JP5101191B2 - Film-form preparation and method for producing the same - Google Patents

Description

  The present invention relates to a film-form preparation and a method for producing the same. More specifically, the present invention relates to a film-form preparation for oral administration in which the bitterness of a bitter drug is masked and a method for producing the same.

  Orally administered drugs may have reduced medication compliance due to discomfort due to drug bitterness or astringency, nausea or vomiting due to medication, refusal of medication, and the like. For example, most antihistamines have a persistent bitterness, despite differences in strength. Mequitazine, which is a third generation antiallergic agent having antihistamine action, is also an antihistamine with relatively little drowsiness, but also has a bitter taste. Conventionally, solid preparations have been the mainstream, and there has been a problem that the residence time in the stomach is long and it takes time until the effect is manifested (for example, see Patent Documents 1 and 2).

  Loperamide hydrochloride is an antidiarrheal agent that acts on opioid receptors and is known to be more effective than other antidiarrheal agents. However, it has a bitter taste that makes it difficult to take sucrose or artificial sweetness. It is used as a solid preparation or syrup preparation mixed with a masking agent such as a material (see, for example, Patent Document 3). However, even in these preparations, the masking effect is not sufficient.

On the other hand, sweeteners such as sucrose and reduced maltose starch syrup are widely used as masking agents. However, when these sweeteners are used, the masking effect is not observed unless they are added in a large amount, and the content ratio of the medicinal ingredients is relatively reduced. Therefore, the amount of intake (such as the number of tablets) increases. Will have to.
Thus, it has also been proposed to use a highly sweet component that exhibits a sweetness several hundred times that of sucrose. For example, oral liquids and tablets that have a high sweetness component such as stevia or acesulfame potassium to conceal the taste of the main ingredient and improve the feeling of taking are disclosed (for example, see Patent Documents 4 and 5). However, acesulfame potassium has the disadvantage of having a slightly bitter aftertaste at high concentrations. Therefore, when added excessively, there is a demerit that sweetness remains for a long time or bitterness is felt. Other high sweetness components also have specific properties because they each show a high sweetness level, and depending on the combination with a drug, there may be cases where a sufficient masking effect is not exhibited or an adverse effect may occur.

As general dosage forms for oral administration, solid preparations such as tablets and capsules are often used. However, since these solid preparations are difficult to swallow as they are, they usually have to be taken with a sufficient amount of water, and even if they are taken with a sufficient amount of water, they may still be difficult to swallow. Therefore, it is insufficient from the aspect of medication compliance. Especially in the elderly and infants, the solid preparation may not be swallowed, the risk of accidentally clogging the solid preparation into the trachea, and the solid preparation sticks to the esophagus, where an esophageal tumor is formed. There is a risk that In addition, in bedridden patients, after putting the solid preparation into the oral cavity, slowly give water, and after a while, the caregiver explores the patient's oral cavity with his / her fingers and confirms that no solid preparation remains. It must be confirmed, and the burden of confirming whether or not it has been taken is heavy.
In order to improve the difficulty of swallowing such a solid preparation and improve the ease and safety of taking it, it is conceivable to make the dosage form a semi-solid form such as jelly (for example, Patent Document 6, 7). However, a semi-solid preparation such as jelly has a problem that the stability of a drug (particularly a drug that is easily hydrolyzed) is lowered and packaging cost is high because it contains a large amount of water. Furthermore, due to aseptic handling during production and storage, it is more difficult to ensure stability in drugs that require pH control.

  In order to solve such a problem, a film-form oral administration agent having a drug-containing layer and a functional layer (a layer having a predetermined function) has been developed (see Patent Documents 8 and 9). The water-swellable gel-forming layer provided in the outermost layer of the film-form preparation swells and gels with moisture such as saliva in the patient's mouth, and the oral dosage form is easy to swallow in size, shape, elasticity, viscosity, etc. To a dosage form having As a result, the patient can easily take the oral administration agent. In addition, since the risk of the oral administration agent becoming clogged in the trachea of the patient during taking is reduced, it can be safely taken even if the patient is an elderly person or an infant. Further, by providing a water-swellable gel-forming layer as the outermost layer of the film-form preparation, the drug is prevented from coming into direct contact with the taste bud cells on the patient's tongue, so the taste of the drug (for example, bitter taste, astringency), smell Etc. can be masked.

