JP5455203B2 - Film preparation and method for producing the same - Google Patents

Description

  The present invention relates to a film preparation and a production method thereof.

  Active ingredients such as pharmaceuticals are generally administered orally (eg, buccal administration, sublingual administration, etc.) or parenteral (eg, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, transnasal administration, etc. It can be administered into the body, such as by pulmonary administration.

  However, in parenteral administration such as intravenous administration, intramuscular administration, and subcutaneous administration, the active ingredient is mostly administered into the body by injection, which is very cumbersome and involves a great deal of physical pain. In addition, there are individual differences and doses of active ingredients are not constant in parenteral administration such as transdermal administration using patches (for example, patches), nasal administration using aerosols, etc., pulmonary administration, etc. There is a problem.

  For oral administration, preparations such as tablets, powders, pills, solutions, capsules and the like are generally well known. These preparations include, for example, oral topical anesthetics and drugs for treating stomatitis. Not suitable for administration. Oral disintegrating tablets such as lozenges are also available, but patients with elderly or xerostomia (dry mice) (dry mouth due to side effects of other drugs such as antihypertensives and tranquilizers, Sjogren's syndrome) The drug cannot be effectively administered in the oral cavity under conditions of limited saliva secretion (including reduction of salivary secretion caused by diseases such as diabetes).

  Furthermore, in tablets and powders, depending on the active ingredient, bitterness and unpleasant odor are strong, and a flavoring agent or the like may be required. In order to prevent bitterness and unpleasant odor, the active ingredient or tablet may be sugar-coated, which is very complicated. Furthermore, regarding powders, conventionally, the bitterness and unpleasant odor of the active ingredient have been prevented by wrapping the powder with wafers or the like. However, wrapping the powder with such an oblate is also very complicated. Therefore, recently, so-called film preparations in which an active ingredient is blended with an edible film have been developed.

  As materials capable of forming an edible film, for example, pullulan, carrageenan, agar, gelatin, chitin, chitosan, starch and the like are known. Pullulan films are strongly hygroscopic and tend to be sticky under high humidity. In addition, pullulan films are hard and very poor in the mouth. Furthermore, films of carrageenan, agar, gelatin and the like have low solubility in cold water, and the gelatin film has very high hygroscopicity and has a drawback that the surface is sticky. Furthermore, the use of gelatin is often limited due to religious reasons, allergy problems, mad cow problems, and the like. Moreover, chitin and chitosan have peculiar odors (raw odor), astringency, and egg flavor, and are not suitable for use in the oral cavity.

  Also, when starch is used as a film material, for example, a film formed from unmodified starch such as wafers is very brittle and is not flexible so it is fragile. Therefore, JP 2000-342193 A (Patent Document 1) discloses an edible film that is formed from hydroxypropylated starch, is soluble in cold water, has low hygroscopicity, and does not stick to the surface under high humidity. Has been. Japanese Patent Application Laid-Open No. 2006-25682 (Patent Document 2) discloses an edible film which contains a galactomannan decomposition product and has a good mouth melt. However, when forming a film from these materials such as starch and galactomannan, heat treatment and, in some cases, boiling are required to dissolve these film materials in water. Moreover, also in the drying process of a film, the heat drying by a hot air is needed and the manufacture is very complicated.

JP 2000-342193 A JP 2006-25682 A

  As described above, when a film is formed from materials such as starch and galactomannan, heat treatment such as boiling dissolution of the film material and heat treatment with hot air in the film drying process are required, and it is insensitive to heat as an active ingredient. When a stable substance is blended in the film, the active ingredient is decomposed during these heat treatments, so that it is very difficult to obtain a film preparation. When film preparations are used as pharmaceuticals, foods, cosmetics, etc., sterilization of film materials, especially heat sterilization such as autoclaving, is essential, and films that denature and harden when heated, such as starch and galactomannan. The material is not suitable for the production of film formulations intended for these applications. In addition, film preparations suitable for pharmaceuticals, foods, cosmetics, etc. have the property of being dissolved in a small amount of water such as saliva in the oral cavity, and the active ingredient being slowly released in the oral cavity for a predetermined period of time, or rapid release. Desired. Furthermore, since the film preparation for these uses is required to be a thin layer, it is desirable that the concentration of the aqueous solution containing the material forming the film is low. In addition, it is known that a thinner film can be formed, so that the density | concentration of the aqueous solution used for manufacture is low.

  Therefore, the present invention aims to provide a film preparation suitable for uses such as pharmaceuticals, foods, and cosmetics, and a method for producing the film preparation, and in particular, it can contain a heat-labile substance as an active ingredient, and oral administration, particularly It aims at providing the film formulation suitable for intraoral administration.

