Film coating composition, oral solid preparation, and method for producing the same

Abstract

To provide film coating compositions in which adhesion between tablets hardly occurs even when coated using PVA with saponification degree of 85.0 to 89.0 mol% and adding no additives other than PVA, to provide oral solid formulations using the same, and to provide manufacturing method thereof.SOLUTION: Provided is a film coating composition containing a PVA polymer having an average saponification degree of 85.0 to 89.0 mol%, which satisfies the following requirement (A) or (B). Requirement (A): The transparency of a solution obtained by adding 130.0 ml of 1-propanol to 100.0 g of a 5.0% by mass aqueous solution of a PVA polymer and stirring the solution is 50.0% or less at 20°C. Requirement (B): The concentration of the supernatant obtained by adding 230.0 ml of 1-propanol to 100.0 g of a 5.0% by weight aqueous solution of a PVA polymer and stirring and by allowing the stirred solution to stand at 20°C for 24 hours is 0.75 mass% or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a film coating composition for use in pharmaceutical oral solid preparations, an oral solid preparation using the same as a coating film, and a method for producing the same. The present invention further relates to a film coating composition for producing a pharmaceutical oral solid preparation having high productivity and high gas barrier properties, an oral solid preparation, and its production. [Background technology]

[0002] Film coating and sugar coating are techniques widely used in pharmaceutical oral solid preparations to cover tablets and other materials containing drugs for the purposes of masking the unpleasant taste of the drug, blocking oxygen, preventing moisture, or improving the aesthetic appearance of the product.

[0003] Film coating is useful in that it can be carried out easily in a short time compared to sugar coating, and the thickness of the coating film can be made thinner, which allows the size of the tablet to be reduced and the resulting oral solid preparation to be easily taken.

[0004] Various polymers, including hydroxypropyl methylcellulose (hereinafter abbreviated as HPMC), have been used as bases for film coating, but in recent years, polyvinyl alcohol (hereinafter abbreviated as PVA) has been attracting attention. Since PVA film has excellent moisture resistance and gas barrier properties, applying a PVA film coating to solid preparations containing strong-smelling drugs, drugs that are easily oxidized, or drugs that easily absorb moisture can improve storage stability and provide an odor masking effect.

[0005] Generally, PVA commercially available for pharmaceutical use or as a pharmaceutical grade is a so-called partially saponified type of PVA with a saponification degree in the range of 85.0 mol% to 89.0 mol%. This is because the common part of the PVA saponification degree specifications in the official books of Japan, the United States, and Europe is 85.0 mol% to 89.0 mol%. In recent years, as the globalization of pharmaceuticals has advanced, pharmaceutical companies need to obtain approvals for pharmaceuticals in the three major regions of Japan, the United States, and Europe. Therefore, there is a background that PVA used as a raw material is preferably PVA with a saponification degree of 85.0 mol% to 89.0 mol% that meets the saponification degree specifications of Japan, the United States, and Europe. At the same time, as PVA used in oral preparations, there is a reason to think that a partially saponified type of PVA with high water solubility is suitable. However, when using PVA with a saponification degree of 85.0 mol% to 89.0 mol% commercially available for pharmaceutical use as a coating base, since the adhesiveness of the PVA aqueous solution is high, solid preparations may adhere to each other during coating, or solid preparations may adhere to the coating machine. Therefore, the spray speed cannot be increased, and there is a problem of low productivity.

[0006] As a method for improving the adhesiveness of PVA, Patent Document 1 discloses a coating composition containing PVA with a saponification degree of 90 mol% or more and water. Patent Document 2 discloses a film coating composition containing PVA and water-soluble polyoxyethylenes, and the examples illustrate a film coating composition of a partially saponified type PVA and polyethylene glycol. Furthermore, the present inventors have disclosed a method of performing coating using a film coating composition containing PVA and a cellulose derivative (Patent Document 3). Any of these methods can improve the adhesiveness of PVA and increase the spray speed compared to when coating is performed with a partially saponified type of PVA alone with a saponification degree of 85.0 mol% to 89.0 mol%, so the coating time can be shortened.

Prior Art Documents

Patent Documents

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 59-42325 [Patent Document 2] Japanese Patent Application Laid-Open No. 8-59512 [Patent Document 3] Japanese Patent Application Laid-Open No. 2013-253030

[0008] However, the PVA of Patent Document 1 does not meet the saponification degree standard of the United States Pharmacopeia (USP), and there is a problem that it cannot be used as a raw material for pharmaceuticals aiming for global expansion. In addition, compared with PVA having a saponification degree of 85.0 mol% to 89.0 mol%, it has low water solubility, so there is a problem that it cannot be used for rapidly dissolving oral solid preparations. Further, the methods described in Patent Document 2 and Patent Document 3 contain polyoxyethylenes and cellulose derivatives as components other than PVA, so there is a problem that they cannot be used for coating solid preparations containing drugs that interact with these. Furthermore, adding additives other than PVA such as polyoxyethylenes and cellulose derivatives is also a factor that reduces the moisture-proof property and gas barrier property inherent in PVA. [Summary of the Invention] [Problems to be Solved by the Invention]

[0009] In view of the above situation, the present invention uses PVA that meets the saponification degree standard of PVA described in the official documents of Japan, the United States, and Europe, that is, PVA having a saponification degree of 85.0 mol% to 89.0 mol%, and even when coating is performed without adding additives other than PVA, it is difficult for tablets to adhere to each other during coating, and it is an object of the present invention to provide a film coating composition having a high productivity, an oral solid preparation using the same, and a method for producing the same. [Means for Solving the Problems]

[0010] As a result of intensive research to solve the above problems, the inventors of the present invention have found that even when the degree of saponification is the same, coating with PVA having a wider degree of saponification distribution makes it difficult for adhesiveness to be exhibited during coating. In terms of an index indicating the degree of saponification distribution, by using PVA of 85.0 mol% to 89.0 mol% that satisfies specific requirements, it can be used as a film coating composition excellent in productivity, and it has been found that the coating film exhibits excellent moisture-proofness and gas barrier properties similar to those of conventional PVA. Through further research, the present invention has been completed.