JP-A-10-167554 JP-A-11-209305 Japanese Patent Laid-Open No. 9-30969 JP 2002-60339 A JP 2003-231647 A Japanese Patent Laid-Open No. 10-7565 JP 2006-131625 A International Publication WO02 / 087622 JP 2006-160617 A

However, depending on the kind of the drug contained in the drug-containing layer, the masking effect is not felt and it may not be suitable for taking (see Comparative Examples and Test Examples).
Accordingly, an object of the present invention is to provide a film-form preparation which is masked so that a specific bitter component is suitable for taking with a specific high sweetener, is excellent in portability, and easy to take, and a method for producing the same. It is in.

As a result of intensive studies to solve the above problems, the present inventors have obtained a film-form preparation comprising a drug-containing layer containing mequitazine or loperamide hydrochloride and a water-swellable gel-forming layer containing a specific highly sweet component, The present inventors have found that the above problems can be solved and have completed the present invention.

That is, the present invention
(1) It has a water-swellable gel-forming layer containing acesulfame potassium or sucralose (highly sweet component) laminated directly or via an intermediate layer on both sides of a drug-containing layer containing mequitazine or loperamide hydrochloride (bitter component) A film-form preparation characterized by:
(2) The film-form preparation according to the above (1), wherein the content of the highly sweet component is 0.5 to 25% by mass in the water-swellable gel-forming layer;
(3) When the content of the bitter component contained in the entire film-form preparation is A [mass%] and the content of the highly sweet component contained in the entire film-form preparation is B [mass%], the ratio A of these components Film-form preparation as described in said (1) or (2) whose / B is the range of 1 / 0.01-1 / 2;
(4) A method for producing a film-form preparation comprising laminating a water-swellable gel-forming layer containing acesulfame potassium or sucralose directly or via an intermediate layer on both sides of a drug-containing layer containing mequitazine or loperamide hydrochloride; And (5) a drug-containing layer containing mequitazine or loperamide hydrochloride is laminated directly or via an intermediate layer on a water-swellable gel-forming layer containing acesulfame potassium or sucralose, and then the two drug-containing layers obtained A method for producing a film-form preparation characterized by attaching
Is to provide.

According to the present invention, a film-form preparation excellent in portability and easy to take and a method for producing the same are provided by masking a specific bitter component with a water-swellable gel-forming layer containing a specific highly sweet component.
Furthermore, according to the present invention, the specific bitterness component loperamide hydrochloride or mequitazine is also a water-swellable gel-forming layer containing a small amount of a specific high-sweetness component, from the viewpoint of bitterness, sweetness, numbness, and feeling of administration. The present invention provides a film-form preparation that is sufficiently maskable and a method for producing the same.

The present invention will be specifically described below.
The bitter component which is an active ingredient used in the present invention is any one selected from mequitazine (an antihistamine) or loperamide hydrochloride (an antidiarrheal) (hereinafter referred to as a bitter component).

The bitter component is held by a base or the like to form a drug-containing layer.
It does not specifically limit as a base used in order to hold | maintain a bitter component, It can select suitably. Specific examples of the base include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymer, crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl. Cellulose such as methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and derivatives thereof or pharmaceutically acceptable salts thereof (for example, sodium salt); α-starch, oxidized starch, sodium carboxymethyl starch, hydroxypropyl starch Starch, dextrin, dextran, and the like Derivatives thereof; sugars such as sucrose, maltose, lactose, glucose, fructose, pullulan, xanthan gum, cyclodextrin; sugar alcohols such as xylitol, mannitol, sorbitol; dimethylaminoethyl (meth) acrylate and (meth) acrylic acid copolymer, (Meth) acrylic acid / ethyl acrylate copolymer, (meth) acrylic acid / methyl (meth) acrylate copolymer, ethyl (meth) acrylate / (meth) acrylated trimethylammonium copolymer, dimethylaminoethyl (meth) acrylate・ Acrylic acid derivatives such as (meth) acrylated methyl copolymer and (meth) acrylic acid / acrylated ethyl copolymer; shellac; polyvinyl acetal diethylaminoacetate; polyvinyl acetate; gum arabic, tragacan Natural rubbers such as rubber gum; polyglucosamines such as chitin and chitosan; proteins such as gelatin, casein and soybean protein; titanium oxide; calcium monohydrogen phosphate; calcium carbonate; talc; stearate; Examples include magnesium silicate; anhydrous silicic acid and the like, and these can be used alone or in combination of two or more.

It is also a preferred embodiment that the base is an edible polymer compound. The edible polymer compound may be either a synthetic polymer compound or a natural polymer compound, and the kind thereof is not particularly limited. The edible polymer compound is preferably a gastric polymer compound or an enteric polymer compound.
Among the edible polymer compounds, preferred are polyvinyl alcohol, polyvinyl pyrrolidone, cellulose and derivatives thereof, or pharmaceutically acceptable salts thereof, vinyl acetate-vinyl pyrrolidone copolymer, polyvinyl acetate, (meth) acrylic acid. Examples include alkyl ester (co) polymers, and particularly preferable examples include polyvinyl alcohol and polyvinyl pyrrolidone.

