JP4585909B2 - Film preparation and method for producing the same - Google Patents

Description

  The present invention relates to a gel-like sheet used for cosmetics, pharmaceuticals, and other applications, and particularly to a cosmetic sheet or a transdermally absorbable preparation used by adhering to the skin.

Conventionally, a gel sheet mainly composed of agar or the like is known. In these, agar as a gel-forming component forms a network structure in water and is used for the purpose of retaining water. However, gel sheets made from agar may be insufficient in strength. In addition, there is a limit to including an oily medicinal component in such a gel sheet.
In addition, the acrylic polymer gel is concerned about the toxicity of the remaining monomer, and is desired to be less irritating to the skin. In addition, there is a problem that a cross-linking agent is often required and manufacturing takes time, and this gel has a limit to contain an oily medicinal component.

On the other hand, many beauty sheets to be applied to the face, hands, and other skins are prepared by blending a water retaining agent and a polymer for supporting the same or a component containing the water retaining agent on the sheet. For example, Patent Document 1 discloses a moisturizing beauty sheet in which a fiber sheet carries a moisturizing agent such as hyaluronic acid or collagen. Patent Document 2 discloses a beauty pack made of chitosan and medium paste, and Patent Document 3 discloses a moisturizing mask that does not contain collagen crosslinked with a cationic biopolymer.
These are generally used by impregnating a water-soluble agent mainly in a paper-like sheet shape, but there are many cases in which the water-holding power is insufficient and the paper-like sheet is uncomfortable. Also, gel-like polymers have been improved in adhesion to the skin, but are not yet sufficient. Furthermore, there is a drawback that it takes time to manufacture such as using a crosslinking agent.

  With respect to these problems, in Patent Document 2, a cellulose ether gel-like sheet having a low degree of molar substitution does not have a monomer problem such as an acrylic polymer, and it takes time to produce a cross-linking agent. It is disclosed that a sheet can be obtained that has sufficient moisture retention and does not cause a sense of incongruity. However, when such a sheet adheres to a living body, the agent such as a moisturizing agent, an anti-wrinkle agent, an anti-smudge agent, and a whitening effect agent to be impregnated will be peeled off before the agent starts to act, There was a problem that the adhesiveness of 60 minutes or more required for the action could not be maintained, and the skin adhesion was poor. Moreover, in order to prepare the water-containing sheet of the low-substituted cellulose ether, after casting an alkaline solution of the low-substituted cellulose ether on the base plate, the sheet is neutralized and solidified with an acid, and the neutralization in the sheet is performed. It can be produced by washing the salt. However, in order to prepare a sheet containing a medicinal component, there is a method of impregnating by adding a medicinal component when making an alkaline solution in advance or by immersing it in a liquid containing the medicinal component after making it into a sheet, For medicinal substances, there are problems such as decomposition with an alkaline solution, inability to dissolve, and even if impregnated with a sheet of an aqueous medicinal component, a sufficient amount cannot be supported in the sheet. There was a problem that an immiscible oily substance could not be carried at the time.

  In order to improve skin adhesion, an alkaline solution of low-substituted cellulose ether and a mixed solution of water-soluble and alkali-soluble cellulose ether having a substitution degree of 1.1 to 1.4 are placed on the base plate. After casting, the sheet is neutralized and solidified with an acid, and the neutralized salt in the sheet is washed to prepare a hydrogel sheet with improved skin adhesion. Since the water-soluble cellulose ether partially melts in the washing step for removing water and the strength of the water-containing sheet is lowered, a water-containing sheet containing a high proportion of the water-soluble cellulose ether could not be produced. The greater the content of this water-soluble cellulose ether, the better the skin adhesion, so the skin adhesion of the obtained sheet was not sufficient.

  Moreover, as for a percutaneous absorption preparation, Patent Document 5 discloses a nicotine-containing film preparation. Patent Document 6 discloses a skin adhesive film preparation in which water-soluble cellulose lower alkyl ether is blended with fibroblast growth factor. Patent Document 7 discloses a mucoadhesive multilayer film preparation having a water-soluble polymer layer containing a drug and an adhesive layer containing an adhesive substance, both of which contain a low-substituted cellulose ether. It is not related to the water-containing sheet.

JP-A-9-238738 Japanese Patent Laid-Open No. 6-48917 JP-T-2001-502678 Japanese Patent Laid-Open No. 2003-300852 JP 2003-95947 A JP-A-7-82171 JP-A-9-235220

  The present invention has been made in view of the above circumstances, and is intended to provide a water-containing gel-like sheet that is a polymer that is not harmful to a living body and that has high adhesion to the skin. An object of the present invention is to provide a water-containing gel-like sheet having high adhesion to the skin.

