Hard capsule comprising film containing opacifier, liquid for preparing hard capsule, and method for preparing hard capsule

Abstract

The present invention addresses the problem of providing a hard capsule film having higher light-blocking properties using calcium carbonate. A hard capsule containing a film containing a cellulose compound and an opacifying agent, the opacifying agent containing calcium carbonate having a median diameter in volume units of 0.7-3.8 [mu] m, and the content of the opacifying agent contained in the film being 3-20 mass% when the total of the film components of the hard capsule excluding moisture is taken as 100 mass%.

Description

Technical Field

[0001] This specification discloses hard capsules containing a film containing a light-shielding agent, a hard capsule preparation liquid, and a method for preparing a hard capsule. Background Art

[0002] Among the ingredients incorporated in pharmaceuticals, quasi-pharmaceuticals, foods, and cosmetics, there are ingredients that are unstable to light. As a method for preventing the deterioration of such ingredients due to light and ensuring quality stability, a method of coating with a film composition having a light-shielding effect is widely used.

[0003] As a light-shielding agent, titanium oxide is usually used. However, among the ingredients incorporated in pharmaceuticals, there are ingredients that are damaged in stability by titanium oxide, or ingredients that are decomposed by free radicals generated from titanium oxide by ultraviolet rays. Depending on the incorporated ingredients, titanium oxide is contraindicated. In addition, in recent years, titanium oxide itself has been pointed out to have carcinogenicity.

[0004] In view of such a situation, attempts have been made to incorporate ingredients other than titanium oxide as light-shielding agents into capsules for pharmaceuticals, quasi-pharmaceuticals, foods, and cosmetics.

[0005] For example, Patent Document 1 discloses an opaque film composition containing a water-soluble metal compound and a water-soluble cellulose derivative, the water-soluble metal compound containing at least 1 metal selected from sodium, potassium, calcium, magnesium, aluminum, manganese, iron, cobalt, nickel, copper, strontium, and barium. Patent Document 2 discloses the capsule-forming composition, which includes: a film-forming agent selected from gelatin, polysaccharide, modified starch, cellulose derivative, or synthetic polymer; and an opacifying agent in the form of calcium carbonate in an amount between 3 to 10% by mass based on the dry mass of the capsule-forming complex. In Patent Document 2, precipitated calcium carbonate is used as calcium carbonate. Patent Document 3 discloses a capsule shell containing gelatin and heavy calcium carbonate.

[0006] Prior Art Documents Patent Documents Patent Document 1: International Publication No. 2008-156027 Patent Document 2: International Publication No. 2019-219693 Patent Document 3: International Publication No. 2021-069590 Summary of the Invention

[0007] Technical Problem to be Solved by the Invention However, as described in Patent Document 2, compared with the case of using titanium oxide, the light-shielding property of the capsule shell using calcium carbonate as a light-shielding agent is not high.

[0008] An object of the present invention is to provide a hard capsule film using calcium carbonate with higher light-shielding properties. Another object is to provide a hard capsule film using calcium carbonate that maintains light-shielding properties while maintaining film strength.

[0009] Technical solutions for solving technical problems An example of an embodiment of the present invention is as follows.

[0010] Item 1. A hard capsule comprising a film containing a cellulose compound and a light-shielding agent, The light-shielding agent contains calcium carbonate with a median particle size in terms of volume unit of 0.7 μ m to 3.8 μ m, When the total of the film components of the hard capsule excluding moisture is set to 100% by mass, the content of the light-shielding agent contained in the film is 3% to 20% by mass.

[0011] Item 2. The hard capsule according to Item 1, wherein the cellulose compound is hydroxypropyl methylcellulose.

[0012] Item 3. The hard capsule according to Item 2, wherein the film further contains (1) a gelling agent, or (2) a gelling agent and a gelling aid.

[0013] Item 4. A hard capsule preparation liquid comprising a cellulose compound, a light-shielding agent, and an aqueous solvent, The light-shielding agent contains calcium carbonate with a median particle size in terms of volume unit of 0.7 μ m to 3.8 μ m, When the total of the components other than the aqueous solvent in the preparation liquid is set to 100% by mass, the content of the light-shielding agent in the total of the film components other than the aqueous solvent is 3% to 20% by mass.

[0014] Item 5. The hard capsule preparation liquid according to Item 4, wherein the cellulose compound is hydroxypropyl methylcellulose.

[0015] Item 6. The hard capsule preparation liquid according to Item 5, which further contains (1) a gelling agent, or (2) a gelling agent and a gelling aid.

[0016] Item 7. A method for preparing a hard capsule, comprising the following steps: Using the hard capsule preparation liquid described in Item 4, preparing a hard capsule by the cold gelling method.

[0017] Advantages of the invention It is possible to provide a hard capsule film with higher light-shielding properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 A is a graph showing the relationship between the transmittance at a measurement light wavelength of 650 nm and Dv50.

[0019] Figure 1 B is a graph showing the relationship between the transmittance at a measurement light wavelength of 420 nm and Dv50. DETAILED DESCRIPTION OF THE INVENTION

[0020] 1. Hard Capsule The hard capsule includes a film containing a cellulose compound and a light-shielding agent. The light-shielding agent contains calcium carbonate having a median particle size (Dv50) of 0.7 μ m to 3.8 μ m.

[0021] In the present specification, a "hard capsule" refers to a type of capsule that is prepared by first preparing a capsule film and then filling the prepared capsule film with the contents. The capsule generally includes a cap portion and a body portion, and is also referred to as a hard capsule or a two-piece capsule. The "hard capsule" of the present invention does not include: soft capsules in which the contents are filled between two films and the films are bonded to each other; seamless capsules in which the contents are dropped into a coagulating liquid together with a film solution; and microcapsules prepared by precipitating a substrate or emulsifying and mixing an active ingredient into the interior.

[0022] As the cellulose compound used in the hard capsule, a water-soluble cellulose ether in which at least one group of an alkyl group or a hydroxyalkyl group has replaced a hydrogen atom of a hydroxyl group of cellulose can be mentioned. Here, as the "alkyl group" in the above alkyl group or hydroxyalkyl group, a linear or branched lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be mentioned, and specifically, methyl, ethyl, butyl, and propyl can be mentioned. As the water-soluble cellulose compound, specifically, lower alkyl celluloses such as methylcellulose; hydroxy lower alkyl celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose; and hydroxy lower alkyl alkyl celluloses such as hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose, and hydroxypropyl methyl cellulose (in the present specification, sometimes also referred to as hypromellose or HPMC) can be mentioned. Among them, hydroxypropyl methyl cellulose is the best cellulose compound in terms of excellent film formability and mechanical strength under low moisture.

[0023] The hydroxypropyl methyl cellulose used for the hard capsule includes hypromellose specified in the Japanese Pharmacopoeia shown in Table 1.

[0024] [Table 1]

[0025] In addition, the hydroxypropyl methylcellulose contains hypromellose having the following molecular weights that has been approved as a food additive in Japan.

