Oral film and production method for same

Abstract

[Problem] To provide: an oral film that uses hydroxypropyl methylcellulose as a film base material component and, due to effective homogenization of the particle size of a disintegrant, has more favorable disintegration than conventional oral films; and a production method for the oral film. [Solution] Provided is an oral film that includes hydroxypropyl methylcellulose as a film base material component and disintegrates in the oral cavity, the oral film containing 10–20 wt% of a partially decomposed starch that has a dextrose equivalent (DE) of 1.4–3.5 and including insoluble particles derived from the partially decomposed starch.

Description

Oral Film and Method for Producing the Same

[0001] The present invention relates to an oral film and a method for producing the same.

[0002] In the case of medical drugs, various forms such as solid tablets and sheet-like film preparations are known. For example, after a solid tablet is taken with water, its shape is disintegrated in the stomach to elute the active ingredient and absorb it into the digestive tract. In this type of tablet, since it is necessary to easily disintegrate in the body in order to efficiently elute the active ingredient when taken, a disintegrant that facilitates the disintegration of the tablet by absorbing moisture is contained.

[0003] The disintegrant exists, for example, in a particulate form in the tablet, swells by supplying water, and destroys the matrix structure of the tablet by its swelling force to cause disintegration (see Patent Document 1). As another disintegrant, a water-conducting type disintegrant that guides moisture inside the tablet to cause disintegration is also known. Examples of this type of disintegrant include calcium carmellose (CMC-Ca), low-substituted hydroxypropyl cellulose (HPC), corn starch, sucrose fatty acid ester, gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene, polyoxypropylene glycol, and the like.

[0004] In addition, in this type of tablet, hydroxypropyl methylcellulose (HPMC), which is a water-soluble polymer, may be used as a constituent material of the wall film (see, for example, Patent Document 2). HPMC does not dissolve but disperses in hot water (for example, about 70°C), swells and thickens upon cooling (for example, less than about 50°C), has the property of being less likely to absorb moisture even in a high-humidity environment, and is a material that is widely used as a food additive and has no toxicity and excellent safety, so it is suitable as a constituent material of the wall film of the tablet.

[0005] On the other hand, oral films such as film formulations have a matrix structure consisting of a soluble base material made of water-soluble polymers and a disintegrant made of water-insoluble particles. In the oral cavity, saliva causes a dissolution process in which the soluble base material is dissolved, and a disintegration process in which the disintegrant disintegrates the matrix structure, resulting in the dissolution of the active ingredient. In film formulations, the above-mentioned constituent materials used in tablets can be used for the soluble base material and disintegrant.

[0006] In oral films, it is preferable from a workability standpoint to mix the constituent materials in a single tank during manufacturing, ensuring uniformity and dispersion of the components. However, when using the above-mentioned disintegrant as a constituent material, the uneven particle size necessitates a separate process to homogenize the particle size of the disintegrant, which may reduce workability.

[0007] Furthermore, while inexpensive and readily available food-derived cornstarch is preferred as a disintegrant for oral films, its property of gelatinizing at high temperatures means that when HPMC is used as the film substrate, if cornstarch is added during high-temperature dispersion, some of the cornstarch gelatinizes and thickens the film. If cornstarch is added after cooling in a thickened state, the particles become non-uniform, leading to problems such as difficulty in properly manufacturing oral films.

[0008] Japanese Patent Publication No. 2023-184766 Japanese Patent Publication No. 2017-176907

[0009] The present invention has been made in view of the above points, and provides an oral film and a method for producing the same, in which, when hydroxypropyl methylcellulose is used as a film substrate component, the particle size of the disintegrant is efficiently made uniform compared to conventional methods, and good disintegration properties are obtained.

[0010] In other words, the first invention relates to an oral film that disintegrates in the oral cavity, with hydroxypropyl methylcellulose as the film substrate component, and is characterized by containing 10 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5, and having insoluble particles derived from the partially hydrolyzed starch product.

[0011] The second invention relates to an oral film that disintegrates in the oral cavity, wherein the film base component is a mixed material of at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate, and hydroxypropyl methylcellulose, and is characterized by containing 5 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5, and having insoluble particles derived from the partially hydrolyzed starch product.

[0012] The third invention relates to an oral film in which, in the first or second invention, the raw material starch of the partially hydrolyzed starch is one or more selected from potato starch, corn starch, or tapioca starch.

[0013] The fourth invention relates to an oral film in which the molecular weight dispersion of the partially hydrolyzed starch is 42,000 to 60,000, in the first or second invention.

[0014] The fifth invention relates to an oral film having a surface layer laminated on one or both sides of the oral film described in the first or second invention.

[0015] The sixth invention relates to a method for producing an oral film, comprising: a stock solution preparation step of preparing a stock solution containing a solvent at 70°C or higher, hydroxypropyl methylcellulose, and a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5; a stirring step of stirring the stock solution obtained from the stock solution preparation step; a cooling step of cooling the stock solution after the stirring step to form insoluble particles derived from the partially hydrolyzed starch product; and a molding step of forming the stock solution after the cooling step into a film.