As a result of intensive studies to achieve the above object, the present inventor has found that a low-substituted cellulose ether having a substitution mole number per drug and anhydroglucose unit (C ₆ H ₁₀ O ₅ ) of 0.05 to 1.0. A film preparation containing a drug in an arbitrary blending amount is obtained by casting a mixture of a wet wet grind and an aqueous solution of a water-soluble cellulose ether on a base plate and drying it. The present inventors have found that a water-containing sheet having excellent skin adhesiveness can be produced simply by moistening with a solution, and the present invention has been completed.
That is, the present invention includes a wet milled product of low-substituted cellulose ether having a substitution mole number per drug and anhydroglucose unit of 0.05 to 1.0 and a water-soluble cellulose ether, and has a skin adhesion time of 100. Provided is a film preparation having a thickness of at least 5 minutes, and a skin-adhesive water-containing sheet obtained by wetting the film preparation.
The present invention also provides a mixture of a wet ground product of a low-substituted cellulose ether having a substitution mole number per drug and anhydroglucose unit of 0.05 to 1.0 and an aqueous solution of a water-soluble cellulose ether on a base plate. And a method for producing a film preparation comprising drying the same.

  A film preparation containing the drug according to the present invention in any proportion, excellent in water retention, excellent in sheet strength and elasticity when containing water, and excellent in adhesion to the skin and feeling in use can be obtained. Furthermore, a skin-adhesive water-containing sheet containing an oily substance is obtained.

Hereinafter, the present invention will be described in more detail.
In the present invention, the low-substituted cellulose ether does not dissolve in water but dissolves in an alkaline solution. In general, cellulose is insoluble in water. However, when a hydrogen atom of a hydroxyl group of a glucose ring constituting cellulose is substituted with an alkyl group or a hydroxyalkyl group, it becomes water-soluble depending on the degree of substitution. However, those with a low degree of substitution are not soluble in water, and instead have a property of dissolving in an alkaline solution. In many cases, when the low-substituted cellulose ether powder is dispersed in water, a part of the powder becomes swollen. When the degree of molar substitution increases, it becomes water-soluble, and conversely loses its ability to dissolve in alkali.

  The molar substitution degree of the main thing of the low substituted cellulose ether which does not melt | dissolve in the water used by this invention but dissolves in an alkali is 0.05-1.0. As examples of various low-substituted cellulose ethers (the parentheses indicate molar substitution degrees), low-substituted methylcellulose having 3 to 15% by mass (0.16 to 0.85) methoxyl groups, and 3 to 15 hydroxyethoxyl groups. Low substituted hydroxyethyl cellulose having a mass% (0.08 to 0.45), low substituted hydroxypropyl cellulose having a hydroxypropoxyl group of 4 to 20% by mass (0.09 to 0.51), and a methoxyl group of 3 Examples include low-substituted hydroxypropylmethylcellulose having 12% by mass and 4 to 20% by mass of hydroxypropoxyl group (0.25 to 1.0 in combination of both substituents). The degree of substitution of cellulose ether can be measured based on the Japanese Pharmacopoeia.

  Such a low-substituted cellulose ether is insoluble in water but dissolves in an aqueous alkali solution and has the property of absorbing water and swelling. A more typical example is low-substituted hydroxypropylcellulose, which is currently marketed under the trade name of low-substituted hydroxypropylcellulose by Shin-Etsu Chemical Co., Ltd. It is widely used as a disintegrant blended in tablets in the material field.

  Methods for producing these low-substituted cellulose ethers are known. For example, as described in JP-A-57-53100, alkali cellulose must first be prepared. This can be done by either immersing a pulp sheet as a starting material in an alkaline aqueous solution such as caustic soda or by pulverizing pulp mixed with an alkaline solution as it is or after dispersing pulp powder in an organic solvent. It is prepared by adding alkali or the like. Next, when alkali cellulose is charged into a reactor and an etherifying agent such as propylene oxide or ethylene oxide is added and then reacted by heating, cellulose ether is obtained. After completion of the reaction, the crude cellulose ether is transferred to another tank, the alkali is neutralized with an acid, and the resulting solid is washed, dried and pulverized to obtain a final product as a powder. Alternatively, the crude cellulose ether immediately after the reaction may be completely dissolved or partially dissolved in water and then neutralized, and the precipitated polymer may be collected, washed, dried and pulverized.