  The content of the base in the drug-containing layer is an amount that enables the layer to be formed, and the amount can be appropriately adjusted according to the type of the base, but is usually 10% by mass in the drug-containing layer. That's it. The drug-containing layer can be formed by setting the base to 10% by mass or more. The upper limit of the content of the base in the drug-containing layer is a value obtained by subtracting the minimum content of the bitter component contained in the drug-containing layer from 100% by mass, and is appropriately set according to the type of the bitter component, etc. Is done.

  The content of the bitter component in the drug-containing layer can be appropriately adjusted according to the efficacy / effect / use / dose and formulation size of the bitter component, but is usually 50% by mass or less, preferably 30% in the drug-containing layer. % Or less. By making content of a bitterness component 50 mass% or less, the fall of the film strength of a film-form preparation can be prevented. In addition, the content lower limit value of the bitter component in the drug-containing layer is appropriately set according to the type of the bitter component to be contained in the drug-containing layer, and is usually about 0.001% by mass.

The basis weight (mass per unit area) of the drug-containing layer can be appropriately adjusted within a range in which the film-form preparation can be orally administered. Preferably the basis weight is 0.1~1000g / m ^2, further preferably 10 to 200 g / m ^2. By making the basis weight of the drug-containing layer 0.1 g / m ² or more, it is possible to form a film with high precision (if less than 0.1 g / m ² , the content of bitter components in the drug-containing layer varies) . On the other hand, by setting the basis weight of the drug-containing layer to 1000 g / m ² or less, it is possible to prevent the film from becoming too strong and difficult to take.

The drug-containing layer can contain a plasticizer in order to impart moderate flexibility to facilitate processing and to prevent cracking and chipping of the drug-containing layer. Examples of the plasticizer include edible ones, specifically glycerin, propylene glycol, glycerin triacetate, polyethylene glycol, sorbitol, diethyl phthalate, triethyl citrate, lauric acid, sucrose, and the like. Alternatively, two or more types can be selected and used.
The amount of the plasticizer contained in the drug-containing layer can be appropriately adjusted according to the type of the base, but is usually 40 parts by weight or less, preferably 100 parts by weight or less based on the total amount of the drug and the base. 35 parts by mass or less, more preferably 30 parts by mass or less. By setting the content of the plasticizer to 40 parts by mass or less, it is difficult for the drug-containing layer to exude from the end of the film-form preparation which is an orally administered agent. In the film-form preparation of the present invention, the highly sweet component in the water-swellable gel-forming layer described later exerts a masking action, but the drug-containing layer is pharmaceutically effective as long as the function is not impaired. Acceptable and commonly used masking agents, excipients, binders, disintegrants, colorants, additives such as inorganic fillers such as titanium oxide can be included.
For example, as masking agents, those that give acidity such as citric acid, tartaric acid, fumaric acid, sweeteners such as saccharin, glycyrrhizic acid, sucrose, fructose, mannitol, refreshing agents such as menthol, mint oil, peppermint, spearmint, natural Or a synthetic fragrance | flavor etc. are mentioned, Among these, 1 type or 2 types can be selected and used.

The high sweetness component in the water-swellable gel-forming layer in the film-form preparation of the present invention is acesulfame potassium (sweetness of about 200) or sucralose (sweetness of about 600), both of which have extremely high sweetness, Exhibits a masking action on the bitter component.
Incidentally, the stevia (sweetness of about 150-300), thaumatin (sweetness of about 3000-5000) and aspartame (sweetness of about 200), which are well-known as high-sweetness components, are used in the comparative examples described later. It does not show masking action on the bitter components such as high sweetness components.
The content of these high-sweetness components is usually 0.5 to 25% by mass, preferably 0.5 to 20% by mass, more preferably 0.5 to 1.0% by mass in the water-swellable gel-forming layer. . By setting the content to 0.5% by mass or more, the masking action can be sufficiently exerted on the bitter component, and by setting the content to 25% by mass or less, the user of the film-form preparation feels comfortable and moderate sweetness. Can be.

