster base, is an aqueous patch that combines excellent percutaneous absorption, stability, and high storage stability, and is extremely effective.

1 is a graph showing the results of an in vitro skin permeability test in Experimental Example 4.

As described above, a basic aspect of the present invention is an aqueous patch comprising a low-water content paste having a water content of 25 to 45% by weight, the paste components of which include 10 to 20% by weight of a water-soluble polymer and 20 to 50% by weight of a polyhydric alcohol, and which contains at least 10 to 40% by weight of glycerin as one type of polyhydric alcohol, and which is applied to a support having a thickness of 0.4 to 0.7 mm (basis weight: 80 to 110 g/ ^m2 ) in a coating amount of 300 to 600 g/ ^m2 .

In the aqueous patch provided by the present invention, examples of the water-soluble polymer used as the main component, which is a base component constituting the plaster, include natural polymers such as gelatin, agar, pullulan, various gums (xanthan gum, gum arabic, locust bean gum, etc.), semi-synthetic polymers such as carmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, etc., and synthetic polymers such as sodium polyacrylate, carboxyvinyl polymer, partially neutralized polyacrylic acid, polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, etc.
These water-soluble polymers can be used alone or in combination of two or more kinds.

The content of the water-soluble polymer in the paste composition is 10 to 20% by weight, and more preferably 10 to 15% by weight.
If the blending amount of the water-soluble polymer is less than 10% by weight, the viscosity of the paste will be too low, making it difficult to mold it into a patch.
If the content exceeds 20% by weight, the viscosity of the paste becomes too high, resulting in poor workability in the process of spreading the paste.

In the aqueous patch provided by the present invention, examples of polyhydric alcohols that are blended as the main component, which is another base component that constitutes the plaster, include glycerin, D-sorbitol solution, propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, polyethylene glycol, polypropylene glycol, 1,3-butanediol, etc., of which D-sorbitol solution, propylene glycol, polyethylene glycol, and glycerin are particularly preferred.

It is important to use a suitable combination of a plurality of the above-mentioned polyhydric alcohols as these polyhydric alcohols, and among these, it is necessary to use glycerin as one type of polyhydric alcohol.
Glycerin is an essential component for maintaining the physical properties of the plaster, and concentrated glycerin as specified in the Japanese Pharmacopoeia is usually used as the glycerin.

The amount of polyhydric alcohol used is 20 to 50% by weight, preferably 30 to 45% by weight.
If the blending amount of the polyhydric alcohol exceeds 50% by weight, the viscosity of the base increases, which undesirably deteriorates workability during production.
Furthermore, if the blending amount of polyhydric alcohol is less than 20% by weight, the basic properties of the patch, such as adhesiveness, shape retention, heat resistance, etc., will deteriorate, which is not preferable.

The amount of glycerin, which is an essential component of the polyhydric alcohol, is preferably in the range of 10 to 40% by weight in order to maintain the physical properties of the paste. It is also preferable that 20% or more of the polyhydric alcohol is glycerin.
If the amount of glycerin as a polyhydric alcohol is less than 10% by weight, the physical properties of the paste cannot be maintained, which may cause the paste to bleed through the support, whereas if it exceeds 40% by weight, there is a concern that it may affect the stability of the drug contained, which is not preferable.

The aqueous patch provided by the present invention is therefore characterized in that it contains 10-20% by weight of a water-soluble polymer and 20-50% by weight of a polyhydric alcohol as base components, and also contains at least 10-40% by weight of glycerin as one type of polyhydric alcohol, and this characteristic allows the desired adhesiveness, shape retention, heat resistance, etc. of the aqueous patch to be maintained.

In the aqueous patch provided by the present invention, examples of the crosslinking agent that crosslinks the water-soluble polymer include ordinary polyvalent metal salts. Specific examples include aluminum chloride, aluminum sulfate, potassium aluminum sulfate, aluminum ammonium sulfate, aluminum hydroxide gel, synthetic hydrotalcite, magnesium aluminometasilicate, and dihydroxyaluminum aminoacetate, with magnesium aluminometasilicate and dihydroxyaluminum aminoacetate being preferred.

These crosslinking agents can be used alone or in combination. The amount of crosslinking agent used varies depending on the type of agent, but is preferably 0.02 to 0.4% by weight. More preferably, it is 0.04 to 0.2% by weight.