In the method for producing a film preparation according to the present invention, a mixed solution of a wet milled product of a low-substituted cellulose ether having a substitution mole number per unit of anhydroglucose of 0.05 to 1.0 and an aqueous solution of a water-soluble cellulose ether. Can be cast on a base plate and dried. This low-substituted cellulose ether wet ground product is obtained by grinding an aqueous dispersion of a low-substituted cellulose ether using a wet pulverizer.
The low-substituted cellulose ether does not require a special stirrer, and can be obtained as an aqueous dispersion by charging the low-substituted cellulose ether into water or adding water into the low-substituted cellulose ether to swell and absorb water. it can. Alternatively, low-substitution cellulose ether and water may be charged into a wet pulverizer and directly wet pulverized.
Examples of the wet pulverizer include a vibrating ball mill, a colloid mill, a homomixer, a propeller homogenizer, a high pressure homogenizer, an ultrasonic homogenizer, a stone mortar wet pulverizer, and the like. For example, Sugino Machine Artemizer, Yoshida Machine Nanomizer, Mizuho Kogyo Microfluidizer, etc.) are advantageous for producing a uniform ground product. The treatment pressure varies depending on the material, but is generally preferably 100 to 250 MPa. If it is less than 100 MPa, it is not well dispersed, and if it exceeds 250 MPa, it may be mechanically difficult to process.

  Further, as disclosed in JP-A No. 2002-204951, an aqueous solution of a low-substituted cellulose ether is uniformly dispersed by adding an acid to the alkali solution of a low-substituted cellulose ether with a high-speed stirrer while mixing with an alkaline solution. There is a method for obtaining a wet ground product of liquid. In this method, there is also an embodiment in which an acid is added to an alkali solution of a low-substituted cellulose ether to produce a neutralized precipitated gel, which is washed with hot water and then wet-ground.

Furthermore, the alkali solution of the low-substituted cellulose ether described above dissolves the crude cellulose ether containing alkali in water immediately after the reaction, even if the low-substituted cellulose ether powder once made into the final product is dissolved in an alkaline aqueous solution. However, the same effect can be obtained as a result. In the latter case, since the crude cellulose ether contains an alkali, the solvent to be dissolved may be only water, but an alkali may be added to ensure dissolution. Either method can be applied to the present invention.
Examples of the alkali used for dissolution include caustic potash and caustic soda, and the concentration thereof can be appropriately determined because it varies depending on the type and degree of substitution of the cellulose ether used, but is usually 2 to 25% by mass, particularly 5 to 12% by mass. % Is preferred. As a typical example, 10% by weight of caustic soda can be used for low-substituted hydroxypropylcellulose having a molar substitution degree of 0.2. Depending on the distribution of substituents, there may be a case where a transparent solution is obtained and a case where the solution is not completely transparent. In the latter case, when the viscosity is clearly increased, it is considered to be dissolved.
Examples of the acid used for neutralization include organic acids such as acetic acid, formic acid and propionic acid, and inorganic acids such as hydrochloric acid and sulfuric acid, and the concentration thereof can be freely selected, but is about 5 to 10% by mass. preferable.

  As a density | concentration of the low substituted cellulose ether at the time of grinding, 2-20 mass% is preferable. If it is less than 2% by mass, the load upon subsequent drying may increase. Due to this grinding treatment, the slurry thickens in a gel or sol form, and if it exceeds 20% by mass, the slurry may not be treated.

  The particle size of the ground product in a wet state with water is preferably an average particle size of 20 microns or less in terms of volume measured by a laser diffraction scattering method. In water dispersions of water-insoluble polymers, it has been known that the particle size in the dispersion affects the film-forming property after drying, but the same applies to low-substituted cellulose ether grounds. When the particle size is smaller, the aqueous dispersion is more densely packed when drying, and adjacent particles are united and fused to form a transparent continuous film. This continuous transparent film has high strength when dried, and becomes a gel-like sheet that absorbs water while keeping its shape after being wet with water, and a skin-adhesive water-containing sheet can be obtained. On the other hand, if it exceeds 20 microns, even if the aqueous dispersion is dried, it becomes a discontinuous film with a partially transparent portion or a powdery deposit. The strength of the deposit is low when it is dried, and the shape cannot be maintained when wet with water, and the intended skin-adhesive water-containing sheet cannot be produced. The lower limit of the particle diameter is not particularly limited, but is preferably about 1 micron.