Furthermore, when the content of the bitter component contained in the entire film-form preparation is A [mass%] and the content of the high-sweet component contained in the entire film-form preparation is B [mass%], the bitter component and the high sweetness The component ratio A / B of the components is preferably in the range of 1 / 0.01 to 1/2, more preferably in the range of 1 / 0.01 to 1/1, A range of 1 / 0.03 is particularly preferable. In addition, the content B of the high sweetness component contained in the whole film-form preparation is usually 0.01 to 10% by mass, preferably 0.01 to 6% by mass, more preferably 0.01 to 0.25% by mass. It is. Thereby, the effect mentioned above is exhibited more notably.
As described above, when the ratio A / B between the bitter component and the high sweetness component is ½ or less, it is possible to prevent the film from becoming impossible. Since it can prevent falling, it is especially preferable.
When changing to another dosage form using a drug having a bitter taste, it is usually prepared as appropriate based on the mixing ratio of the bitter component and the high sweetness component in the masked conventional drug. In the present invention, as shown in the examples described later, it is found that the masking effect is sufficiently exerted even in an amount considerably smaller than that predicted from the masked conventional drug, for example, near the lower limit in the above range. It was.

In the film-form preparation of the present invention, the gel-forming agent for retaining the high sweetness component in the water-swellable gel-forming layer is not particularly limited and can be appropriately selected according to the purpose of addition.
Specifically, as long as it can swell with water to form a gel, the type thereof is not particularly limited, and it may be cross-linked or non-cross-linked. Examples include carboxyvinyl polymer, starch and derivatives thereof, agar, alginic acid, arabinogalactan, galactomannan, cellulose and derivatives thereof, carrageen, dextran, tragacanth, gelatin, pectin, hyaluronic acid, gellan gum, collagen, casein, xanthan gum and the like. Of these, one type or two or more types can be selected and used.

The gel-forming agent contained in the water-swellable gel-forming layer preferably has an ionic functional group that can react with a polyvalent metal ion from the viewpoint of improving its strength. Examples of the ionic functional group that can react with the polyvalent metal ion include a carboxyl group, a sulfonic acid group, a phosphoric acid group, and a phenolic hydroxyl group.
Specific examples of the gel-forming agent having an ionic functional group capable of reacting with a polyvalent metal ion include a carboxyvinyl polymer, and in order to retain the high sweetness component, a crosslinked carboxyvinyl polymer is used. Preferably cross-linked polyacrylic acid is particularly preferred. This is because the crosslinked carboxyvinyl polymer, particularly the crosslinked polyacrylic acid does not adversely affect the film-forming ability and can exhibit an appropriate gel strength during swelling.
Crosslinking can be performed with a crosslinking agent according to the type of gel forming agent to be crosslinked. The carboxyvinyl polymer can be crosslinked by, for example, a polyvalent metal compound. Specific examples of such polyvalent metal compounds include calcium chloride, magnesium chloride, aluminum chloride, aluminum sulfate, potassium alum, iron chloride alum, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, and phosphoric acid. Aluminum, iron citrate, magnesium oxide, calcium oxide, zinc oxide, zinc sulfate and the like can be mentioned, and one or more of these can be selected and used.

The water-swellable gel-forming layer preferably contains a film-forming agent in order to improve the film-forming property.
The type of the film forming agent is not particularly limited as long as it has film forming ability. Specific examples of the film forming agent include polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, hydroxyalkyl cellulose (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose), alkylcellulose (for example, Methyl cellulose, ethyl cellulose), carboxyalkyl cellulose (for example, carboxymethyl cellulose), (meth) acrylic acid and its ester, xanthan gum, carrageenan, alginic acid, and the like. One or more of these may be selected and used. it can.
The amount of the film-forming agent contained in the water-swellable gel-forming layer can be appropriately adjusted according to the type and the like, but is preferably 30 to 85% by mass of the water-swellable gel-forming layer.
By setting the amount of the film-forming agent to 30% by mass or more, the water-swellable gel-forming layer has a film-forming ability, reinforces the masking action by the highly sweet component, and is set to 85% by mass or less. It prevents that the gel formation ability by a forming agent falls.

The film forming agent contained in the water-swellable gel-forming layer is preferably water-soluble.
When the film-forming agent is water-soluble, water easily enters the water-swellable gel-forming layer, and the water-swellable gel-forming layer can be rapidly swollen and gel-formed in the cavity.
Examples of the water-soluble film forming agent include polyvinyl alcohol; hydroxyalkyl cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; polyvinylpyrrolidone; xanthan gum; carrageenan; alginic acid, and the like. Can be selected and used.