[0026] <Molecular weight> Unsubstituted structural unit: 162.14 Substituted structural unit: approximately 180 (degree of substitution 1.19), approximately 210 (degree of substitution 2.37) Polymer: approximately 13,000 (n = approximately 70) to approximately 200,000 (n = approximately 1000).

[0027] The ratio (Mw / Mn) of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) of commercially available hydroxypropyl methylcellulose is generally in the range of 1.5 to 4. It should be noted that when calculating this ratio (Mw / Mn), both the weight-average molecular weight (Mw) and the number-average molecular weight (Mn) can be determined by gel permeation chromatography (size exclusion chromatography). The principle and method of gel permeation chromatography are not limited. For example, reference can be made to the description in the "Size-Exclusion Chromatography" section of the "Chromatography" chapter in "USP30 The United States Pharmacopeia / NF25 The National Formulary".

[0028] Examples of commercially available hydroxypropyl methylcellulose include the TC-5 series, SB-4 series (registered trademarks), METOLOSE (registered trademark) series of Shin-Etsu Chemical Co., Ltd., the AnyCoat-C (registered trademark) series of LOTTE (formerly Samsung) Fine Chemical Co., Ltd., and the METCEL (registered trademark) series of DOW.

[0029] In addition, the hydroxypropyl methylcellulose that is the subject of the present invention includes hydroxypropyl methylcellulose having a viscosity of 3 to 50 mPa·s at 20°C ± 0.1°C in its 2 mass% aqueous solution.

[0030] Hydroxypropyl methylcellulose may be used alone or in any combination of two or more thereof, and a hydroxypropyl methylcellulose having a "hypromellose viscosity value" of 300 to 5000, preferably 300 to 1500, and more preferably 300 to 960 may be used. Here, the "hydroxypropyl methylcellulose viscosity value" refers to the sum of the values ​​obtained by multiplying the viscosity (mPa·s) of a 2 mass % aqueous solution of hydroxypropyl methylcellulose used for the production of capsule films at 20°C±0.1°C by its ratio (parts by mass) relative to 100 parts by mass of the total amount of hydroxypropyl methylcellulose. Specifically, when hydroxypropyl methylcellulose having a viscosity of 6 mPa·s in a 2 mass % aqueous solution is used alone in the production of capsule films, the "hydroxypropyl methylcellulose viscosity value" is 600 as "6 mPa·s×100 parts by mass". When 30 parts by mass of hydroxypropyl methylcellulose having a viscosity of 4 mPa·s in a 2% by mass aqueous solution and 70 parts by mass of hypromellose having a viscosity of 6 mPa·s are used in combination in the production of a capsule film, the "hydroxypropyl methylcellulose viscosity value" is 540 as "4 mPa·s×30 parts by mass+6 mPa·s×70 parts by mass".

[0031] Generally speaking, if the molecular weight is low, the viscosity value becomes low. In addition, when the molecular weight is low, that is, the viscosity value is low, the solubility of the hard capsule becomes good, but on the other hand, there is a tendency to be easily broken.

[0032] Therefore, for oral pharmaceuticals that emphasize solubility, the viscosity value of hydroxypropyl methylcellulose is preferably 300 to 960. On the other hand, for inhalation pharmaceuticals and food applications that emphasize resistance to breakage, the viscosity value is preferably 500 to 1500.

[0033] The content of the cellulose compound in the hard capsule film is the remainder after deducting the total amount of the film components other than the cellulose compound, such as the gelling agent, gelling aid, sunscreen, plasticizer, lubricant, chelating agent, colorant, sunscreen, etc., which are described later. However, the film components other than the cellulose compound do not include water.

[0034] The cellulose compound can be accelerated to gel during film formation by adding (1) a gelling agent, or (2) a gelling agent and a gelling aid.

[0035] Examples of the gelling agent include gelling agents such as carrageenan, pectin, and gellan gum that can gel the hard capsule preparation liquid. They can be used alone or in any combination of two or more. Among the above gelling agents, carrageenan has a high gelling strength and exhibits excellent gelling properties even when used in a small amount in the coexistence of specific ions, so it is the best gelling agent. It should be noted that carrageenan is generally known to have three types: κ-carrageenan, ι-carrageenan, and λ-carrageenan. In the present invention, κ-carrageenan and ι-carrageenan having higher hardness and gelling ability can be preferably used, and κ-carrageenan is more preferably used. In addition, pectin can be classified into LM pectin and HM pectin according to the degree of esterification, and gellan gum can also be classified into acylated gellan gum (natural gellan gum) and deacylated gellan gum according to the presence or absence of acylation, but in the present invention, they can all be used without distinction.

[0036] The content of the gelling agent contained in the film of the hard capsule is not limited as long as the film of the hard capsule can be formed by the cold gelling method. As the content of the gelling agent, when the total of the film components of the hard capsule other than water is set to 100% by mass, 0.05 to 10% by mass, preferably 0.1 to 9.5% by mass, more preferably 0.2 to 9% by mass, and further preferably 0.3 to 8% by mass can be cited.

[0037] The gelling aid can be selected according to the type of the gelling agent used. The gelling aid has the effect of promoting the gelling of the gelling agent. Or, by directly changing the gelling temperature or cloud point temperature of the cellulose compound, it sometimes helps to promote gelling. As the gelling aid that can be used in combination when using carrageenan as the gelling agent, for κ-carrageenan, compounds that can generate one or more of sodium ions, potassium ions, ammonium ions, and calcium ions in an aqueous solution can be cited, such as sodium chloride, potassium chloride, potassium phosphate, ammonium chloride, ammonium acetate, and calcium chloride. Compounds that can generate sodium ions, potassium ions, or calcium ions in an aqueous solution are preferred. In addition, for ι-carrageenan, compounds that can generate calcium ions in water can be cited, such as calcium chloride. In addition, as the gelling aid that can be used in combination when using gellan gum as the gelling agent, compounds that can generate one or more of sodium ions, potassium ions, calcium ions, and magnesium ions in water can be cited, such as sodium chloride, potassium chloride, calcium chloride, and magnesium sulfate. In addition, citric acid or sodium citrate can also be used as an organic acid or its water-soluble salt.

[0038] In addition, in the present invention, calcium carbonate used as a light-shielding agent also generates a small amount of calcium ions in the hard capsule preparation liquid. Therefore, when using gellan gum and / or ι-carrageenan as the gelling agent, the hard capsule preparation liquid can be gelled even without adding a gelling aid.

[0039] The content of the gelling aid contained in the film of the hard capsule can be set according to the content of the gelling agent. When the total of the film components of the hard capsule excluding moisture is set to 100% by mass, the content of the gelling aid can be in the range greater than 0 and 2.2% by mass or less, preferably 0.1 to 2.1% by mass, more preferably 0.2 to 1.9% by mass, and further preferably 0.3 to 1.6% by mass. When using gellan gum and / or ι-carrageenan as the gelling agent, when the total of the film components of the hard capsule excluding moisture is set to 100% by mass, the content of the gelling aid can be in the range of 0 or more and 2.2% by mass or less, preferably 0.1 to 2.1% by mass, more preferably 0.2 to 1.9% by mass, and further preferably 0.3 to 1.6% by mass.