[0011] That is, the present invention relates to the following film coating compositions for oral solid preparations and the like. [1] A film coating composition for oral solid preparations containing a polyvinyl alcohol-based polymer having an average degree of saponification measured according to JIS K6726 of 85.0 mol% to 89.0 mol%, wherein the polyvinyl alcohol-based polymer satisfies the following requirement (A) or requirement (B), and is a polyvinyl alcohol-based polymer. A film coating composition for oral solid preparations, characterized in that it is a polyvinyl alcohol-based polymer. Requirement (A): With respect to 100.0 g of a 5.0 mass% aqueous solution of the polyvinyl alcohol-based polymer, 130.0 ml of 1-propanol is added and stirred, and the transparency of the resulting liquid at 20 ° C is 50.0% or less. Requirement (B): With respect to 100.0 g of a 5.0 mass% aqueous solution of the polyvinyl alcohol-based polymer, 230.0 ml of 1-propanol is added and stirred, and the concentration of the supernatant obtained by allowing the stirred liquid to stand at 20 ° C for 24 hours is 0.75 mass% or more. [2] A film coating composition for oral solid preparations containing a polyvinyl alcohol-based polymer having an average degree of saponification measured according to JIS K6726 of 85.0 mol% to 89.0 mol%, wherein the polyvinyl alcohol-based polymer satisfies the following requirement (A) and requirement (B), and is a polyvinyl alcohol-based polymer. A film coating composition for oral solid preparations, characterized in that it is a polyvinyl alcohol-based polymer. Requirement (A): For 100.0 g of a 5.0 mass% aqueous solution of a polyvinyl alcohol-based polymer, 130.0 ml of 1-propanol is added, and the transparency of the resulting liquid at 20 °C is 50.0% or less after stirring. Requirement (B): For 100.0 g of a 5.0 mass% aqueous solution of a polyvinyl alcohol-based polymer, 230.0 ml of 1-propanol is added, and the concentration of the supernatant obtained by allowing the stirred liquid to stand at 20 °C for 24 hours is 0.75 mass% or more. [3] An oral solid preparation film coating composition containing a polyvinyl alcohol-based polymer having an average saponification degree of 85.0 mol% to 89.0 mol% measured according to JIS K6726, wherein the polyvinyl alcohol-based polymer satisfies the following requirement (C). The oral solid preparation film coating composition is characterized by being a polyvinyl alcohol-based polymer. Requirement (C): Using a liquid chromatography where the detector is an electrified particle detector and the column is Thermo Scientific's Acclaim TM 300 (Catalog number: 060266, carbon content: 8%, maximum pressure: 4500 psi, particle diameter: 3 μm, pore diameter: 300 Å, stationary phase: C18, surface area: 100 m 2 / g, length: 150 mm, diameter: 4.6 mm, pH: 2.5 to 7.5, material: Glass Lined Tubing (glass-lined tube)), the polyvinyl alcohol-based polymer is measured under the following measurement conditions, and after baseline correction, in the relationship between the retention time and the detection intensity obtained, when the data sampling period is 500 milliseconds, the retention time T i [min] at the time of the detection intensity P i [pA], in formulas (1) and (2), T i and P i represented by T n and T w satisfies formula (3). [Measurement conditions] · Concentration of polyvinyl alcohol-based polymer aqueous solution: 0.1 mass% · Injection volume of polyvinyl alcohol-based polymer aqueous solution: 2 μL · Column temperature: 50 °C · Flow rate: 1.0 ml / min · Eluent: A mixed solvent of water and methanol · Gradient conditions of the eluent: In the measurement time from 0 minutes to 10 minutes, the mixing ratio of water and methanol in the eluent changes at a constant rate from 95:5 to 15:85, and in the measurement time from 10 minutes to 15 minutes, the mixing ratio of water and methanol in the eluent is constant at 15:85. [Formula] T n = Σ(T i ×P i ) / Σ(P i ) Equation (1) T w = Σ(T i 2 ×P i ) / Σ(T i ×P i ) Equation (2) {(T w / T n ) - 1} × 1000 > 20 Equation (3) [4] The polyvinyl alcohol-based polymer is a polyvinyl alcohol-based polymer that satisfies the requirement that the viscosity of a 4 mass% aqueous solution measured according to JIS K6726 is 2.0 mPa·s or more and 10.0 mPa·s or less. The film coating composition for oral solid preparations according to any one of [1] to [3] above. [5] An oral solid preparation, characterized in that a tablet containing a drug is coated with the film coating composition according to any one of [1] to [4] above. [6] A method for producing an oral solid preparation, comprising the step of applying or spraying an aqueous solution and / or an aqueous solution containing the film coating composition according to any one of [1] to [4] above onto a tablet containing a drug to coat the surface of the tablet with the film coating composition. [7] The oral solid preparation according to [5] above, wherein the coating amount is 1 to 10 mass% based on the total amount of the tablet. [Effect of the Invention]

[0012] According to the present invention, it can be used for pharmaceutical preparations in Japan, the United States, and Europe. Even when coating is performed with PVA alone, adhesion between tablets is less likely to occur, thereby shortening the coating time, having excellent moisture-proof properties, and being able to form a highly water-soluble coating film. A film coating composition, an oral solid preparation using the same, and a method for producing the same can be provided.

Brief Description of the Drawings

[0013]

Figure 1

Embodiments for Carrying Out the Invention

[0014] Hereinafter, the present invention will be described in detail. [PVA-based Polymer] First, the PVA-based polymer used in the film coating composition for oral solid preparations of the present invention will be described in detail. The PVA-based polymer used in the present invention preferably has an average saponification degree of 85.0 mol% to 89.0 mol% and a saponification degree distribution wider than that of conventional PVA-based polymers. The average saponification degree of the PVA-based polymer is measured according to the saponification degree measurement method of JIS K6726.

[0015] Two indicators can be mentioned as indicators representing the saponification degree distribution in the present invention. The first is a method represented by the amounts of the PVA component that precipitates and the PVA component that does not precipitate when a certain amount of 1-propanol is added to and mixed with an aqueous solution in which the PVA-based polymer is completely dissolved, and it can be defined by the transparency and concentration of the aqueous solution. Regarding this indicator in the present invention, it is preferable to use a PVA-based polymer that satisfies either or both of the following requirements (A) and (B), and the meaning of these requirements will be explained.

[0016] "Requirement (A): With respect to 100.0 g of a 5.0 mass% aqueous solution of a polyvinyl alcohol-based polymer, 130.0 ml of 1-propanol is added, and the transparency of the liquid obtained by stirring at 20 °C is 50.0% or less." It is preferable that the stirring is performed uniformly. The stirring method is not particularly limited, but for example, a method of stirring at 500 rpm using a stirrer is preferable. Also, the dropping rate of 1-propanol is not particularly limited, but for example, 10 ml / min is preferable.

[0017] Incidentally, the "transparency of the liquid at 20 °C" refers to, for example, the transparency of the liquid after standing at 20 °C for a predetermined time (for example, 30 minutes or more, about 30 minutes to 1 hour) until bubbles in the liquid cannot be visually confirmed. The transparency is preferably 30.0% or less, more preferably 20.0% or less.

[0018] Here, the measurement of transparency is carried out by using a spectrophotometer specified in JIS K0115, using a quartz or glass absorption cell with an optical path length of 20 mm, and obtaining the transmittance at 430 nm with water as a reference. The meaning of the transparency obtained here is that since a PVA component with a high degree of saponification is difficult to dissolve in 1-propanol, when a certain amount of 1-propanol is added to an aqueous solution of a PVA-based polymer, the high-saponification component precipitates and becomes a turbidity component. Therefore, the fact that the transparency becomes 50.0% or less under the above conditions indicates that it contains a large amount of the high-saponification component, that is, the saponification degree distribution on the high-saponification side is wide.