Another feature of the aqueous patch provided by the present invention is that the amount of water contained in the paste base during preparation is reduced.
The amount of water to be added is 25 to 45% by weight, more preferably 30 to 40% by weight, based on the weight of the paste.
If the water content exceeds 45% by weight, the viscosity of the paste decreases, causing a deterioration in shape retention, stickiness of the paste, and strike-through. Also, the adhesive strength decreases significantly, making it difficult to obtain sufficient adhesion to the application site, which is undesirable.
If the water content is less than 25% by weight, the viscosity of the paste will be too high, resulting in poor workability in the spreading step.

The aqueous patch provided by the present invention can also contain medicinal ingredients. Examples of medicinal ingredients that can be contained in the aqueous patch of the present invention include, but are not limited to, anti-inflammatory analgesics such as loxoprofen sodium, ketoprofen, flurbiprofen, ibuprofen, zaltoprofen, fenbufen, pranoprofen, piroxicam, meloxicam, felbinac, mefenamic acid, indomethacin, and diclofenac sodium, diphenhydramine, methyl salicylate, glycol salicylate, dibucaine, procaine, oxybuprocaine, lidocaine, glycyrrhetinic acid, betamethasone valerate, hydrocortisone acetate, dexamethasone acetate, deprodone propionate, cloconazole hydrochloride, lanoconazole, oxiconazole, miconazole nitrate, and isoconazole nitrate, as needed. The medicinal ingredients may be used alone or in combination of two or more kinds.

In addition, the aqueous patch provided by the present invention may contain, as necessary, excipients such as kaolin, titanium oxide, silicic anhydride, zinc oxide, and bentonite; stabilizers such as edetate, tartaric acid, citric acid, sodium bisulfite, and diisopropanolamine; antioxidants such as tocopherol acetate, ascorbic acid, butylhydroxytoluene, and tocopherol; refreshing agents such as L-menthol, peppermint oil, and dl-camphor; substances derived from chili pepper such as chili powder and chili pepper extract, capsaicin, dihydroxycapsaicin, and the like. Capsaicin analogues such as capsaicin and capsinoids, warming stimulants such as vanillylamide nonylate and benzyl nicotinate; preservatives such as methylparaben and propylparaben; plasticizers such as fatty acid esters, crotamiton, and vegetable oils; surfactants such as polyglycerin fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, propylene glycol fatty acid esters, sorbitan monooleate, and oleyl ether can be blended in appropriate amounts.

Another feature of the aqueous patch provided by the present invention is that it uses a thin support that is not laminated with a film or the like.
That is, the support used in the aqueous patch provided by the present invention is desirably thin and highly flexible so as to follow the movement of the body, in order to prevent the patch preparation from peeling off after application.
The nonwoven fabric used as the support has elasticity, and is preferably a nonwoven fabric having a longitudinal and/or transverse elongation rate of 100% or more.

The fiber material of such nonwoven fabrics may be polyethylene, polypropylene, rayon, polyester, nylon, polyamide, polyurethane, etc. Manufacturing methods include needle punching, hydroentanglement (spunlace), thermal bonding, chemical bonding, spunbonding, and meltblown, but nonwoven fabrics manufactured by the spunlace method are particularly preferred from the viewpoint of preventing bleeding of the paste.

The nonwoven fabric used in the present invention as a thin support is preferably a nonwoven fabric having a thickness of 0.4 to 0.7 mm and a basis weight of 80 to 110 g/ ^m2 .
As such a support, for example, a patch fabric manufactured by Japan Vilene Co., Ltd. can be used.

As the plastic film, which is a release film that covers the surface of the paste applied to the support, polyethylene, polypropylene, polyester, or polyvinyl chloride can be used alone or in combination, and further, those whose surfaces have been subjected to silicone treatment, corona discharge treatment, roughening treatment, plasma treatment, etc. can also be used.

In the present invention, the paste is preferably applied thinly in order to reduce the overall thickness of the aqueous patch, and the amount of the paste to be applied is preferably about 300 to 600 g/ ^m2 .

The method for producing the aqueous patch provided by the present invention is not particularly limited, and the patch can be produced according to any method known in the art.
For example, an aqueous patch can be formed by spreading a patch base composed of the above-mentioned base components on a support and covering the surface of the aqueous base with a plastic film.