[0040] When using hydroxypropyl methylcellulose as the cellulose compound, as the gelling agent used in combination, carrageenan, especially κ-carrageenan, can be preferably cited. In addition, as the gelling aid used in combination therewith, potassium chloride can be preferably cited.

[0041] The light-shielding agent contains calcium carbonate. Calcium carbonate includes calcium carbonate produced by crushing limestone and calcium carbonate produced industrially. Calcium carbonate produced by crushing limestone is called heavy calcium carbonate. In addition, calcium carbonate produced industrially is called light calcium carbonate, or precipitated calcium carbonate or synthetic calcium carbonate.

[0042] Any one of calcium carbonates can be used for the hard capsule film, but heavy calcium carbonate is preferred.

[0043] The particle size of calcium carbonate can be represented by the median particle size (central diameter). Preferably, the median particle size in volume units, i.e., Dv50, can be used. The median particle size of the particles can be determined by a Coulter counter, laser diffraction scattering method, etc.

[0044] It should be noted that the definitions of the laser diffraction method and the particle size, average particle size, volume fraction, etc. obtained by this method are based on JIS Z 8825.

[0045] The Dv50 of calcium carbonate is as Figure 1 shown in A. When measuring the transmittance of a film with a film thickness of 100 μ μm containing 7% by mass of calcium carbonate relative to the film components using light with a wavelength of 650 nm, when the transmittance is set to 40% or less, the Dv50 is preferably 0.5 μ μm to 7 μ μm. When the transmittance is set to 30% or less, the Dv50 is preferably 0.6 μ μm to 5 μ μm. When the transmittance is set to 20% or less, the Dv50 is preferably 0.9 μ μm to 3.8 μ μm. As Figure 1As shown in B, when measuring the transmittance of a film with a film thickness of 100 μ μm and containing 7% by mass of calcium carbonate relative to the film composition, when the transmittance is set to 20% or less, Dv50 is preferably 0.4 μ μm to 6 μ μm, and when the transmittance is set to 10% or less, Dv50 is preferably 0.7 μ μm to 3.4 μ μm. Therefore, the Dv50 of calcium carbonate is preferably 0.7 μ μm to 3.8 μ μm. Here, a film thickness of 100 μ μm means that the measured value of the film thickness of the film can be 100 μ μm, or the measured value of the film thickness of the film can be converted to 100 μ μm. The definition of transmittance will be described later.

[0046] As commercially available heavy calcium carbonate, precipitated calcium carbonate A (Bihoku Pulverizing Industry, Dv50: 2.16 μ μm, named precipitated calcium carbonate, but the manufacturer presents it as heavy calcium carbonate), Aragen (CALFINE, Dv50: 5.05 μ μm), Caltex5 (Maruo Calcium, Dv50: 1.82 μ μm), ACE-30 (CALFINE, Dv50: 1.89 μ μm), ACE-35 (CALFINE, Dv50: 2.04 μ μm), CALMIGEN A (Bihoku Pulverizing Industry, Dv50: 2.12 μ μm), NANOX 25A (Maruo Calcium, Dv50: 3.02 μ μm), NANOX 30 (Maruo Calcium, Dv50: 2.21 μ μm), Calcy F (Sankyo Seifun, Dv50: 2.44 μ μm), Kristone SS food additive (CALFINE, Dv50: 3.02 μ μm), etc.

[0047] As precipitated calcium carbonate, Carpin F (Yabashi Kogyo, Dv50: 2.63 μ μm), CALESSEN I (Shiraishi Kogyo, Dv50: 0.39 μ μm), CAL·ACE-ST (Maruo Calcium, Dv50: 0.51 μ μm), etc. can be used.

[0048] The above value of Dv50 is the median particle diameter in volume units, representing the measured value based on the laser diffraction method described in JIS Z 8825.

[0049] When the total of the film components of the hard capsule excluding moisture is set to 100% by mass, the content of the light-shielding agent in the film of the hard capsule is, for example, 3% to 20% by mass. Preferably, it is 6% to 20% by mass.

[0050] The film of the hard capsule may contain, as needed, a plasticizer, a lubricant, a chelating agent, a coloring agent, a light-shielding agent, residual moisture (also simply referred to as moisture), etc. as the film components of the hard capsule.

[0051] As the plasticizer, there is no particular limitation as long as it can be used in pharmaceutical or food compositions. For example, dioctyl adipate, polyester adipate, epoxidized soybean oil, epoxydized hexahydrophthalic acid diester, kaolin, triethyl citrate, glycerol, glycerol fatty acid ester, sesame oil, dimethyl polysiloxane·silica mixture, D-sorbitol, medium-chain triglyceride, sugar alcohol solution derived from corn starch, triacetin, thick glycerol, castor oil, phytosterol, diethyl phthalate, dioctyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 1500, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 600, polyethylene glycol 6000, isopropyl myristate, cottonseed oil·soybean oil mixture, glycerol monostearate, isopropyl linoleate, etc. It should be noted that when using a plasticizer, when the total of the film components of the hard capsule excluding moisture is set to 100% by mass, a range of usually 15% by mass or less can be cited. It can be preferably added in a range of 13% by mass or less, more preferably 11% by mass or less, and further preferably 8% by mass or less.

[0052] Examples of the chelating agent include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid or their salts, metaphosphate, dihydroxyethylglycine, lecithin, β-cyclodextrin, or a combination thereof.

[0053] As the lubricant, there is no particular limitation as long as it can be used in pharmaceutical or food compositions. For example, calcium stearate, magnesium stearate, sodium stearyl fumarate, carnauba wax, starch, sucrose fatty acid ester, light anhydrous silicic acid, polyethylene glycol, talc, hydrogenated vegetable oil, etc.