  As a result of intensive studies, the present inventors can sterilize by heating even when a polysaccharide produced by a microorganism, particularly a microorganism belonging to the genus Bifidobacterium, is dissolved in water, that is, in an aqueous solution. It has been found that it can be modified during heating and does not harden. Furthermore, the present inventors have found that the polysaccharide produced by such a microorganism can be easily formed into a film from an aqueous solution without being heated and dissolved in water at a low concentration and without being dried by heating. Therefore, the present inventors added a low concentration aqueous solution containing polysaccharides produced by microorganisms by heat sterilization, and then added an active ingredient, particularly a heat labile substance, to this aqueous solution and dried at room temperature without further heating. From this aqueous solution, it was found that a thin film preparation suitable for uses such as pharmaceuticals, foods and cosmetics can be easily formed, and the present invention has been completed.

  A film base containing a polysaccharide produced by a microorganism belonging to the genus Bifidobacterium, and an active ingredient in the film base.

  In the film preparation of the present invention, preferably, the microorganism is Bifidobacterium longum.

  In the film preparation of the present invention, preferably, the polysaccharide produced by the microorganism is Bifida polysaccharide (BPS).

  In the film preparation of the present invention, preferably, the active ingredient is a substance that acts in the oral cavity.

  In the film preparation of the present invention, the active ingredient is preferably a substance that is absorbed in the oral cavity.

  In the film preparation of the present invention, preferably, the active ingredient is a water-soluble or water-dispersible substance.

  In the film preparation of the present invention, preferably, the active ingredient is a heat labile substance.

  In the film preparation of the present invention, preferably, the active ingredient is an orally administered drug.

  In the film preparation of the present invention, preferably, the active ingredient is a therapeutic agent for stomatitis.

  In the film preparation of the present invention, preferably, the active ingredient is an oral local anesthetic.

  In the film preparation of the present invention, preferably, the active ingredient is an oral antibacterial substance.

  In the film preparation of the present invention, preferably, the active ingredient is an oral deodorizing substance.

  In the film preparation of the present invention, preferably, the active ingredient is a salivary secretion enhancer.

  In the film preparation of the present invention, the active ingredient is preferably selected from the group consisting of dexamethasone, lactoferrin, catechin, lidocaine and cevimeline.

  The film preparation of the present invention preferably further contains a plasticizer.

  The film preparation of the present invention is suitable for pharmaceuticals, foods or cosmetics.

  The film preparation of the present invention is suitable for oral administration.

  The present invention also provides an aqueous solution by dissolving a polysaccharide produced by a microorganism belonging to the genus Bifidobacterium in water, adding an active ingredient to the aqueous solution, drying the solution after applying the aqueous solution, and forming a film. The present invention relates to a method for producing the above film preparation.

  In the method for producing a film preparation of the present invention, preferably, the active ingredient is added after heat sterilization of the aqueous solution.

  In the manufacturing method of the film formulation of this invention, Preferably, the density | concentration of the polysaccharide of the aqueous solution containing the polysaccharide which the said microorganisms produced is 0.05 to 2 weight%.

  In the manufacturing method of the film formulation of this invention, Preferably, the density | concentration of the polysaccharide of the aqueous solution containing the polysaccharide which the said microorganisms produced is 0.2 to 1 weight%.

  According to the present invention, a low-concentration aqueous solution is prepared by dissolving a polysaccharide, particularly a polysaccharide produced by a microorganism of the genus Bifidobacterium, in water without any particular heating, and preferably after heat sterilization, After the application of the aqueous solution, it is possible to provide a simple method for producing a film preparation characterized by drying to form a film without further heating. Moreover, this invention can provide the film formulation which contains the film base containing the polysaccharide which microorganisms produced by such a manufacturing method, and an active ingredient in this film base.

  Conventionally, as described above, film materials such as pullulan, carrageenan, agar, gelatin, chitin, chitosan, starch, and galactomannan have been known as edible film materials. However, the present inventors have clarified that none of these is suitable for the use of film preparations, particularly oral film preparations. First, pullulan has a good film-forming property even after being heated and dissolved, but the formed film is hard and unsatisfactory and is not suitable for an oral film preparation. Further, it was found that pullulan is difficult to form a thin film at a concentration of 1% or less when it is used as an aqueous solution, and is not suitable for production of a film preparation. When film preparations were produced using carrageenan, agar, and gelatin as film materials, it was found that these films were difficult to dissolve in cold water, that is, they did not melt well in the oral cavity and were not suitable for oral film preparations. Furthermore, when a film preparation is produced using chitin or chitosan as a film material, these films have a strong discomfort in the oral cavity due to chitin and chitosan-specific odors (raw odor), astringency, and taste, etc. The pH drop due to the acid during the dissolution process becomes a problem. Furthermore, in the case of film materials such as starch and galactomannan, heat treatment is indispensable at the time of dissolution and film drying, and there is a problem that it is impossible to mix a thermally unstable substance as an active ingredient. In addition, when these conventional film materials are used, it is very difficult to achieve both excellent sustained release of the active ingredient and excellent film forming properties.