[0016] The seventh invention relates to a method for producing an oral film, comprising: a stock solution preparation step of preparing a stock solution containing a solvent at 70°C or higher, a mixed material of at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate and hydroxypropylmethylcellulose, and a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5; a stirring step of stirring the stock solution obtained from the stock solution preparation step; a cooling step of cooling after the stirring step to form insoluble particles derived from the partially hydrolyzed starch product; and a molding step of forming the stock solution after the cooling step into a film.

[0017] According to the first invention, the oral film uses hydroxypropyl methylcellulose as a film substrate component and disintegrates in the oral cavity. It contains 10 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5, and has insoluble particles derived from the partially hydrolyzed starch product. Compared to conventional products, the particle size of the disintegrant can be efficiently made uniform, resulting in an oral film with good disintegration properties.

[0018] According to the second invention, the oral film is made of a mixed material of at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate, and hydroxypropyl methylcellulose as the film base component, and is an oral film that disintegrates in the oral cavity, containing 5 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5, and having insoluble particles derived from the partially hydrolyzed starch product, thereby enabling efficient homogenization of the particle size of the disintegrant compared to conventional products, and providing an oral film with good disintegration properties.

[0019] According to the oral film of the third invention, in the first or second invention, the raw material starch of the partially hydrolyzed starch is one or more selected from potato starch, corn starch, or tapioca starch, so the raw material is inexpensive and readily available, which is economically advantageous.

[0020] According to the oral film of the fourth invention, in the first or second invention, the molecular weight dispersion of the partially hydrolyzed starch is 42,000 to 60,000, which makes it possible to improve the heat resistance of the partially hydrolyzed starch.

[0021] According to the fifth invention, since a surface layer is laminated on one or both sides of the oral film described in the first or second invention, it is possible to improve strength and impart appropriate functionality.

[0022] The method for producing an oral film according to the sixth invention includes a stock solution preparation step of preparing a stock solution containing a solvent at 70°C or higher, hydroxypropyl methylcellulose, and a partially hydrolyzed starch having a dextrose equivalent (DE) of 1.4 to 3.5; a stirring step of stirring the stock solution obtained from the stock solution preparation step; a cooling step of cooling after the stirring step to form insoluble particles derived from the partially hydrolyzed starch; and a molding step of forming the stock solution after the cooling step into a film. As a result, the disintegrant can be formed with a uniform particle size without performing a separate step to homogenize the particle size of the disintegrant, and an oral film with good disintegration properties can be obtained more efficiently than conventional methods.

[0023] The method for producing an oral film according to the seventh invention includes a stock solution preparation step of preparing a stock solution containing a solvent at 70°C or higher, a mixed material of at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate and hydroxypropyl methylcellulose, and a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5; a stirring step of stirring the stock solution obtained from the stock solution preparation step; a cooling step of cooling after the stirring step to form insoluble particles derived from the partially hydrolyzed starch product; and a molding step of forming the stock solution after the cooling step into a film. As a result, the disintegrant can be formed with a uniform particle size without performing a separate step to homogenize the particle size of the disintegrant, and an oral film with good disintegration properties can be obtained more efficiently than conventional methods.

[0024] The present invention relates to an oral film that disintegrates in the oral cavity, using hydroxypropyl methylcellulose as the film substrate component. This oral film is suitably used as a film formulation and the like. The oral film of the present invention is manufactured by a manufacturing method that includes a stock solution preparation step, a stirring step, a cooling step, and a molding step. The oral film of the present invention will be described in detail below, along with its manufacturing method, using the oral film according to the first and second embodiments as examples.

[0025] An oral film according to the first embodiment of the present invention uses hydroxypropyl methylcellulose, a water-soluble polymer, as a film substrate component, and contains 10 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5 as a disintegrant, and has insoluble particles derived from the partially hydrolyzed starch product.

[0026] Hydroxypropyl methylcellulose (HPMC) is a nonionic, water-soluble cellulose ether. It is poorly soluble and dispersed in hot water above approximately 70°C, but dissolves in cold water below approximately 50°C to form a viscous aqueous solution. When the aqueous solution is heated above a certain temperature, it gels, and when cooled, it returns to its original state. HPMC has properties that prevent interaction with other substances, exhibits excellent stability such as low moisture absorption even in high humidity environments, and is non-toxic and highly safe, making it suitable as a base material component for oral films.

[0027] Partially hydrolyzed starch products are hydrolyzed products obtained by enzymatically hydrolyzing raw starch. Raw starch is composed of amylose and amylopectin, etc. Amylose is a high-molecular-weight compound formed by α-D-glucopyranose linked in a linear chain by α-1,4 bonds. Amylopectin is a high-molecular-weight compound in which α-D-glucopyranose has a linear portion linked by α-1,4 bonds and a branched portion linked by α-1,6 bonds.