[0054] As a coloring agent and a light-shielding agent, there is no particular limitation as long as it can be used in pharmaceutical or food compositions. As coloring agents, examples include catechu tannic acid powder, turmeric extract, methylrosanilinium chloride, yellow iron oxide, yellow ferric oxide, OPASPRAY K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene solution, β-carotene, photochrom 201, licorice extract, gold leaf, sasamorpha extract, black iron oxide, light anhydrous silicic acid, dragon's blood (Daemonorops draco (kekketsu)), zinc oxide, titanium oxide, ferric oxide, bisazo yellow, Food Blue No. 1 and its aluminum lake, Food Blue No. 2 and its aluminum lake, Food Yellow No. 4 and its aluminum lake, Food Yellow No. 5 and its aluminum lake, Food Green No. 3 and its aluminum lake, Food Red No. 2 and its aluminum lake, Food Red No. 3 and its aluminum lake, Food Red No. 102 and its aluminum lake, Food Red No. 104 and its aluminum lake, Food Red No. 105 and its aluminum lake, Food Red No. 106 and its aluminum lake, sodium hydroxide, talc, sodium copper chlorophyllin, copper chlorophyll, defatted hull barley green tea extract powder, defatted hull barley green tea extract, phenol red, sodium fluorescein, d-borneol, malachite green, octyldodecyl myristate, methylene blue, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, ammonium manganese phosphate, sodium riboflavin phosphate, rose oil, curcumin, chlorophyll, carminic acid pigment, Food Red No. 40 and its aluminum lake, water-soluble annatto, sodium iron chlorophyllin, dunaliella carotene, capsicum pigment, carrot carotene, potassium norbixin, sodium norbixin, palm oil carotene, betanin, grape skin pigment, blackcurrant pigment, monascus pigment, safflower red pigment, safflower yellow pigment, marigold pigment, sodium riboflavin phosphate, madder pigment, gromwell pigment, aluminum, sweet potato carotene, shrimp pigment, krill pigment, orange pigment, cocoa pigment, cocoa charcoal pigment, persimmon pigment, crab pigment, carob pigment, fish scale foil, silver, Clerodendrum trichotomum pigment, gardenia blue pigment, gardenia red pigment, gardenia yellow pigment, dioscorea pigment, chlorophyllin, sorghum pigment, bone charcoal pigment, bamboo pigment, sheanut) pigments, purple gromwell root pigment, brazilin, vegetable carbon black pigment, sappanwood pigment, spirulina pigment, onion pigment, tamarind pigment, corn pigment, tomato pigment, peanut pigment, phaffia yeast pigment, pecan pigment, monascus yellow pigment, annatto, astaxanthin, purple sweet potato pigment, purple corn pigment, purple yam pigment, soot pigment, lac dye, rutin, sophora japonica extract, whole buckwheat herb extract, hematoxylin, red cabbage pigment, red rice pigment, carrot root pigment, adzuki bean pigment, phyllanthus emblica extract, sepia pigment, ying shen le pigment, elderberry pigment, olive tea, bilberry pigment, gooseberry pigment, cranberry pigment, beautyberry pigment, strawberry pigment, deep sweet cherry pigment, cherry pigment, thimbleberry pigment, dewberry pigment, pineapple juice, bilberry pigment, grape juice pigment, blackcurrant pigment, blackberry pigment, plum pigment, blueberry pigment, berry juice, boysenberry pigment, european blueberry pigment, mulberry pigment, morrello cherry pigment, raspberry pigment, redcurrant pigment, lemon juice, loganberry pigment, chlorella powder, cocoa, saffron pigment, perilla pigment, chicory pigment, laver pigment, hibiscus pigment, malt extract, red pepper powder, red beet juice, carrot juice, etc.

[0055] As sunscreen agents, examples include titanium oxide, iron(III) oxide, yellow iron(III) oxide, black iron oxide, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 4 Aluminum Lake, FD&C Yellow No. 5 Aluminum Lake, FD&C Green No. 3 Aluminum Lake, FD&C Red No. 2 Aluminum Lake, FD&C Red No. 3 Aluminum Lake, FD&C Red No. 102 Aluminum Lake, FD&C Red No. 104 Aluminum Lake, FD&C Red No. 105 Aluminum Lake, FD&C Red No. 106 Aluminum Lake, FD&C Red No. 40 Aluminum Lake.

[0056] The prepared capsule film preferably contains a few percent of residual moisture. Generally, when the formed capsules are dried in the range of 30°C to 100°C, it stabilizes at a specific saturated residual moisture value corresponding to the solid component amount of the capsules and their composition. Of course, in the case of drying at high temperature, the time to stabilize to the saturated moisture value is shorter. The residual moisture also depends on the environmental humidity during the storage of the capsules and changes almost reversibly. That is, when the saturated moisture value after sufficient drying at 30 to 100°C is stored at a certain temperature and relative humidity for several days, it converges to a certain value. In the present invention, the saturated moisture value after storing at 43% relative humidity at room temperature for several days is used.

[0057] In order to maintain non-fragility, it is rather preferable to contain a small amount of residual moisture. As the saturated moisture value of the residual moisture at room temperature and a relative humidity of 43%, it is preferably at least 1% or more, more preferably 2% or more, and further preferably 3% or more, relative to the total mass of the hard capsule film. On the other hand, when there is too much residual moisture, in the case of long-term storage, it may react with the drug filled inside, so it is preferably 8% or less, more preferably 6% or less.

[0058] The residual saturated moisture content can be expressed by the moisture content under loss on drying, and its measurement can be carried out as follows.

[0059] <Method for Measuring the Moisture Content in a Capsule Film Based on the Loss on Drying Method> Add a saturated aqueous solution of potassium carbonate to a desiccator, add a sample (hard capsule or film) into an atmosphere with a constant humidity state and seal it, and condition the humidity at 25 °C for 1 week. It should be noted that in the presence of a saturated aqueous solution of potassium carbonate, an atmosphere with a relative humidity of about 43% can be formed. After measuring the mass (wet mass) of the conditioned sample, then heat and dry this sample at 105 °C for 2 hours, and measure the mass of the sample again (dry mass). Based on the difference between the mass before drying (wet mass) and the mass after drying (dry mass), calculate the proportion (moisture content) of the water mass reduced by heating and drying at 105 °C for 2 hours according to the following formula.

[0060] [Equation 1]

[0061] The film of the above-mentioned hard capsule has light-shielding properties. The light-shielding properties can be evaluated by the transmittance. The transmittance can be calculated according to the following method.

[0062] <Evaluation of Light-Shielding Properties> When evaluating the transmittance of a hard capsule, it is important to make the thickness of the test film consistent for comparison. Therefore, for example, regarding the transmittance of a hard capsule, a preparation solution with the same component composition as each component of the hard capsule preparation solution is used, a film is prepared by the casting method, and the transmittance is evaluated using this cast film.

[0063] The method for preparing a cast film is as follows.

[0064] When preparing a cast film by the cold gelation method, a metal applicator is set on a glass surface or a PET film maintained at room temperature, and a preparation solution at about 50 - 60 °C is poured and allowed to move at a certain speed to prepare a uniform wet film with a dried film thickness of 100 μ μm. Then, the wet film is dried at room temperature to about 30 °C for about 10 hours, and thus a cast film can be obtained.

[0065] In the case of preparing a cast film by the hot gelation method, a metal coater is set on a glass surface or a PET film maintained at 60 °C, and a preparation liquid at room temperature is poured and moved at a certain speed to prepare a uniform wet film with a dried film thickness of 100 μ μm. Then, after drying the wet film at about 60 °C for about 1 hour, it is further dried at room temperature for about 10 hours, whereby a cast film can be obtained. In addition, in order to obtain a film with a uniform film thickness of 100 μ μm, a coater with a gap of 0.4 mm to 1.5 mm can be appropriately used respectively.