  However, in the present invention, a film preparation containing a heat-labile substance as an active ingredient can be provided by using a polysaccharide produced by a microorganism, in particular, a polysaccharide produced by Bifidobacterium as a film material. it can. This is because the polysaccharides produced by these microorganisms have excellent film-forming properties even after heat treatment including heat sterilization and do not require heat treatment even in the drying step. In the film preparation of the present invention, the solubility of a small amount of water such as saliva in the oral cavity is appropriately controlled by using polysaccharides produced by microorganisms, in particular, polysaccharides produced by Bifidobacterium. It is easy to mouth in the oral cavity, and the sustained release of the active ingredient can be adjusted arbitrarily. Therefore, this invention can achieve coexistence with the outstanding sustained release property of the active ingredient, and the outstanding film forming property.

  In addition, the polysaccharide produced by the microorganism can impart excellent flexibility to the film preparation, and in particular, it is not necessary to add a plasticizer or the like, and its production is very simple. Furthermore, since the film preparation of the present invention uses polysaccharides produced by microorganisms, it has low hygroscopicity and excellent storage stability. In addition, the polysaccharides produced by the microorganisms used in the present invention can be applied to the oral cavity without any uncomfortable feelings such as bitterness, astringency, taste and smell.

  Furthermore, the polysaccharide produced by the microorganism used in the present invention can be dissolved in water at a low concentration of 2% by weight or less, desirably 1% by weight or less, and heat treatment such as boiling is performed at the time of dissolution. There is no need. Also, there is no need to heat at all in the drying process during film formation. Therefore, in the present invention, a film preparation can be produced by a very simple operation, which is very economical.

  Moreover, the film formulation of this invention can mix | blend a pharmaceutical ingredient, a food ingredient, a cosmetic ingredient, etc. as an active ingredient, and is very useful as a pharmaceutical, foodstuff, cosmetics, etc. In particular, the film preparation of the present invention is very useful as a pharmaceutical or food suitable for oral administration, particularly oral administration, because of the above-mentioned advantages. In particular, the film preparation of the present invention comprises dexamethasone which is a therapeutic agent for stomatitis, lactoferrin which is an oral antibacterial substance, catechin which is an oral deodorant, and lidocaine which is an oral local anesthetic ( Lidocaine) and cavimeline (hydrochloride hydrate), which is a salivary secretion enhancer, are suitable for oral administration. Adding ingredients such as dexamethasone, catechin, lidocaine, cevimeline to conventional films, etc. requires heating or boiling to dissolve film materials such as starch and heating and drying with hot air during film formation. For this reason, it was not preferable, and it was impossible to blend a very heat-labile substance such as lactoferrin. Moreover, it has been very difficult to apply these active ingredients directly to the oral cavity, particularly to administer them with sustained release in the oral cavity.

Furthermore, in the film preparation of the present invention, the sustained release of the active ingredient can be arbitrarily set, so that the active ingredient can be released as an immediate release. Therefore, in the present invention, when an immediate-release film preparation is used, the film can be dissolved quickly even in a small amount of water, and the elderly and dry mouth patients (hypertensive agents, mental stability) Active ingredients even under limited conditions of salivary secretion, such as dry mouth due to side effects of other drugs such as drugs and reduced salivary secretion caused by diseases such as Sjogren's syndrome and diabetes) For example, salivary gland muscarinic (M ₃ ) receptor agonist cevimeline hydrochloride hydrate, oral antibacterial lactoferrin can be administered directly in the oral cavity, which is very beneficial. .

The time-dependent release | release behavior of DM of the film formulation manufactured from the 0.5% BPS (Bifida polysaccharide) aqueous solution (no heat sterilization) containing 0.75 mg dexamethasone (DM) is shown. The time-dependent release | release behavior of DM of the film formulation manufactured from the 0.5% BPS (Bifida polysaccharide) aqueous solution (with heat sterilization) containing 0.75 mg dexamethasone (DM) is shown. The time-dependent release | release behavior of DM of the film formulation manufactured from the 0.75% BPS (Bifida polysaccharide) aqueous solution (with heat sterilization) containing 0.75 mg dexamethasone (DM) is shown. The time-dependent release behavior of lactoferrin in a film preparation produced from a 0.5% BPS (Bifida polysaccharide) aqueous solution (with heat sterilization) containing 3.0 mg of lactoferrin (LF) is shown. The time-dependent release behavior of catechin of a film preparation produced from a 0.5% BPS (Bifida polysaccharide) aqueous solution (with heat sterilization) containing 1.5 mg of catechin is shown. The time-dependent release behavior of lidocaine in a film preparation produced from a 0.5% BPS (Bifida polysaccharide) aqueous solution (with heat sterilization) containing 1.5 mg of lidocaine is shown. FIG. 2 shows the release behavior of lidocaine over time in a film preparation produced from a 0.6% BPS (Bifida polysaccharide) aqueous solution (with heat sterilization) containing 1.5 mg of lidocaine.