[0028] As raw material starch, any known starch can be used as appropriate. Examples include starches from corn (cornstarch), wheat, barley, rye, rice, sweet potato (sweet potato), potato (potato starch), peas, edamame, tapioca, as well as starches from glutinous grains such as glutinous wheat, glutinous millet, and glutinous barnyard millet, and waxy cornstarch and glutinous rice starch. In particular, using one or more raw materials selected from potato starch, cornstarch, or tapioca starch is preferable because they are inexpensive, readily available, and economically advantageous.

[0029] The enzyme used to decompose the raw material starch is not particularly limited as long as it can hydrolyze the α-1,4 linkage of starch, and various enzymes such as α-amylase [1,4-α-D-glucan glucanohydrolase (EC 3.2.1.1)] are preferably selected. Many of these enzymes are derived from the genera Aspergillus, Bacillus, etc., and from the perspective of kinetic reaction theory, a higher optimal temperature is desirable to increase reactivity. The enzyme used to decompose starch is preferably an α-amylase derived from thermophilic bacteria of the same genus with an optimal temperature of 70 to 90°C.

[0030] The partially hydrolyzed starch product used as a disintegrant in the oral film of the present invention is prepared by enzymatically breaking down the α-1,4 bonds of the raw material starch, adjusting the dextrose equivalent (DE) to 1.4 to 3.5, preferably 2.2 to 3.0. The dextrose equivalent (DE) is one of the indicators for understanding the degree of starch degradation in the partially hydrolyzed starch product. Dextrose is another name for glucose, and starch is a polymer that uses glucose as its constituent unit. A DE of 0 indicates that the starch has not been decomposed, and the closer the DE value is to 0, the less the starch has been decomposed and the closer it is to starch. Generally, when the DE is 10 or less, it is called dextrin. A DE of 100 indicates that the starch has been completely decomposed to glucose, and the closer the DE value is to 100, the more the starch has been decomposed and the lower the molecular weight has been. The dextrose equivalent is measured by methods such as the Lehn-Einon method, the Bertrand method, and the Wilstetter-Schubel method. In this example, the Wilstetter-Schudel method, a common method for quantifying reducing sugars, is used.

[0031] In partially hydrolyzed starch products, if the dextrose equivalent is too low, the product gels during the manufacturing process, making it difficult to produce using general equipment. If the dextrose equivalent is too high, the amount of polymer responsible for water retention decreases, making it difficult to obtain practical gelling properties. Furthermore, the lower the dextrose equivalent (DE), the lower the degree of starch degradation in the partially hydrolyzed starch product, resulting in higher viscosity. This tends to reduce the productivity of partially hydrolyzed starch products. Conversely, the higher the dextrose equivalent (DE), the higher the degree of starch degradation in the partially hydrolyzed starch product, resulting in lower viscosity. This leads to good productivity of partially hydrolyzed starch products. When the dextrose equivalent is between 1.4 and 3.5, the degradation of starch is suppressed to a relatively mild degree, making it easily soluble in water (liquid) and convenient to handle.

[0032] Unlike typical partially hydrolyzed starch products, which dissolve at room temperature, maintain a moderate viscosity, and gelatinize at relatively high temperatures, this partially hydrolyzed starch product gels at room temperature and changes from a gel-like state to a liquid state at relatively high temperatures. The temperature at which the properties of this partially hydrolyzed starch product change tends to be higher as the degree of hydrolysis of the partially hydrolyzed starch product, i.e., the dextrose equivalent (DE), decreases, for example, above 70°C, preferably 75°C or higher, and more preferably 95°C or higher. Furthermore, the partially hydrolyzed starch product exhibits a property of softening more slowly as the temperature at which the change in properties occurs increases.

[0033] In oral films, appropriate functional components are added according to the intended use, such as pharmacoactive ingredients. Therefore, it is preferable to reduce the amount of disintegrant used, for example, to allow for the addition of more functional components. In the oral film of the present invention, by using a partially hydrolyzed starch product with a dextrose equivalent of 1.4 to 3.5 as a disintegrant, appropriate disintegration function can be imparted with a composition amount of about 10 to 20% by weight. If the amount of the partially hydrolyzed starch product is too low, its function as a disintegrant may be insufficient. If the amount is too high, the amount of functional components that can be added will decrease, which is undesirable.

[0034] In the partially hydrolyzed starch used in the oral film of the present invention, the weight-average molecular weight (Mw) is preferably 200 million to 520 million, and more preferably 220 million to 330 million. The weight-average molecular weight (Mw) is one of the average molecular weight indicators used when understanding the properties of natural polymer compounds such as starch, and is defined by the following formula (i). In formula (i), M ｉ N is the molecular weight of the molecules present in the polymer. ｉ Molecular weight M ｉ This is the number of molecules.