[0066] The evaluation of light-shielding properties can be carried out, for example, by measuring the intensity of transmitted light passing through the object to be measured using an ultraviolet-visible spectrophotometer (for example, Shimadzu UV-1850) and calculating the transmittance. The transmittance can be calculated as follows: The cast film prepared by the above method is cut into strips of 10 mm × 20 mm, and is vertically placed on the light path of the ultraviolet-visible spectrophotometer in a way that blocks the light path, and light with a wavelength of 650 nm or 420 nm is irradiated. The intensity of the transmitted light passing through the cast film and the intensity of the transmitted light of the blank without the cast film are measured. The value of the intensity of the transmitted light passing through the cast film is divided by the value of the intensity of the transmitted light of the blank, whereby the transmittance is calculated. There is an inverse relationship between the transmittance and the light-shielding property. The lower the transmittance, the higher the light-shielding property. The transmittance can also be used to correct the calculated value by the film thickness. The corrected transmittance can be calculated by setting the theoretical value of the film thickness of the film to 100 μ μm, multiplying the value obtained by dividing the theoretical value by the measured value of the film thickness of the film ( μ μm) by the value obtained by converting the calculated transmittance into absorbance, and then converting it back into transmittance.

[0067] The film of the above hard capsule has a specified strength. The strength can be evaluated according to the following method.

[0068] <Evaluation of strength> For the cast film prepared by the above method, a dumbbell-shaped test piece cut into a dumbbell shape of 5 mm × 75 mm (specified in JIS K-7161-2-1BA) is produced. Using this dumbbell-shaped test piece, a tensile test can be performed, for example, using a small bench-top testing machine (EZ-LX manufactured by Shimadzu Corporation). Specifically, both ends of the film are fixed to a bracket (gap length: 59 mm), and the film is stretched at a stretching speed of 50 mm / min to obtain the elongation rate of the film and the stress (tensile stress)-elongation rate (strain) curve generated in the film. From the integral value of the tensile stress-elongation rate curve up to the fracture point, the toughness (toughness, MJ / m3) can be obtained as an index of non-breakability (Literature: Aqueous Polymeric Coating For Pharmaceutical Dosage Forms, 4th edition, CRC Press, 2017, Chapter 4).

[0069] The above strength is preferably maintained under the environment of general use conditions. Therefore, for example, it is preferable to condition the dumbbell-shaped test piece prepared and cut into a dumbbell shape for more than 1 week at 25°C and a relative humidity of 22% (using a saturated potassium acetate brine solution), and then perform a tensile test in a temperature and humidity environment identical to the conditioning conditions to evaluate the mechanical strength.

[0070] The toughness as an index of non-breakability is preferably 2.0 MJ / m3 or more. When the toughness is less than 0.6 MJ / m3, the film is significantly prone to breakage even during general handling.

[0071] 2. Hard capsule preparation liquid The hard capsule preparation liquid (hereinafter, also simply referred to as "preparation liquid") for preparing the hard capsule of the present method contains an aqueous solvent and the film component described in the above 1. As the aqueous solvent, water, ethanol, and a mixture thereof are preferred, and water is more preferred.

[0072] The content of the above film component contained in the preparation liquid is not limited as long as the film of the hard capsule can be formed by the cold gelation method, and the content of each component in the hard capsule after preparation is not limited as long as it is the content in the above hard capsule. That is, in the preparation liquid, when the total of the components other than the aqueous solvent in the preparation liquid is set to 100% by mass, the content of each component in the hard capsule after preparation is not limited as long as it is the content in the above hard capsule. For example, the following concentrations can be cited as the final concentration in the preparation liquid. It should be noted that the final concentration refers to the concentration in the finally completed solution, that is, the concentration in the solution actually used for preparing the capsule.

[0073] Regarding the cellulose compound, it is 10 to 30% by mass, preferably 12 to 20% by mass, more preferably 14 to 18% by mass; the sunscreen is 0.6 to 10% by mass, preferably 1 to 6% by mass, more preferably 2 to 4% by mass. When there are components other than the base agent and the hardening improver, regarding the gelling agent, examples include 0.005 to 0.5% by mass, preferably 0.01 to 0.45% by mass, more preferably 0.015 to 0.4% by mass. In addition, when using a gelling aid, as its concentration, examples include 0.5% by mass or less, 0.02 to 0.5% by mass, preferably 0.03 to 0.40% by mass, more preferably 0.04 to 0.35% by mass. When including a lubricant, a colorant, a sunscreen, a chelating agent, a fragrance, etc., their contents can be appropriately set within the range of 0.5% by weight or less respectively.

[0074] When the total content of the film components other than the aqueous solvent in the preparation liquid is set to 100% by mass for the whole preparation liquid, examples include the range of 10 to 30% by mass, preferably 12 to 25% by mass, more preferably 14 to 20% by mass.

[0075] 3. Method for preparing hard capsules The method for preparing the hard capsule preparation liquid (also referred to as the impregnation liquid) is not particularly limited. For example, the following methods can be used without limitation: after dissolving the gelling agent and the gelling aid as needed in purified water heated to about 70 to 80 °C, dispersing the water-soluble cellulose compound, cooling it to the desired temperature of the impregnation liquid (usually 35 to 60 °C, more preferably 40 to 60 °C), and dissolving the water-soluble cellulose compound to prepare a uniform capsule preparation liquid (impregnation liquid); and dispersing the water-soluble cellulose compound in hot water at about 70 to 80 °C, temporarily cooling it, dissolving the water-soluble cellulose compound, adding the gelling agent and the gelling aid as needed and dissolving them, heating again, adjusting to about 30 to 50 °C, preparing a uniform capsule preparation liquid (impregnation liquid), and adjusting to the desired impregnation liquid temperature, etc. Furthermore, in the molding method using thermal gelation described later, the following method can be used: without adding the gelling agent and the gelling aid, dispersing the water-soluble cellulose compound in hot water at about 70 to 90 °C, temporarily cooling it to near room temperature or below room temperature, dissolving the water-soluble cellulose compound, and preparing hard capsules.

[0076] The viscosity of the capsule preparation liquid is not particularly limited. Preferably, the viscosity of the capsule preparation liquid can be such that at the temperature (temperature of the impregnating liquid) used when impregnating the pins for capsule molding (30 to 80 °C, preferably 40 to 60 °C), the viscosity of the capsule preparation liquid becomes 100 to 20,000 mPa·s, preferably 300 to 10,000 mPa·s. Generally, as the solvent content of the capsule preparation liquid, 60 to 90% by mass, preferably 70 to 85% by mass, can be cited. As the total content of the film components of the hard capsule other than the solvent of the capsule preparation liquid, 10 to 40% by mass, preferably 15 to 30% by mass, can be cited.

[0077] The viscosity specified in the present invention means the viscosity measured under the conditions of a rotation speed of 60 rpm and a measurement time of 1 minute at a specified temperature using a B-type rotational viscometer, using rotor No. 2 when the viscosity is less than 500 mPa·s, using rotor No. 3 when the viscosity is 500 mPa·s or more and less than 2000 mPa·s, and using rotor No. 4 when the viscosity is 2000 mPa·s or more.

[0078] The concentrations of the respective components contained in the capsule preparation liquid are as described later.