[0019] "Requirement (B): With respect to 100.0 g of a 5.0 mass% aqueous solution of a polyvinyl alcohol-based polymer, 230.0 ml of 1-propanol is added, and the concentration of the supernatant obtained by allowing the stirred liquid to stand at 20 °C for 24 hours is 0.75 mass% or more." It is preferable that the stirring is performed uniformly. The stirring method is not particularly limited, but for example, it is preferable to stir at 500 rpm using a stirrer. Also, the dropping rate of 1-propanol is not particularly limited, but for example, 10 ml / min is preferable.

[0020] The concentration of the supernatant liquid is preferably 0.75% by mass or more, and more preferably 0.80% by mass or more.

[0021] Here, the supernatant liquid can be obtained, for example, by adding 230.0 ml of 1-propanol to 100.0 g of a 5.0% by mass aqueous solution of a PVA-based polymer, stirring the solution, allowing the stirred solution to stand at 20 °C for 24 hours, and collecting 30 to 60% by weight based on the total amount of the solution from the liquid layer of the obtained solution.

[0022] Here, as a method for measuring the concentration of the supernatant liquid, for example, about 80 g of the supernatant liquid is slowly collected onto a petri dish using a dropper so as not to contain precipitation components, dried at 60 °C for 5 hours, then dried at 105 °C for 24 hours, and can be calculated from the weight of the collected liquid and the change in weight before and after drying. The meaning of the supernatant liquid concentration obtained here is that since PVA components with a low degree of saponification are difficult to precipitate when 1-propanol is added, when a certain amount of 1-propanol is added to an aqueous solution of a PVA-based polymer, the low degree of saponification components exist in a dissolved state in the liquid. That is, when the concentration of the supernatant liquid is 0.75% by mass or more, it indicates that the degree of saponification distribution on the low degree of saponification side is wide.

[0023] The PVA-based polymer used in the film coating composition of the present invention usually has an average degree of saponification in the range of 85.0 mol% to 89.0 mol% and satisfies the above requirement (A), that is, has a wide degree of saponification distribution on the high degree of saponification side, or satisfies the above requirement (B), that is, has a wide degree of saponification distribution on the low degree of saponification side, and preferably satisfies both requirement (A) and requirement (B), that is, has wide distributions on both the high degree of saponification side and the low degree of saponification side. The PVA-based polymer used in the film coating composition of the present invention has a broad saponification degree distribution in order to satisfy the above requirement (A) and / or the above requirement (B).

[0024] When the transparency measured under the conditions of requirement (A) of the PVA-based polymer to be used is 50.0% or less, even if a coating test is performed using such a PVA-based polymer, adhesion between tablets is unlikely to occur, coating defects can be prevented, and the coating time can be shortened, which is preferable.

[0025] Also, when the supernatant concentration measured under the conditions of requirement (B) of the PVA-based polymer to be used is 0.75% by mass or more, even if a coating test is performed using such a PVA-based polymer, adhesion between tablets is unlikely to occur, coating defects can be prevented, and the coating time can be shortened, which is preferable.

[0026] The second index representing the saponification degree distribution in the present invention is a method represented by the correlation between the retention time and the detection intensity by measuring a PVA-based polymer by liquid chromatography using an electrified particle detector. Regarding this index in the present invention, it is preferable to use a PVA-based polymer that satisfies the following requirement (C), and the meaning of the requirement will be explained.

[0027] "Requirement (C): The detector is an electrified particle detector, and the column is Acclaim from Thermo Scientifi TM 300 (Catalog number: 060266, carbon content: 8%, maximum pressure: 4500 psi, particle size: 3 μm, pore size: 300 Å, stationary phase: C18, surface area: 100 m 2 / g, length: 150 mm, diameter: 4.6 mm, pH: 2.5 to 7.5, material: Glass Lined Tubing (glass-lined tube)) is used to measure the polyvinyl alcohol-based polymer under the following measurement conditions. After baseline correction, in the relationship between the retention time and the detection intensity, when the data sampling period is 500 milliseconds, the retention time T in all the data obtained between 5.0 minutes and 12.0 minutes of the retention time iWhen the detection intensity at [minute] is P i When [pA], in Formula (1) and Formula (2), T i and P i The T represented by using n and T w Satisfies Formula (3). [Measurement conditions] · Concentration of PVA polymer aqueous solution: 0.1 mass% · Injection volume of PVA polymer aqueous solution: 2 μL · Column temperature: 50 °C · Flow rate: 1.0 ml / min · Eluent: Mixed solvent of water and methanol · Gradient conditions of the eluent: In the measurement time from 0 minute to 10 minutes, the mixing ratio of water and methanol in the eluent changes at a constant rate from 95:5 to 15:85, and in the measurement time from 10 minutes to 15 minutes, the mixing ratio of water and methanol in the eluent is constant at 15:85.

[0028] [Formula] T n = Σ(T i ×P i ) / Σ(P i ) Formula (1) T w = Σ(T i 2 ×P i ) / Σ(T i ×P i ) Formula (2) {(T w / T n ) - 1} × 1000 > 20 Formula (3)

[0029] Under the above requirements, there are no particular restrictions on the charged particle detector and liquid chromatography to be used. For example, as the charged particle detector, CORONA VEO of Thermo Scientific can be used. Also, as the liquid chromatography, ULTIMATE3000 of Thermo Scientific can be used.

[0030] When measuring a PVA-based polymer by liquid chromatography using an electrified particle detector, a sample solution containing PVA separated from the column is atomized and dried with nitrogen inside the electrified particle detector to form fine particles, and the PVA fine particles are + charged with N ions and measured, whereby they are detected.

[0031] As the column used in the liquid chromatography of the present invention, usually, a reversed-phase ODS column filled with chemically bonded porous spherical silica gel whose surface is modified with an octadecylsilyl group as a stationary phase is Acclaim TM 300 (Catalog number: 060266, carbon content: 8%, maximum pressure: 4500 psi, particle size: 3 μm, pore size: 300 Å, stationary phase: C18, surface area: 100 m 2 / g, length: 150 mm, diameter: 4.6 mm, pH: 2.5 to 7.5, material: Glass Lined Tubing).

[0032] The PVA-based polymer as the measurement sample is dissolved in purified water and measured as an aqueous solution. The concentration of the PVA-based polymer aqueous solution is usually 0.1% by mass. The measurement conditions are usually a flow rate of 1 ml / min, a column temperature of 50 °C, and an injection volume of 2 μL of the PVA-based polymer aqueous solution.