[0035]

[0036] As can be seen from equation (i), the weight-average molecular weight (Mw) is highly sensitive to the size of the constituent molecules. Therefore, even the influence of very small amounts of large molecules can be taken into account in the average molecular weight value. In the case of partially hydrolyzed starch products, the smaller the weight-average molecular weight, the better the productivity of the partially hydrolyzed starch product tends to be. If the weight-average molecular weight is too small, the amount of polymer responsible for water retention decreases, making it difficult to obtain practical gelling properties. Conversely, the larger the weight-average molecular weight, the lower the productivity tends to be with general equipment. If it is too large, the partially hydrolyzed starch product gels during the manufacturing process, making it difficult to produce. A weight-average molecular weight of 200 million to 520 million allows for a balance between practical gelling properties and productivity. The known high-performance liquid chromatography method is used to measure the weight-average molecular weight.

[0037] In the partially hydrolyzed starch used in the oral film of the present invention, the number-average molecular weight (Mn) is preferably 4,000 to 12,000, and more preferably 4,300 to 7,000. The number-average molecular weight (Mn) is an index that represents the average molecular weight per molecule and is defined by the following formula (ii). In formula (ii), M ｉ and N ｉ This is the same as formula (i) above. If the number-average molecular weight of the partially hydrolyzed starch product is too small, the amount of polymer responsible for water retention decreases, making it difficult to obtain practical gelling properties. If the number-average molecular weight is too large, the partially hydrolyzed starch product gels during the manufacturing process, making it difficult to manufacture using general equipment. A number-average molecular weight (Mn) of 4000 to 12000 allows for both practical gelling properties and productivity. The known high-performance liquid chromatography method is used to measure the number-average molecular weight.

[0038]

[0039] In the gel-like starch partial hydrolyzate of the present invention, the jelly strength is preferably 900 g to 4300 g, more preferably 960 g to 2400 g. The jelly strength is an index for grasping the hardness of the gel-like substance and is measured in accordance with JIS-K-6503 (2001). If the jelly strength is too small, the performance of forming a gel is low and it becomes difficult to maintain the shape in the high-temperature zone. If the jelly strength is too large, it becomes too hard and is unsuitable for a disintegrant. By having the jelly strength of 900 g to 4300 g, it has appropriate elasticity and is suitable as a disintegrant.

[0040] In addition, in the starch partial hydrolyzate, the molecular weight dispersity is preferably 42,000 to 60,000, more preferably 46,000 to 58,000. The molecular weight dispersity is an index for grasping how wide the molecular weight distribution is and is calculated by (weight-average molecular weight Mw / number-average molecular weight Mn). If the molecular weight dispersity is too small, the amount of the polymer responsible for water retention decreases, making it difficult to obtain practical gelling properties. If it is too large, the starch partial hydrolyzate gels during the manufacturing process, making it difficult to manufacture with general equipment. When the molecular weight dispersity is 42,000 to 60,000, the heat resistance of the starch partial hydrolyzate can be improved.

[0041] The stock solution preparation step is a step of obtaining a stock solution containing a solvent at 70°C or higher, hydroxypropyl methylcellulose, and a starch partial hydrolyzate having a dextrose equivalent (DE) of 1.4 to 3.5. The solvent is not particularly limited as long as it is a liquid having excellent safety for oral administration, and examples thereof include ion-exchanged water, distilled water, pure water, ultrapure water, and the like. In the stock solution preparation step, plasticizers such as edible glycerin, stabilizers, sweeteners, pH adjusters, colorants, flavoring agents, antioxidants, flavor correctors, and the like are added as necessary.

[0042] When HPMC is added to a solvent at 70°C or higher, it exists in a dispersed state without dissolving in the solvent. On the other hand, since partial starch hydrolyzates generally gelatinize and thicken when added to a high-temperature solvent, they function as thickeners as disclosed in, for example, JP 2017-176907 (the above Patent Document 3). In addition, corn starch, which has been widely used as a disintegrant, has a gelatinization start temperature around 60 to 70°C. Therefore, when added to a solvent at 70°C or higher together with HPMC, gelatinization starts, which may cause deterioration in handling and a decrease in disintegration properties. In contrast, the partial starch hydrolyzate having a dextrose equivalent of 1.4 to 3.5 used in the oral film of the present invention exhibits the property of softening while maintaining a predetermined viscosity in a temperature range exceeding 70°C, so that the stock solution can be appropriately adjusted without causing the above problems.

[0043] In the stock solution preparation step, the procedure for preparing the stock solution is not particularly limited. For example, it is preferable to add the partial starch hydrolyzate to a room-temperature solvent, heat it to 70°C or higher, and then add and disperse HPMC in the high-temperature solvent. By adding the partial starch hydrolyzate to the room-temperature solvent and then heating it, splashing of the high-temperature solvent is suppressed and it is safe.