[0079] The method for preparing (molding) hard capsules is not particularly limited as long as it includes the step of preparing capsules using the capsule preparation liquid according to the present invention. Hard capsules are usually obtained by impregnating a mold pin, which is a template for the capsule, in an aqueous solution in which a capsule film substance is dissolved, and curing and drying the attached film when lifted, thereby obtaining the desired capsule shape and thickness (impregnation method). Specifically, the method for preparing hard capsules is manufactured through the following steps: a step of preparing a capsule preparation liquid by the above method or preparing it by purchasing a capsule preparation liquid, etc.; and a preparation step of impregnating a capsule molding pin in the capsule preparation liquid and then lifting it to gel the solution attached to the capsule molding pin, and then drying the gelled film at 20 to 80 °C. Depending on the situation, it is also possible to form the capsule without going through the gelling process, but by increasing the viscosity caused by cooling and drying.

[0080] More specifically, hard capsules prepared by the cold gelling method can be prepared through the following molding steps.

[0081] (1) A step (impregnation step) of impregnating a capsule molding pin in a capsule preparation liquid (impregnating liquid) containing a cellulose compound (and, if necessary, a gelling agent and a gelling aid), (2) A step (gelling step) of lifting the capsule molding pin from the capsule preparation liquid (impregnating liquid) to gel the capsule preparation liquid attached to the outer surface of the pin, (3) A step (drying step) of drying the gelled capsule film (gelled film) formed on the outer surface of the capsule molding pin (4) Step of detaching the dried capsule film (film) from the capsule forming pin (detaching step).

[0082] It should be noted that, if necessary, the following heating step may be carried out after the step (4) above.

[0083] (5) Step of heat-treating the gelled capsule film (gelled film) at 30 to 150°C before, after or simultaneously with the drying step (3) after the above gelling step (2), or after the detaching step (4) (heating step).

[0084] It should be noted that, when using a solution not containing a gelling agent such as carrageenan as the capsule preparation liquid (impregnation liquid), the water-soluble cellulose compound itself can be gelled at a temperature of 60°C or higher, and the above gelling step (2) (thermal gelling method) can be carried out using a capsule forming pin heated to 60°C or higher. Specifically, in the impregnation step (1), the capsule forming pin heated to 60 to 150°C, preferably 60 to 120°C, more preferably 70 to 90°C according to the liquid temperature is impregnated in a capsule preparation liquid (impregnation liquid) adjusted to a constant temperature of 25 to 50°C, preferably 35 to 45°C. Then, in the gelling step (2), the capsule forming pin is lifted from the capsule preparation liquid (impregnation liquid) to gel the capsule base solution attached to the outer surface of the pin.

[0085] On the other hand, when using a solution containing a gelling agent such as carrageenan as the capsule preparation liquid (impregnation liquid), the solution can be gelled at a temperature of 50°C or lower. The temperature around the capsule manufacturing machine is usually set to 35°C or lower, preferably 30°C or lower, preferably at room temperature, and the capsule preparation liquid attached to the outer surface of the capsule forming pin is naturally cooled to carry out the above gelling step (2) (cold gelling method). Specifically, in the impregnation step (1), the capsule forming pin adjusted to 10 to 30°C, preferably 13 to 28°C, more preferably 15 to 25°C according to the liquid temperature is impregnated in a capsule preparation liquid (impregnation liquid) adjusted to a constant temperature of 35 to 60°C, preferably 40 to 60°C. Then, in the gelling step (2), the capsule forming pin is lifted from the capsule preparation liquid (impregnation liquid) to gel the capsule preparation liquid attached to the outer surface of the pin.

[0086] The drying step (3) can be carried out at room temperature. Usually, it can be carried out by blowing air at room temperature. The detaching step (4) is carried out by pulling out the dried capsule film formed on the surface of the capsule forming pin from the capsule forming pin.

[0087] The heating step (5) as an optional step can be carried out after the gelling step (2), i.e., after the capsule preparation liquid has gelled (solidified). As long as the heating treatment is carried out after the gelling step (2), it can be at any stage, before or after the drying step (3), or heating and drying can be carried out simultaneously. Further, it can also be carried out after the detachment step (4). Preferably, after the gelling step (2), the gelled capsule membrane is subjected to a drying step at room temperature, and the heating treatment is carried out at the drying or semi-drying stage. The heating temperature is not particularly limited as long as it is in the range of 30 to 150 °C, preferably in the range of 40 to 100 °C, and more preferably in the range of 50 to 80 °C. The heating treatment can generally be carried out by blowing air at 30 to 150 °C.

[0088] The capsule membrane thus prepared can be provided as a hard capsule in a state where the main body part and the cap part are fitted together as a pair or in a non-fitted state after being cut and adjusted to a specified length.

[0089] The film thickness of the hard capsule is generally in the range of 50 to 200 μ m. In particular, among the currently commercially available capsules, the thickness of the side wall portion of the capsule is generally 70 to 150 μ m, and more preferably 80 to 120 μ m. As the size of the hard capsule, there are size 00, size 0, size 1, size 2, size 3, size 4, size 5, etc., and any size of hard capsule can be used in the present invention. It should be noted that, in particular, a curing method that does not involve a gelling phenomenon and relies only on the evaporation and drying of water from the capsule preparation liquid can also obtain a capsule membrane.

[0090] 4. Filling of Contents into Hard Capsules and Uses The method of filling the contents into the hard capsule is not particularly limited.

[0091] The filling of the contents into the hard capsule can be carried out using known capsule filling machines described in, for example, Japanese Patent Laid-Open No. 2007-144014, Japanese Patent Laid-Open No. 2000-226097, etc., such as a fully automatic capsule filling machine (model name: LIQFILsuper80 / 150, manufactured by Kairi Capsule Co., Ltd.), a capsule filling and sealing machine (model name: LIQFILsuperFS, manufactured by Kairi Capsule Co., Ltd.), etc.

[0092] In the above filling method, the temporary and formal joining of the hard capsule is ensured by a locking mechanism shown in, for example, U.S. Patent No. 3508678, U.S. Patent No. 3823843, U.S. Patent No. 4040536, U.S. Patent No. 4822618, U.S. Patent No. 5769267, etc. In order to stably maintain the above-mentioned locking mechanism, the strength of the hard capsule is also important.

[0093] In addition to using the above-described locking mechanism based on the fitting (Japanese original text "すりあわせ") of the cap and the main body, in order to perform more reliable sealing to prevent malicious opening and entry of foreign substances, and in order to reliably prevent leakage of the liquid filling, the fitting portion may also be sealed by a belt-like seal described in Japanese Patent Application Laid-Open No. 2005-187412 or Japanese Patent Application Laid-Open No. 2009-504630.

[0094] The use of the hard capsule of the present invention is not particularly limited. Preferred examples include oral preparations and inhalation preparations.

[0095] The oral preparation is preferably rapidly dissolved in the stomach or intestine. In order to dissolve the capsule membrane in the intestine and release the drug in the intestine, an enteric capsule having a coating of an enteric base material attached to the surface of the capsule membrane may also be prepared. The capsule membrane itself may also be made of an enteric base material in whole or in part to form an enteric capsule. The enteric capsule is not particularly limited as long as it has the property of not dissolving in the stomach but dissolving in the intestine. For example, it refers to a capsule that hardly dissolves in a dilute hydrochloric acid solution (Japanese Pharmacopoeia 1 solution) at pH 1.2 for 2 hours or more and dissolves in a buffer solution (Japanese Pharmacopoeia 2 solution) at pH 6.8.