[0033] As the eluent, usually, a mixed solvent of water and methanol is used. Furthermore, usually, the measurement is performed with a gradient applied to the eluent. As the gradient conditions of the eluent for each measurement time, usually, the mixing ratio of water and methanol in the eluent at 0 minutes of the measurement time is 95:5, and at a constant rate from 0 minutes to 10 minutes (for example, in the mixing ratio of water and methanol, the ratio of water is decreased by 8 per minute, and the ratio of methanol is increased by 8 per minute), the ratio of water and methanol is changed so that the mixing ratio of water and methanol at 10 minutes becomes 15:85. From 10 minutes to 15 minutes of the measurement time, the mixing ratio of water and methanol in the eluent is set to a constant ratio of 15:85.

[0034] In the time zone when the ratio of water in the eluent is high, the highly saponified component in the PVA-based polymer is separated, and as the ratio of methanol increases, the low-saponified component in the PVA-based polymer is gradually separated. When there is a dead space part in the column, accurate measurement may not be possible with only the gradient from 0 to 10 minutes. Therefore, usually, in order to prevent this, the eluent is flowed for 5 minutes under the above conditions. After 15 minutes, in order to expel the low-saponified component remaining in the column, it is preferable to flow for 5 minutes with the mixing ratio of water and methanol being 5:95. When continuously measuring the PVA-based polymer, it is preferable to flow the eluent with the mixing ratio of water and methanol being constant at 95:5 for about 7 to 10 minutes to equilibrate the inside of the column to the initial state.

[0035] When measuring a sample of a PVA-based polymer under the above conditions, a graph showing the correlation between the retention time and the detection intensity can be obtained. By subtracting the so-called baseline peak obtained when measuring without injecting any sample solution under the above measurement conditions from this graph and performing baseline correction, a graph of the detection intensity for each retention time can be obtained. Figure 1 shows a chart of the retention time and intensity in the retention time from 5.0 minutes to 12.0 minutes when measuring PVA (JP-05 manufactured by Nippon Gohsei, Poval) with an average saponification degree of 88.2 mol% measured according to JIS K6726 and a 4 mass% aqueous solution viscosity of 5.3 mPa·s measured according to JIS K6726.

[0036] In the present invention, it is preferable that the data sampling period indicating the frequency at which the data processing device receives the signal sent from the detector is 500 milliseconds, that is, the detection intensity data is obtained at a rate of once every 0.5 seconds, and it is more preferable that the data sampling period is shorter than 2 seconds. By plotting these data, a chart as shown in FIG. 1 can be obtained.

[0037] Under these liquid chromatography conditions, at the initial stage of measurement where the proportion of water in the eluent is high, the highly saponified component in the sample PVA-based polymer elutes, and as the proportion of methanol in the eluent increases, the lowly saponified component elutes. Therefore, as a chart of the ion intensity for each retention time detected by the corona detector, in the case of a PVA-based polymer with a narrow saponification degree distribution, a sharp peak having a peak top near a retention time of 9.5 minutes can be obtained. However, even if the saponification degree is the same, when measuring a PVA-based polymer with a wide saponification degree distribution, the position of the peak top does not change, but a broad peak is obtained.

[0038] In all the obtained data of the retention time and the detection intensity, when the detection intensity at the retention time T i [min] is P i [pA], it can be expressed as in Formula (1) and Formula (2). The T n and T w shown here correspond to the number average molecular weight M n and the weight average molecular weight M w in the measurement of the molecular weight distribution using gel permeation chromatography (hereinafter abbreviated as GPC). n and the weight average molecular weight M w have corresponding meanings. Using these T n and T w , the so-called polydispersity M w / M n corresponding to T w / T n in the measurement of the molecular weight distribution can be used to define the spread of the saponification degree distribution as in Formula (3).

[0039] In formula (3), the value of {(T w / T n ) - 1} × 1000 is usually greater than 20 and more preferably greater than 25 (for example, 25 to 90), and even more preferably greater than 30 (for example, 30 to 85). That is, the larger the value represented by {(T w / T n ) - 1} × 1000, the broader the degree of saponification distribution of the PVA - based polymer. When coating is performed using a PVA - based polymer with this value exceeding 20, adhesion between tablets is less likely to occur, so the spray speed during coating can be increased, thereby shortening the coating time. On the other hand, a PVA - based polymer with {(T w / T n ) - 1} × 1000 ≤ 20 has a narrow degree of saponification distribution. Even when a coating test is performed using such a PVA - based polymer, adhesion between tablets is likely to occur, resulting in coating defects or an extended coating time.

[0040] The PVA - based polymer used in the present invention satisfies at least one, preferably two, and more preferably three of the above requirements (A) to (C). Conventionally, it has been difficult to quantitatively measure the degree of saponification distribution, but in the present invention, it has been found that the degree of saponification distribution can be measured by the above requirements (A), (B), or (C).

[0041] As a method for producing the PVA - based polymer used in the present invention, known methods such as saponifying a polymer of a vinyl ester - based monomer are used. Examples of such a vinyl ester - based monomer include vinyl acetate.

[0042] The method for polymerizing vinyl acetate is not particularly limited, and examples thereof include conventionally known bulk polymerization, solution polymerization, suspension polymerization, emulsion polymerization, etc. Among them, solution polymerization using methanol as a solvent is industrially preferable. For this solution polymerization, known initiators such as peroxide-based and azo-based initiators can be used, and the degree of polymerization of the obtained polyvinyl acetate can be adjusted by changing the mixing ratio of vinyl acetate and methanol and the polymerization yield. Also, a commercially available polyvinyl acetate resin can be used as a raw material for obtaining the PVA-based polymer of the present invention.

[0043] As a method for saponifying the obtained polyvinyl acetate, a saponification method using a conventionally known alkali catalyst or acid catalyst can be applied. Among them, a method of adding an alkali such as sodium hydroxide to a methanol solution of polyvinyl acetate or a mixed solution of methanol, water, methyl acetate, etc. of polyvinyl acetate, and stirring and mixing while alcoholyzing the acetyl group of polyvinyl acetate is industrially preferable. Thereafter, the obtained lump, gel, or granular material is pulverized, the added alkali is neutralized if necessary, then the solid matter and the liquid component are separated, and the solid matter is dried to obtain a PVA-based polymer.

[0044] The PVA-based polymer used in the present invention can be produced by carrying out the saponification reaction in a system that is more heterogeneous than usual. Specific methods include a method of carrying out saponification by increasing the concentration of the methanol solution of polyvinyl acetate during saponification (for example, 55% by mass or more), a method of carrying out saponification by lowering the stirring speed when adding and mixing the alkali (for example, 20 rpm or less), a method of carrying out saponification by shortening the stirring and mixing time when adding and mixing the alkali, a method of carrying out saponification in a short time by increasing the amount of alkali, and adjusting the temperature of the methanol solution of polyvinyl acetate and the added alkali, etc., to give a temperature gradient or temperature distribution to the saponification reaction system for saponification.

[0045] In addition, there is a method of performing a saponification reaction by adding solvents such as water and methyl acetate that affect the saponification reaction rate in a non-uniform state. By performing these operations, unevenness is likely to occur in the degree of saponification in the produced PVA-based polymer. As a result, even if the average degree of saponification is the same as that of the PVA-based polymer produced by the conventional method, a PVA-based polymer with a wide degree of saponification distribution can be produced.