[0044] The stirring step is a step of stirring the stock solution obtained from the stock solution preparation step. As described above, in the stock solution, HPMC is dispersed without dissolving in the solvent, and the partial starch hydrolyzate exists in a softened (liquid) state while maintaining a predetermined viscosity. By stirring this stock solution, the dispersed HPMC and the partial starch hydrolyzate with changed properties are uniformly mixed. The conditions for stirring the stock solution only need to be such that uniform mixing is possible, and are appropriately set according to the size of the apparatus and container, etc.

[0045] The cooling step is a process in which the mixture is cooled after the stirring step to form insoluble particles derived from partially hydrolyzed starch. These insoluble particles derived from partially hydrolyzed starch are insoluble granular substances formed when at least a portion of the partially hydrolyzed starch changes its properties from a liquid state during the cooling process of the raw solution from a relatively high temperature (70°C or higher), due to the property of partially hydrolyzed starch with a dextrose equivalent of 1.4 to 3.5 that changes its properties at high temperatures. Since these insoluble particles are uniformly mixed with HPMC during the stirring step, the particle size becomes relatively uniform, and they penetrate between the HPMC components, which are the film substrate components, thereby imparting disintegration function to the oral film. Thus, unlike partially hydrolyzed starch, which is generally used as a thickener, or corn starch, which gelatinizes at high temperatures, the present invention includes partially hydrolyzed starch with a dextrose equivalent (DE) of 1.4 to 3.5 as a disintegrant, thereby appropriately forming insoluble particles derived from partially hydrolyzed starch that impart disintegration properties to a film mainly composed of HPMC.

[0046] The means of cooling in the cooling process are not particularly limited, as long as it is possible to lower the temperature of the raw material after stirring to a level in which a change in the properties of the partially decomposed starch occurs. For example, it is possible to cool using known cooling devices, but slow cooling at room temperature is economically advantageous and preferred. The liquid temperature after cooling is preferably less than 40°C. If the liquid temperature after cooling is too high, insoluble particles may not be sufficiently formed, and it may not be possible to impart appropriate disintegration function. By sufficiently cooling the raw material after stirring in the cooling process, appropriate disintegration function can be imparted.

[0047] After cooling, degassing may be performed as needed. In the undiluted solution after stirring, for example, if there are too many bubbles, the molded film may become brittle and lack strength, and if there are uneven bubbles, the appearance may deteriorate. By performing degassing to properly remove bubbles from the undiluted solution after stirring, the strength and appearance of the film can be improved. The conditions for degassing should be such that degassing is performed appropriately without impairing the required film strength and appearance, and should be set as appropriate depending on the state of the bubbles and the equipment. In addition, since the molded film may become prone to collapse due to water entering the pores caused by bubbles, it is also possible to leave bubbles in the degassing process or adjust the degassing process as appropriate to increase the film's ability to collapse, as long as the required film strength and appearance are not impaired.

[0048] The molding process involves forming the raw material after the cooling process into a film. The molding method is not particularly limited as long as it can be formed into a film, but known coating methods such as gravure coating, reverse coating, roll coating, bar coating, spray coating, air knife coating, comma coating, and dipping are preferably employed.

[0049] An oral film according to a second embodiment of the present invention has a film substrate component made of a mixed material of hydroxypropyl methylcellulose (HPMC) and other water-soluble polymers, and contains 5 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5 as a disintegrant, and has insoluble particles derived from the partially hydrolyzed starch product.

[0050] Other water-soluble polymers used in the mixed materials constituting the film substrate components are at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate. These water-soluble polymers are suitable as edible materials because they are highly safe and have excellent solubility.

[0051] By using a mixed material of HPMC and other water-soluble polymers as the film substrate component, the disintegration function by the disintegrant is promoted. The mixing ratio of each material constituting the mixed material is not particularly limited as long as HPMC is the main component, but it is preferable that the ratio of HPMC to other water-soluble polymers is approximately 6:4 to 9:1. If the mixing ratio of HPMC is too low, the prepared solution may separate, and a uniform film cannot be coated. If the mixing ratio of HPMC is too high, the cost of the mixed material will increase, which is undesirable. If the mixing ratio of the mixed material is within the above range, the disintegration function by the disintegrant can be appropriately promoted.

[0052] In the oral film of the second embodiment, by using a partially hydrolyzed starch product with a dextrose equivalent of 1.4 to 3.5 as a disintegrant for a film substrate component composed of a mixed material of HPMC and other water-soluble polymers, appropriate disintegration function can be imparted with a blending amount of about 5 to 20% by weight. If the amount of the partially hydrolyzed starch product is too small, its function as a disintegrant may be insufficient. If the amount is too large, it is undesirable because it reduces the amount of functional components that can be added. In the oral film of the second embodiment, because the film substrate component is composed of a mixed material of HPMC and other water-soluble polymers, good disintegration can be obtained even with a relatively small amount of partially hydrolyzed starch product with a dextrose equivalent of 1.4 to 3.5 used as a disintegrant.