[0096] In addition, the drug can also be slowly released from the hard capsule. In the case where the drug is slowly dissolved, a slow-release film may be coated on the surface of the capsule membrane.

[0097] The inhalation preparation is a drug in which a single dose is sealed in a hard capsule in advance and is loaded into a device disclosed in U.S. Patent No. 4,069,819, U.S. Patent No. 4,210,140, U.S. Patent No. 7,669,596, U.S. Patent Application Publication No. 2010-0300440, etc. By perforating with a small pin or breaking the capsule, the drug inside can be inhaled at an appropriate flow rate.

[0098] The content of the hard capsule preparation is not particularly limited, and examples include pharmaceuticals, quasi-pharmaceuticals, cosmetics, and foods for humans or animals without limitation.

[0099] The shape of the content is also not particularly limited. For example, it may be a liquid, a gel, a powder, a granule, a tablet, a pill, or a hybrid shape thereof.

[0100] As the contents of hard capsules, in the case of pharmaceuticals, for example, one or more drug components selected from tonics, antipyretics, analgesics, anti-inflammatory drugs, psychotropic drugs, anti-anxiety drugs, antidepressants, hypnotics, sedatives, antispasmodics, drugs acting on the central nervous system, cerebral metabolism improvers, cerebral circulation improvers, antiepileptics, sympathomimetics, gastrointestinal drugs, antacids, anti-ulcer agents, antitussives, expectorants, antiemetics, respiratory stimulants, bronchodilators, anti-allergy drugs, dental and oral drugs, antihistamines, cardiotonics, antiarrhythmics, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, antihyperlipidemics, cholagogues, antibiotics, chemotherapeutics, diabetes therapeutics, anti-osteoporosis agents, antirheumatics, skeletal muscle relaxants, antispasmodics, hormonal agents, alkaloid anesthetics, sulfonamides, gout therapeutics, anticoagulants, anti-cancer agents, etc. It should be noted that these pharmacodynamic components are not particularly limited, and well-known pharmacodynamic components can be widely cited. Specifically, as examples, the components described in paragraphs

[0055] to

[0060] of WO2006 / 070578 pamphlet can be cited. WO2006 / 070578 is incorporated herein by reference.

[0101] In addition, in the case of foods, for example, docosahexaenoic acid, eicosapentaenoic acid, alpha-lipoic acid, royal jelly, isoflavones, agaricus, malpighia, aloe vera, turmeric, L-carnitine, oligosaccharides, cocoa, catechins, capsaicin, chamomile, agar, tocopherols, linolenic acid, xylitol, chitosan, GABA, citric acid, chlorella, glucosamine, Korean ginseng, coenzyme Q10, brown sugar, collagen, chondroitin, polyporus, squalene, stevia, ceramides, taurine, saponins, lecithin, dextrin, houttuynia cordata, niacin, natto bacteria, bittern, lactic acid bacteria, saw palmetto, honey, coix seed, Japanese apricot extract, pantothenic acid, hyaluronic acid, vitamin A, vitamin K, vitamin C, vitamin D, vitamin B1, vitamin B2, vitamin B6, vitamin B12, quercetin, protein, propolis, mulukhiya, folic acid, lycopene, linoleic acid, rutin, ganoderma lucidum and other functional components, etc. However, it is not limited thereto.

[0102] Examples Examples are shown below to more specifically illustrate the embodiments of the present invention.

[0103] However, the interpretation of the present invention should not be limited to these examples.

[0104] 1. Experimental Example 1: Measurement of Transmittance and Strength of Membrane Capsule Membrane In the case of evaluating the transmittance and strength of hard capsules, the measured values vary depending on the thickness of the capsule film, particularly the film thickness of the capsule body part into which the metal indenter is pressed. In the evaluation of transmittance and strength, it is important to make the thickness of the test film consistent for comparison. Therefore, in the evaluation of transmittance and strength that depends on the composition of each component of the hard capsule, instead of the hard capsule formed by the dipping method, for each component composition of the hard capsule film, a film having the same component composition as that of the hard capsule is produced by the casting method, and the transmittance and strength are evaluated using this film. Hereinafter, instead of the hard capsule formed by the dipping method, a film having the same component composition as that of the hard capsule is produced and evaluated. However, the uniformity of the thickness of this film is excellent, the reproducibility of the evaluation is excellent, and it well reflects the transmittance and strength as the capsule film.

[0105] 1-1. Hard Capsule Preparation Liquid The compositions of the hard capsules prepared by adding calcium carbonate as standards, examples, and comparative examples are shown in Tables 2-1 and 2-2. For HPMC, jellies were prepared by changing the mixing ratios of HPMC shown in the following i, ii, and iii.

[0106] i. Degree of substitution type 2910, Shin-Etsu Chemical, viscosity value 6 ii. Degree of substitution type 2910, LOTTE Fine Chemical, viscosity value 4.5 iii. Degree of substitution type 2208, Shin-Etsu Chemical, viscosity value 4 HPMC with a viscosity value of 530 was prepared by mixing in a ratio of viscosity value 6:viscosity value 4.5:viscosity value 4 of 6:2:2. HPMC with a viscosity value of 570 was prepared by mixing in a ratio of viscosity value 6:viscosity value 4.5 of 8:2.

[0107] As heavy calcium carbonate, precipitated calcium carbonate A (Bihoku Pulverizing Industry, Dv50: 2.16 μ μm), Aragen (CALFINE, Dv50: 5.05 μ μm), Caltex5 (Maruo Calcium, Dv50: 1.82 μ μm), ACE-35 (CALFINE, Dv50: 2.04 μ μm), CALMIGEN A (Bihoku Pulverizing Industry, Dv50: 2.12 μ μm), NANOX 25A (Maruo Calcium, Dv50: 3.02 μ μm), NANOX 30 (Maruo Calcium, Dv50: 2.21 μ μm), Calcy F (Sankyo Seifun, Dv50: 2.44 μm).

[0108] As the precipitated calcium carbonate, Carpin F (Yabashi Kogyo, Dv50: 2.63 μ m), CALESSEN I (Shiraishi Kogyo, Dv50: 0.39 μ m), and CAL·ACE-ST (Maruo Calcium, Dv50: 0.51 μ m) were used. The above Dv50 value is the median particle size in volume units and represents the measured value based on the laser diffraction method described in JIS Z 8825.

[0109] Titanium oxide was added as a light-shielding agent to the standard product.