The present invention will be explained in more detail below with reference to examples, comparative examples, and test examples, but the present invention is not limited to these.

Examples 1 to 4: (Ketoprofen-containing/low water content aqueous patch)
Based on the formulation (wt %) shown in Table 1 below, additives were uniformly mixed to prepare a paste base, which was then spread onto a support (spunlace nonwoven fabric; thickness: 0.5-0.6 mm/basis weight: 100 g/ ^m2 ) so that the coating amount of the paste was 430 g/ ^m2 . The surface of the paste base was covered with a plastic film, and the resulting patch was cut into a rectangle measuring 10 cm x 14 cm to prepare an aqueous patch with low water content of the present invention.

Comparative Examples 1 to 3: (Ketoprofen-containing aqueous patches)
Based on the formulation (wt %) shown in Table 2 below, additives were uniformly mixed to prepare a paste base, which was then spread onto a support (spunlace nonwoven fabric; thickness: 0.5-0.6 mm/basis weight: 100 g/ ^m2 ) so that the coating amount of the paste was 430 g/ ^m2 . The surface of the paste base was covered with a plastic film, and the resulting patch was cut into a rectangle of 10 cm x 14 cm to prepare an aqueous patch for comparison.

In addition, as Examples 5 and 6, aqueous patches with low water content of the present invention containing the active ingredients flurbiprofen and felbinac were prepared in a similar manner.

Experimental Example 1: Investigation into the Presence or Absence of Bleed-Through of Paste to the Backing The patch preparations of each of the Examples and Comparative Examples in which the paste was spread on a nonwoven fabric were observed for the presence or absence of bleed-through of the paste to the backing during storage.
The bleed-through of the paste to the backing was visually examined after storing the test patch preparations at room temperature for one week after production.
The results are shown in Table 3 below.

Experimental Example 2: Adhesion Test Inclined Ball Tack Method In order to examine the adhesive strength of the paste of each of the patch preparations of the Examples and Comparative Examples, an adhesive strength test was carried out using the inclined ball tack method according to the Japanese Pharmacopoeia.
The patch was placed with the adhesive side facing up on an inclined acrylic plate at an angle of 30 degrees to the horizontal, and the top 10 cm and bottom 15 cm were covered with suitable paper, leaving a 5 cm wide adhesive surface in the middle. A series of steel balls with diameters ranging from 3.2 mm to 18.3 mm were rolled from the top of the inclined surface to determine the maximum ball number that could be stopped by the adhesive surface in the center.
If the ball number is No. 10 or more, the adhesive strength is good.
The results are shown in Table 4 below.

The adhesive strength of the patches of Examples 1 to 4 (active ingredient: ketoprofen), Example 5 (active ingredient: flurbiprofen) and Example 6 (active ingredient: felbinac) was good, whereas the adhesive strength of the patches of Comparative Examples 1 to 3 was significantly lower than that of the preparations of the Examples.

Experimental Example 3: Investigation of the water content, polyhydric alcohol, glycerin and water-soluble polymer contents in the adhesive base of the patches of each Example and Comparative Example, and their effects on shape retention, etc. Tables 5 and 6 below show a comparison of the water content, blended amount of polyhydric alcohol/concentrated glycerin and water-soluble polymer content in the patches of each Example and Comparative Example.

Underlined: Outside the range of the compounding amounts specified in this invention

The patches of each Example and Test Example were visually examined for the presence or absence of bleed-through of the plaster onto the support and the shape retention of the plaster on the support after storage for one week after manufacture, and the results are shown in Tables 5 and 6.

Each of the patches of Examples 1 to 4 (active ingredient: ketoprofen), Example 5 (active ingredient: flurbiprofen) and Example 6 (active ingredient: felbinac) is a paste having the basic aspect of the present invention.
○: Water-soluble polymer is 10 to 20% by weight,
○: Contains 20 to 50% by weight of polyhydric alcohol, and
○: Contains 10 to 40% by weight of glycerin (concentrated glycerin);
○: A paste having a low moisture content of 25 to 45% by weight.
The above requirements are satisfied, and the plaster body does not bleed through to the support, does not run, and has good shape retention.