[0053] In the second embodiment, the stock solution preparation step prepares a stock solution containing a solvent at 70°C or higher, a mixed material of at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate, and hydroxypropyl methylcellulose, and a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5. Subsequently, using the stock solution obtained in this stock solution preparation step, an oral film according to the second embodiment is obtained by going through a stirring step, a cooling step, and a molding step similar to those in the first embodiment.

[0054] As described above, the oral film of the present invention uses hydroxypropyl methylcellulose as the main component of the film substrate and contains an appropriate amount of partially hydrolyzed starch with a dextrose equivalent (DE) of 1.4 to 3.5 as a disintegrant. Therefore, without performing a separate process to homogenize the particle size of the disintegrant during film manufacturing, insoluble particles derived from partially hydrolyzed starch that impart disintegration function can be formed with a substantially uniform particle size during the raw material preparation process, stirring process, and cooling process. As a result, the particle size of the disintegrant (insoluble particles) can be efficiently homogenized compared to conventional methods, improving workability and enabling the production of an oral film with good disintegration properties.

[0055] In the oral film of the present invention, it is preferable to laminate a surface layer on one or both sides thereof. The surface layer is a layer that improves the strength of the oral film and imparts appropriate functionality. Functions that can be imparted by the surface layer include masking effects such as reducing taste, aroma, and bitterness. Appropriate materials can be used for the surface layer depending on the purpose. Furthermore, the laminated surface layer may be a single layer or multiple layers.

[0056] [Preparation of Oral Films] Oral films of prototype examples 1-1 to 3-4 and comparative examples 1 to 3 were prepared by adding each material described later in predetermined mixing ratios, based on the following steps. Disintegrant and additives were added to deionized water, which is the solvent, so that the solvent concentration of the stock solution was 75%, and the mixture was heated to approximately 80°C. Then, the film substrate components were added to obtain the stock solution (raw material preparation step). The obtained stock solution was thoroughly stirred for 20 minutes using a stirring device (manufactured by Shashin Kagaku Co., Ltd.; "Kakuhunter") (stirring step). After stirring, it was left at room temperature for 30 minutes to cool to below 40°C, and degassing treatment was performed for 25 minutes while gradually reducing the pressure using a stirring device to prevent boiling over, and then it was left at room temperature for 90 minutes to cool (cooling step). The cooled material was formed into a film using a coating device (manufactured by Yoshimitsu Seiki Co., Ltd.; "Baker Applicator") (forming step) to obtain an oral film weighing 69 mg.

[0057] [Materials Used] ・F1: Film base component: Hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.; "Metholose SE-06") ・F2: Film base component: Polyvinyl alcohol (manufactured by Nippon Vinegar & Polyvinyl Alcohol Co., Ltd.; "POVASEAL 05PS") ・F3: Film base component: Low-substituted hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.; "NISSO HPC SSL") ・D1: Disintegrant: High-melting point dextrin, dextrose equivalent: 2.6, molecular weight dispersion: 53314 ・A1: Additive: Glycerin (manufactured by Shin-Nippon Rika Co., Ltd.; "Food-grade glycerin-S")

[0058] [Prototype Example 1-1] Prototype Example 1-1 is an oral film in which the film base component is F1 and D1 is 5% by weight as a disintegrant. The mixing ratio of each material is 87.0% by weight for F1, 5.0% by weight for D1, and 8.0% by weight for A1 (additive).

[0059] [Prototype Example 1-2] Prototype Example 1-2 is an oral film in which the film base component is F1 and D1 is 10% by weight as a disintegrant. The mixing ratio of each material is 82.0% by weight for F1, 10.0% by weight for D1, and 8.0% by weight for A1 (additive).

[0060] [Prototype Example 1-3] Prototype Example 1-3 is an oral film in which the film base component is F1 and D1 is 15% by weight as a disintegrant. The mixing ratio of each material is 77.0% by weight for F1, 15.0% by weight for D1, and 8.0% by weight for A1 (additive).

[0061] [Prototype Example 1-4] Prototype Example 1-4 is an oral film in which the film base component is F1 and D1 is 20% by weight as a disintegrant. The mixing ratio of each material is 72.0% by weight for F1, 20.0% by weight for D1, and 8.0% by weight for A1 (additive).

[0062] [Prototype Example 2-1] Prototype Example 2-1 is an oral film in which the film base components are F1 and F2, and D1 is used as a disintegrant at a concentration of 5.0% by weight. The proportions of each material are as follows: F1: 68.1% by weight, F2: 18.9% by weight, D1: 5% by weight, and A1 (additive): 8.0% by weight.