The water-swellable gel-forming layer may contain a plasticizer in order to impart appropriate flexibility to the water-swellable gel-forming layer. Examples of the plasticizer include glycerin, propylene glycol, polyethylene glycol, sorbitol, glycerin triacetate, diethyl phthalate, triethyl citrate, lauric acid, sucrose, and the like. Can be used.
The amount of the plasticizer can be appropriately adjusted according to the type of the gel forming agent and the film forming agent, but usually 2 to 25 parts by mass with respect to 100 parts by mass of the total amount of the gel forming agent and the film forming agent, Preferably it is 4-21 mass parts, More preferably, it is 6-17 mass parts. By setting the plasticizer content to 25 parts by mass or less, the stiffness of the water-swellable gel-forming layer can be maintained, and by setting it to 2 parts by mass or more, the effect as a plasticizer can be sufficiently exhibited. .

The basis weight of the water-swellable gel-forming layer can be appropriately adjusted within a range in which the film-form preparation can be orally administered. Preferably the basis weight is 0.1~1000g / m ^2, further preferably 10 to 200 g / m ^2. By making the basis weight of the water-swellable gel-forming layer 0.1 g / m ² or more, it is possible to form a film with high precision (if less than 0.1 g / m ² , a highly sweet component in the water-swellable gel-forming layer) The content varies.) On the other hand, by setting the basis weight of the water-swellable gel-forming layer to 1000 g / m ² or less, it is possible to prevent the film from becoming too strong and difficult to take.

  Although the gel-forming agent and the highly sweet component in the water-swellable gel-forming layer are different in degree, they all have a masking action, but in order to mask the bitter component contained in the drug-containing layer, The masking agent used may be contained in the water-swellable gel forming layer. When the water-swellable gel-forming layer contains a masking agent, the masking action of the bitter component by the water-swellable gel-forming layer can be improved. Commonly used masking agents include, for example, those that give acidity such as citric acid, tartaric acid, fumaric acid, sweeteners such as saccharin, glycyrrhizic acid, sucrose, fructose, mannitol, menthol, mint oil, peppermint, spearmint, etc. These can be selected from one kind or two or more kinds of them.

  When the water-swellable gel-forming layer contains the film-forming agent such as polyvinyl alcohol, these film-forming agents can also serve as a masking agent together with the high-sweetness component. Thus, it is preferable to use a film forming agent having a masking action.

The water-swellable gel-forming layer may contain additives such as preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate and edible lake colorants. Addition of additives to the water-swellable gel-forming layer generally reduces the strength of the water-swellable gel-forming layer, so that water can easily enter the water-swellable gel-forming layer and form a water-swellable gel. The moisture that has entered the layer is preferred because swelling and gel formation of the gel forming agent are likely to occur.
The water-swellable gel-forming layer can further contain additives such as pharmaceutically acceptable excipients, binders, disintegrants, and colorants as long as the function is not impaired.

  The layers constituting the film-form preparation (for example, between the water-swellable gel-forming layer and the water-swellable gel-forming layer, between the drug-containing layer and the water-swellable gel-forming layer, between the drug-containing layer and the drug-containing layer) An intermediate layer can be provided in the middle), and the components of the intermediate layer can be appropriately selected according to the purpose. For example, when an intermediate layer is provided for the purpose of adhesion between layers, a pharmaceutically acceptable adhesive is contained. Among such adhesives, specific examples of adhesives that exhibit adhesiveness when used in a solvent-containing state include carboxyvinyl polymer, polyacrylic acid such as sodium polyacrylate, or a pharmaceutically acceptable salt thereof. Non-toxic salts, acrylic acid copolymers or pharmaceutically acceptable salts thereof, hydrophilic cellulose derivatives such as carboxymethyl cellulose and sodium salt, pullulan, povidone, karaya gum, pectin, xanthan gum, tragacanth, alginic acid, gum arabic, Saccharides or derivatives thereof or pharmaceutically acceptable salts thereof may be mentioned, and specific examples of adhesives that exhibit adhesiveness upon heating (that is, heat-sealable) include polyvinylpyrrolidone, polyvinyl acetate, and vinyl acetate. Examples include copolymers with vinyl pyrrolidone. It can be used to select the kind or two or more kinds.

The film-form preparation of the present invention can be produced according to the following procedure.
<Manufacture of a laminate in which a water-swellable gel-forming layer and then a drug-containing layer are laminated on the holding substrate surface>
A coating liquid containing the above-mentioned high sweetness component, gel-forming agent, and film-forming agent used as necessary on a holding substrate surface such as a plastic film or backing sheet that has been subjected to a release treatment with a silicone resin release agent or the like ( After applying or spraying a solution, suspension, or solvent (purified water, for example), this was dried to form a water-swellable gel-forming layer, and the water-swellable gel-forming layer was laminated on the holding substrate surface The laminated body 1 is manufactured.
Next, on the surface of the water-swellable gel-forming layer of the laminate 1, a coating liquid (solution or dispersion, solvent containing an additive such as the bitter component, base, excipient, binder, disintegrant, etc.) (For example, ethanol) is laminated by application or spraying, and then dried to form a drug-containing layer. The method for forming the drug-containing layer is not limited to the above method. For example, the drug-containing layer is formed on the upper surface of the water-swellable gel-forming layer by printing using a known method applying a principle such as a screen printing method. It can also be formed. In this way, a laminate 2 is prepared in which a water-swellable gel-forming layer and a drug-containing layer are sequentially laminated on the upper surface of the holding substrate.