Further, as the water-soluble cellulose ether used in the present invention (in parentheses indicate the degree of molar substitution), alkyl cellulose such as methyl cellulose (methoxyl group: 1.5 to 2.0), hydroxyethyl cellulose (hydroxyethyl group) : 1.0-3.0), hydroxyalkyl cellulose such as hydroxypropylcellulose (hydroxypropyl group: 2.0-3.0), hydroxypropylmethylcellulose (methoxyl group: 1.1-2.0, hydroxypropyl group) : 0.1-0.4), hydroxyethyl methylcellulose (methoxyl group: 1.1-2.0, hydroxyethyl group: 0.1-0.4), etc., hydroxyalkylalkylcellulose, carboxymethylcellulose (carboxymethyl group) : 0.5-2.5) To create a film preparation containing low surface tension, in that the droplets of surfactant is high oil less can uniformly emulsify, hydroxypropylmethylcellulose is suitable.
Furthermore, the aqueous solution viscosity of the water-soluble cellulose ether is a 2% by mass aqueous solution at 20 ° C., preferably 3 to 4,000 mPa · s, particularly preferably 3 to 100 mPa · s. If it is less than 3 mPa · s, the strength of the formed film may be reduced or the adhesion to the skin may be reduced. If it exceeds 4,000 mPa · s, a high-concentration solution cannot be prepared. It may take time and it may be difficult to degas the solution.

  A method for producing these water-soluble cellulose ethers is described, for example, in JP-A-10-158302. In order to manufacture, it is first necessary to prepare alkali cellulose. This can be done by immersing the starting pulp sheet in an alkaline aqueous solution such as caustic soda, or by pulverizing the pulp as it is mixed with the alkaline solution or after dispersing the pulp powder in an organic solvent. And by adding an alkali. Next, when alkali cellulose is charged into a reactor and an etherifying agent such as propylene oxide or ethylene oxide is added and then reacted by heating, cellulose ether is obtained. After completion of the reaction, the crude cellulose ether is transferred to another tank, and those having the property of being difficult to dissolve in hot water such as methylcellulose are subjected to necessary neutralization washing with hot water. Cellulose ethers that dissolve in both hot and cold water, such as carboxymethylcellulose, are washed in a poor solvent such as methanol containing water after being subjected to the necessary neutralization treatment, dried and pulverized to form the final product as a powder. To do.

  According to the method for producing a film preparation of the present invention, the water-soluble cellulose ether is preferably mixed with a drug or a ground product of low-substituted cellulose ether as an aqueous solution. The concentration of the aqueous solution of the water-soluble cellulose ether for mixing can be selected in consideration of the blending ratio of the low-substituted cellulose ether and the water-soluble cellulose ether, the concentration used for casting, and the like.

The blending ratio (mass ratio) of the low-substituted cellulose ether and the water-soluble cellulose ether in the film preparation of the present invention is preferably (98/2) to (40/60), more preferably (95/5) to (50/50). When the ratio between the low-substituted cellulose ether and the water-soluble cellulose ether is greater than 98/2, when adhering to the skin, agents such as a moisturizing agent, an anti-wrinkle agent, an anti-smudge agent, and a whitening effect agent begin to act. Before the time (about 20 minutes), it may be peeled off and the stickiness of 60 minutes or more required for the drug to act may not be maintained. In order to prepare a film containing an oily substance, a water-soluble cellulose ether and an oily substance are mixed to become an emulsified state and uniformly supported in the film, but the ratio of the low-substituted cellulose ether to the water-soluble cellulose ether When the ratio is larger than 98/2, the effect is small, and a stable emulsion may not be formed well, resulting in a non-uniform film.
On the other hand, when the ratio between the low-substituted cellulose ether and the water-soluble cellulose ether is smaller than 40/60, the film strength after wetting is weak, and a part of the film remains on the skin after peeling, and the water-containing sheet has a poor usability. There is a risk of becoming.