  The present invention provides a film preparation containing a polysaccharide produced by a microorganism and a film preparation containing an active ingredient in the film base and a method for producing the film preparation.

  As the “polysaccharide produced by a microorganism” that can be used in the present invention, a polysaccharide produced by a microorganism belonging to the genus Bifidobacterium is particularly preferable, and these are collectively referred to as Bifida polysaccharide (BPS) and be called. Of the genus Bifidobacterium, Bifidobacterium longum is particularly preferable.

  As polysaccharides produced by Bifidobacterium longum, polysaccharides consisting only of glucose (Japanese Patent Laid-Open No. 7-255465); polysaccharides consisting of glucose, galactose, uronic acid, etc. (Appl. Microbial. Biotechnol. 43, 995-) 1000); a polysaccharide produced by Bifidobacterium longum JBL05, particularly a polysaccharide containing galactose, glucose, rhamnose and pyruvic acid obtained from Bifidobacterium longum JBL05 (NITE BP-82) (galactose: glucose) : Rhamnose = 4: 2: 1 (molar ratio), 4-7 wt% pyruvic acid) (International Publication No. 2007/007562 pamphlet).

  The polysaccharide produced by the microorganism can be easily dissolved in water without heating. An edible film can be easily formed by applying an aqueous solution containing polysaccharides produced by microorganisms and drying it at room temperature (usually about 1 to 30 ° C.) without further heating. . Therefore, polysaccharides produced by microorganisms have excellent film-forming properties.

  Among the polysaccharides produced by microorganisms, the polysaccharides produced by the genus Bifidobacterium, especially Bifidobacterium longum, have a high water retention capacity that can be used as a moisturizing agent, and can be easily applied to water without heating. Can be dissolved to form a low-concentration polysaccharide aqueous solution. For starch, which is well known as a material capable of forming a film as in the past, it was necessary to prepare an aqueous solution by heating or boiling, so the aqueous solution must be concentrated to form a low-concentration aqueous solution. Was impossible in the manufacturing process. Further, when a heated starch aqueous solution is applied to form a film, a heat treatment with hot air is required even during drying. In addition, conventionally, a heating and drying process using such hot air has been essential, so it has been very difficult to blend a thermally unstable substance.

  In the manufacturing method of the film formulation of this invention, the density | concentration of the polysaccharide of the aqueous solution containing the polysaccharide which microorganisms produced is 0.05 to 2 weight%, More preferably, it is 0.2 to 1 weight%. If the concentration is less than 0.05% by weight, the strength of the formed film may be significantly reduced, and the film may be broken. If the concentration exceeds 2% by weight, the flexibility of the formed film is likely to occur. Decreases and becomes hard, and when the film preparation is administered into the oral cavity, the dissolution rate of the film in the oral cavity may be significantly reduced. Therefore, in the present invention, when the concentration is 2% by weight or less, desirably 1% by weight or less, it becomes easy to form a thin film having excellent flexibility, and a thin film particularly suitable for oral administration is provided. be able to.

  Moreover, the above-mentioned polysaccharides produced by microorganisms do not denature or harden even when heat is applied, can be heat sterilized, and their film-forming properties are not significantly reduced after heat sterilization. In the method for producing a film preparation of the present invention, in particular, an aqueous solution containing polysaccharides produced by microorganisms can be sterilized by heating as it is, and for example, heat sterilization in an autoclave is possible. In the autoclave treatment, it is usually sufficient to sterilize by heating at a temperature of 115 to 135 ° C, preferably 120 to 130 ° C for 15 to 60 minutes, preferably 20 to 30 minutes. At this time, the pressure in the autoclave may be adjusted to 1.7 to 2.0 atm to be autoclaved.

  By sterilizing polysaccharides produced by microorganisms, the film preparation of the present invention can be used more safely and stably, particularly in applications such as pharmaceuticals, foods, and cosmetics.