<Method 1 for producing film-form preparation>
On the drug-containing layer of the laminate 2 produced as described above, a coating liquid containing a highly sweet component used in producing the laminate 1 is applied or sprayed and laminated, and then dried. A water-swellable gel-forming layer is formed, and a laminate 3 is produced in which water-swellable gel-forming layers are laminated on both sides of the drug-containing layer. From the viewpoint of maintaining the quality of the obtained film-form preparation and productivity, drying is preferably performed at about 60 to 130 ° C. for 20 to 900 seconds. The same applies to the following manufacturing method 2.
The film-form preparation of the present invention can be prepared by peeling the holding substrate from the laminate 3 thus prepared.

<Method 2 for producing film-form preparation>
The drug-containing layers of the two laminates 2 produced as described above are heat-sealed, for example, under conditions of 60 to 120 ° C., 1 to 5 kgf / cm ² and 0.1 to 10 seconds, The film-form preparation of the present invention can be prepared by peeling the holding substrate.

<Method 3 for producing film-form preparation>
The laminate 4 is obtained by thermally fusing the drug-containing layers of the two laminates 2 under conditions of, for example, 60 to 120 ° C., 1 to 5 kgf / cm ² , and 0.1 to 10 seconds. By laminating the two holding substrates from the laminate 4 and thermally bonding the surface of the water-swellable gel-forming layer of the laminate 1 to the exposed water-swellable gel-forming layer under the above conditions. A body 5 is obtained.
By peeling the holding substrate from the laminate 5, the film-form preparation of the present invention having a thick water-swellable gel-forming layer on both sides of the drug-containing layer can be prepared.

<Method 4 for producing film-form preparation>
After applying or spraying a coating liquid for forming an intermediate layer containing an adhesive component on the water-swellable gel-forming layer of the laminate 1 and laminating it, this is dried to form an intermediate layer, A laminate 6 is obtained in which a water-swellable gel-forming layer and an intermediate layer are sequentially laminated on the upper surface of the holding substrate.
The laminate 7 is peeled off from the laminate 4 and the surface of the intermediate layer of the laminate 6 is heat-sealed to the exposed water-swellable gel-forming layer under the above conditions. can get.
A book having a water-swellable gel-forming layer formed on both sides of the drug-containing layer by peeling the holding substrate from the laminate 7, and further having a water-swellable gel-forming layer laminated on the outside via an intermediate layer The film-form preparation of the invention can be prepared.

  As in the production methods 3 and 4 for the film-form preparation, the masking action against bitterness can be further improved by increasing the thickness of the water-swellable gel-forming layer.

An adhesive may be used instead of heat-sealing in the film-form preparation method. However, the adhesive used must be pharmaceutically acceptable. As the pharmaceutically acceptable adhesive, the same components as those of the intermediate layer described above can be used.
The film-form preparation of the present invention prepared as described above is processed into a form that can be punched into a circle, an ellipse, a polygon or the like of about 5 to 20 mm, and enclosed and shipped with a laminate film or the like.

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

Preparation Example 1-1 [Preparation of Gel Forming Layer Coating Liquid Containing High Sweetness Component etc.]
A coating solution containing a highly sweet component for the water-swellable gel-forming layer was prepared as follows. The compounding ratio (mass basis) of each component is shown in Tables 1-2.
Purified water [Nippon Pharmacopoeia purified water (Kominato Pharmaceutical Co., Ltd.), the same shall apply hereinafter] is supplied to a glass container, and calcium chloride is added therein and dissolved by stirring for 10 minutes at room temperature. Carbopol 974P (manufactured by Noveon, Inc., hereinafter the same)] was added and stirred at room temperature for about 1 hour to completely dissolve it to obtain a solution. Next, while stirring the solution, polyvinyl alcohol [Gosenol EG-05T (manufactured by Nippon Gosei Co., Ltd.), saponification degree 86.5-89.0, the same applies hereinafter] was added, and the mixture was heated to 70 ° C. for about 2 hours. Stir to dissolve completely. After cooling to room temperature, a highly sweet ingredient and glycerin [Japanese Pharmacopoeia Concentrated Glycerin (Asahi Denka Co., Ltd.), the same shall apply hereinafter] are added and dissolved by stirring for 10 minutes to form a water-swellable gel-forming layer. A liquid was obtained. Polyacrylic acid is a gel-forming agent that can be crosslinked by polyvalent metal ions (calcium chloride), polyvinyl alcohol is a film-forming agent, and glycerin is a plasticizer.