The drug used in the present invention is not particularly limited, but is particularly effective for oily substances that are not miscible with water.
Examples of the drug used in the present invention include anti-wrinkle agents such as retinol, anti-stain agents such as cysteine, whitening effect agents, glycerin, hyaluronic acid, collagen, squalene, docosahexaenoic acid, eicosapentaenoic acid, saccharides and amino acids, placenta extract, Moisturizing ingredients such as sorbitol and polyethylene glycol, softening agents such as olive oil, cetyl alcohol, lanolin and stearyl alcohol, blood circulation promoters such as tocophenol, anti-inflammatory agents such as glycyrrhizic acid, and skin beautification such as various vitamin C Drugs such as components are listed, and it is preferable for the drug sheet to contain one or more of these. If necessary, a water-soluble organic solvent such as alcohol may be added. When used in a transdermally absorbable preparation, examples of the local anesthetic include tetracaine, diethylaminoethyl parabutylaminobenzoate, oxybuprocaine, lidocaine, dibucaine, propitocaine and the like. As an analgesic and anti-inflammatory agent, aspirin, acetaminophen, etenzamide, ibuprofen, indomethacin, ketoprofen, glycyrrhizic acid, flufenamic acid, phenylbutazone, naproxen, oxyphenbutazone, diclofenac sodium, benzydamine, mepyrizole, istipendil hydrochloride, bufexamac, Vendazac, azulene, piroxicam, diflunisal and the like can be mentioned. Examples of the anti-inflammatory steroid include triamcinolone acetonide, dexamethasone, hydrocortisone acetate, fluocinolone acetonide, prednisolone, betamethasone valerate and the like. Antibiotics include penicillin, gentamicin, cephalexin, erythromycin, chloramphenicol, tetracycline and the like. Of these, retinol, squalene, docosahexaenoic acid, eicopentaenoic acid, olive oil, and tocophenol are particularly preferred oily substances that are liquid at room temperature and are not miscible with water.

  The content of the drug varies depending on the type, but is preferably about 50% by mass or less in the film preparation. If it exceeds 50% by mass, the strength of the sheet after wetting decreases, and there is a risk that it will remain on the skin when it is peeled off from the skin. In addition, an oily component such as acrylic or agar that is usually used can carry only a few mass% of the oily component, but the film of the present invention has an advantage that it can carry about 30 to 40 mass%. This is considered to be because the low-substituted cellulose ether not only retains moisture but also retains oily substances, and has a high effect of suppressing breathing.

The film preparation of the present invention can be obtained by casting a mixture of a drug, a low-substituted cellulose ether wet ground product and an aqueous solution of water-soluble cellulose ether on a base plate and drying the mixture.
Although the density | concentration of the liquid mixture used for casting is not specifically limited and can be prepared according to the objective of use, For example, it is the range of 2-30 mass% in solid content concentration.
The method for casting the mixed solution is not particularly limited, and may be cast by a normal method. The material of the base plate to be used is not particularly limited, and examples thereof include glass and Teflon (registered trademark). For example, it is cast on a glass plate with an appropriate thickness using a casting blade. The thickness is not particularly limited and can be adjusted according to the purpose of use, but is usually in the range of about 0.1 to 10 mm.

  Although there is no restriction | limiting in particular in the drying temperature at the time of film preparation, 60-80 degreeC is preferable. It is preferable to dry until the moisture in the film is approximately 10% by mass or less. If the drying is insufficient, the film formation becomes insufficient and the sheet strength after wetting may be reduced. Further, by removing the moisture in the film, the storage stability of a drug that is susceptible to moisture is improved.

  The film preparation obtained by drying can be used as a high moisture content sheet by wetting with water at the time of use. The amount of water to be moistened may be selected according to the purpose of use, but it is preferable that the film is completely absorbed by water, and approximately 90% by mass is preferable when the film of the present invention absorbs water.

As a skin adhesion test method, for example, a film is punched into a circular shape with a diameter of 2.5 cm, and a sample for evaluation is applied to the circular film. The time until the water-containing sheet is naturally peeled is measured.
The skin adhesion time is 100 minutes or longer, and the upper limit is not particularly limited, but is considered to be approximately 400 minutes.
The impregnating moisturizing agent, anti-wrinkle agent, anti-smudge agent, whitening effect agent and the like begins to act for about 20 minutes, and the minimum time required for the agent to act is 60 minutes or more, Furthermore, it takes more than 100 minutes for the drug to fully function. Therefore, in 60 minutes or less, there is a possibility that the impregnating moisturizing agent, anti-wrinkle agent, anti-smudge agent, whitening effect agent and the like may not work, and in 100 minutes or less, there is a possibility that the medicine cannot work completely.