[0063] [Prototype Example 2-2] Prototype Example 2-2 is an oral film in which the film base components are F1 and F2, and D1 is used as a disintegrant at a concentration of 10.0% by weight. The proportions of each material are as follows: F1: 64.2% by weight, F2: 17.8% by weight, D1: 10% by weight, and A1 (additive): 8.0% by weight.

[0064] [Prototype Example 2-3] Prototype Example 2-3 is an oral film in which the film base components are F1 and F2, and D1 is used as a disintegrant at a concentration of 15.0% by weight. The proportions of each material are as follows: F1 60.3% by weight, F2 16.7% by weight, D1 15% by weight, and A1 (additive) 8.0% by weight.

[0065] [Prototype Example 2-4] Prototype Example 2-4 is an oral film in which the film base components are F1 and F2, and D1 is used as a disintegrant at a concentration of 20.0% by weight. The proportions of each material are as follows: F1: 56.4% by weight, F2: 15.6% by weight, D1: 20% by weight, and A1 (additive): 8.0% by weight.

[0066] [Prototype Example 3-1] Prototype Example 3-1 is an oral film in which the film base components are F1 and F3, and D1 is used as a disintegrant at a concentration of 5.0% by weight. The proportions of each material are 56.0% by weight for F1, 24.0% by weight for F3, 5% by weight for D1, and 15.0% by weight for A1 (additive).

[0067] [Prototype Example 3-2] Prototype Example 3-2 is an oral film in which the film base components are F1 and F3, and D1 is used as a disintegrant at a concentration of 10.0% by weight. The proportions of each material are 52.5% by weight for F1, 22.5% by weight for F3, 10% by weight for D1, and 15.0% by weight for A1 (additive).

[0068] [Prototype Example 3-3] Prototype Example 3-3 is an oral film in which the film base components are F1 and F3, and D1 is used as a disintegrant at a concentration of 15.0% by weight. The proportions of each material are as follows: F1: 49.0% by weight, F3: 21.0% by weight, D1: 15% by weight, and A1 (additive): 15.0% by weight.

[0069] [Prototype Example 3-4] Prototype Example 3-4 is an oral film in which the film base components are F1 and F3, and D1 is used as a disintegrant at a concentration of 20.0% by weight. The proportions of each material are as follows: F1 45.5% by weight, F3 19.5% by weight, D1 20% by weight, and A1 (additive) 15.0% by weight.

[0070] [Comparative Example 1] Comparative Example 1 is an oral film that does not contain a disintegrant and is comparable to Prototype Examples 1-1 to 1-4. The mixing ratio of each material is 92.0% by weight for F1 and 8.0% by weight for A1 (additive).

[0071] [Comparative Example 2] Comparative Example 2 is an oral film that does not contain a disintegrant and is comparable to Prototype Examples 2-1 to 2-4. The proportions of each material are 72.0% by weight for F1, 20.0% by weight for F2, and 8.0% by weight for A1 (additive).

[0072] [Comparative Example 3] Comparative Example 3 is an oral film that does not contain a disintegrant and is comparable to the prototype examples 3-1 to 3-4. The proportions of each material are 59.5% by weight for F1, 25.5% by weight for F3, and 15.0% by weight for A1 (additive).

[0073] [Disintegration Evaluation] Disintegration tablets were measured for the oral films of prototype examples 1-1 to 3-4 and comparative examples 1 to 3, assuming use in the oral cavity. The oral films of prototype examples 1-1 to 3-4 and comparative examples 1 to 3 used in the disintegration tablet measurement were left in a 50-60% RH environment for 3 days or more after preparation to stabilize the moisture content of the films.

[0074] For disintegration tablet measurement, a disintegration tablet measuring device (manufactured by Okada Seikou Co., Ltd.; oral (rapid) disintegration tablet measuring device "Tricope Tester") was used. Test pieces of oral films from prototype examples 1-1 to 3-4 and comparative examples 1 to 3 were fixed to the measuring device, and distilled water was dropped at a dropping rate of 0.5 ml / min to measure the time until the central part of the test piece disintegrated. For disintegration evaluation, the time until the oral film test pieces of comparative examples 1 to 3 disintegrated was measured and set as the reference value. If the test pieces of each prototype example 1-1 to 3-4 disintegrated 8 seconds or more faster than the corresponding reference value, it was marked as "◎ (Excellent)", if they disintegrated 4 seconds or more but less than 8 seconds faster than the corresponding reference value, it was marked as "○ (Good)", and if they disintegrated less than 4 seconds faster than the corresponding reference value or slower than the reference value, it was marked as "× (Unacceptable)". The measurement results, along with the formulations of each prototype example and comparative example, are shown in Tables 1 to 3 below.