Preparation Example 1-2 [Preparation of coating liquid for gel forming layer in comparative example]
A coating solution was prepared in the same procedure as in Preparation Example 1-1 except that the high sweetness component was not included.

  A coating solution containing a bitter component for forming a drug-containing layer was prepared as follows. The amount of each component added is as shown in Tables 1 and 2.

Preparation Example 2-1 [Preparation of coating solution containing mequitazine or loperamide hydrochloride]
Purified water is supplied to a glass container, and glycerin is added to the glass container with sufficient stirring at room temperature, dissolved by stirring for 10 minutes at room temperature, and a bitter component (mequitazine or loperamide hydrochloride) is added thereto. Dispersed. Polyvinylpyrrolidone was added thereto and stirred at room temperature for about 1 hour to dissolve, thereby preparing a coating solution for forming a drug-containing layer.

Preparation Example 2-2 [Preparation of coating solution containing diphenhydramine hydrochloride in Reference Example]
A coating solution was prepared in the same procedure as in Preparation Example 2-1, except that diphenhydramine hydrochloride was used as a bitter component.

Preparation Example 3 [Formation of water-swellable gel-forming layer on holding substrate surface]
After sufficiently defoaming the coating liquid prepared in Preparation Example 1-1 or Preparation Example 1-2, the coating amount after drying is a predetermined basis weight (18 g / m ² for a mequitazine preparation, and for a loperamide hydrochloride preparation) Using an applicator with a gap adjusted to 5 g / m ² and 18 g / m ² for the diphenhydramine hydrochloride preparation of the reference example, a release film made of polyethylene terephthalate as a holding substrate (product name: Lintec Corporation) SP-PET3801) is spread-coated on the surface opposite to the silicone resin release agent treated surface and dried with hot air at 80 ° C. for 6 minutes to obtain a laminate A having a water-swellable gel-forming layer on the holding substrate surface. It was.

Preparation Example 4 [Formation of drug-containing layer on water-swellable gel-forming layer]
After sufficiently defoaming the coating solution prepared in Preparation Example 2-1 or Preparation Example 2-2, the coating amount after drying is a predetermined basis weight (52.5 g / m ² for mequitazine preparation, loperamide hydrochloride preparation The water-swellable gel-forming layer of the laminate A prepared in Preparation Example 3 using an applicator whose gap was adjusted to 50 g / m ² , and 105 g / m ² for the diphenhydramine hydrochloride preparation of Reference Example) The coating was spread on the substrate and dried with hot air at 80 ° C. for 6 minutes to form a drug-containing layer, whereby a laminate B was obtained.

Examples 1 to 8, Comparative Examples 1 to 8 and Reference Examples 1 and 2
Two laminates B obtained in Preparation Example 4 were prepared, the drug-containing layers were pressure-bonded and heat-sealed at 100 ° C. for 2 seconds, and then two polyethylene terephthalate films, which are holding substrates, were peeled off. Thus, the film-form preparation of the present invention having a water-swellable gel-forming layer containing a highly sweet component on both sides of the drug-containing layer containing a bitter component was obtained. This was punched out using a 15 mmφ punching die. A laminate having a water-swellable gel-forming layer containing a high-sweetness component on both sides of the drug-containing layer containing the bitter component was obtained, and the film-form preparation of the present invention was obtained by punching using a 15 mmφ punching die. . (Examples 1-4: Bitterness component is mequitazine (containing 2 mg per tablet), Examples 5-8: Bitterness component is loperamide hydrochloride (containing 0.5 mg per tablet))

As is clear from the above table, Comparative Examples 1 to 8 are those in which mequitazine or loperamide hydrochloride is used as a bitter component and the water-swellable gel-forming layer does not contain a high sweet component, or stevia as a high sweet component. This is the case if it contains thaumatin or aspartame.
In Reference Examples 1 and 2, the water-swellable gel-forming layer contains acesulfame potassium or sucralose as a high sweetness component, and the drug-containing layer contains diphenhydramine hydrochloride (an antihistamine drug, 25 mg per tablet) as a bitter component It is.