Next, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples.
Example 1
Preparation of low-substituted cellulose ether wet milled product 2360 g of pure water at 25 ° C. was put into a twin-screw kneader having an internal volume of 5 L, and low-substituted hydroxypropylcellulose powder (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree 0.25) ) 150 g was added and dispersed uniformly. Thereto, 490 g of a 49 mass% NaOH aqueous solution at 25 ° C. was added and dissolved to obtain a NaOH aqueous solution of low-substituted hydroxypropylcellulose. (Low-substituted hydroxypropylcellulose concentration: 5% by mass, NaOH concentration: 8% by mass)
Next, 378 g of glacial acetic acid was added to the above solution for neutralization to obtain a gel-like precipitate. This was slurried with 20 times the amount of hot water relative to low-substituted hydroxypropylcellulose, and dehydrated with a centrifugal dehydrator. This operation was performed again to obtain a low-substituted hydroxypropylcellulose washed product.
Next, pure water was added to the washed product so that the solid content concentration was 4% by mass to obtain a wet grinding raw material. Using a mortar mill (Serendipitter MKCA6-3INV Masuyuki Sangyo Co., Ltd.), wet polishing with clearance of upper and lower mortar of 60 microns, rotation speed of 1500 rpm (circumferential speed of 11.7 m / sec), and processing speed of 1.0 kg / min. This operation was repeated 5 times to obtain a wet ground product of low-substituted hydroxypropylcellulose. The resulting slurry thickened and became creamy. When the average particle diameter was measured with a HORIBA LA-90 laser diffraction / scattering particle size distribution analyzer, it was 10 microns.

Production of film 87.5 g (solid content 3.5 g) of 4% by mass of low-substituted hydroxypropylcellulose and 10% by mass of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution is methoxyl group 1) .87, hydroxypropoxyl group 0.23, and the viscosity of a 2 mass% aqueous solution at 20 ° C. was 6 mPa · s.) 15 g (solid content: 1.5 g) of the aqueous solution was stirred and mixed at 300 rpm. It was. Thereto was added α-tocopherol (1.07 g) and ascorbic acid (1.07 g), and the mixture was stirred and mixed at 300 rpm to obtain a uniform creamy emulsion.
This emulsion was cast into a glass plate with a film thickness of 1.5 mm and dried in a blowing oven at 60 ° C. to obtain a transparent continuous film of 70 μm having the following composition.
Low substitution cellulose ether / water-soluble cellulose ether: 7/3 (mass ratio)
Low-substituted hydroxypropylcellulose 46.4% by mass
Hydroxypropyl methylcellulose 19.9% by mass
α-Tocopherol 14.2% by mass
Ascorbic acid 14.2% by mass
Water 5.3% by mass
This film was punched into a circular shape with a diameter of 2.5 cm to obtain a sample for evaluation.
A water-containing sheet obtained by applying a small amount of water to the circular film and adsorbing the water was adhered to the back of the hand, and the test for the time until peeling, the feeling of use, and the state after peeling was performed. The results are shown in Table 1.

Example 2
75.0 g (solid content: 3.0 g) of 4% by mass of low-substituted hydroxypropylcellulose prepared by the method described in Example 1 and 10% by mass of hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution) The degree is 2.5 of hydroxypropoxyl group, and the viscosity of 2% by weight aqueous solution at 20 ° C. was 6 mPa · s.) 20.0 g (solid content: 2.0 g) of aqueous solution was stirred and mixed at 300 rpm. went. Thereto was added α-tocopherol (1.07 g) and ascorbic acid (1.07 g), and the mixture was stirred and mixed at 300 rpm to obtain a uniform creamy emulsion.
This emulsion was cast into a glass plate with a film thickness of 1.0 mm and dried in a blow oven at 60 ° C. to obtain a 60-micron transparent continuous film having the following composition.
Low substitution cellulose ether / water-soluble cellulose ether: 6/4 (mass ratio)
Low substituted hydroxypropylcellulose 40.0% by mass
Hydroxypropyl cellulose 26.6% by mass
α-Tocopherol 14.2% by mass
Ascorbic acid 14.2% by mass
5.0% by weight of water
This film was punched into a circular shape with a diameter of 2.5 cm to obtain a sample for evaluation.
A water-containing sheet obtained by applying a small amount of water to the circular film and adsorbing the water was adhered to the back of the hand, and the test for the time until peeling, the feeling of use, and the state after peeling was performed. The results are shown in Table 1.

Example 3
Preparation of low-substituted cellulose ether wet ground product The same method as in Example 1 except that low-substituted hydroxypropylcellulose described in Example 1 was replaced with low-substituted methylcellulose (molar substitution degree of methoxyl group 0.28). A low-substituted cellulose ether wet grind was obtained. The resulting slurry thickened and became creamy. When the average particle size was measured with a HORIBA LA-90 laser diffraction / scattering particle size distribution analyzer, it was 16 microns.