[0046] In addition to the above method, PVA obtained by blending two or more types of PVA powders having different degrees of saponification so that the weight-average degree of saponification becomes the target value can also be used in the present invention as a form of the PVA-based polymer. In this case, the PVA-based polymer can be obtained, for example, by mixing two types of PVA (a) and PVA (b). The average degree of saponification of PVA (a) measured according to the degree-of-saponification measurement method of JIS K6726 is, for example, 85 mol% or more (for example, 85 to 99 mol%), preferably 88 mol% or more (for example, 88 to 99 mol%), more preferably 90 mol% or more (for example, 90 to 99 mol%), and still more preferably 92 mol% or more (for example, 92 to 99 mol%) of PVA (a). The average degree of saponification of PVA (b) is, for example, 99 mol% or less (for example, 60 to 99 mol%), preferably 95 mol% or less (for example, 60 to 95 mol%), more preferably 90 mol% or less (for example, 65 to 90 mol%), and still more preferably 88 mol% or less (for example, 65 to 88 mol%). The mixing ratio of PVA (a) and PVA (b) is such that the mass ratio of PVA (a):PVA (b) is, for example, 5:95 to 95:5, preferably 10:90 to 90:10, more preferably 15:85 to 85:15, and still more preferably 20:80 to 80:20. In addition, the weight-average degree of saponification of the PVA-based polymer obtained by mixing PVA(a) and PVA(b) (that is, when the degree of saponification of PVA(a) is A mol%, the degree of saponification of PVA(b) is B mol%, and the mixing ratio of PVA(a) and PVA(b) is A’:B’, the weight-average degree of saponification C = (A × A’ + B × B’) / 100) is, for example, 83 to 89 mol%, preferably 85 to 89 mol%, more preferably 86 to 89 mol%.

[0047] Since the PVA-based polymer used in the present invention is mainly used in the film coating composition of oral solid pharmaceutical preparations, the range of the degree of saponification is required to be within the standards of the degree of saponification of PVA described in three official compendiums: the pharmaceutical additive standard, the United States Pharmacopeia, and the European Pharmacopeia. Also, since it is required to dissolve rapidly in the body, it is 85.0 mol% to 89.0 mol%. When the average degree of saponification is less than 85.0 mol%, it cannot be used as a raw material for globally sold pharmaceutical preparations. Also, since the proportion of hydrophobic groups increases, the hydrophilicity decreases, and when preparing an aqueous solution, there is a tendency to precipitate at high temperatures, resulting in difficult handling. On the other hand, when the average degree of saponification is greater than 89.0 mol%, it cannot be used as a raw material for globally sold pharmaceutical preparations. Due to the improvement in crystallinity accompanying the increase in the hydroxyl groups of PVA, the solubility in water decreases, and when used for the film coating of oral solid preparations, there is a problem that the dissolution rate decreases.

[0048] The degree of polymerization of the PVA-based polymer used in the present invention is not particularly limited, but the viscosity of a 4 mass% aqueous solution (measured according to JIS K6726) is preferably 2.0 mPa·s or more and 10.0 mPa·s or less, more preferably 3.0 mPa·s or more and 7.0 mPa·s or less. When the viscosity of a 4 mass% aqueous solution is 2.0 mPa·s or more, it is preferable because the strength of the film formed on the tablet surface after coating becomes high. When the viscosity of a 4 mass% aqueous solution is 10 mPa·s or less, it is preferable because the viscosity is low, the spray speed during coating can be increased, and productivity is improved. The coating composition of the present invention may, if necessary, be added with additives such as drugs usually used in pharmaceutical preparations, plasticizers such as glycerin, polyethylene glycol, propylene glycol, and triethyl citrate, inorganic compounds such as titanium oxide, talc, and colloidal silica, lubricants such as magnesium stearate, calcium stearate, and stearic acid, polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, surfactants, coloring agents, pigments, sweeteners, coating agents, antifoaming agents, and pH adjusters. These additives can be used singly or in combination of two or more. When these are added, the content is preferably 100 parts by mass or less, more preferably 50 parts by mass or less, and still more preferably 20 parts by mass or less with respect to 100 parts by mass of the PVA-based polymer.

[0049] [Oral solid preparation] The oral solid preparation of the present invention comprises at least a tablet containing a drug and the film coating composition of the present invention for coating the tablet. The drug is not particularly limited as long as it is a drug administrable orally.

[0050] Tablets containing a drug may be formulated with various additives commonly used in this field, such as excipients, binders, disintegrants, lubricants, anti - aggregating agents, solubilizing aids for pharmaceutical compounds, etc. Examples of excipients include saccharides such as sucrose, lactose, mannitol, glucose, etc., starches, crystalline cellulose, calcium phosphate, calcium sulfate, etc. Examples of binders include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, macrogols, gum arabic, gelatin, agar, starch, etc. Examples of disintegrants include low - substituted hydroxypropyl cellulose, carmellose or its salts, croscarmellose sodium, sodium carboxymethyl starch, crospolyvinylpyrrolidone, crystalline cellulose, and crystalline cellulose - carmellose sodium, etc. Also, examples of lubricants and anti - aggregating agents include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hydrogenated oils, polyethylene glycols, sodium benzoate, etc. Further, examples of solubilizing aids for pharmaceutical compounds include organic acids such as fumaric acid, succinic acid, malic acid, adipic acid, etc. These additives can be used singly or in combination of two or more. Also, the content of these additives can be appropriately determined according to the type of drug, etc.

[0051] The oral solid preparation in the present invention can be prepared by coating a tablet containing a drug with the film - coating composition of the present invention.

[0052] Next, the manufacturing method of the oral solid preparation of the present invention will be described. As a method for coating tablets with the film coating composition of the present invention, there is no particular limitation, and conventionally known coating means can be used. Generally, spray coating is performed. In that case, it can be carried out using a pan coating apparatus, a drum type coating apparatus, etc., and an air spray, an airless spray, etc. can be used for the spray apparatus attached to these apparatuses.

[0053] As a method for coating tablets with the film coating composition of the present invention, for example, using the coating apparatus described above, a solution in which the film coating composition of the present invention to which additives are added as necessary is dissolved or dispersed in water or an organic solvent such as ethanol or a mixture thereof is prepared for tablets containing a drug, and the solution is applied or sprayed simultaneously with drying to coat the tablet surface.

[0054] The coating amount of the film coating composition coated on the surface of the tablet varies depending on the type, shape, size, surface state of the solid preparation, and further the properties of the drug and additives contained in the solid preparation. However, based on the total amount of the tablet, it is preferably 1 to 10% by mass, more preferably 1 to 7% by mass, and particularly preferably 2 to 6% by mass. If the coating amount is too small, a complete film cannot be obtained, and a sufficient moisture-proof effect, oxygen barrier property, and odor masking effect cannot be obtained. On the other hand, if the coating amount is too large, there is a problem that the time required for coating becomes long.