[0110] The preparation liquid for the hard capsules prepared by the cold gelation method was prepared as follows. Carrageenan and potassium chloride were added to pure water and stirred for dispersion. After heating to 80 °C, the dissolution of the materials was confirmed. While maintaining the liquid temperature at 80 °C, HPMC was added and dispersed, and then left standing for 30 minutes. Bubbles were removed by vacuum degassing. Next, while stirring with a Three-One Motor, the temperature was lowered to 50 °C to 60 °C. After stirring with the Three-One Motor for 1 hour, calcium carbonate was added and stirred to disperse the calcium carbonate sufficiently and uniformly, thereby preparing a jelly-like capsule preparation liquid. The calcium carbonate was previously made into an aqueous dispersion of 11 to 22% by mass, and after homogenization treatment (9000 rpm, 15 minutes) using a homogenizer (manufactured by IKA, generator used: S25N-25F), it was added.

[0111] The preparation liquid for the hard capsules prepared by the hot gelation method was prepared as follows. After heating pure water to 80 °C, HPMC was added and dispersed, and then left standing for 30 minutes. Bubbles were removed by vacuum degassing. Next, while stirring with a Three-One Motor, the temperature was lowered to room temperature. After stirring with the Three-One Motor for 1 hour, calcium carbonate was added and stirred to disperse the calcium carbonate sufficiently and uniformly, thereby preparing a colloidal capsule preparation liquid. The calcium carbonate was previously made into an aqueous dispersion of 11 to 22% by mass, and after homogenization treatment (9000 rpm, 15 minutes) using a homogenizer (manufactured by IKA, generator used: S25N-25F), it was added.

[0112] 1-2. Method for forming the film The preparation of the cast film using the cold gelation method was carried out as follows. A metal coater was set on a glass surface or a PET film maintained at room temperature, and the capsule preparation liquid at 50 °C to 60 °C was poured and moved at a certain speed to prepare a uniform film of 100 μ m. Then, it was dried at room temperature to 30 °C for about 10 hours.

[0113] The preparation of the cast film using the thermal gelation method is carried out as follows. A metal coater is set on a glass surface or a PET film maintained at 60 °C, and the preparation solution at room temperature is poured and moved at a certain speed to prepare a uniform film of 100 μ μm. Then, after drying at 60 °C for 1 hour, it is dried at room temperature for about 10 hours. In order to obtain a uniform film thickness of 100 μ μm, coaters with gaps of 0.4 mm to 1.5 mm can be appropriately used respectively. The film thickness of the prepared cast film is 100 μ μm ± 10 μ μm or less.

[0114] 1-3. Measurement of Transmittance The evaluation of light-shielding property is carried out by evaluating the transmittance using an ultraviolet-visible spectrophotometer (Shimadzu UV-1850). The transmittance is obtained by dividing the value of the transmitted light intensity when measuring with the sample film by the value of the transmitted light intensity of the sample blank without the sample film set. The dried cast film is cut into strips of 10 mm × 20 mm and placed vertically as the sample film in a way that blocks the light path of the ultraviolet-visible spectrophotometer, and the light intensity of the transmitted light is measured, and the transmittance at the measurement wavelengths of 650 nm and 420 nm is calculated.

[0115] 1-4. Evaluation of Strength For the cast film prepared by the above method, it is cut into a dumbbell shape (specified in JIS K-7161-2-1BA) of 5 mm × 75 mm to make a dumbbell-shaped test piece. The dumbbell-shaped test piece is placed statically in a glass desiccator equipped with a saturated salt solution, and the desiccator is stored in a constant temperature bath at 25 °C for more than one week for humidity conditioning. As the low humidity condition (25 °C, 22% RH), a saturated salt solution of potassium acetate is used.

[0116] Using the dumbbell-shaped test piece conditioned in the desiccator as described above, a tensile test is carried out under the conditions of a tensile speed of 50 mm / min and a distance between chucks of 59 mm. The device used is a universal testing machine EZ-LX manufactured by Shimadzu Corporation. Through the tensile test, the elongation rate of the test piece and the test force applied at this time are evaluated. The nominal stress σ obtained by dividing the test force by the initial cross-sectional area and the nominal strain obtained by dividing the elongation rate of the test piece by the initial length are calculated respectively. The toughness (MJ / m3) of the film is obtained from the area under the stress-strain curve obtained.

[0117] The measurement of toughness is carried out 8 times for each test piece, and the average value and standard deviation (1SD) are obtained.

[0118] 2. Results Table 2-1 and Table 2-2 show the compositions of the standard product, examples, and comparative examples, the transmittances at 420 nm and 650 nm, and the film thickness converted to 100μ Transmittance, toughness, and standard deviation of toughness at m.

[0119] [Table 2-1]

[0120] [Table 2-2]

[0121] In Comparative Examples 1 to 3, the transmittance at a light wavelength of 650 nm was measured to be more than 20%, but in Examples 1 to 15, it was less than 20%. In addition, in Comparative Examples 1 to 3, the transmittance at a light wavelength of 420 nm was measured to be more than 10%, but in Examples 1 to 15, it was less than 10%. In Comparative Examples 4 to 7, the transmittance was of the same level as that of the films in the examples, but the toughness was less than 2.0 MJ / m3, and the strength of the film was inferior to that of the films in the examples. Therefore, it is considered that the addition amount of calcium carbonate is preferably less than 25% by mass.

[0122] Figure 1 represents converting the film thickness to 100 μ m, and is a graph showing the relationship between transmittance and Dv50. Figure 1 A is the graph when the measurement light wavelength is set to 650 nm. The range where the transmittance is 20% or less is where Dv50 is 0.9 to 3.8 μ m. Figure 1 B is the graph when the measurement light wavelength is set to 420 nm. The range where the transmittance is 10% or less is where Dv50 is 0.7 to 3.4 μ m.

Claims

1. A hard capsule, characterized in that, comprising a film, the film comprising a cellulose compound and a light-shielding agent, The light blocker contains calcium carbonate with a median particle size of 0.7 μ m to 3.8 μ m in volume units, When the total of the film components of the hard capsule other than moisture is set to 100% by mass, the content of the light-shielding agent contained in the film is 3% to 20% by mass.

2. The hard capsule according to claim 1, wherein, The cellulose compound is hydroxypropyl methylcellulose.

3. The hard capsule according to claim 2, wherein, The film further comprises (1) a gelling agent, or (2) a gelling agent and a gelling aid.

4. A hard capsule preparation liquid, characterized in that, comprising a cellulose compound, a light-shielding agent and an aqueous solvent, The sunscreen agent contains calcium carbonate with a median particle size of 0.7 μ m to 3.8 μ m When the total of the components other than the aqueous solvent in the preparation liquid is set to 100% by mass, the content of the light-shielding agent in the total of the film components other than the aqueous solvent is 3% to 20% by mass.

5. The hard capsule preparation liquid according to claim 4, wherein, The cellulose compound is hydroxypropyl methylcellulose.

6. The hard capsule preparation liquid according to claim 5, wherein, The hard capsule preparation liquid further comprises (1) a gelling agent, or (2) a gelling agent and a gelling aid.

7. A method for preparing hard capsules, characterized in that, comprising the following steps: using the hard capsule preparation liquid according to claim 4, preparing a hard capsule by a cold gelling method.

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