Production of film 87.5 g (solid content of 3.5 g) of 4% by mass of low-substituted methylcellulose and 10% by mass of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd. And 15 g (solid content: 1.5 g) of an aqueous solution having a hydroxypropoxyl group of 0.21 and a viscosity of 2% by mass at 20 ° C. of 100 mPa · s was mixed at 300 rpm. Thereto was added 1.5 g of α-tocopherol and 0.64 ascorbic acid, followed by stirring and mixing at 300 rpm to obtain a uniform creamy emulsion.
This emulsion was cast into a glass plate with a film thickness of 1.5 mm and dried in a blowing oven at 60 ° C. to obtain a transparent continuous film of 70 μm having the following composition.
Low substitution cellulose ether / water-soluble cellulose ether: 7/3 (mass ratio)
Low-substituted methylcellulose 46.4% by mass
Hydroxypropyl methylcellulose 19.9% by mass
α-Tocopherol 20.0% by mass
Ascorbic acid 8.6% by mass
Water 5.1% by mass
This film was punched into a circular shape with a diameter of 2.5 cm to obtain a sample for evaluation.
A water-containing sheet obtained by applying a small amount of water to the circular film and adsorbing the water was adhered to the back of the hand, and the test for the time until peeling, the feeling of use, and the state after peeling was performed. The results are shown in Table 1.

Example 4
Preparation of low-substituted cellulose ether wet ground product The low-substituted hydroxypropylcellulose described in Example 1 was replaced with low-substituted hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd., with a molar substitution degree of methoxyl group 0.13, hydroxypropoxyl group 0). A low-substitution cellulose ether wet ground product was obtained in the same manner as in Example 1 except that the wet-ground product was replaced with the same. The resulting slurry thickened and became creamy. It was 16 microns when the average particle diameter was measured with a HORIBA LA-90 laser diffraction scattering type particle size distribution analyzer.

Preparation of film 112.5 g (solid content 4.5 g) of 4% by mass of low-substituted hydroxypropylmethylcellulose and 10% by mass of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution rate is methoxyl group 1) .8, hydroxypropoxyl group 0.16, and the viscosity of a 2 mass% aqueous solution at 20 ° C. was 5 mPa · s.) 2.5 g (solid content: 0.25 g) of an aqueous solution was stirred and mixed at 300 rpm. Went. Α-tocopherol (1.07 g) and glycerin (1.07 g) were added thereto, followed by stirring and mixing at 300 rpm to obtain a uniform creamy emulsion.
This emulsion was cast into a glass plate with a film thickness of 1.5 mm and dried in a blowing oven at 60 ° C. to obtain a transparent continuous film of 70 μm having the following composition.
Low substitution cellulose ether / water-soluble cellulose ether: 9/1 (mass ratio)
Low substituted hydroxypropyl methylcellulose 60.0% by mass
Hydroxypropyl methylcellulose 6.6% by mass
α-Tocopherol 14.2% by mass
Glycerin 14.2% by mass
5.0% by weight of water
This film was punched into a circular shape with a diameter of 2.5 cm to obtain a sample for evaluation.
A water-containing sheet obtained by applying a small amount of water to the circular film and adsorbing the water was adhered to the back of the hand, and the test for the time until peeling, the feeling of use, and the state after peeling was performed. The results are shown in Table 1.

Comparative Example 1
A 10% by mass aqueous dispersion of a low-substituted hydroxypropylcellulose powder (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree 0.25), which is a raw material of the wet ground product produced in Example 1, was prepared, and HORIBA LA-90 When the average particle diameter was measured by a laser diffraction / scattering particle size distribution analyzer, it was 150 microns. 35.0 g of this aqueous dispersion (solid content of 3.5 g) and 10% by mass of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree is 1.87 methoxyl group, 0.23 hydroxypropoxyl group, The viscosity of a 2 mass% aqueous solution at 20 ° C. was 6 mPa · s.) 15 g (solid content: 1.5 g) of an aqueous solution was stirred and mixed at 300 rpm. Thereto were added α-tocopherol (1.07 g) and ascorbic acid (1.07 g), followed by stirring and mixing at 300 rpm.
When this dispersion was cast into a glass plate with a thickness of 1.0 mm and dried in a blast oven at 60 ° C., it had white discontinuous powder deposits and a transparent film portion. The film strength was weak. Furthermore, when it was moistened with a small amount of water, the shape collapsed and an adhesion test to the skin was impossible.