  In this invention, an active ingredient is mix | blended in the film formed from the aqueous solution containing the polysaccharide which the above-mentioned microorganisms produced, The film formulation containing a film base and an active ingredient can be manufactured. The active ingredient that can be blended in the film preparation of the present invention is not particularly limited, and includes pharmaceutical ingredients, food ingredients, cosmetic ingredients, and the like.

  As the active ingredient, a substance that acts in the oral cavity, a substance that is absorbed in the oral cavity, and the like are particularly preferable. Further, from the production method of the present invention, the active ingredient is preferably a water-soluble or water-dispersible substance, and surprisingly, it may be a thermally unstable substance.

  The drug component may be either an orally administered drug or a parenterally administered drug. However, since the film preparation of the present invention is desirably administered orally, drugs such as orally administered drugs and transdermally absorbable drugs are particularly preferred.

Examples of the pharmaceutical ingredient include a therapeutic agent for stomatitis (for example, dexamethasone (available from WAKO), triamcinolone acetonide, dipotassium glycyrrhizinate, sodium azulene sulfonate, hydrocortisone acetate, etc.);
Oral local anesthetics (eg, lidocaine (available from WAKO, eg, lidocaine hydrochloride (SIGMA Co.)), ethyl paraaminobenzoate, oxyprocaine, tetracaine, procaine, parabutylaminobenzoic acid, diethylamino Ethyl);
Salivary secretion enhancers (for example, cevimeline (hydrochloride hydrate) which is a muscarinic (M ₃ ) receptor agonist of salivary glands, pilocarpine hydrochloride, anethole trithione, etc.).

  Food ingredients include (oral) antibacterial substances (for example, lactoferrin, epigallocatechin gallate, propolis, etc.); (oral) deodorant substances (for example, catechin, parsley seed oil, rosemary extract) , Champignon extract, green tea extract, etc.), but not limited thereto.

  Cosmetic ingredients include, but are not limited to, vitamins (eg, vitamin C, vitamin E, multivitamin, etc.), arbutin, ellagic acid, CoQ10, collagen, hyaluronic acid and the like. In addition, although these cosmetic ingredients are not orally administered drugs, they can be made into film cosmetics with excellent portability and are very useful.

  In the present invention, as described above, after preparing an aqueous solution containing polysaccharides produced by microorganisms, preferably after heat sterilization, the active ingredient is preferably added to the aqueous solution. By doing so, a thermally unstable substance can be easily incorporated into the film, which is very beneficial. In addition, as described above, in the present invention, it is not necessary to further heat and dry the film after the application of the aqueous solution containing the polysaccharide produced by the microorganism. Suitable for compounding unstable substances. Among these, the present invention is particularly suitable for blending drugs such as dexamethasone, lidocaine and cevimeline, and antibacterial and deodorant substances such as lactoferrin and catechin.

  The compounding amount of the active ingredient is not particularly limited, and may be appropriately selected according to the type of the active ingredient, the desired use and purpose, and is usually 0.01 to 40% by weight based on the weight of the film base. The content is preferably 0.1 to 30% by weight, more preferably 1 to 20% by weight. If the blending amount of the active ingredient is less than 0.01% by weight, the content of the active ingredient is small, so that there is a risk of problems such as an increase in the amount of the administered film and difficulty in taking it. There is a risk of problems such as a decrease in film forming property and flexibility. Two or more active ingredients may be used in appropriate combination.

  In addition, since the film base that can be formed from the polysaccharide produced by the microorganism of the present invention has sufficient flexibility, it is not particularly necessary to add a plasticizer. However, when an aqueous solution containing polysaccharides produced by microorganisms is applied to a substrate and dried to form a film, and then the formed film is peeled from the substrate, sufficient flexibility is required, so glycerin, polyethylene glycol, Plasticizers such as polyhydric alcohols such as propylene glycol and sugar alcohols such as sorbitol and mannitol may be added to the film alone or in admixture of two or more. The blending amount of the plasticizer is not particularly limited, and is usually 0.1 to 25% by weight, preferably 0.5 to 20% by weight, more preferably 1 to 10% by weight with respect to the total weight of the film preparation. is there. If the blending amount of the plasticizer is less than 0.1% by weight, there is a risk of the film being easily cracked in a low humidity environment. If it exceeds 25% by weight, the film is applied to the substrate at the time of film production. There is a risk that the adhesion of the film increases and the film is difficult to peel off from the substrate.

  Further, in the film preparation of the present invention, in addition to the above-mentioned components, usual additives that can be incorporated into the edible film, such as colorants, flavors, sweeteners, corrigents, pH adjusters, preservatives , Thickeners, antistatic agents and the like can be appropriately blended in appropriate amounts.