Sensory test Using the film-form preparations of Examples 1 to 8, Comparative Examples 1 to 8, and Reference Examples 1 and 2 obtained above, the following sensory evaluation tests were conducted by 5 panelists of the formulation developers.
A film-form preparation sample of each example was placed in the mouth, swollen in the mouth for 20 seconds, swallowed, and according to the evaluation criteria shown below, the degree of bitterness, the degree of sweetness, the degree of numbness (tongue 10 minutes after swallowing) The degree of numbness), feeling of taking, and comprehensive evaluation were performed to determine whether there was a problem as a product. The results are shown in Tables 3 and 4.

[Evaluation criteria]
1. Degree of bitterness ◎: Does not feel bitterness ○: Feels slightly bitter but has no problem as a product ×: Feels bitterness Degree of sweetness ◎: Good balance of sweetness (appropriate sweetness)
○: Sweetness remains slightly, but is acceptable ×: Sweetness balance is poor (sweetness remains in the aftertaste or sweetness is insufficient)
3. Degree of numbness (degree of tongue numbness 10 minutes after swallowing)
◎: No numbness of the tongue remains ○: Some numbness of the tongue remains, but there is no problem as a product ×: The numbness of the tongue remains Feeling of taking (delicious)
◎: Delicious ○: Delicious but slightly bitter or sweet (no problem as a product)
×: Not delicious

5. Comprehensive evaluation Based on the evaluations shown in the above 1 to 4, comprehensive evaluation was made to determine whether the bitter taste felt due to insufficient masking or the sweetness felt due to excessive addition of a high-intensity sweetener is unpleasant when taken. Otherwise, there was no problem as a product, and if it was unpleasant, it was determined as a problem as a product.
○: There is no problem as a product ×: There is a problem as a product

As is apparent from the results shown in Tables 3 and 4, the film-form preparation of the present invention obtained by adding acesulfame potassium or sucralose as a high-sweetness component to mequitazine or loperamide hydrochloride, which is a bitter drug, It was excellent in all evaluations of the degree of sweetness, the degree of numbness, and the feeling of taking, and as a comprehensive evaluation, it became a film-form preparation suitable for taking. Furthermore, the masking effect was sufficient even with a considerably smaller amount of sweetener than expected from conventional drugs.
On the other hand, with other high sweetness components, the degree of bitterness, the degree of sweetness, the degree of numbness, and the feeling of ingestion were not sufficient and the film-form preparation was insufficient.
Further, it can be seen that diphenhydramine hydrochloride, which is a drug having another bitter taste, has a problem in all evaluation items even if masked with acesulfame potassium, and does not become a product containing a drug having a medicinal dose.

The effects of the present invention are as follows when compared with, for example, Patent Document 3 described above. In the case of the solution described in Patent Document 3, it is described that 7.5 mg of stevia is mixed with 0.5 mg of loperamide hydrochloride.
When calculating the predicted amount in consideration of the sweetness of stevia (sweetness 150 to 300) and acesulfame potassium (sweetness 200), acesulfame potassium is 5.6 with respect to 0.5 mg of loperamide hydrochloride. About 11.25 mg should be added. However, as is clear from the above test examples, even when acesulfame potassium is only 0.01 to 0.35 mg relative to 0.5 mg of loperamide hydrochloride, the masking effect on loperamide hydrochloride is sufficiently shown.

  The film-form preparation of the present invention is suitably used in the field of oral administration that does not require water.

Claims (5)

  A film-form preparation comprising a water-swellable gel-forming layer containing acesulfame potassium or sucralose laminated on both sides of a drug-containing layer containing mequitazine or loperamide hydrochloride directly or via an intermediate layer.   The film-form preparation according to claim 1, wherein the content of acesulfame potassium or sucralose is 0.5 to 25% by mass in the water-swellable gel-forming layer.   When the content of mequitazine or loperamide hydrochloride contained in the whole film-form preparation is A [mass%], and the content of acesulfame potassium or sucralose contained in the whole film-form preparation is B [mass%], these component ratios A The film-form preparation according to claim 1 or 2, wherein / B is in the range of 1 / 0.01 to 1/2.   A method for producing a film-form preparation comprising laminating a water-swellable gel-forming layer containing acesulfame potassium or sucralose directly or via an intermediate layer on both sides of a drug-containing layer containing mequitazine or loperamide hydrochloride.   Laminating a drug-containing layer containing mequitazine or loperamide hydrochloride directly or via an intermediate layer on a water-swellable gel-forming layer containing acesulfame potassium or sucralose, and then affixing the obtained two drug-containing layers to each other A method for producing a film-form preparation characterized by