[0055] The oral solid preparation of the present invention may be an undercoating using a composition containing various polymers that can be commonly used for coating pharmaceutical preparations, such as hydroxypropylmethylcellulose, under the film layer formed by the film coating composition of the present invention, or an overcoating using a composition containing various polymers that can be commonly used for coating pharmaceutical preparations on the film layer formed by the film coating composition of the present invention. It may be a multilayer film-coated oral solid preparation in which a film containing a plurality of components is formed.

Examples

[0056] Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. In the following examples and comparative examples, unless otherwise specified, “%” and “parts” represent mass basis.

[0057] <Liquid Chromatography Measurement Conditions> · Detector: Charged Particle Detector · Column: Thermo Scientific, Acclaim TM 300 (Catalog No.: 060266, Carbon content: 8%, Maximum pressure: 4500 psi, Particle size: 3 μm, Pore size: 300 Å, Stationary phase: C18, Surface area: 100 m 2 / g, Length: 150 mm, Diameter: 4.6 mm, pH: 2.5 - 7.5, Material: Glass Lined Tubing · Concentration of PVA - based polymer aqueous solution: 0.1 mass% · Injection volume of PVA - based polymer aqueous solution: 2 μL · Column temperature: 50 °C · Flow rate: 1.0 ml / min · Eluent: Mixed solvent of water and methanol · Gradient conditions of the eluent: In the measurement time from 0 minute to 10 minutes, the mixing ratio of water and methanol in the eluent changes at a constant rate from 95:5 to 15:85 (in the mixing ratio of water and methanol, the proportion of water is decreased by 8 per minute, and the proportion of methanol is increased by 8 per minute), and in the measurement time from 10 minutes to 15 minutes, the mixing ratio of water and methanol in the eluent is kept constant at 15:85. When measuring the PVA - based polymer under the above conditions and performing baseline correction, in the relationship between the retention time and the detection intensity obtained, when the data sampling period is 500 milliseconds, the retention time T in all the data obtained between 5.0 minutes and 12.0 minutes of the retention time i [min] of the detection intensity at this time is P i [pA], in formulas (1) and (2), T i and P i are used, the T represented by n and Tw satisfies Formula (3). [Formula] T n = Σ(T i ×P i ) / Σ(P i ) Formula (1) T w = Σ(T i 2 ×P i ) / Σ(T i ×P i ) Formula (2) {(T w / T n ) - 1} × 1000 > 20 Formula (3)

[0058] <Synthesis Method of PVA - based Polymer> (Comparative Synthesis Example 1) A commercially available polyvinyl acetate resin (JMR - 30LL, degree of polymerization 590, manufactured by Nippon Vinyl Acetate - Poval) was vacuum - dried at 100 °C to remove moisture, and then dissolved in methanol to obtain a 46% by mass methanol solution of polyvinyl acetate. 500 parts by mass of this solution was heated to 40 °C, 16 parts by mass of a 3% by mass methanol solution of sodium hydroxide adjusted to 35 °C was added, and after stirring at 300 rpm for 1 minute using a propeller - type stirring blade, the saponification reaction was carried out by allowing it to stand at 40 °C for 40 minutes. The obtained gel - like substance was pulverized, immersed in a mixed solvent consisting of 570 parts by mass of methanol, 230 parts by mass of methyl acetate, and 17 parts by mass of water, and the saponification reaction was further carried out at 40 °C for 1 hour while stirring slowly. After that, a 1% by mass acetic acid aqueous solution was added to adjust the pH to 8 - 9 for neutralization, and then the solid matter and the liquid were separated. The solid matter was dried at 60 °C for 8 hours to obtain a PVA - based polymer. The average degree of saponification of this PVA-based polymer measured by the method of JIS K6726 was 88.3 mol%, and the viscosity of a 4 mass% aqueous solution was 5.3 mPa·s. Also, 130 ml of 1-propanol was added to 100 g of a 5.0 mass% aqueous solution of this PVA-based polymer, and the transparency at 20 °C of the liquid obtained by uniformly stirring was 99.4%. Further, 230 ml of 1-propanol was added to 100 g of a 5.0 mass% aqueous solution of this PVA-based polymer, and the supernatant liquid concentration after allowing the uniformly stirred liquid to stand at 20 °C for 24 hours was 0.62 mass%. Furthermore, when this PVA-based polymer was measured using LC-CAD under the above measurement conditions, the value of {(T w / T n ) - 1} × 1000 represented by formula (3) was 12. Table 1 shows the average degree of saponification, the viscosity of a 4 mass% aqueous solution, the transparency and the supernatant liquid concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD for Comparative Synthesis Example 1.

[0059] (Synthesis Example 1) A PVA-based polymer was obtained in the same manner as in Comparative Synthesis Example 1, except that when a sodium hydroxide solution was added to a methanol solution of polyvinyl acetate and stirred, the stirring was carried out at 60 rpm for 30 seconds to make the mixing non-uniform compared to the normal conditions. The average degree of saponification of this PVA-based polymer measured by the method of JIS K6726 was 88.2 mol%, and the viscosity of a 4 mass% aqueous solution was 5.2 mPa·s. Also, 130 ml of 1-propanol was added to 100 g of a 5.0 mass% aqueous solution of this PVA-based polymer, and the transparency at 20 °C of the liquid obtained by uniformly stirring was 18.5%. Further, 230 ml of 1-propanol was added to 100 g of a 5.0 mass% aqueous solution of this PVA-based polymer, and the supernatant liquid concentration after allowing the uniformly stirred liquid to stand at 20 °C for 24 hours was 0.83 mass%. Furthermore, when this PVA-based polymer was measured using LC-CAD under the above measurement conditions, the value of {(T w / T n ) - 1} × 1000 represented by formula (3) was 43. Table 1 shows the average degree of saponification, the viscosity of a 4 mass% aqueous solution, the transparency and the supernatant liquid concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD for Synthesis Example 1.

[0060] (Synthesis Example 2) When adding a sodium hydroxide solution to a methanol solution of polyvinyl acetate and stirring, the stirring speed was 20 rpm and carried out for 60 seconds. Except that the mixing was carried out to be more non-uniform than the normal conditions, a PVA-based polymer was obtained in the same manner as in Comparative Synthesis Example 1. Table 1 shows the average saponification degree, 4 mass% aqueous solution viscosity, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD of Synthesis Example 2.

[0061] (Synthesis Example 3) When carrying out the saponification reaction, the methanol solution concentration of polyvinyl acetate was 55 mass%, and except that the sodium hydroxide solution added to 500 parts by mass of this solution was 23 parts by mass, a PVA-based polymer was obtained in the same manner as in Comparative Synthesis Example 1. Table 1 shows the average saponification degree, 4 mass% aqueous solution viscosity, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD of Synthesis Example 3.