In contrast, the patch of Comparative Example 1 is a high water content paste in which the water content exceeds the 25 to 45 weight % specified in the present invention, and furthermore, the amount of polyhydric alcohol blended is outside the range of 20 to 50 weight % of the present invention.
Furthermore, in the patch of Comparative Example 2, the blend amount of the water-soluble polymer is outside the range of 10 to 20% by weight of the present invention, and in Comparative Example 3, the blend amount of glycerin is outside the range of 10 to 40% by weight of the present invention.
As a result, in the patches of Comparative Examples 1 to 3, bleed-through of the paste to the backing was observed, and further the shape retention of the paste was poor, resulting in sagging.

Experimental Example 4: In vitro skin permeability test For the patches of Example 1 and Comparative Example 1 based on the formulations shown in Tables 1 and 2, an in vitro skin permeability test was carried out using hairless rat skin.

Methods
The flank skin of a male rat (HWY, 8 weeks old) was fixed to a vertical diffusion cell for permeation testing, which was kept at 37°C, and the preparation to be tested was applied to the stratum corneum side of the excised skin, and 10 mL of phosphate buffered saline (PBS) was added to the inside (dermis layer side) as a receiver liquid. After that, 0.2 mL of the receiver liquid was collected over time, and the amount of ketoprofen permeated was measured by liquid chromatography, and the cumulative amount of permeation (μg/ ^cm2 ) was calculated.

<Results>
The experiment was performed using 4 animals per group, and the average cumulative permeation amount (μg/cm ² ) of ketoprofen at 4, 6, 8, 22 and 24 hours after the start of the test is shown in Table 7 below, and the change in the cumulative permeation amount over time is shown in FIG.

As can be seen from the results shown in the table and the figure, the aqueous patch of Example 1, which is a formulation of the present invention, was a patch that exhibited significantly higher skin permeability than the aqueous patch of Comparative Example 1.

Judging from the above results, it can be seen that the specific paste of the present invention, i.e., the above-mentioned paste having a low water content, when prepared into a patch using as a support a thin nonwoven fabric not laminated with a film or the like, will result in an aqueous patch which does not suffer from bleed-through of the paste from the support during production or storage and which maintains good adhesive strength during use.
It is also found that the skin permeability of the contained drug is extremely good.

Other formulation examples of the formulation of the present invention are shown below in Tables 8 and 9. However, the present invention is not limited to these.

As described above, according to the present invention, a thin aqueous patch is provided which uses a thin nonwoven fabric that is not laminated with a film or the like as a support and which has a small amount of applied paste, and which is free from bleed-through of the paste onto the support during production and storage and which further maintains excellent adhesive strength.
Therefore, the aqueous patch of the present invention containing a medicinal ingredient such as an anti-inflammatory analgesic is an aqueous patch that combines excellent transdermal absorbability, stability, and high storage stability, and has great industrial applicability.

Claims (5)

The aqueous patch is characterized in that the aqueous patch contains, as its base components, 10-20% by weight of a water-soluble polymer including an acrylic polymer, 20-50% by weight of a polyhydric alcohol, and also contains 10-40% by weight of at least glycerin as a type of polyhydric alcohol and a crosslinking agent, and is coated in an amount of 300-600 g/ ^m2 on a support having a thickness of 0.4-0.7 mm and a basis weight of 80-110 g/ ^m2 , and has an adhesive strength of ball number (No.) 10 or more as measured by "3.2 Inclined Ball Tack Test" of "General Test 6.12 Adhesion Test" in the Japanese Pharmacopoeia, wherein the acrylic polymer is one or more selected from sodium polyacrylate, partially neutralized polyacrylic acid, and polyacrylic acid. The aqueous patch according to claim 1, wherein the water-soluble polymer other than the acrylic polymer is one or more selected from gelatin, agar, pullulan, various gums, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, polyvinyl alcohol, and polyvinylpyrrolidone. The aqueous patch according to claim 1, wherein the other polyhydric alcohol is one or more selected from D-sorbitol solution, propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, polyethylene glycol, polypropylene glycol, and 1,3-butanediol. The aqueous patch according to any one of claims 1 to 3, further comprising a medicinal ingredient in the paste. The aqueous patch according to claim 4, wherein the active ingredient is selected from the group consisting of loxoprofen sodium, ketoprofen, flurbiprofen, ibuprofen, zaltoprofen, fenbufen, pranoprofen, piroxicam, meloxicam, felbinac, mefenamic acid, indomethacin, and diclofenac sodium.

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