Comparative Example 2
The low-substituted hydroxypropyl cellulose powder (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree 0.25), which is a raw material of the wet ground product produced in Example 1, was finely pulverized by a dry jet mill, and 10% by mass thereof. When an average particle size was measured with a HORIBA LA-90 laser diffraction / scattering particle size distribution analyzer, it was 60 microns. 35.0 g of this aqueous dispersion (solid content of 3.5 g) and 10% by mass of hydroxypropylmethylcellulose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree: methoxyl group 1.87, hydroxypropoxyl group 0.23) The viscosity of the 2 mass% aqueous solution at 20 ° C. was 6 mPa · s.) 15 g (solid content: 1.5 g) of the aqueous solution was stirred and mixed at 300 rpm. Thereto were added α-tocopherol (1.07 g) and ascorbic acid (1.07 g), followed by stirring and mixing at 300 rpm.
When this dispersion was cast into a glass plate with a thickness of 1.0 mm and dried in a blast oven at 60 ° C., it had white discontinuous powder deposits and a transparent film portion. The film strength was weak. Furthermore, when it was moistened with a small amount of water, the shape collapsed and an adhesion test to the skin was impossible.

Comparative Example 3
The low-substituted hydroxypropylcellulose powder (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree 0.25), which is a raw material of the wet ground product produced in Example 1, was finely pulverized in a dry jet mill, and 7% by mass Using a mortar-type pulverizer (Serendipitter MKCA6-3INV Masuko Sangyo Co., Ltd.), an upper and lower mortar clearance of 80 microns, a rotational speed of 1500 rpm (peripheral speed of 11.7 m / sec), and a processing speed of 1.5 kg. This operation was repeated 5 times to obtain a wet-ground product of low-substituted hydroxypropylcellulose. The resulting slurry became a slightly thickened slurry. When the average particle diameter was measured with a HORIBA LA-90 laser diffraction / scattering particle size distribution analyzer, it was 40 microns.
50.0 g (solid content 3.5 g) of this aqueous dispersion and 10% by mass of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., molar substitution degree is 1.87 methoxyl group, 0.23 hydroxypropoxyl group, The viscosity of a 2 mass% aqueous solution at 20 ° C. was 6 mPa · s.) 15 g (solid content: 1.5 g) of an aqueous solution was stirred and mixed at 300 rpm. Thereto were added α-tocopherol (1.07 g) and ascorbic acid (1.07 g), followed by stirring and mixing at 300 rpm.
When this dispersion was cast into a glass plate with a thickness of 1.0 mm and dried in a blast oven at 60 ° C., it had white discontinuous powder deposits and a transparent film portion. The film strength was weak. Furthermore, when it was moistened with a small amount of water, the shape collapsed and an adhesion test to the skin was impossible.

Comparative Example 4
1.07 g of glycerin and 1.07 g of ascorbic acid were added to 125.0 g (solid content: 5.0 g) of a wet mass of 4% by mass of low-substituted hydroxypropylcellulose prepared by the method described in Example 1, and 300 rpm was added. The mixture was stirred and mixed to obtain a uniform creamy emulsion. The film was cast into a glass plate with a film thickness of 1.5 mm and dried in a blast oven at 60 ° C. to obtain a transparent continuous film of 50 microns having the following composition.
Low substituted hydroxypropyl methylcellulose 66.4% by mass
Glycerin 14.2% by mass
Ascorbic acid 14.2% by mass
Water 5.2% by mass
This film was punched into a circular shape with a diameter of 2.5 cm to obtain a sample for evaluation.
A water-containing sheet obtained by applying a small amount of water to the circular film and adsorbing the water was adhered to the back of the hand, and the test for the time until peeling, the feeling of use, and the state after peeling was performed. The results are shown in Table 1.

  In Table 1, the evaluation of “flexibility” is: ○: flexible and stretchable, Δ: flexible and not very stretchable, ×: no flexibility, “adhesion” is evaluated as: : Skin adhesion is good, △: Skin adhesion is not very good, X: Skin adhesion is bad, evaluation of “skin condition after peeling” is ○: Moist and smooth, △: Somewhat Based on moist feeling, x: no change.

  From Table 1, it can be seen that the examples are water-containing sheets having excellent skin adhesion and excellent usability.

Claims (5)

  It contains a wet milled product of low-substituted cellulose ether having a substitution mole number per drug and anhydroglucose unit of 0.05 to 1.0 and a water-soluble cellulose ether, and has a skin adhesion time of 100 minutes or more. Characteristic film preparation.   The film preparation according to claim 1, wherein the drug is an oily substance.   The film preparation according to claim 1 or 2, wherein the wet ground product of the low-substituted cellulose ether has an average particle size of 20 microns or less.   A skin-adhesive water-containing sheet obtained by wetting the film preparation according to any one of claims 1 to 3.   A mixture of a low-substitution cellulose ether wet grind and a water-soluble cellulose ether aqueous solution having a substitution mole number per drug and anhydroglucose unit of 0.05 to 1.0 is cast on a base plate. The manufacturing method of the film formulation which comprises making it dry.