[0062] (Synthesis Example 4) When carrying out the saponification reaction, a band heater was wound around the upper half of the container of the mixed solution of the methanol solution of polyvinyl acetate and sodium hydroxide and heated to 50 °C. A temperature gradient was provided so that the temperature during the saponification reaction was 50 °C in the upper half and room temperature (25 °C) in the lower half, and except that the standing time was 50 minutes, a PVA-based polymer was obtained in the same manner as in Comparative Synthesis Example 1. Table 1 shows the average saponification degree, 4 mass% aqueous solution viscosity, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD of Synthesis Example 4.

[0063] (Synthesis Example 5) 500 parts by mass of a 46% by mass methanol solution of polyvinyl acetate were each divided into 250 parts by mass in separate containers, heated to 40°C, and a 3% by mass methanol solution of sodium hydroxide adjusted to 35°C was added, 10 parts by mass to one and 6 parts by mass to the other. After stirring both at 300 rpm for 1 minute, they were allowed to stand at 40°C for 40 minutes and saponification reactions were carried out separately, and then a PVA-based polymer was obtained in the same manner as in Comparative Synthesis Example 1, except that the resulting gel-like substances were ground together. The average degree of saponification, 4% by mass aqueous solution viscosity, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD of Synthesis Example 5 are shown in Table 1.

[0064] (Synthesis Example 6) 40 parts by mass of a commercially available PVA resin (JL-05E manufactured by Nippon Gohsei, degree of saponification: 80.2 mol%, 4% by mass aqueous solution viscosity: 5.1 mPa·s) and 60 parts by mass of a commercially available PVA resin (JT-05 manufactured by Nippon Gohsei, degree of saponification: 94.0 mol%, 4% by mass aqueous solution viscosity: 5.6 mPa·s) were placed in a polyethylene bag, and the bag was shaken about 100 times to uniformly mix the PVA powder, thereby preparing a PVA-based polymer having a wide degree of saponification distribution. The average degree of saponification, 4% by mass aqueous solution viscosity, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD of Synthesis Example 6 are shown in Table 1.

[0065] (Synthesis Example 7) 90 parts by mass of a commercially available PVA resin (JP-05 manufactured by Nippon Gohsei, degree of saponification: 87.5 mol%, 4% by mass aqueous solution viscosity: 5.3 mPa·s) and 10 parts by mass of a commercially available PVA resin (JT-05 manufactured by Nippon Gohsei, degree of saponification: 94.0 mol%, 4% by mass aqueous solution viscosity: 5.6 mPa·s) were placed in a polyethylene bag, and the bag was shaken about 100 times to uniformly mix the PVA powder, thereby preparing a PVA-based polymer having a wide degree of saponification distribution. The average degree of saponification, 4% by mass aqueous solution viscosity, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) when measured by LC-CAD of Synthesis Example 7 are shown in Table 1.

[0066] (Synthesis Example 8) 8 parts by mass of a commercially available PVA resin (JL-05E manufactured by Nippon Vinyl Alcohol Co., Ltd., degree of saponification: 80.2 mol%, viscosity of 4 mass% aqueous solution: 5.1 mPa·s) and 92 parts by mass of a commercially available PVA resin (JP-05 manufactured by Nippon Vinyl Alcohol Co., Ltd., degree of saponification: 88.8 mol%, viscosity of 4 mass% aqueous solution: 5.3 mPa·s) were placed in a polyethylene bag, and the bag was shaken about 100 times to uniformly mix the PVA powder, thereby preparing a PVA-based polymer with a wide saponification degree distribution. Table 1 shows the average saponification degree, viscosity of 4 mass% aqueous solution, transparency and supernatant concentration when 1-propanol was added, and the value of formula (3) measured by LC-CAD in Synthesis Example 8.

[0067] <Coating Conditions> Apparatus: High Coater (HC-FZ-Labo, manufactured by Freund Industries Co., Ltd.) Tablet charge amount: 1000 g Supply air temperature: 70 - 80 °C Exhaust air temperature: 44 - 52 °C Supply air volume: 0.6 m 3 / min Number of spray guns: 1 Spray gun air volume (atomized air): 30 L / min Spray gun air volume (pattern air): 9 L / min Spray speed: Adjusted by the discharge amount of the tube pump Pan rotation speed: 18 rpm

[0068] <Evaluation of Coating Time> In the coating test, when spray-applying the coating solution, the spray rate was started at 3.0 g / min. When sticking between tablets and between tablets and the pan did not occur, the spray rate was gradually increased until sticking between tablets or between tablets and the pan occurred. Thereafter, once the spray rate was decreased, it was confirmed that the sticking did not occur at a rate where sticking between tablets or between tablets and the pan did not occur, and the coating test was continued at that spray rate for 10 minutes to confirm that no sticking occurred, and that spray rate was set as the maximum spray rate. On the other hand, when sticking between tablets or between tablets and the pan occurred at the initial spray rate of 3.0 g / min, the spray rate was gradually decreased, and it was confirmed that no sticking occurred at that spray rate for 10 minutes, and that spray rate was set as the maximum spray rate. Further, from the maximum spray rate, the shortest coating time for applying a coating of 3 mass% in terms of solid content to the tablets was calculated.

[0069] <Evaluation of water vapor permeability> A solution or dispersion of a coating composition with a solid content concentration of 12 mass% was cast onto a PET sheet and dried in a thermo-hygrostat at 25°C × 65% RH to obtain a film with a thickness of 100 μm. The water vapor permeability of the obtained film was measured at 25°C and a water vapor permeability with a relative humidity difference of 65% according to the method of JIS K7129 using an L80-5000 type water vapor permeation meter (manufactured by Systech Instruments).

[0070] (Example 1) 30 parts by mass of the PVA-based polymer of Synthesis Example 1 was added to 220 parts by mass of purified water, and the mixture was stirred for 1 hour while heating to 80°C to prepare a coating solution (PVA-based polymer concentration: 12 mass%). Using this coating solution, a coating test was carried out on plain tablets mainly composed of lactose and corn starch, and the maximum spray rate, shortest coating time, and water vapor permeability of the coating composition were evaluated. The maximum spraying rate of the film coating solution using the PVA polymer of Synthesis Example 1 was 4.85 g / min, and the coating time for applying a 3 mass% coating was 52 minutes. Also, the water vapor permeability was 32 g / m 2 ·day. The results are shown in Table 2.

[0071] (Examples 2 to 8) Coating tests were carried out in the same manner as in Example 1, except that the PVA polymers of Synthesis Examples 2 to 8 were used instead of the PVA polymer of Synthesis Example 1, and the maximum spraying rate, the shortest coating time, and the water vapor permeability were evaluated. The results are shown in Table 2.

[0072] (Comparative Example 1) Coating tests were carried out in the same manner as in Example 1, except that the PVA polymer of Comparative Synthesis Example 1 was used instead of the PVA polymer of Synthesis Example 1, and the maximum spraying rate, the shortest coating time, and the water vapor permeability were evaluated. The results are shown in Table 2.