  The thickness of the film preparation of the present invention is not particularly limited and may be appropriately selected according to the type of active ingredient, desired use and purpose, and is usually 5 to 500 μm, preferably 10 to 300 μm, more preferably 20 ~ 200 μm. If the thickness is less than 5 μm, the film strength may be low and the film may be easily broken, and if it exceeds 500 μm, the solubility in the oral cavity is deteriorated.

  As described above, in the present invention, the polysaccharide produced by the above microorganism is dissolved in water to prepare an aqueous solution, the above-mentioned active ingredient is added to this aqueous solution, and the aqueous solution containing the active ingredient is mixed with metal, glass, plastic, etc. The film preparation of the present invention can be easily produced by coating the substrate, preferably a plastic substrate, followed by drying to form a film and removing the film from the substrate. In addition, since the manufacturing method of this invention does not require a heating at the time of preparation of aqueous solution and drying of a film, it is very simple.

  Therefore, the method for producing a film preparation of the present invention can produce a film preparation at room temperature, is very simple, and is very economical. Moreover, since the manufacturing method of this invention does not require heat processing separately, a heat unstable substance can be mix | blended in a film base, and it is very useful. In addition, as described above, in the production method of the present invention, even when an aqueous solution containing the polysaccharide produced by the above-described microorganism is heat sterilized (for example, autoclaved), excellent film-forming properties are not lost. In addition, a film preparation suitable for uses such as food and cosmetics can be provided more safely and stably. In particular, the film preparation of the present invention is excellent in mouth melting feeling in the oral cavity, and can provide a film preparation suitable for oral administration.

Example 1
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.5% BPS aqueous solution was prepared (pH: 5.99, viscosity: 30 mPa · s (20 ° C.)).
As an active ingredient, 0.75 mg of dexamethasone (DM) (obtained from WAKO) was added as an active ingredient to 3 g of the 0.5% BPS aqueous solution prepared above.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Example 2
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.5% BPS aqueous solution was prepared (pH: 5.99, viscosity: 30 mPa · s (20 ° C.)).
A 0.5% BPS aqueous solution was sterilized by heating in an autoclave (121 ° C., 15 minutes, 2 atm).
As an active ingredient, 0.75 mg of dexamethasone (DM) (obtained from WAKO) was added as an active ingredient to 3 g of the 0.5% BPS aqueous solution prepared above.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Example 3
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.75% BPS aqueous solution was prepared (pH: 5.9, viscosity: 48 mPa · s (20 ° C.)).
A 0.75% BPS aqueous solution was sterilized by heating in an autoclave (121 ° C., 15 minutes, 2 atm).
As an active ingredient, 0.75 mg of dexamethasone (DM) (obtained from WAKO) as an active ingredient was added to 3 g of the 0.75% BPS aqueous solution prepared above.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Example 4
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.5% BPS aqueous solution was prepared (pH: 5.99, viscosity: 30 mPa · s (20 ° C.)).
A 0.5% BPS aqueous solution was sterilized by heating in an autoclave (121 ° C., 15 minutes, pressure 2 atm).
The oral antibacterial substance lactoferrin (LF) (obtained from WAKO) 3.0 mg was blended as an active ingredient in 3 g of the 0.5% BPS aqueous solution prepared above.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Example 5
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.5% BPS aqueous solution was prepared (pH: 5.99, viscosity: 30 mPa · s (20 ° C.)).
A 0.5% BPS aqueous solution was sterilized by heating in an autoclave (121 ° C., 15 minutes, 2 atm).
1.5 mg of catechin (available from WAKO) was blended as an active ingredient in 3 g of the 0.5% BPS aqueous solution prepared above.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Example 6
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.5% BPS aqueous solution was prepared (pH: 5.99, viscosity: 30 mPa · s (20 ° C.)).
A 0.5% BPS aqueous solution was sterilized by heating in an autoclave (121 ° C., 15 minutes, 2 atm).
As an active ingredient, 3 mg of the 0.5% BPS aqueous solution prepared above was combined with 1.5 mg of lidocaine (hydrochloride) (obtained from WAKO) as an oral oral anesthetic.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Example 7
A polysaccharide (Bifida polysaccharide (BPS)) produced by Bifidobacterium longum (Bifidobacterium longum) as a microorganism was dissolved in water at room temperature (25 ° C.). Thus, a 0.6% BPS aqueous solution was prepared (pH: 5.99, viscosity: 38 mPa · s (20 ° C.)).
The 0.6% BPS aqueous solution was sterilized by heating in an autoclave (121 ° C., 15 minutes, 2 atm).
1.5 mg of lidocaine (hydrochloride) (obtained from WAKO), which is an oral local anesthetic, was added as an active ingredient to 3 g of the 0.6% BPS aqueous solution prepared above.
The above aqueous solution was applied to a disposable plastic petri dish having a diameter of 54 mm and dried at room temperature (30 ° C.) without further heating to obtain a thin, uniform and flexible film having a thickness of 30 μm. In addition, Nikon DIGIMICRO STAND MS-1C type was used for film thickness measurement.