[0075]

[0076]

[0077]

[0078] [Results and Discussion] Prototypes 1-1 to 1-4 are examples of oral films using HPMC as the film substrate component. In these oral films, as shown in Table 1, the disintegration properties improved in prototypes 1-2 to 1-4 when high-melting-point dextrin was used as the disintegrant. In prototype 1-1, which contained a small amount of high-melting-point dextrin (5% by weight), the disintegration time was the same as in comparative example 1, and no improvement in disintegration properties was observed. On the other hand, in prototypes 1-2 to 1-4, which showed improved disintegration properties, there was a tendency for the disintegration time to become faster as the amount of high-melting-point dextrin increased. In particular, extremely good disintegration properties were obtained with an amount of 20% by weight (prototype 1-4).

[0079] Examples 2-1 to 2-4 are examples of oral films in which the film substrate component is a mixture of HPMC and another water-soluble polymer, polyvinyl alcohol. As shown in Table 2, in all of these oral films, the disintegration properties were improved, and there was a tendency for the disintegration time to be faster as the amount of high-melting-point dextrin increased. Furthermore, as in Example 2-1, disintegration properties could be improved even with a small amount of high-melting-point dextrin (5% by weight), and particularly excellent disintegration properties were obtained when the amount was 10% by weight or more (Examples 2-2 to 2-4).

[0080] Examples 3-1 to 3-4 are examples of oral films in which the film substrate component is a mixture of HPMC and another water-soluble polymer, low-substituted hydroxypropyl cellulose. In these oral films, as shown in Table 3, the disintegration properties were improved in all of Examples 3-1 to 3-4, and there was a tendency for the disintegration time to be faster as the amount of high-melting-point dextrin increased. Furthermore, as in Example 2-1, disintegration properties could be improved even with a small amount of high-melting-point dextrin (5% by weight), and particularly excellent disintegration properties were obtained with a blend of 20% by weight (Example 2-4).

[0081] As described above, in oral films using HPMC as the film substrate component, the disintegration properties can be improved by including an appropriate amount of high-melting-point dextrin as a disintegrant, and the disintegration properties can be further improved by increasing the amount of high-melting-point dextrin. Furthermore, when the film substrate component is a mixture of HPMC and other water-soluble polymers, it was found that even a small amount of high-melting-point dextrin can adequately improve disintegration properties, thus promoting the disintegration function of high-melting-point dextrin.

[0082] In the oral film of the present invention, when hydroxypropyl methylcellulose is used as the film substrate component, a partially hydrolyzed starch product with a dextrose equivalent (DE) of 1.4 to 3.5 is used as the disintegrant, resulting in more efficient and uniform particle size of the disintegrant compared to conventional methods, thus achieving good disintegration properties. Therefore, the oral film of the present invention is promising as an alternative to oral films using hydroxypropyl methylcellulose as the film substrate component. Furthermore, the method for manufacturing the oral film of the present invention is advantageous because it is possible to form insoluble particles derived from partially hydrolyzed starch with a substantially uniform particle size without performing a separate step to uniformize the particle size of the disintegrant during film manufacturing, thus improving workability compared to conventional methods.

Claims

1. An oral film having hydroxypropyl methylcellulose as a film substrate component, which disintegrates in the oral cavity, and characterized in that it contains 10 to 20% by weight of a partially hydrolyzed starch having a dextrose equivalent (DE) of 1.4 to 3.5, and has insoluble particles derived from the partially hydrolyzed starch.

2. An oral film that disintegrates in the mouth, comprising a mixed material of at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate, and hydroxypropylmethylcellulose as a film substrate component, wherein the oral film contains 5 to 20% by weight of a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5, and has insoluble particles derived from the partially hydrolyzed starch product.

3. The oral film according to claim 1 or 2, wherein the raw material starch of the partially hydrolyzed starch is one or more selected from potato starch, corn starch, or tapioca starch.

4. The oral film according to claim 1 or 2, wherein the molecular weight dispersion of the partially hydrolyzed starch is 42,000 to 60,000.

5. An oral film comprising an oral film according to claim 1 or 2, wherein a surface layer is laminated on one or both sides of the oral film.

6. A method for producing an oral film, comprising: a stock solution preparation step of preparing a stock solution containing a solvent at 70°C or higher, hydroxypropyl methylcellulose, and a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5; a stirring step of stirring the stock solution obtained from the stock solution preparation step; a cooling step of cooling the stock solution after the stirring step to form insoluble particles derived from the partially hydrolyzed starch product; and a molding step of forming the stock solution after the cooling step into a film.

7. A method for producing an oral film, comprising: a stock solution preparation step of preparing a stock solution containing a solvent at 70°C or higher, a mixed material of at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl alcohol, polyvinyl alcohol, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or cellulose acetate and hydroxypropyl methylcellulose, and a partially hydrolyzed starch product having a dextrose equivalent (DE) of 1.4 to 3.5; a stirring step of stirring the stock solution obtained from the stock solution preparation step; a cooling step of cooling after the stirring step to form insoluble particles derived from the partially hydrolyzed starch product; and a molding step of forming the stock solution after the cooling step into a film.

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