[0073] (Comparative Example 2) Coating tests were carried out in the same manner as in Example 1, except that a commercially available partially saponified PVA (manufactured by Nippon Gohsei, Poval JP-05, saponification degree: 88.2 mol%, viscosity of 4 mass% aqueous solution: 5.3 mPa·s) was used instead of the PVA polymer of Synthesis Example 1, and the maximum spraying rate, the shortest coating time, and the water vapor permeability were evaluated. The results are shown in Table 2. The transparency when 1-propanol of the used JP-05 was added, the supernatant concentration, and the value of formula (3) when measured by LC-CAD are shown in Table 1.

[0074] (Comparative Example 3) 24 parts by mass of commercially available partially saponified PVA (manufactured by Nippon Gohsei, degree of saponification: 88.2 mol%, viscosity of 4% by mass aqueous solution: 5.3 mPa·s) and 6 parts by mass of PEG6000 (manufactured by Wako Pure Chemical Industries, average molecular weight 5400 - 6600) were placed in a polyethylene bag and mixed 100 times or more to prepare a uniform film coating composition. This film coating composition was added to 220 parts by mass of purified water and stirred for 1 hour while heating to 80°C, and then cooled for 30 minutes to prepare a coating solution (PVA:PEG6000 = 8:2, aqueous solution concentration: 12% by mass). A coating test was carried out in the same manner as in Example 1 except that this coating solution was used, and the maximum spray rate, the shortest coating time, and the water vapor permeability were evaluated. The results are shown in Table 2.

[0075]

Table 1

[0076]

Table 2

[0077] As is clear from Table 2, by using the PVA-based polymers with a wide degree of saponification distribution of Synthesis Examples 1 - 8 that satisfy Requirement (A) and / or (B) used in Examples 1 - 7, the spray rate can be increased compared with Comparative Examples 1 - 2, and a predetermined amount of film coating can be applied to tablets in a short time. The fact that the spray rate is high in this way means that sticking between tablets and between tablets and bread is less likely to occur. That is, it was confirmed that the film coating composition of the present invention is less likely to cause sticking between tablets and between tablets and bread when coating tablets. In addition, the films formed by the coating compositions of Examples 1 to 8 have a low water vapor permeability similar to that of conventional PVA. Furthermore, compared with the films formed from a coating composition containing PVA and a plasticizer such as Comparative Example 3 in which productivity is improved by containing a plasticizer, the water vapor transmission rate is lower. Therefore, by using the film coating composition of the present invention, it becomes possible to manufacture tablets with a highly moisture-proof film in a short time.

Industrial Applicability

[0078] The film coating composition of the present invention can be used for pharmaceutical preparations in Japan, the United States, and Europe. Even when coating is performed with PVA alone, adhesion between tablets is less likely to occur, thereby shortening the coating time, and it has excellent moisture-proof properties and can form a highly water-soluble coating film. Therefore, manufacturing oral solid preparations using the film coating composition of the present invention is extremely useful industrially.

Claims

1. A film coating composition for oral solid preparations, comprising a polyvinyl alcohol-based polymer having an average saponification degree of 85.0 mol% to 89.0 mol% as measured according to JIS K6726, wherein the polyvinyl alcohol-based polymer satisfies the following requirement (B), and the oral solid preparation contains none of the compounds represented by the following formula I and salts of the compounds represented by the following formula I with at least one selected from calcium, magnesium, and zinc. A film coating composition for oral solid preparations. Requirement (B): With respect to 100.0 g of a 5.0 mass% aqueous solution of the polyvinyl alcohol-based polymer, 230.0 ml of 1-propanol is added, and the concentration of the supernatant obtained by allowing the stirred solution to stand at 20 °C for 24 hours is 0.75 mass% or more. 【Chemical Formula 1】 (In the formula, R １ and R ２ one of them is hydrogen and the other is alkyl having 1 to 5 carbon atoms.)

2. The composition according to claim 1, for coating tablets.

3. The composition according to claim 1 or 2, wherein the oral solid preparation contains none of the compounds represented by the following formula I and salts of the compounds represented by the following formula I having a solubility in water of less than 2 mg / mL at 21 to 24 °C. [Chemical Formula 2] (In the formula, one of R1 and R2 is hydrogen, and the other is alkyl having 1 to 5 carbon atoms.)

4. The composition according to any one of claims 1 to 3, wherein the oral solid preparation contains none of the compounds represented by the following formula I and their salts. [Chemical Formula 3] (In the formula, one of R1 and R2 is hydrogen, and the other is alkyl having 1 to 5 carbon atoms.)

5. The composition according to any one of claims 1 to 4, wherein in requirement (B), the concentration is 0.75 to 0.87 mass%.

6. The composition according to any one of claims 1 to 5, wherein the oral solid preparation is not any of the following (1) to (4). (1) Containing one or more selected from vitamin B1, fursultiamine hydrochloride, disethiamine hydrochloride, octothiamine, ciclotiamine, bisibuthiamine, bisbentiamine, benfotiamine, fursultiamine, prosultiamine, hyaluronic acid, salts of hyaluronic acid, chondroitin, salts of chondroitin, chondroitin sulfate, salts of chondroitin sulfate, sialic acid, muramic acid, glucosamine, glucosamine salts, N-acetylglucosamine, N-methyl-L-glucosamine (2) Containing ibuprofen and ethenzamide Containing a polyvinyl alcohol-based polymer coated with a film composed of an inner layer and an outer layer, and the outer layer satisfies requirement (B) Containing a compound represented by the following formula I or a salt thereof 【Chemical Formula 4】 (In the formula, R １ and R ２ One of them is hydrogen and the other is alkyl having 1 to 5 carbon atoms.)

7. The composition according to any one of claims 1 to 6, wherein the polyvinyl alcohol-based polymer satisfies the requirement that the viscosity of a 4% by mass aqueous solution measured according to JIS K6726 is 2.0 mPa·s or more and 10.0 mPa·s or less.

8. The composition according to any one of claims 1 to 7, wherein the polyvinyl alcohol-based polymer satisfies the requirement that the viscosity of a 4% by mass aqueous solution measured according to JIS K6726 is 3.0 mPa·s or more and 7.0 mPa·s or less.

9. The composition according to any one of claims 1 to 8, for coating with a coating amount of 1 to 10% by mass based on the total amount of the tablets.

10. An oral solid preparation comprising a tablet containing a drug and the composition according to any one of claims 1 to 9 for coating the tablet.

11. The oral solid preparation according to claim 10, wherein the coating amount of the composition is 1 to 10% by mass based on the total amount of the tablets.

12. A method for producing an oral solid preparation, comprising the step of applying or spraying an aqueous solution and / or an aqueous solution containing the composition according to any one of claims 1 to 9 onto a tablet containing a drug to coat the surface of the tablet with the composition.

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