Evaluation of Release Behavior of Film-Containing Active Ingredient The film preparation prepared in the example was immersed in physiological saline, and the release amount of each active ingredient accompanying dissolution of the film was determined under the following measurement conditions.

(Measurement condition)
Into a petri dish with a diameter of 54 mm, 10 ml of 37 ° C. physiological saline (conditions assuming the oral cavity) was added, and the film preparation prepared in each example was immersed therein, and a shaking incubator (ASONE SI-300: 37 ° C., The sample was sampled over time while shaking at 300 rpm), methanol was added to the removed sample, the mixture was sufficiently stirred and centrifuged (10000 rpm, 5 minutes) to separate the polysaccharide, and then the active ingredient was analyzed by HPLC. The amount of determined.

(HPLC conditions)
Dexamethasone (DM)
Column: Cosmosil 5C ₁₈ -MS-II (4.6 × 150 mm)
Flow rate: 0.8 ml / min Eluent: 10 mM phosphate buffer (pH 2.3): CH ₃ CN = 7: 3
Detection: 220nm
Sample injection volume: 10 μl (Shimadzu auto injector SIL-10A)
Catechin column: Cosmosil 5C ₁₈ -MS-II (4.6 × 150 mm)
Flow rate: 0.8 ml / min Eluent: 0.1% Citric acid: CH ₃ CN = 870: 130
Detection: 280nm
Sample injection volume: 10 μl (Shimadzu auto injector SIL-10A)
[T. Fu. , Et al. , J .; Chromatogr. B, 875, 363-367 (2008)]
Lidocaine column: Cosmosil 5C ₁₈ -MS-II (4.6 × 150 mm)
Flow rate: 0.8 ml / min Eluent: 50 mM phosphate buffer (pH 3.0): CH ₃ CN = 850: 150
Detection: 220nm
Sample injection volume: 10 μl (Shimadzu auto injector SIL-10A)
[A. Kodate, et al. , J .; Pharm. Biomedicai. Anal. 47, 190-194 (2008)]

  Regarding lactoferrin (LF), the film preparation was immersed in 10 ml of physiological saline at 37 ° C., and the sample (25 μl over time) was shaken in a shaking incubator (As One SI-300: 37 ° C., 300 rpm). ) Was sampled in a 96-well microplate, and the amount of lactoferrin (LF) was measured using a multi-plate reader (Dainippon Pharmaceutical Co., Ltd., Viento) using the BCA method.

  As shown in the graph of FIG. 1, when the release amount (mg) of dexamethasone (DM) is taken on the vertical axis and the release time (minute) is taken on the horizontal axis, the film preparation (0.5% BPS) produced in Example 1 is taken. (Using aqueous solution) showed sustained release that released the entire amount of dexamethasone (0.75 mg) over about 20 minutes. Moreover, even when 0.25% BPS aqueous solution was used, the film preparation showed the same sustained release property.

  As shown in the graph of FIG. 2, the film preparation produced in Example 2 also exhibited sustained release that released the entire amount of dexamethasone (0.75 mg) over about 20 minutes.

  As shown in the graph of FIG. 3, in the film preparation produced in Example 3, compared to Example 1 (FIG. 1) and Example 2 (FIG. 2), the initial release amount of dexamethasone (DM) was suppressed, Over 20-30 minutes, it showed a slow sustained release that released the entire amount of dexamethasone (0.75 mg).

  From the results of Examples 1 to 3, according to the film preparation of the present invention, dexamethasone (DM) can be administered into the oral cavity as an active ingredient, and by providing sustained release, the conventional oral ointment Compared with application by (marketed drug dexartin (manufactured by Nippon Kayaku Co., Ltd. (containing 1 mg / g dexamethasone)), the effect of administration could be dramatically improved.

  Moreover, as shown in the graph of FIG. 4, when the release amount (mg) of lactoferrin (LF) is taken on the vertical axis and the release time (minutes) is taken on the horizontal axis, the film preparation produced in Example 4 is about 15 In a minute, it showed a sustained release property that released the entire amount of lactoferrin (3.0 mg).

  Furthermore, as shown in the graph of FIG. 5, when the release amount (mg) of catechin is taken on the vertical axis and the release time (minute) is taken on the horizontal axis, the film preparation produced in Example 5 is instantaneously It showed an immediate release property that released the entire amount of catechin (1.5 mg).

  As shown in the graph of FIG. 6, when the release amount (mg) of lidocaine is taken on the vertical axis and the release time (minutes) is taken on the horizontal axis, the film preparation (0.5% BPS) produced in Example 6 is taken. (Using aqueous solution) showed immediate release, which instantaneously released the total amount of lidocaine (1.5 mg).

  Moreover, as shown in the graph of FIG. 7, the film preparation (using a 0.6% BPS aqueous solution) produced in Example 7 showed a rapid release property that instantaneously releases the total amount (1.5 mg) of lidocaine.

  From the results of Examples 4 to 7, according to the film preparation of the present invention, in addition to dexamethasone (DM) which is a therapeutic agent for stomatitis, lactoferrin which is an oral antibacterial substance, catechin having a deodorizing action, and oral local anesthetic It was possible to formulate an active ingredient such as lidocaine into a film formulation and to administer it not only in a sustained release but also in the oral cavity with an immediate release.

  Since the film preparation of the present invention can be sterilized, it is very useful as foods such as pharmaceuticals and functional foods, and cosmetics. In addition, the film preparation of the present invention is very useful for administration of pharmaceuticals, in particular, orally administered drugs, in particular, orally administered drugs used in dentistry and oral surgery. Further, the film preparation of the present invention can be applied to a heat-labile substance such as lactoferrin, which is very useful.

In the film preparation of the present invention, the active ingredient can be administered as sustained release or immediate release. Therefore, in the present invention, when an immediate-release film preparation is used, the film can be dissolved quickly even in a small amount of water, and the elderly and dry mouth patients (hypertensive agents, mental stability) Active ingredients even under limited conditions of salivary secretion, such as dry mouth due to side effects of other drugs such as drugs and reduced salivary secretion caused by diseases such as Sjogren's syndrome and diabetes) For example, active ingredients such as cevimeline (hydrochloride hydrate), a salivary gland muscarinic (M ₃ ) receptor agonist, and lactoferrin, an antibacterial agent, can be administered significantly directly in the oral cavity. It is beneficial.

Claims (21)

  A film base containing a polysaccharide produced by a microorganism belonging to the genus Bifidobacterium, and an active ingredient in the film base.   The film formulation of Claim 1 whose said microorganisms are Bifidobacterium longum (Bifidobacterium longum).   The film formulation of Claim 1 or 2 whose polysaccharide which the said microorganisms produced is Bifida polysaccharide (Bifida polysaccharide (BPS)).   The film formulation of any one of Claims 1-3 whose said active ingredient is a substance which acts in an oral cavity.   The film formulation of any one of Claims 1-4 whose said active ingredient is a substance absorbed in an oral cavity.   The film preparation according to any one of claims 1 to 5, wherein the active ingredient is a water-soluble or water-dispersible substance.   The film formulation of any one of Claims 1-6 whose said active ingredient is a substance unstable to heat.   The film formulation of any one of Claims 1-7 whose said active ingredient is an orally administered drug.   The film formulation of any one of Claims 1-8 whose said active ingredient is a stomatitis therapeutic agent.   The film formulation according to any one of claims 1 to 9, wherein the active ingredient is an oral local anesthetic.   The film formulation according to any one of claims 1 to 10, wherein the active ingredient is an oral antibacterial substance.   The film formulation of any one of Claims 1-11 whose said active ingredient is an intraoral deodorizing substance.   The film formulation of any one of Claims 1-12 whose said active ingredient is a salivary secretion enhancer.   The film formulation according to any one of claims 1 to 13, wherein the active ingredient is selected from the group consisting of dexamethasone, lactoferrin, catechin, lidocaine and cevimeline.   The film preparation according to any one of claims 1 to 14, further comprising a plasticizer. The film formulation of any one of Claims 1-15 used for a pharmaceutical, a foodstuff, or cosmetics. The film formulation of any one of Claims 1-16 used for intraoral administration.   A polysaccharide produced by a microorganism belonging to the genus Bifidobacterium is dissolved in water to prepare an aqueous solution, an active ingredient is added to the aqueous solution, and the aqueous solution is applied and dried to form a film. The manufacturing method of the film formulation of any one of -17.   The manufacturing method of the film formulation of Claim 18 which adds an active ingredient after heat-sterilizing the said aqueous solution.   The manufacturing method of the film formulation of Claim 18 or 19 whose density | concentration of the polysaccharide of the aqueous solution containing the polysaccharide which the said microorganisms produced is 0.05 to 2 weight%.   The manufacturing method of the film formulation of any one of Claims 18-20 whose density | concentration of the polysaccharide of the aqueous solution containing the polysaccharide which the said microorganisms produced is 0.2 to 1 weight%.

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